WO1999002219A1

WO1999002219A1 - Method and system for the intramural delivery of radioactive agents

Info

Publication number: WO1999002219A1
Application number: PCT/US1998/012439
Authority: WO
Inventors: William A. Albright, Jr.
Original assignee: Localmed, Inc.
Priority date: 1997-07-11
Filing date: 1998-06-11
Publication date: 1999-01-21
Also published as: AU8144298A

Abstract

Hyperplasia in re-canalized blood vessels is inhibited by delivering a radioactive substance intramurally to a target site within the blood vessel. Usually, the radioactive substance is delivered using a catheter (110) having infusion ports (128) at its distal end (120). Optionally, the distal end (120) of the catheter (110) is radially expanded to engage the fusion ports (128) directly against the blood vessel wall. Further optionally, the infusion ports (128) can be modified or distributed in the manner which increases the delivery of a radioactive substance near each end of the treatment region.

Description

METHOD AND SYSTEM FOR THE INTRAMURAL DELIVERY OF RADIOACTIVE AGENTS

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to methods for inhibiting restenosis in a blood vessel after an initial treatment for opening a stenotic region in the blood vessel . More particularly, the present invention relates to brachytherapy methods which rely on the localized delivery of radiation via intramural delivery of a radioactive agent for inhibiting of hyperplasia following balloon angioplasty and other interventional treatments.

Percutaneous translumenal 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. While PTA has gained wide acceptance, it continues to be limited by the frequent occurrence of restenosis. Restenosis afflicts approximately up to 50% of all angioplasty patients and is the result at least in part of smooth muscle cell proliferation referred to as hyperplasia. Many different strategies have been proposed to reduce the restenosis rate resulting from hyperplasia, including mechanical ( e . g . , prolonged balloon inflations during angioplasty, stenting, and the like) and pharmacological, ( e . g. , the administration of anti- proliferative drugs following angioplasty) .

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 and organs distant to the site of interest, 2) a large amount of agent is usually required to achieve therapeutic concentrations at the site of interest, and 3) exposure of the agent to degradation and elimination by distant organ system. The localized delivery of drugs into the vessel wall, in contrast, 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 intramural delivery of a variety of drugs have been proposed for the inhibition of restenosis following angioplasty and other primary intravascular treatments . The most common drugs suggested in the patent and medical literature include heparin, urokinase, streptokinase, tissue plasminogen activator (tPA) , and the like, but these drugs generally only limit thrombosis and have no effect on hyperplasia. Other specific drugs and classes of drugs are listed in the references cited in the Background of the Art section below. To date, however, no one drug or combination of drugs has proven to be entirely effective in inhibiting post-angioplasty hyperplasia. Thus, there is a continuing need to identify specific treatment agents, administration protocols, and combinations of treatment agents and administration protocols which are more effective in at least some respects than the previous drugs and treatment protocols for inhibiting post-angioplasty restenosis.

As an alternative to intravascular and intramural drug delivery, use of intravascular brachytherapy for the inhibition of hyperplasia has been proposed. A variety of catheters, guidewires, and stents have been configured for positioning a radioactive source within a blood vessel after angioplasty and other interventional treatments. In most cases, the devices have been configured to position a solid radioactive source, such as a wire, strip, pellet, or the like, within the blood vessel. It has also been proposed to deliver liquid radioactive medium to inflate a balloon catheter within the blood vessel. In the latter case, the balloon has been specially configured to prevent leakage of the radioactive material from the balloon into the blood vessel or blood stream.

While holding great promise, the temporary or permanent placement of a radioactive source in the blood vessel lumen and/or adjacent to the blood vessel wall suffers from a number of drawbacks. In particular, the use of a catheter to maintain a radioactive material at the intravascular treatment site is problematic. Frequently, it is desirable to use rather low dosage sources, such as β- emitters . While easier to introduce and presenting less risk to hospital personnel, such low-dosage sources must be maintained at the treatment site for prolonged periods of time, usually at least hours, and in some cases preferably for days. Intravascular catheters, even when provided with perfusion capability, are not well suited for such long term placement. Radioactive stents, in contrast, are ideally suited for long-term placement, but suffer from the need for permanent implantation. In the first place, stents can be difficult to deliver and properly locate. The need to further locate a stent in order to optimize the delivery of a radioactive coating or component is even more difficult. Moreover, when using either catheters or stents, it can be difficult to provide uniform delivery of the radioactive dose to the blood vessel wall.

For these reasons, it would be desirable to provide improved methods for inhibiting restenosis and hyperplasia following angioplasty and other intravascular treatments. In particular, it would be desirable to provide improved methods, systems, and the like, for delivering radioactive dosages to the blood vessel . Preferably, the radioactive dosages will be delivered directly into the blood vessel wall (and potentially into the perivascular space) in amounts sufficient to inhibit hyperplasia using radiopharmaceuticals which decay sufficiently rapidly to avoid overdosing of the patient to radioactivity. More preferably, the methods and systems will be safer and/or more effective than previous intravascular brachytherapy methods and systems, and will be capable of successfully delivering low dosage radiopharmaceuticals of the type previously utilized in diagnostic procedures. At least some of these objectives will be met by the present invention.

2. Description of the Background Art

The use of intravascular catheters for delivering particular drugs and classes of drugs is described in U.S. Patent Nos. 5,180,366; 5,171,217; 5,049,132; and 5,021,044; and PCT Publications WO 93/08866 and WO 92/11895. Riessen et al . (1994) JACC 23:1234-1244 is a review article discussing the use of catheters and stents for the local delivery of therapeutic agents into the blood vessel wall .

Devices and methods for exposing intravascular and other treatment locations to radioactive materials are described in the following: U.S. Patent Nos. 5,618,266; 5,540,659; 5,503,613; 5,498,227; 5,484,384; 5,411,466; 5,354,257; 5,302,168; 5,213,561; 5,199,939; and 5 , 059 , 166 , European applications 688 580; 633 041; and 593 136, and International Publications W096/14898 and WO96/13303. U.S. Patent No. 5,443,447 describes a device for spraying a radioactive material over the lining of a body cavity for therapy and diagnosis.

A preferred infusion catheter for delivering the radioactive material in accordance with the methods of the present invention is described in co-pending 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 co-pending 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 . SUMMARY OF THE INVENTION

The present invention provides methods for inhibiting hyperplasia in blood vessels, particularly in blood vessels which have undergone a conventional recanalization procedure. The methods comprise intramurally delivering a radioactive substance to a target site within the blood vessel .

The term "hyperplasia" refers to the excessive growth of the vascular smooth muscle cells which can result from an injury to the blood vessel wall resulting from angioplasty or other recanalization procedures. Such hyperplastic cell growth results in restenosis of the blood vessel lumen that was opened by the recanalization procedure. By inhibiting hyperplasia, the present invention can eliminate the need for subsequent angioplasty, atherectomy, bypass, and other procedures intended to restore blood perfusion. The brachytherapy methods of the present invention can be combined with other methods for controlling restenosis, such as stent placement which provides for vascular remodeling but which generally does not successfully inhibit hyperplasia.

The term "recanalized" is defined as the condition of the blood vessel after an initial corrective procedure has been performed to at least partially resolve 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. Usually, the corrective procedure will comprise an interventional procedure, such as balloon angioplasty, atherectomy, rotational atherectomy, laser angioplasty, or the like, where the lumen of the treated blood vessel is enlarged to at least partially alleviate a stenotic condition which existed prior to the treatment.

Alternatively, the corrective procedure could involve coronary artery bypass, vascular graft implantation, endarterectomy, or the like. The phrase "intramural delivery" is defined as localized delivery of the radioactive 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. Intramural delivery of the radioactive substance results in a retention of the substance in the blood vessel wall and/or the perivascular space surrounding the blood vessel even after the delivery is stopped and the catheter removed. The length of retention will depend on the pharmacokinetics of the radioactive substance. Such pharmacokinetics can be quite complex and depend on a number of factors, including the specific chemical composition of the radioactive substance as well as the nature of the tissue.

Preferably, retention will cover a period of at least one day, where retention is defined as maintaining at least 50% of the initial weight of radioactive substance which is initially delivered and retained within the blood vessel wall and/or perivascular space. As described in more detail below, such retention lengths will typically be greater than the half- lives of the radioactive substances being used. Thus, the total dose of radioactivity delivered to the target site within the blood vessel will depend primarily on the type and activity of the radiopharmaceutical employed and the amount of substance initially delivered into the blood vessel wall. The catheter-based delivery methods described below will preferably have a delivery efficiency of at least 1%, i.e. at least 1% of the substance delivered through the catheter will be introduced into and maintained within the blood vessel wall and/or perivascular space at the beginning of the retention periods defined above. Preferably, the delivery efficiencies will be at least 2%, more preferably being at least 3%, still more preferably being at least 4%, and in some cases being 5%, 10%, or greater. The amount of radioactive substance which is not delivered into the wall will enter directly into blood circulation and be eliminated by normal body processes. It will be understood that in some cases, some portion of the radioactive substance which is intially maintained in the blood vessel wall and/or perivascular space will be eluted or otherwise lost back into blood or into surrounding tissue over time. Thus, the radioactive dose rate will decrease over time because of decay and in at least some cases because of loss of the substance from the target site.

The phrase "radioactive substance" is defined to include any substance that can be delivered through a catheter into the wall of a blood vessel and which can emit radiation into the blood vessel wall, including α-radiation, 3-radiation, γ-radiation, and the like. The preferred radioactive substances will be low activity radioisotopes having relatively short half-lives, preferably below one week, usually being between eight hours and one week, preferably being between one day and five days, more preferably being between two days and five days. Radioactive substances will be selected to provide a total intramural dose in the range from one Gray (Gy; 1 Gy = 100 rads) to 50 Gy, preferably from 5 Gy to 40 Gy, and more preferably from 15 Gy to 25 Gy. The total dosage will depend, of course, both on the initial activity of the radioactive substance delivered into the blood vessel wall as well as the half-life of the substance. Preferably, the radioactive substance will have an initial activity in the range from 1 curie (Ci) to 100 Ci, preferably from 2 Ci to 25 Ci , more preferably from 5 Ci to 10 Ci .

Radioactive substances having the activities and half-lives set forth above will be able to provide the total radioactive dosages set forth above. Usually, a single radioisotope will be employed, but it will be possible to combine two or more radioisotopes, e.g. in order to balance the initial activity and residual activity.

Preferred radioactive substances include radioactive iodine (¹³¹I) , preferably being delivered with an initial activity in the range from 1 Ci to 15 Ci, more preferably from 2 Ci to 10 Ci. A second preferred radioactive substances is radioactive thallium (²⁰¹T1) , delivered with an initial activity in the range from 1 Ci to 15 Ci , preferably from 2 Ci to 10 Ci. A third preferred radioactive material is radioactive gallium (⁶⁷Ga) , delivered with an initial activity in the range from 1 Ci to 20 Ci, preferably from 5 Ci to 15 Ci. A fourth preferred radioactive material is radioactive indium (^11:LIn) , delivered with an initial activity in the range from 1 Ci to 15 Ci, preferably from 2 Ci to 10 Ci . In many cases, it will be possible to use conventional diagnostic formulations of these radioactive substances with little or no modification .

The radioactive substances will typically be provided as a solution, e.g. a dissolved salt, or as a particulate form which is suspended in a liquid carrier. Optionally, the radioactive substances may be incorporated in solid carrier to enhance or modify the characteristics of the suspension. Suitable solid carriers include macroreticular particles, microreticular particles, liposomes, microcapsules, and the like. Alternatively or additionally, the radioactive substances may be modified or combined with other substances in order to enhance their penetration into and/or persistence within the blood vessel wall. For example, the radioactive substances may be covalently or non-covalently bound to materials which specifically or non-specifically bind to components of the blood vessel wall. The ability to form pharmaceutically acceptable suspensions of these substances is well described in the medical and patent literature relating to radiopharmaceutical diagnostic substances. See, e.g.,

DIAGNOSTIC NUCLEAR MEDICINE, Sandier et al . , eds . , Williams & Wilkins, Baltimore, Third Edition.

In a first particular aspect of the present invention, the method for inhibiting hyperplasia in a recanalized blood vessel comprises advancing a distal end of the catheter to the target site within the recanalized blood vessel . A volume of the radioactive substance is then delivered through the distal end of the catheter. Usually, the catheter is introduced percutaneously to the patient's vasculature and advanced translumenally to the target site. The radioactive substance is then delivered from a proximal end of the catheter, through one or more lumens in the catheter body, and to the distal end from where it is released into the blood vessel wall. Optionally, the distal end of the catheter is expanded to engage infusion ports therein against the blood vessel wall to enhance intralumenal penetration. In a second particular aspect of the present invention, the method for inhibiting hyperplasia in a recanalized blood vessel comprises advancing the distal end of an infusion catheter to a target site within the recanalized blood vessel. The distal end of the infusion catheter is expanded to engage infusion ports therein against the lumenal 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. An amount of the radioactive substance sufficient to inhibit hyperplasia at said target site is then delivered through the infusion ports, usually at a predetermined infusion pressure which is independent of the balloon inflation pressure.

In a third particular aspect of the present invention, 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 then advanced to the target site, usually within one to ten minutes, preferably within five minutes, and an amount of the radioactive substance sufficient to inhibit hyperplasia at said target site 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, including combinations of such procedures. In yet another aspect of the present invention, a drug delivery catheter comprises a catheter body having a proximal end, a distal end, and an infusion lumen therebetween. An infusion matrix is disposed at the distal end of the catheter body and is fluidly attached to the infusion lumen to deliver drugs, usually a radiopharmaceutical , therethrough. The infusion matrix is adapted to deliver a volume of liquid carrier at a controlled rate where the rate is increased or greater near each end of the infusion matrix relative to the rate over the middle of the infusion matrix. It will be appreciated that uniform delivery of a radiopharmaceutical (referred to as an "isodose") over a discrete length of blood vessel wall will result in non-uniform irradiation of the wall. Such non- uniformity results from the cumulative nature of radiation emission. By uniformly distributing a radioisotope over a discrete length of the blood vessel wall, the total radiation experienced by any point along the length will depend on the amount and distance of all radioisotope sources on either side of it. For that reason, those points near the end of the length will necessarily receive less total radiation (i.e. from all points along the treatment region) than those near the middle. In order to enhance the uniformity of the radiation dosage along the treated length, it is therefore desirable to deliver increased amounts of the radioactive substance near each end of the length. This can be accomplished by providing catheters having a matrix which is adapted to deliver more radioactive substance near the ends. For example, when using a catheter having infusion tubes with apertures along its length, the number and/or areas of the apertures can be increased near each end of the treatment length in order to increase the amount of radioactive substance delivered at each end. A wide variety of other catheter modifications can be provided for other types of delivery catheters.

BRIEF DESCRIPTION OF THE DRAWINGS

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. 9A and 9B illustrate modified infusion catheters having an increased number of drug infusion ports (Fig. 9A) and infusion ports having increased areas (Fig. 9B) at each of the delivery matrix defined by said ports, respectively.

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 radioactive substance to a coronary artery in combination with an angioplasty balloon catheter in accordance with the method of the present invention. Fig. 12 is a cross-sectional view taken along line

12-12 of Fig. 11.

Fig. 13 is an alternative cross-sectional view similar to Fig. 12.

DESCRIPTION OF THE SPECIFIC EMBODIMENT

The methods of the present invention rely on the intramural delivery of a radioactive substance to an intravascular target site to inhibit hyperplasia following a conventional recanalization procedure. Intramural delivery of a radioactive substance 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 radioactive substance will be delivered using intravascular catheter delivery systems. A variety of catheter systems useful for the direct intramural infusion of the radioactive substance into the blood vessel wall are well- described in the patent literature. Most commonly, balloon catheters having expandable distal ends capable of engaging the inner wall of a blood vessel and infusing the radioactive substance directly therein are well-described in the patent literature. See, for example, U.S. Patent Nos. 5,318,531; 5,304,121; 5,295,962; 5,286,254; 5,254,089; 5,213,576; 5,197,946; 5,087,244; 5,049,132; 5,021,044; 4,994,033; and 4,824,436. 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 Dispatch™ from SciMed Life Systems, Inc., Maple Grove, Minnesota. Also suitable are the MIC Balloon (Cordis) and the Channel Balloon (Boston Scientific) . 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 (phonophoresis devices) are described in U.S. Patent Nos. 5,362,309; 5,318,014; and 5,315,998. Other iontophoresis and phonophoresis drug delivery catheters are described in U.S. Patent Nos. 5,304,120; 5,282,785; and 5 , 267 , 985. Finally, sleeve catheters having drug delivery lumens intended for use in combination with conventional angioplasty balloon catheters are described in U.S. Patent Nos. 5,364,356 and 5,336,178. Any of the catheters described in the above-listed patents may be employed for delivering the radioactive substance according to the method of the present invention. Full disclosures of each of these patent references are hereby incorporated herein by reference. The radioactive substances used in the methods of the present invention will be incorporated into conventional pharmaceutical compositions suitable for intramural delivery. In the case of continuous catheter delivery, the radioactive substances will be incorporated into an acceptable fluid carrier, e.g., being formulated with sterile water, isotonic saline, a 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 radioactive substance, typically in solution or in the form of a radioisotopic particle in the liquid formulation, may vary widely, from 1% to 50%, typically being from 1% to 25% by weight. General methods for preparing such pharmaceutical formulations are described in Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Philadelphia, Pennsylvania, 1985. The pharmaceutical formulations delivered according to the methods of the present invention may include other active agents in addition to the radioactive substance. In particular, the formulations may include anti-coagulants and anti-thrombotic agents, such as heparin, low molecular weight heparin, and the like.

Referring now to Figs. 1-6, a particular drug delivery catheter in the form of a sleeve infusion catheter 110 useful for delivering the radioactive substance according to the methods of the present invention will be described. Such infusion catheters are described in greater detail in co-pending 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. As illustrated in Figs. 1-6, 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. Usually, 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 mm² to 2 mm², typically about 1.25 mm².'

Referring now to Figs. 7-9, 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. After the balloon B is deflated, the sleeve 112 may be advanced distally over the balloon, as illustrated in

Fig. 8. By then inflating the balloon, the expansible portion 113 of the sleeve 112 will be expanded, as illustrated in Fig. 9.

Referring to Figs. 9A and 9B, the infusion sleeve 112 may be modified to provide for increased delivery of the radioactive substance at each end of the delivery length defined by the apertures. In the embodiment of Fig. 9A, infusion ports 128a are spaced more closely together at the distal and proximal ends of the radially expansible portion 113 when compared to the spacing over the central portion thereof. By providing the more ports per unit length, the amount of radioactive substance delivered at each end of the treatment region will, of course, be greater. As an alternative to adjusting the density of the infusion ports 128, it will also be possible to employ infusion ports 128b having larger cross-sectional areas at each end of the expansible region, as illustrated in Fig. 9B . A variety of other techniques and approaches will be available for controlling the release rates of the drug infusion matrices and other types of catheters. For example, for catheters which employ a substantially continuous infusion membrane, it will be possible to make the membrane more permeable at each end when compared to the permeability over a central region thereof. In balloon catheters which deliver drug directly through the balloon membrane it will be possible to form more holes and/or larger holes, in a manner analogous to that described in connection with the sleeve catheters of the present invention. By delivering increased amounts of the radioactive substance at each end of the treatment region within a blood vessel, the uniformity of dosage over that length will be enhanced for the reasons described above. 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 O. Such guiding catheters are commercially available through a number of suppliers, including Medtronic, Minneapolis, Minnesota, available under the tradename Sherpa™. 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. According to the method of the present invention, 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. Preferably, 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 balloon may then be expanded to treat other regions within the coronary vasculature in a conventional manner. After the angioplasty treatment is completed, the infusion sleeve 112 will be advanced distally over the balloon catheter BC until the radially expansible portion is properly positioned over the balloon. Such positioning can be confirmed by proper alignments of radiopaque markers on the infusion sleeve 112 (not shown) with markers on the balloon catheter, typically within the balloon itself. After the infusion sleeve is properly positioned, the balloon B on the balloon catheter BC will be inflated to engage the infusion ports 128 against the inner wall of coronary artery.

The radioactive substance is then delivered through the hub 118 for treatment of the affected region within the blood vessel . The total amount of radioactive substance delivered will depend on both the initial activity of the substance as well as the substance half-life, generally as described above. The initial dose will be selected in order to provide a total dose in the range from 1 Gy to 50 Gy, preferably from 5 Gy to 40 Gy, more preferably from 15 Gy to 25 Gy, as described above. Infusion pressures will typically be in the range from 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 atmospheres to 6 atmospheres, usually from 1 atmosphere to 2 atmosphere. Treatment periods will typically not exceed five minutes, usually not exceeding three minutes, in order not to occlude the blood vessel for a longer time than is tolerable to the patient. Treatment periods may be increased if the delivery catheters are provided with perfusion capability. In order to increase the total amount of radioactive substance delivered to the blood vessel wall, the delivery procedure can be repeated one, two, three, or more times, with each time incrementally increasing the amount of radioactive substance which is retained within the blood vessel wall.

While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.

Claims

WHAT IS CLAIMED IS;

1. A method for inhibiting hyperplasia in a blood vessel, said method comprising intramurally delivering a radioactive substance to a target location in the blood vessel .

2. A method as in claim 1, wherein an amount of radioactive substance is delivered which is sufficient to provide an intramural dose in the range from 1 Gy to 50 Gy.

3. A method as in claim 1, wherein the amount is sufficient to deliver a dose in the range from 15 Gy to 25 Gy.

4. A method as in claim 1, wherein the radioactive substance is delivered over a predetermined length of the blood vessel .

5. A method as in claim 4, wherein increased amounts of the radioactive substance are delivered near each end of the predetermined length in order to enhance dose uniformity over the length.

6. A method for inhibiting hyperplasia in a recanalized blood vessel, said method comprising: advancing a distal end of a catheter to a target site within the recanalized blood vessel; and delivering through the distal end of the catheter into the blood vessel wall a dose of radioactive substance sufficient to inhibit hyperplasia at the target site.

7. A method as in claim 6, wherein the dose is in the range from 1 Gy to 50 Gy.

8. A method as in claim 6, wherein the dose is in the range from 15 Gy to 25 Gy.

9. A method as in claim 6, wherein the radioactive substance has an initial activity when delivered of at least 1 Ci and a half-life of at least 8 hours.

10. A method as in claim 6, wherein the radioactive substance has an initial activity in the range from 1 Ci to 100 Ci and a half-life in the range from 8 hours to one week.

11. A method as in claim 6, wherein iodine (¹³¹I) is delivered with an initial activity in the range from 1 Ci to 15 Ci.

12. A method as in claim 6, wherein thallium ²⁰ⁱ _T2 j__s delivered with an initial activity in the range from 1 Ci to 20 Ci .

13. A method as in claim 6, wherein the distal end of the catheter is introduced percutaneously to a patient's vasculature and advanced transvascularly to the target site.

14. A method as in claim 6, wherein the radioactive substance is delivered from a proximal end of the catheter, through a lumen in the catheter, to the distal end.

15. A method as in claim 6, further comprising expanding the distal end of the catheter to engage a plurality of infusion ports against the blood vessel wall, wherein the radioactive substance is delivered through said infusion ports.

16. A method as in claim 15, wherein infusion ports are formed over a length of the catheter body from 1 cm to 20 cm.

17. A method as in claim 16, wherein the number and/or area of the infusion ports is increased at each end of the length to increase the amount of radioactive substance delivered near said ends.

18. A method for inhibiting hyperplasia in a recanalized blood vessel, said method comprising: advancing a distal end of an infusion catheter to a target site within the recanalized blood vessel; expanding the distal end of the infusion catheter to engage ports on the catheter against the lumenal wall of the blood vessel; and delivering through the infusion ports into the blood vessel wall a dose of radioactive substance sufficient to inhibit hyperplasia at the target site.

19. A method as in claim 18, wherein the dose is in the range from 1 Gy to 50 Gy.

20. A method as in claim 18, wherein the dose is in the range from 15 Gy to 20 Gy.

21. A method as in claim 18, wherein the radioactive substance has an initial activity when delivered of at least 1 Ci and a half-life of at least 8 hours.

22. A method as in claim 18, wherein the radioactive substance has an initial activity in the range from 1 Ci to 100 Ci and a half-life in the range from 8 hours to one week.

23. A method as in claim 18, wherein iodine (¹³¹I) is delivered with an initial activity in the range from 1 Ci to 15 Ci.

24. A method as in claim 18, wherein thallium (²⁰¹T1) is delivered with an initial activity in the range from 1 Ci to 20 Ci .

25. A method as in claim 18, wherein the distal end of the catheter is introduced percutaneously to a patient's vasculature and advanced translumenally to the target site.

26. A method as in claim 18, wherein the radioactive substance is delivered from a proximal end of the catheter, through a lumen in the catheter, to the infusion ports at the distal end.

27. A method as in claim 18, wherein the expanding step comprises: positioning a balloon within the distal end of the infusion catheter; and inflating the balloon to a predetermined inflation pressure.

28. A method as in claim 27, wherein the delivering step comprises supplying fluid to the infusion ports at a predetermined infusion pressure, wherein the inflation pressure is independent of the inflation pressure.

29. A method as in claim 18, wherein the expanding step comprises inflating the distal end of the infusion catheter having the infusion ports with a fluid carrying the radioactive substance with an inflation pressure to release the radioactive substance-containing fluid through the infusion ports.

30. A method as in claim 18, wherein infusion ports are formed over a length of the catheter body from 1 cm to 20 cm.

31. A method as in claim 18, wherein the number and/or area of the infusion ports is increased at each end of the length to increase the amount of radioactive substance delivered near said ends.

32. A method for recanalizing a blood vessel, said method comprising: enlarging the blood vessel lumen at a target site; advancing the distal end of an infusion catheter to the target site; and delivering through the distal end of the infusion catheter into the blood vessel wall a dose of radioactive substance sufficient to inhibit hyperplasia at said target site.

33. A method as in claim 32, wherein the dose is in the range from 1 Gy to 50 Gy.

34. A method as in claim 32, wherein the dose is in the range from 15 Gy to 20 Gy.

35. A method as in claim 32, wherein the radioactive substance has an initial activity when delivered of at least 1 Ci and a half-life of at least 8 hours.

36. A method as in claim 32, wherein the radioactive substance has an initial activity in the range from 1 Ci to 100 Ci and a half-life in the range from 8 hours to one week.

37. A method as in claim 32, wherein iodine (¹³¹I) is delivered with an initial activity in the range from 1 Ci to 15 Ci.

38. A method as in claim 32, wherein thallium (^20ir-] j__s delivered with an initial activity in the range from 1 Ci to 20 Ci .

39. A method as in claim 32, wherein the enlarging step comprises balloon angioplasty, atherectomy, laser recanalization, or stent placement.

40. A method as in claim 39, wherein the enlarging step comprises advancing an angioplasty balloon catheter to the treatment site, inflating a balloon at the distal end of the angioplasty balloon catheter to recanalize the blood vessel, and withdrawing the angioplasty balloon catheter.

41. A method as in claim 40, wherein the infusion catheter is advanced to the target site within one to ten minutes of withdrawing the angioplasty balloon catheter.

42. A method as in claim 40, further comprising placing the infusion catheter over the balloon angioplasty catheter after the withdrawal thereof, advancing the balloon angioplasty catheter together with the infusion catheter to the target site, and reinflating the balloon on the balloon angioplasty catheter to expand the distal end of the infusion catheter so that it contacts the blood vessel wall.

43. A method as in claim 32, wherein the distal end of the catheter is introduced percutaneously to a patient's vasculature and advanced translumenally to the target site.

44. A method as in claim 32, wherein the radioactive substance is delivered from a proximal end of the catheter, through a lumen in the catheter, to the distal end.

45. A method as in claim 32, further comprising expanding the distal end of the catheter to engage a plurality of infusion ports against the blood vessel wall, wherein the radioactive substance is delivered through said infusion ports.

46. A method as in claim 45, wherein infusion ports are formed over a length of the catheter body from 1 cm to 20 cm.

47. A method as in claim 45, wherein the number and/or area of the infusion ports is increased at each end of the length to increase the amount of radioactive substance delivered near said ends.

48. A catheter for delivering a radiopharmaceutical drug, said catheter comprising: a catheter body having a proximal end, a distal end, and an infusion lumen therebetween; an infusion matrix at the distal end of the catheter body, said infusion matrix providing for controlled rate delivery of a liquid carrier over a discrete length of the matrix; wherein the matrix is adapted to deliver the liquid carrier at an increased rate near the proximal and distal ends of the matrix length than over a middle portion of the matrix length.

49. A catheter as in claim 48, wherein the infusion matrix comprises a plurality of infusion tubes having a multiplicity of infusion ports formed thereover, wherein the number and/or size of the infusion ports is greater near each end of the infusion tube than in the middle.