WO2001062241A1

WO2001062241A1 - Method for the prevention or reduction of vascular access dysfunction

Info

Publication number: WO2001062241A1
Application number: PCT/US2001/005846
Authority: WO
Inventors: Theodore M. Danoff; Diane K. Jorkasky
Original assignee: Smithkline Beecham Corporation
Priority date: 2000-02-23
Filing date: 2001-02-22
Publication date: 2001-08-30
Also published as: AU2001243248A1

Abstract

This invention provides a method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein, in a mammal, preferably a human, in need thereof, which comprises administering to the subject N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof in a dose of from about 0.1 mg to about 2,400 mg.

Description

METHOD FORTHEPREVENTION ORREDUCTIONOFVASCULARACCESS

DYSFUNCTION

Field of Invention

The present invention relates to a method for the prevention or reduction of vascular access dysfunction in mammals, including humans.

More particularly, the method comprises administrating to a mammal, particularly a human patient, in association with the insertion, maintenance or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein, an effective oral or parental dose of N-(3',4'-dimethoxycinnamoyl)anthranilic acid (Tranilast) represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the method comprises treating patients undergoing repair of their indwelling shunt or fistula or the vessels that feed or drain the shunt or fistula using surgery or percutaneous intervention, with or without stent placement, by administering to the subject an effective amount of N-(3',4'-dimethoxycinnamoyl)anthranilic acid (Tranilast) represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

Complications associated with vascular access treatment is a major cause of morbidity in many disease states. For example, vascular access dysfunction in hemodialysis patients is generally caused by outflow stenoses in the venous circulation. Schwam S. J., et al., Kidney Int. 36: 707-711, 1989. Vascular access related morbidity accounts for about 23 percent of all hospital stays for advanced renal disease patients and contributes to as much as half of all hospitalization costs for such patients. Feldman H. I., J. Am. Soc. Nephrol. 7: 523 - 535, 1996. Additionally, vascular access dysfunction in chemotherapy patients is generally caused by outflow stenoses in the venous circulation and results in a decreased ability to administer medications to cancer patients. Often the outflow stenoses is so severe as to require intervention.

Additionally, vascular access dysfunction in total parenteral nutrition (TPN) patients is generally caused by outflow stenoses in the venous circulation and results in reduced ability to care for these patients.

Up to the present time, there has not been any effective drug for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein in a mammal, particularly a human patient.

2. DESCRIPTION OFTHE RELATEDART

Tranilast is sold commercially as a drug for the treatment of allergic diseases, e.g., allergic bronchitis, allergic asthma, atopic dermatitis, and the like, based on the activity exhibited by the drug for inhibiting release of chemical mediators (The Journal of Allergy and Clinical Immunology. Vol. 57, No. 5, pp. 396-407, (1976)).

More recently, in Biochemical Pharmacology. Vol. 36, No. 4, pp. 469-474 (1987), it was reported that Tranilast inhibits fibroblast proliferation and collagen accumulation.

United States Patent No. 5,385,935 ('935) claims the use of Tranilast in the inhibition of restenosis associated with arterial coronary intervention and indicates that a treatment period of at least three consecutive months is required for efficacy. The requirement of a three plus month treatment period was premised, in part, upon a publication in the Japanese College of Cardiology (1988), cited in the '935 patent. This publication discloses the treatment of patients subjected to the PTCA procedure with Tranilast in a daily oral dose of 300 mg for 30 consecutive days after the PTCA procedure. The clinical data obtained from this study did not indicate any significant efficacy for inhibiting a restenosis effect associated with the PTCA procedure at the tested dosage and duration.

The '935 patent demonstrated that an extended period of Tranilast treatment was effective for lowering the incidence of post-surgery restenosis associated with PTCA. It was found that dosing patients with Tranilast for a period of at least about three months (i.e., a term of at least about 90 consecutive days of treatment, as used herein the phrase "at least three consecutive months" means at least 90 days) reduced the incidence of restenosis associated with the PTCA procedure. In one clinical study, when patients were administered Tranilast in a daily oral dose of 600 mg for three consecutive months after the PTCA procedure, the incidence of restenosis was less than about 20%. As reported in the '935 patent, the incidence of restenosis associated with the PTCA procedure usually is about 40%. The '935 patent does not contain any disclosure regarding the ability of Tranilast to effect vascular events as disclosed herein.

Additionally, in Nobuyoshi M. et al., J Am Coll. Cardiol. 1988; 12: 616 to 623, it was observed that most cases of restenosis after successful arterial coronary angioplasty occur within 6 months after the procedure, particularly between 1 and 3 months after coronary angioplasty.

Notwithstanding, the percent diameter stenosis measurement is reported to correlate poorly with the physiologic significance of lesions (Harrison D.G. et al. Circulation 1984; 69:1111-9). Furthermore, because significant changes sometimes occur in the adjacent normal coronary segment after coronary angioplasty (Brayden G.P. et al. Clin. Res. 1983; 31: 702A), use of percent stenosis in a restenosis study has shortcomings. As such, a treatment that demonstrates efficacy in the prevention or reduction of restenosis does not correspond or lead one to anticipate with any degree of certainty that the treatment would have a beneficial or therapeutically significant effect on the prevention or reduction of cardiovascular events associated with arterial coronary intervention. Moreover, a treatment with Tranilast that demonstrates efficacy in the prevention or reduction of restenosis in a coronary artery does not correspond or lead one to anticipate with any degree of certainty that the treatment would have a beneficial or therapeutically significant effect on the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein in a mammal, particularly a human, in need thereof.

Nothing in the known art teaches Tranilast as exhibiting a therapeutic effect on vessels other than coronary arteries. Further, nothing in the known art teaches or suggests that Tranilast could be efficaciously administered for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein.

Numerous advantages would be realized if Tranilast could be efficaciously administered for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein in a mammal, particularly a human, in need thereof.

It has now surprisingly been discovered that Tranilast can be suitably administered in the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein. SUMMARY OF THE INVENTION

This invention relates to a method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein, or actual treatment, in a mammal, preferably a human, in need thereof, which comprises administering to the subject N-(3',4 - dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof in a dose of from about 0.1 mg to about 2,400 mg.

Other objects, features and advantages of the present invention will become apparent from the following description and examples.

DETAILED DESCRIPTION OF THE INVENTION

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.

By the phrase "prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter" as used herein, is meant that the incidence of vascular thrombosis and or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter in Tranilast treated patients collected over the observation period are prevented or reduced in comparison to untreated patients.

By the phrase "in association with the insertion or repair of an indwelling shunt, fistula or catheter" as used herein, is meant that the treatment with Tranilast can commence immediately, for example within 4 to 8 hours, after insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, such as dialysis treatment; within a few days, for example about 7 days, preferably about 1 or 2 days, after insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, such as dialysis treatment; or for a period of days, for example about 30 days, preferably about 14 days, preferably about 7 days, prior to insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, such as dialysis treatment. Also contemplated within the phrase "in association with the insertion or repair of an indwelling shunt, fistula or catheter" is a dosing protocol in which a dose or several doses, are skipped, for example in the morning of or on the day of insertion, repair or treatment. Also contemplated within the phrase "in association with the insertion or repair of an indwelling shunt, fistula or catheter" is a dosing protocol in which a day of drug treatment or several days of drug treatment, are skipped.

By the term "treatment" and derivatives thereof, is meant prophylactic and therapeutic therapy.

Included in term "treatment", when used herein to refer surgical procedures, are procedures selected from access surgery, placement of fistula or shunt, catheter insertion, actual disease treatment, such as dialysis treatment, and declotting of an access shunt, fistula or catheter. Further, treatment for insertion access also includes repair/revision of the access. For example, a patient experiencing a failure in a dialysis access shunt will have the access repaired, for instance, by angioplasty. Tranilast is useful after the repair to prevent restenosis.

By the term "collected over the observation period" as used herein, means a period of up to or about 12 months, preferably 12 months.

The present invention relates to a method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, or actual treatment, into a vein in a mammal, particularly a human, which comprises administering to the subject N-(3',4'- dimethoxycinnamoyl)anthranilic acid (Tranilast) or a pharmaceutically acceptable salt thereof in a dose of from about 0.1 mg to about 2,400 mg.

The present invention further relates to a method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, or actual treatment, into a vein in a mammal, particularly a human, which comprises administering to the subject N-(3',4'- dimethoxycinnamoyl)anthranilic acid (Tranilast) or a pharmaceutically acceptable salt thereof in a daily dose of from about 0.1 mg to about 2,400 mg for a treatment period of at least one week, preferably at least two weeks, in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, or actual treatment.

A preferred daily dosage amount of Tranilast for use in the present invention is about 25 mg to about 1,500 mg. A more preferred daily dosage amount of Tranilast for use in the present invention is from about 100 mg to about 1,000 mg. Particularly preferred is a daily dosage amount of from about 300 mg to about 900 mg of Tranilast for use in the present invention. Particularly preferred is a daily dosage amount of about 600 mg of Tranilast for use in the present invention.

A contemplated treatment period for use in the present invention is about 85 days in association with the insertion or repair of an indwelling shunt, fistula or catheter, or actual treatment. A contemplated treatment period for use in the present invention is about 70 days in association with the insertion or repair of an indwelling shunt, fistula or catheter, or actual treatment. An additional contemplated treatment period for use in the present invention is about 50 days in association with the insertion or repair of an indwelling shunt, fistula or catheter, or actual treatment. A preferred treatment period for use in the present invention is about 28 days in association with the insertion or repair of an indwelling shunt, fistula or catheter, or actual treatment. An additional contemplated treatment period for use in the present invention is 14 days in association with the insertion or repair of an indwelling shunt, fistula or catheter, or actual treatment.

A preferred method of use in the current invention is a method for preventing or reducing vascular thrombosis and or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter associated with insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, in dialysis patients.

A preferred method of use in the current invention is a method for preventing or reducing vascular thrombosis and/or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter associated with insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, in cancer patients.

A preferred method of use in the current invention is a method for preventing or reducing vascular thrombosis and/or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter associated with insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, in total parenteral nutrition (TPN) patients.

The efficacy of the presently invented method is demonstrated by the Examples below.

The invention also provides for the use of Tranilast or a pharmaceutically acceptable salt thereof in the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, or actual treatment, into a vein in a mammal, particularly a human, which comprises administering to the subject N-(3',4'-dimethoxycinnamoyl)anthranilic acid (Tranilast) or a pharmaceutically acceptable salt thereof in a daily dose of from about 0.1 mg to about 2,400 mg for a treatment period of at least one week, preferably at least two weeks, in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, or actual treatment in a mammal, particularly a human.

The invention also provides for a pharmaceutical composition for use in the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, or actual treatment, into a vein in a mammal, particularly a human, which comprises N-(3',4 - dimethoxycinnamoyl)anthranilic acid (Tranilast) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Tranilast is generally described in United States Patent 3,940,422. Tranilast and pharmaceutically acceptable salts and compositions thereof can be readily prepared by known methods such as described in United States Patent 3,940,422.

When Tranilast or a pharmaceutically acceptable salt thereof is employed therapeutically, it can be administered orally or parentally in appropriate dosage forms, such as powder, granules, tablets, capsules, injectable solutions, and the like.

A Tranilast pharmaceutical composition can be formulated by admixing suitable carriers such as excipients, disintegrators, binders, brighteners, and the like, and preparing in accordance with conventional molding methods and dosage forms.

For example, a powdered dosage form can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, binders, brighteners, and the like.

Tablets can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, disintegrators, binders, brighteners, and the like, and compressing the mixture with conventional molding equipment. The tablets also can be coated to provide film coated tablets, sugar-coated tablets, enteric-coated tablets, and the like.

Capsules can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, brighteners, and the like, and filling the mixture in capsules, or by forming granules containing Tranilast or a pharmaceutically acceptable salt thereof with conventional molding equipment, and filling the formed granules in capsules.

When a pharmaceutical composition of the present invention is employed therapeutically, the daily or non daily dosage of Tranilast or a pharmaceutically acceptable salt thereof as an active ingredient will be an efficacious, nontoxic quantity selected from the range of about 0.1 mg to about 2,400 mg of active compound, preferably from about 25 mg to about 1,500 mg of active compound, preferably from about 100 mg to about 1,000 mg of active compound, particularly preferred is a dosage amount of from about 300 mg to about 900 mg, particularly preferred is a dosage amount of about 600 mg, per adult patient preferably by oral administration in association with the insertion or repair of an indwelling shunt, fistula or catheter. A treatment period of at least one week, preferably at least two weeks, is also contemplated herein. The dosage and term of administration can be changed depending upon the weight and age and sex of the patient, the severity of the condition to be treated, and the like.

When treating a human patient in need of prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein, or actual treatment, in a mammal, particularly a human, the above indicated dose may be split and administered preferably daily or from 1-6 times a month, preferably about 2 times a week, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral administration is preferred.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

No unacceptable toxicological effects are expected when compound of the invention is administered in accordance with the present invention.

Contemplated Equivalents - It is known that certain procedures, such as in dialysis treatment, require an indwelling shunt, fistula or catheter, to be placed into an artery and a vein. It is contemplated herein that the administration of N-(3',4'- dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof, in accordance with the present invention, and in association with the insertion or repair of an indwelling shunt, fistula or catheter, into a non-coronary artery will have a therapeutic effect in preventing or reducing associated arterial access dysfunction.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLE I

Efficacy of the invented method for the prevention or reduction of vascular access dysfunction in association with the insertion of an indwelling catheter into the vein of a patient is demonstrated by the following.

One hundred fifty prospective dialysis patients, who undergo successful insertion of an indwelling, large bore catheter, into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex, distribution of vascular condition or condition of lesions after insertion. One group (about 50 patients) receives Tranilast in a daily dose of 600 mg (hereinafter identified as group I), and another group (about 100 patients) does not receive Tranilast (hereinafter identified as group II). In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drugs are administered for 3 consecutive months following catheter insertion.

The comparative clinical data collected over the observation period of 6 months demonstrate the efficacy of 3 month Tranilast treatment for the prevention or reduction of vascular access dysfunction in patients after catheter insertion.

EXAMPLE II

Efficacy of the invented method for the prevention or reduction of vascular access dysfunction in association with the insertion of an indwelling shunt into the vein of a patient is demonstrated by the following.

One hundred fifty prospective cancer patients, who undergo successful insertion of an indwelling shunt into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex, distribution of vascular condition or condition of lesions after insertion. One group (about 50 patients) receives Tranilast in a daily dose of 900 mg, preferably in two 450 mg tablets administered 12 hours apart (hereinafter identified as group III), and another group (about 100 patients) does not receive Tranilast (hereinafter identified as group TV). In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drugs are administered every other day for 30 days following shunt insertion.

The comparative clinical data collected over the observation period of 12 months demonstrate the efficacy of every other day administration over 30 days Tranilast treatment for the prevention or reduction of vascular access dysfunction in patients after shunt insertion.

EXAMPLE III

One hundred fifty prospective total parenteral nutrition (TPN) patients, who will undergo insertion of an indwelling catheter into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex or distribution of vascular condition prior to insertion. One group (about 50 patients) receives Tranilast in a daily dose of 1000 mg, preferably in two 500 mg injections administered 12 hours apart (hereinafter identified as group V), and another group (about 100 patients) does not receive Tranilast (hereinafter identified as group VI). In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drugs are administered for 2 consecutive months commencing 1 month prior to catheter insertion.

The comparative clinical data collected over the observation period of 12 months demonstrate the efficacy of 2 month Tranilast treatment for the prevention or reduction of vascular access dysfunction in patients after catheter insertion.

EXAMPLE IV

Efficacy of the invented method for the prevention or reduction of vascular access dysfunction in association with the insertion of an indwelling fistula into the vein of a patient is demonstrated by the following.

One hundred fifty prospective dialysis patients, who will undergo insertion of an indwelling fistula into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex, distribution of vascular condition or condition of lesions after insertion. One group (about 50 patients) receives Tranilast in a daily dose of 900 mg, preferably in two 450 mg tablets administered 12 hours apart (hereinafter identified as group VII), and another group (about 100 patients) does not receive Tranilast (hereinafter identified as group VIII). In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drugs are administered for 30 consecutive days after fistula insertion.

The comparative clinical data collected over the observation period of 6 months demonstrate the efficacy of 30 days Tranilast treatment for the prevention or reduction of vascular access dysfunction in patients after fistula insertion.

EXAMPLE V

One hundred fifty prospective cancer patients, who will undergo insertion of an indwelling catheter into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex, distribution of vascular condition or condition of lesions after insertion. One group (about 50 patients) receives Tranilast in a daily dose of 100 mg, preferably in two 50 mg tablets administered 12 hours apart (hereinafter identified as group LX), and another group (about 100 patients) does not receive Tranilast (hereinafter identified as group X). In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drugs are administered for 30 consecutive days following catheter insertion.

The comparative clinical data collected over the observation period of 9 months demonstrate the efficacy of 30 days Tranilast treatment for the prevention or reduction of vascular access dysfunction in patients after catheter insertion.

EXAMPLE VI

One hundred fifty prospective dialysis patients, who undergo successful insertion of an indwelling shunt into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex or distribution of vascular condition prior to insertion. One group (about 50 patients) receives Tranilast in a daily dose of 1200 mg, preferably in two 600 mg tablets administered 12 hours apart (hereinafter identified as group XI), and another group (about 100 patients) does not receive Tranilast (hereinafter identified as group XII). In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drags are administered for 6 consecutive weeks commencing 2 weeks prior to catheter insertion.

The comparative clinical data collected over the observation period of 12 months demonstrate the efficacy of 6 weeks Tranilast treatment for the prevention or reduction of vascular access dysfunction in patients after catheter insertion.

Example VII

Efficacy for the invented method for preventing or reducing the incidence and severity of vascular stenosis following indwelling catheter placement is demonstrated by the following.

Four hundred patients who have indwelling catheters placed into central vessels are studied. The catheters are intended for the delivery of total parenteral nutrition or medications, including chemotherapy and analgesics, or for vascular access for hemodialysis or plasmapharesis. After stratification for catheter type, the patients are randomized into two groups. One group does not receive tranilast (herein referred to as group XIII) and the other group receives tranilast in a daily dose of 900 mg, preferably in two 450 mg tablets administered 12 hours apart (herein referred to as group XIV). The tranilast is administered starting within 1 hour of catheter insertion and continuing for 1 month. The patency of the vessel is assessed at the time of catheter insertion, 1 month, 6 months and 1 year after catheter placement regardless of whether the catheter is removed from the vessel during the follow-up period. The patency of the central vessels is assessed by ultrasonography, MRI and/or angiography.

The comparative clinical data collected over the observation period demonstrate the efficacy of 1 month Tranilast treatment for prevention or reduction of the degree of vessel stenosis in patients with indwelling catheters.

Example VIII

Efficacy for the invented method for preventing hemodialysis vascular access dysfunction is demonstrated by the following.

Two hundred patients having an arteriovenous shunt placed for hemodialysis access are studied. The patients are randomized into two groups. One group does not receive tranilast (herein referred to as group XV) and the other group receives tranilast in a daily dose of 600 mg, preferably in two 300 mg tablets administered 12 hours apart (herein referred to as group XVI). The tranilast is administered starting 4 days prior to access surgery and continued for 10 days following access surgery. The patency of the venous outflow is assessed 1, 2, 3, 4 and 6 months after surgery and every 3 months thereafter until the access becomes unusable either due to clotting or inadequate flow. The patency is assessed either by imaging techniques such as ultrasonography, angiography or MRI/MRA, or by functional techniques such as venous outflow pressures or by recirculation.

The comparative clinical data collected over the observation period demonstrate the efficacy of 2 weeks of Tranilast treatment for prolonging the period of good function of the arteriovenous shunt and/or slowing the rate of stenosis of the venous outflow tract of the shunt.

Example LX Efficacy for the invented method for preventing/delaying hemodialysis vascular access dysfunction following repair of a hemodialysis vascular access is demonstrated by the following.

Two hundred patients who are having angioplasty of a venous stenosis in their arteriovenous shunt are studied. The arteriovenous shunts are used for hemodialysis access. The patients are randomized into two groups. One group does not receive tranilast (herein referred to as group XVII) and the other group receives tranilast as a single oral 2000 mg dose at the time of the angioplasty (herein referred to as group XVIII). The patency of the venous outflow is assessed 1, 2, 3, 4 and 6 months after surgery and every 3 months thereafter until the access becomes unusable either due to clotting or inadequate flow. The patency is assessed either by imaging techniques such as ultrasonography, angiography or MRI MRA, or by functional techniques such as venous outflow pressures or by recirculation.

The comparative clinical data collected over the observation period demonstrate the efficacy of a single dose of tranilast treatment for prolonging the period of good function of the arteriovenous shunt and/or slowing the rate of stenosis of the venous outflow tract of the shunt following angioplasty of a preexisting venous outflow obstruction.

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein, in a mammal in need thereof, which comprises administering to the subject an effective amount of N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the mammal is a human.

3. The method of claim 2 wherein N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is administered in a dose of from about 0.1 mg to about 2,400 mg.

4. The method of claim 2 wherein the dosage is from about 25 mg to about 1,500 mg of N-(3',4 -dimethoxycinnamoyl)anthrani!ic acid or a pharmaceutically acceptable salt thereof.

5. The method of claim 2 wherein the dosage is from about 100 mg to about 1,000 mg of N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof.

6. The method of claim 2 wherein the dosage is from about 300 mg to about 900 mg of N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof.

7. The method of claim 2 wherein the dosage is about 600 mg of N-(3',4 - dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof.

8. The method of claim 2 wherein the treatment period commences about 7 days prior to access placement.

9. The method of claim 2 wherein the vascular access failure is vascular access clotting.

10. The method of claim 2 wherein the vascular access failure event is vascular thrombosis.

11. The method of claim 2 wherein the vascular access failure is the need for an unclotting procedure.

12. A method in accordance with claim 2 wherein the dosage is administered orally.

13. The method of claim 2 wherein the subject is a dialysis patient.

14. The method of claim 2 wherein the subject is a cancer patient.

15. The method of claim 2 wherein the subject is a patient receiving total parenteral nutrition.

16. Use of N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein, in a mammal in need thereof.

17. A use according to claim 16 wherein the mammal is a human.

18. A use according to claim 16 wherein N-(3',4 -dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is administered in a dose of from about 0.1 mg to about 2,400 mg.

19. A use according to claim 16 wherein N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is administered in a dosage of from about 25 mg to about 1,500 mg.

20. A use according to claim 16 wherein N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is administered in a dosage of from about 100 mg to about 1,000 mg.

21. A use according to claim 16 wherein N-(3',4 -dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is administered in a dosage of from about 300 mg to about 900 mg.

22. A use according to claim 16 wherein N-(3',4'-dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is administered in a dosage of about 600 mg.

23. A use according to claim 16 wherein the treatment period commences about 7 days prior to access placement.

24. A use according to claim 16 wherein the vascular access failure is vascular access clotting.

25. A use according to claim 16 wherein the vascular access failure event is vascular thrombosis.

26. A use according to claim 16 wherein the vascular access failure is the need for an unclotting procedure.

27. A use according to claim 16 wherein the dosage is administered orally.

28. A use according to claim 16 wherein the subject is a dialysis patient.

29. A use according to claim 16 wherein the subject is a cancer patient.

30. A use according to claim 16 wherein the subject is a patient receiving total parenteral nutrition.

31. A pharmaceutical composition for use in the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein, in a mammal in need thereof comprising N-(3',4- dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. A composition according to claim 31 wherein the mammal is a human.

33. A composition according to claim 32 wherein N-(3',4 - dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is in a dose of from about 0.1 mg to about 2,400 mg.

34. A composition according to claim 32 wherein N-(3',4- dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is in a dosage of from about 25 mg to about 1,500 mg.

35. A composition according to claim 32 wherein N-(3',4- dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is in a dosage of from about 100 mg to about 1,000 mg.

36. A composition according to claim 32 wherein N-(3',4 - dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is in a dosage of from about 300 mg to about 900 mg.

37. A composition according to claim 32 wherein N-(3',4 - dimethoxycinnamoyl)anthranilic acid or a pharmaceutically acceptable salt thereof is in a dosage of about 600 mg.

38. A composition according to claim 32 wherein the treatment period commences about 7 days prior to access placement.

39. A composition according to claim 32 wherein the vascular access failure is vascular access clotting.

40. A composition according to claim 32 wherein the vascular access failure event is vascular thrombosis.

41. A composition according to claim 32 wherein the vascular access failure is the need for an unclotting procedure.

42. A composition according to claim 32 wherein the dosage is administered orally.

43. A composition according to claim 32 wherein the subject is a dialysis patient.

44. A composition according to claim 32 wherein the subject is a cancer patient.

45. A composition according to claim 32 wherein the subject is a patient receiving total parenteral nutrition.