WO1991018639A1

WO1991018639A1 - Method for using fibronectin in conjunction with percutaneous transluminal coronary angioplasty

Info

Publication number: WO1991018639A1
Application number: PCT/US1991/003805
Authority: WO
Inventors: Edward Gaj, Jr.; Hikosuke Yorihiro
Original assignee: Alpha Therapeutic Corporation
Priority date: 1990-05-30
Filing date: 1991-05-29
Publication date: 1991-12-12
Also published as: CA2084078A1; JPH05507223A; EP0531442A4; AU7956391A; EP0531442A1

Abstract

This invention relates to an improved percutaneous transluminal angioplasty procedure which incorporates the administration of fibronectin to the patient to inhibit or at least reduce restenosis.

Description

METHOD FOR USING FIBRONECTIN IN CONJUNCTION WITH PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY

Field of the Invention

This invention relates to a percutaneous transluminal angioplasty procedure which includes administering a fibronectin solution to an angioplasty patient to inhibit or at least reduce restenosis.

Background of the Invention Restricted blood flow to body tissues may be caused by a narrowing of arteries. Such narrowing (or stenosis) can have a number of causes, one of which is athero¬ sclerosis, i.e., the gradual deposition of fatty material, generally referred to as atherosclerotic plaque, on the inside walls of the arteries. A buildup of athero¬ sclerotic plaque within an artery restricts the flow of blood through the artery and, thus, to the organs supplied by the affected artery.

Percutaneous transluminal angioplasty (hereinafter referred to as ^■■angioplasty" or "balloon angioplasty") is a procedure for reopening arteries narrowed by deposits of atherosclerotic plague. In the angioplasty procedure, a small guiding catheter is inserted into a vein or artery and passed to the site of the narrowing or stenosis. A smaller balloon-tipped catheter is passed through the guiding catheter and positioned so that the balloon is within the stenotic region of the artery. Once in position, the balloon is inflated to enlarge the inner diameter of the artery. In successful angioplasty, when the balloon is deflated, the stenosis or restriction of the artery is less severe, and more blood passes through the artery to the organ or tissue which was distal to the stenosis.

The primary success rate of angioplasty procedures is report to approach 90%. However, in approximately 25% to 50% of patients who undergo angioplasty, restenosis occurs, i.e., the artery becomes restricted again within a short period of time. Although the mechanism of restenosis is complex and not completely understood, it appears that injury to the walls of the artery which results from the angioplasty procedure itself plays a prominent roll. It is known, for example, that a tear into or splitting of plaque and denuding a portion of the endothelium is probably associated with every angioplasty procedure.

Althoughpercutaneoustransluminal angioplasty offers a valuable alternative to surgery for patients with stenotic arteries, restenosis in a significant number of patients is a critical problem. It is therefore desirable to provide a method for use in conjunction with the angioplasty procedure that will reduce or eliminate restenosis.

Summary of the Invention

In accordance with practice of the present invention, a method is provided for enlarging the stenotic region of a patient's artery, for example, by balloon angioplasty, while inhibiting or at least reducing restenosis by infusing the patient with fibronectin. The method includes the steps of inserting a balloon-tipped catheter into the artery so that the balloon of the catheter is positioned within the stenotic region. The balloon is inflated one or more times to enlarge the internal diameter of the artery in the stenotic region, and the catheter and balloon are then removed. The infusion of the fibronectin is commenced prior to, during, or shortly after the angioplasty procedure. The amount of fibronectin infused is sufficient to maintain the patient's plasma fibronectin concentration at least at normal levels for a sufficient period of time to inhibit or at least reduce restenosis. Preferably, concentrations of fibronectin are maintained, at the stenotic region, at from about 350 μg/cc to about 500 μg/cc by maintaining the systemic concentrations at about 350 μg/cc to about 500 μg/cc for up to about 24 hours.

An alternate method of obtaining the required levels of fibronectin at the stenotic region is to deliver the fibronectin directly to the site of the stenosis and thereby maintain the local concentrations of fibronectin, within the stenotic artery, at from about 350 μg/cc to about 500 μg/cc for up to about 24 hours.

In one embodiment of practice of the present inven- tion, systemic administration of fibronectin is provided continuously by intravenous means. The infusion is continued for up to about 24 hours after the angioplasty procedure has been completed.

In a second embodiment of practice of the present invention, systemic administration of fibronectin is provided through the catheter during the angioplasty procedure. In a third embodiment of practice of the present invention, systemic administration is provided by injection of fibronectin as a bolus. The bolus injection is provided before, during or after the angioplasty procedure.

In a fourth embodiment of practice of the present invention, local administration of fibronectin is provided through a catheter whereby the delivery method maintains the local concentrations of fibronectin at the desired levels at the site of the stenosis.

Detailed Description

In carrying out the process of the present invention, a patient who has undergone a percutaneous transluminal coronary angioplasty procedure (angioplasty or balloon angioplasty) is treated with fibronectin. As is described below in greater detail, the treatment may be started before, during, or subsequent to the angioplasty procedure.

Angioplasty is a method for treating the narrow or stenotic segment of an artery, which generally involves the insertion of a catheter containing a balloon into a stenotic artery. When the balloon has reached the stenotic region, the balloon is inflated, resulting in pushing back of the narrowed wall of the artery to thereby improve blood flow through the artery.

In one type of angioplasty procedure, the angioplasty is conducted by inserting a small guiding catheter through an introducer sheath and passing it through an artery into the narrowed stenotic segment of the artery. A smaller balloon-tipped catheter comprising a pair of lumens is then passed through the guiding catheter and positioned so that the balloon of the balloon-tipped catheter lies within the stenotic region of the artery. A first lumen extends to the balloon and is used for passing a fluid, preferably saline, to the balloon to inflate the balloon and to pass fluid out from the balloon when the balloon is deflated. The second lumen extends through the balloon to the distal tip of the catheter. The second lumen can be open at the distal tip and, as is described below in greater detail, can be used for introducing a fibronectin solution through the catheter into the patient's stenotic artery.

Treatment with fibronectin is performed to inhibit or at least reduce restenosis that occurs in a significant number of patients as a result of the angioplasty procedure. Damage to the artery in the form of small tears or splits in the artery wall or a striping of endothelial cells from the artery wall is a common side effect of the procedure. As a result of this damage, the body's repair mechanisms are activated. Often, the repair of the damage to the artery results in a thick "scar mass" that results in a second stenosis or restenosis of the region of the artery. Without being bound by theory, it is thought that infusing a patient with fibronectin aids in the orderly aggregation of cells, thus preventing restenosis upon repair of the damage resulting from angioplasty.

Fibronectin, also known as cold insoluble globulin (CIG) is a multi-functional glycoprotein present in plasma at a concentration of about 350 icrograms per cubic centimeter (μg/cc) . Fibronectin has been found to have a molecular weight of about 440,000 and to consist of two nearly identical 220,000-molecularweight subunits. Fibro¬ nectin compositions or concentrates can be made up of varying ratios of both the dimer (the 440,000-dalton unit) and the monomer (the 220,000-dalton unit). Fibronectin for use in accordance with practice of the present invention may be obtained from plasma in accordance with procedures disclosed in U.S. Patent No. 4,305,871, which issued to Shanbrom on December 15, 1981 U.S. Patent No. 4,424,206, which issued to Ohmura on January 3, 1984, or in accordance with procedures outlined in U.S.S.N. 363,968, filed June 9, 1989 and assigned to the assignee of the present application. U.S. Patents Nos. 4,424,206, 4,305,871, and application serial No. 363,968 are incorporated herein by this reference. The above methods describe the purification of fibronectin from plasma, alternatively, fibronectin may also be derived from recombinant DNA sources.

In accordance with practice of the present invention, it is desired to maintain the fibronectin levels, at the stenotic region, at about normal concentration for a sufficient period of time, after the angioplasty procedure has been completed, to inhibit or at least reduce restenosis. In order to maintain normal fibronectin levels, fibronectin must be administered to the patient because, during surgical procedures, such as angioplasty, plasma fibronectin concentrations in the blood are reduced by phagocytes. This is a result of fibronectin's involvement in opsonization of debris. In accordance with practice of this invention, since the normal level of plasma fibronectin is about 350 μg/cc, it is desired that sufficient fibronectin is administered to maintain the concentrations, at the stenotic region, at least at 350 μg/cc subsequent to the angioplasty procedure. Preferably, sufficient fibronectin is used to maintain the concentration of fibronectin, at the stenotic region, at from about 350 μg/cc to about 500 μg/cc. The concentration may be maintained at this desired level either by infusions, which maintain the systemic concentrations of fibronectin at about 350 μg/cc to about 500 μg/cc, or by local delivery, which maintains the local concentration of fibronectin at the site of the stenosis at about 350 μg/cc to about 500 μ/cc.

It may be useful to determine fibronectin concentrations throughout the procedure. In such cases, an immunoturbidimetric procedure, such as that described by Saba, T.M. et al, "Evaluation of a Rapid Immunoturbidi- metric Assay for Opsonic Plasma Fibronectin in Surgical and Trauma Patients," J. Lab. Clin. Med.. 98. 482 (1981), may be used. Such a procedure may be completed in about 10 minutes and gives an opportunity to monitor the patient's fibronectin concentrations throughout the angioplasty and recovery periods and adjust fibronectin levels as may be required to overcome individual differences.

Samples of blood, for the determination of fibronectin concentrations, are taken about 30 minutes before the commencement of the angioplasty procedure or about 30 minutes before the commencement of fibronectin, infusion if it is to be started prior to the angioplasty procedure. After the initial blood sample, additional blood samples are taken about every 30 to 120 minutes for up to about 24 hours after the completion of the angioplasty. The blood samples are then assayed for fibronectin.

In accordance with practice of this invention, systemic delivery of the fibronectin may be by a variety of methods, such as continuous infusion, by bolus infusion, or by administration from the balloon angioplasty catheter. The fibronectin may be infused with other medications or nutrients, such as glucose or buffered salt solutions, such as phosphate buffered saline (PBS, 137mM NaCl, 2.7mM KC1, 8mM NaHP0₄, 1.5mM KH₂P0₄) . Also, fibronectin may be delivered locally into the stenotic region by, for example, a catheter.

For systemic administration, continuous infusion of fibronectin may, for example, be achieved by intravenous means. For continuous infusion, the concentration of fibronectin in the solution is preferably up to about 20 mg/cc. The infusions deliver a total of about 200 mg to about 1000 mg of fibronectin. Continuous infusion of fibronectin may be commenced before, during or after the angioplasty procedure. If infusion is started before the angioplasty procedure, it is continued during the angioplasty and after the angioplasty has been completed.

When continuous infusion of fibronectin is used, the infusion should be continued to maintain the concentration of fibronectin in the patient's blood at the desired level for a sufficient period of time to inhibit or at least reduce restenosis. Preferably, fibronectin administration is continued for at least 2 hours after the angioplasty procedure has been completed and, more preferably, is continued for about 24 hours. It does not appear necessary to maintain the fibronectin administration beyond about 24 hours after completion of the procedure. The systemic concentrations of fibronectin are maintained at normal levels by the infusion until such time as platelet deposition over the damaged area of the stenotic region would be expected to be complete. It is estimated that such deposition takes place during about the first 24 hours after the angioplasty procedure. To ensure that the fibronectin concentrations are maintained at desired levels, blood samples may be monitored throughout the procedure. The rate of delivery or concentration of fibronectin delivered is varied as required.

Systemic delivery of the fibronectin may also be achieved by bolus infusion. For a bolus infusion, an injection of a fibronectin solution is administered. Bolus injections may be given as a single dose or, alternately, multiple doses (multiple bolus injections) may be required. The bolus injection may be administered either intravenously or intracoronarily and may be given prior to, during, and/or after the angioplasty procedure. For bolus injections, fibronectin solutions of about 20 g/cc are injected.

To ensure that the patient's plasma fibronectin concentrations are maintained at desired levels, blood samples may be monitored throughout the procedure. If required, multiple bolus infusions are administered to maintain the desired fibronectin levels.

For systemic administration, fibronectin can also be delivered via an angioplasty catheter during a balloon angioplasty procedure.

An alternate method for the delivery of fibronectin in accordance with practice of the present invention, is as a local treatment rather than a systemic infusion. In this procedure, the fibronectin solution is administered to maintain the local fibronectin concentrations, i.e., the plasma concentrations of fibronectin at the site of the stenosis, at the desired levels. For local treatment, the fibronectin solution may be delivered via the angioplasty guide catheter, after the balloon catheter has been removed. Alternately, the fibronectin may be delivered from the second lumen of the balloon angioplasty catheter at the completion of the balloon angioplasty procedure. After the balloon is deflated, the balloon catheter is drawn back, into the guide catheter, so that it is positioned upstream from the stenotic site. Fibronectin may then be delivered. A third method for delivering the fibronectin locally is via a second catheter. The second catheter may be introduced into the artery, after the completion of the angioplasty procedure and removal of the angioplasty catheter, and positioned upstream from the site of the stenosis. The fibronectin solution is then delivered directly to the stenotic region of the artery.

The concentration of fibronectin in the fibronectin solution for use in the local treatment regimen is up to about 20 mg/cc. Preferably, fibronectin administration is continued for at least 2 hours after the angioplasty procedure has been completed and, more preferably, is continued for about 24 hours. The local concentrations of fibronectin are maintained at about normal levels by the local fibronectin delivery procedure until such time as platelet deposition over the damaged area of the stenotic region would be expected to be complete. It is estimated that such deposition takes place during about the first 24 hours after the angioplasty procedure. While it is preferred that systemic or local fibronectin concentrations are from about 350 μg/cc up to about 500 μg/cc, higher localized and transient, systemic levels of fibronectin may be encountered when bolus, balloon angioplasty or local delivery methods are employed. These higher levels will be diluted as the fibronectin is distributed throughout the body and is eliminated from the system and will be necessary to maintain the minimum required fibronectin level of 350 μg/cc at the site of the stenosis. If required, fibronectin concentrations are monitored throughout the procedure to maintain them at desired levels. Additional bolus or continuous infusions are administered, if required, to maintain the desired fibro¬ nectin levels.

Various features and advantages of the angioplasty procedure provided in accordance with practice of the present invention are illustrated in the following prophetic examples. It is to be understood, however, that the examples merely illustrate the invention and are not intended to limit the scope of the invention, which is defined in the claims.

Example 1 Preparation of Fibronectin Solution Fibronectin is initially separated from human blood plasma that has been collected and tested according to procedures approved by the U.S. Food and Drug Adminis¬ tration. The plasma is frozen at a temperature of about -20*C and is subsequently thawed at O'C to 5*C and pooled. During the thawing process, a precipitate forms (herein¬ after called the "cryoprecipitate") which is collected by centrifugation and purified further.

410 grams of such cryoprecipitate are dissolved in distilled water which contains about 80 units of heparin per milliliter (ml) at a pH of 7. The solution is mixed at a temperature of about 30*C for about 30 minutes to provide a cryoprecipitate/heparin solution.

A polyethylene glycol (PEG) solution having a PEG concentration of 31.5%, 0.22% sodium citrate dihydrate, and 0.08% citric acid monohydrate at a pH of 6.2 is added to the cryoprecipitate/heparin solution to provide a PEG concentration of 3.5%. The resulting solution is mixed for 30 minutes at a temperature of 25*C. A precipitate is formed (the first PEG precipitate) which is separated from the solution by centrifugation. The first PEG precipitate is found to contain fibronectin, fibrinogen and immunoglobulins. The supernatant which contains Factor VIII is set aside. 155 grams of the first PEG precipitate is dissolved in distilled water in an amount which comprises about 8 times the total weight of the precipitate to form the first PEG precipitate solution. Glycine is added to the solution to a final concentration of 1.7M, and the pH of the solution is adjusted to about 6.6. The temperature of the solution is maintained at about 25*C, and the solution is centrifuged, and the supernatant, which contains fibronectin, is recovered. The PEG solution is added to 1260 ml of the super¬ natant to provide a solution with a PEG concentration of about 9% (the second PEG solution) . The second PEG solution is mixed for approximately 30 minutes at a temperature of about 25'C, during which time a precipitate is formed (the second PEG precipitate) . The solution is centrifuged, and the precipitate recovered.

The second PEG precipitate is then subjected to two identical citrate/glycine washes in succession. 48 grams of the second PEG precipitate is suspended in a solution having a glycine concentration of about 1.8M and containing sodium citrate at a concentration of about 0.25M. The pH of the solution is adjusted to 6.7 and maintained at a temperature of 20'C. After the suspension is mixed thoroughly by mixing for 30 minutes, it is centrifuged to recover the first glycine-washed fibronectin precipitate. The citrate wash procedure is then repeated.

The glycine-washed fibronectin precipitate is reconstituted in an aqueous solution of 0.005M sodium citrate and 1% glycine to provide a final bulk solution. The solution is then filtered, placed into final con¬ tainers, and lyophilized. For use, the lyophilized fibronectin is reconstituted by the addition of sterile water, PBS, or other fluid carriers suitable for intravenous use. The volume of the solution to be used for reconstituting the fibronectin is adjusted depending on the desired concentration of fibronectin in the final solution.

Example 2

Infusion of Fibronectin in Conjunction with Percutaneous Transluminal Coronary Angioplasty

A percutaneous transluminal coronary angioplasty procedure is conducted by inserting a small guiding catheter through an introducer sheath and passing it through the femoral artery and dorsal aorta into the narrowed coronary artery of the heart. A smaller balloon- tipped catheter is then passed through the guiding catheter and positioned so that the balloon of the balloon-tipped catheter lies within the stenotic region of the coronary artery. The balloon-tipped catheter comprises a pair of lumens. A first lumen extends to the balloon and is used for passing a fluid, preferably saline, to the balloon to inflate the balloon and to pass fluid from the balloon when the balloon is deflated. A second lumen extends through the balloon to the distal tip of the catheter. The second lumen is open at the distal tip and is provided for passing a fibronectin solution through the catheter into the occluded portion of the artery.

A saline solution is then passed through a lumen into the balloon thereby inflating the balloon. The balloon is inflated several times and is then deflated by removing a portion of the saline solution.

A fibronectin solution, prepared in accordance with Example 1, and at a concentration of from about 1 mg/cc to about 20 mg/cc, is introduced into the artery through the second lumen in the catheter. The fibronectin is delivered at a rate of from about 100 cc/min to about 150 cc/min for the duration of the angioplasty procedure.

Blood samples are taken from the patient 30 minutes prior to the commencement of the angioplasty, and then every 120 minutes thereafter, for up to 24 hours after the completion of the angioplasty. The samples are analyzed for their fibronectin concentration using the immunotur¬ bidimetric procedure. The information derived from these tests is then used to predict adjustments that may be required to the patient's blood fibronectin concentrations. Subsequent bolus or continuous infusion of fibronectin is administered as required to maintain the fibronectin concentrations in the range of 350 μg/cc to 500 μg/cc for about 24 hours after the completion of the angioplasty.

Examples 3-5 below demonstrate continuous infusion of fibronectin for various time periods and which is initiated at either before, during, or after the angio- plasty procedure.

Example 3

Continuous Infusion of Fibronectin

Thirty minutes prior to the start of an angioplasty procedure, an intravenous drip of 5 mg/cc fibronectin in a solution of PBS is initiated by placing a catheter in the median cubital vein of the patient. The drip infusion is continued during the angioplasty procedure and for up to 24 hours after the procedure is completed. The flow rate of the intravenous drip is commenced at 0.5 cc/min.

Blood samples are taken from the patient 30 minutes prior to the commencement of the infusion or angioplasty procedure, and then every 120 minutes after, for up to 24 hours after the completion of the angioplasty. The samples are analyzed for their fibronectin concentration using the immunoturbidimetric procedure. The information derived from these tests is then used to predict adjust- ments that may be required to the flow rate of the intravenous drip to maintain the patient's fibronectin concentration in the range of 350 μg/cc to 500 μg/cc. If required, adjustments are made so that the fibronectin blood concentration is maintained at the desired level for at least 24 hours after the angioplasty procedure has been completed.

Example 4 Continuous Infusion of Fibronectin

The procedure of Example 3 is repeated except that the infusion is initiated during the angioplasty procedure.

Example 5

Continuous Infusion of Fibronectin The procedure of Example 3 is repeated except that the infusion is initiated at the completion of the angioplasty procedure.

Examples 6-11 demonstrate bolus infusion of fibro¬ nectin before, during, and after the angioplasty procedure is commenced.

Example 6

Intravenous Bolus Infusion of Fibronectin An intravenous bolus infusion is given by injecting a solution of fibronectin containing 1 mg of fibronectin in PBS. The injection is given about 30 minutes before the angioplasty procedure is commenced.

Blood samples are taken from the patient 30 minutes prior to the commencement of the bolus infusion or angioplasty procedure, and then every 120 minutes after, for up to 24 hours after the completion of the angioplasty. The samples are analyzed for their fibronectin concentration using the immunoturbidimetric procedure. The information derived from these tests is then used to predict adjustments that may be required to the patient's fibronectin concentration. Multiple bolus injections are administered as required to maintain the fibronectin concentration at 350 μg/cc to 500 μg/cc for at least 24 hours after completion of the angioplasty procedure.

Example 7 Intravenous Bolus Infusion of Fibronectin The procedure of Example 6 is repeated except that the injection is given during the angioplasty procedure.

Example 8 Intravenous Bolus Infusion of Fibronectin The procedure of Example 6 is repeated except that the injection is given immediately after the angioplasty procedure is completed.

Example 9 Intracoronary Bolus Infusion of Fibronectin

The procedure of Example 6 is repeated except that an intracoronary bolus infusion is given.

Example 10 Intracoronary Bolus Infusion of Fibronectin

The procedure of Example 9 is repeated except that the injection is given during the angioplasty procedure.

Example 11 Intracoronary Bolus Infusion of Fibronectin

The procedure of Example 9 is repeated except that the injection is given immediately after the angioplasty procedure is completed. Example 12

Local Delivery of Fibronectin A percutaneous transluminal coronary angioplasty procedure is conducted by inserting a small guiding catheter through an introducer sheath and passing it through the femoral artery and dorsal aorta into the narrowed coronary artery of the heart. A smaller balloon- tipped catheter is then passed through the guiding catheter and positioned so that the balloon of the balloon-tipped catheter lies within the stenotic region of the coronary artery.

A saline solution is then passed through a lumen into the balloon thereby inflating the balloon. The balloon is inflated several times and is then deflated by removing a portion of the saline solution. The balloon catheter is then removed from the guide catheter.

A fibronectin solution, prepared in accordance with Example 1, and at a concentration of about 500 μg/cc, is introduced into the artery through the guide catheter. The fibronectin is delivered at a rate of from about 1 cc/min to about 1.5 cc/min for about 24 hours after the completion of the angioplasty procedure to maintain the concentration at the stenotic region at 350 μg/cc to 500 μg/cc. The above descriptions of exemplary embodiments of processes for treating arterial damage resulting from angioplasty procedures are for illustrative purposes. Because of variations which will be apparent to those skilled in the art, the present invention is not intended to be limited to the particular embodiments described above. The scope of the invention is defined in the following claims.

Claims

WHAT IS CLAIMED IS :

1. A method for enlarging the stenotic region of a patient's artery, the method comprising the steps of: a) inserting a balloon-tipped catheter into the artery so that the balloon of the catheter is position within the stenotic region; b) inflating the balloon one or more times to thereby enlarge the internal diameter of the artery in the stenotic region; and c) infusing the patient with a sufficient amount of fibronectin for a sufficient time to inhibit or at least reduce restenosis.

2. The method according to claim 1 wherein the fibronectin infusion step is started prior to balloon inflation.

3. The method according to claim 1 wherein the fibronectin infusion is started during the time that the balloon-tipped catheter is in the patient's artery.

4. The method according to claim 1 wherein the fibronectin infusion is started after the balloon-tipped catheter has been removed from the patient's artery.

5. The method according to claim 1 wherein a sufficient amount of fibronectin is infused to maintain a systemic level of fibronectin in the patient's blood of at least 350-500 μg/cc.

6. The method according to claim 1 wherein a sufficient amount of fibronectin is infused to maintain a level of fibronectin at the stenotic region of at least 350-500 μg/cc.

7. A method for inhibiting or at least reducing restenosis subsequent to enlarging the stenotic region of a patient's artery by balloon angioplasty, the method comprising administering a sufficient amount of fibronectin to the patient for a sufficient length of time to inhibit or at least reduce restenosis of the artery.

8. The method according to claim 7 wherein the fibronectin is administered as a continuous infusion.

9. The method according to claim 7 wherein the fibronectin is administered as a bolus infusion.

10. The method according to claim 7 wherein the fibronectin is administered by infusion from the balloon angioplasty catheter.

11. The method according to claim 7 wherein the fibronectin is administered directly to the stenotic region.

12. The method according to claim 7 wherein the amount of fibronectin administered is sufficient to maintain a systemic concentration of fibronectin in the patient's blood of at least about 350 μg/cc.

13. The method according to claim 7 wherein the amount of fibronectin administered is sufficient to maintain the concentration of fibronectin, at the stenotic region, of at least about 350 μg/cc.

14. The method according to claim 7 wherein the fibronectin administration is begun before the commencement of the angioplasty procedure.

15. The method according to claim 7 wherein the fibronectin administration is begun during the angioplasty procedure.

16. The method according to claim 7 wherein the fibronectin administration is begun after the completion of the angioplasty procedure.

17. An improved angioplasty procedure wherein a balloon-tipped catheter is positioned within a stenotic region of a patient's artery and the balloon of the catheter is inflated to enlarge the interior diameter of the artery, the improvement comprising administration of a sufficient amount of fibronectin to the patient for a sufficient time to inhibit or at least reduce restenosis.

18. The method according to claim 17 wherein the fibronectin is administered as a continuous infusion.

19. The method according to claim 17 wherein the fibronectin is administered as a bolus infusion.

20. The method according to claim 17 wherein the fibronectin is administered as an infusion from the balloon angioplasty catheter.

21. The method according to claim 17 wherein the fibronectin is administered directly to the stenotic region.

22. The method according to claim 17 wherein the amount of fibronectin administered is sufficient to maintain a systemic concentration of fibronectin in the patient's blood of at least about 350 μg/cc.

23. The method according to claim 17 wherein the amount of fibronectin administered is sufficient to maintain the concentration of fibronectin, at the stenotic region, of at least about 350 μg/cc.

24. The method according to claim 17 wherein the fibronectin is administered during the angioplasty procedure.

25. The method according to claim 17 wherein the fibronectin infusion is begun before the commencement of the angioplasty procedure.

26. The method according to claim 17 wherein the fibronectin infusion is begun after the completion of the angioplasty procedure.