Note: Descriptions are shown in the official language in which they were submitted.
CA 02361581 2001-08-02
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METHOD FOR THE PREVENTION OR REDUCTION OF CARDIOVASCULAR
EVENTS ASSOCIATED WITH CORONARY INTERVENTION
Field of Invention
The present invention relates to a method for the prevention or reduction of
cardiovascular events associated with coronary intervention.
More particularly, the method comprises administrating to a mammal,
particularly a
human patient, after coronary intervention an oral or parental dose of N-
(3',4'-
dimethoxycinnamoyl)anthranilic acid (N-5~ (Tranilast) represented by the
following
formula (I) or a pharmaceutically acceptable salt thereof as an active
ingredient.
CH3p ' ' CONH
CH30 HOOC (I)
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
Coronary intervention is a percutaneous procedural approach to the treatment
of
ischemic heart disease such as angina pectoris and myocardial infarction.
Coronary
intervention technically involves mechanical revascularization of a stenosed
lesion in a
coronary artery by means of a balloon catheter, mechanical stent placement, an
atherectomy
catheter and the like. As a consequence, coronary intervention often causes
restenosis due
to damaged intima and media cells. Patients who experience restenosis may
require
revascularization procedures to correct the condition. Other cardiovascular
events
associated with coronary intervention include myocardial infarction and death.
Up to the present time, there has not been any effective drug for the
prevention or
reduction of cardiovascular events associated with coronary intervention.
2. DESCRIPTION OF THE RELATED ART
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.
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United States Patent No. 5,385,935 ('935) claims the use of Tranilast in the
inhibition of restenosis associated with coronary intervention but 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
indicates that the lack of efficacy for inhibiting a restenosis effect with
Tranilast after the 30
day protocol was due to a too short duration of treatment.
Conversely, the '935 patent demonstrated that an extended period of Tranilast
treatment was effective for lowering the incidence of post-procedure
restenosis associated
with PTCA. It was found that dosing patients with Tranilast for a duration of
at least about
three months (i.e., a term of at least about 90 consecutive days of treatment)
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%.
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 coronary
angioplasty occur
within 6 months after the procedure, particularly between 1 and 3 months after
coronary
angioplasty.
Thus, restenosis is considered to take place predominantly in the healing
phase after
coronary angioplasty and, using Tranilast, to require at least three months of
treatment in
order to show a therapeutic effect.
Numerous advantages would be realized if Tranilast could be efficaciously
administered for the prevention or reduction of cardiovascular events
associated with
coronary intervention for a treatment period of less than three months. The
advantages of a
shorter dosing protocol include: increased patient compliance, less total
medication taken by
the patient, reduced side effect profile and providing a more cost effective
treatment.
It has now surprisingly been discovered that Tranilast can be suitably
administered
in the prevention or reduction of cardiovascular events associated with
coronary
intervention for a period of less than three months.
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SUMMARY OF THE INVENTION
This invention relates to a method for the prevention or reduction of
cardiovascular
events associated with coronary intervention in a mammal, particularly a
human, which
comprises administering to the subject N-(3',4'-dimethoxycinnamoyl)anthranilic
acid (N-5~
or a pharmaceutically acceptable salt thereof in a daily dose of from greater
than 300 mg to
about 1,200 mg for a treatment period of up to 89 days in association with
coronary
intervention.
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.
Illustrative of acceptable salts for use herein are inorganic salts such as
sodium or
calcium salt, or organic salts formed with amines such as morpholine,
piperidine, arginine,
and the like.
As coronary intervention in the present invention, for example, Percutaneous
Transluminal Coronary Angioplasty (PTCA), Directional Coronary Atherectomy and
Stent
placement can be included.
By the term "cardiovascular events" as used herein, is preferably meant
myocardial
infarction, death and the need for revascularization procedures associated
with coronary
intervention. Also included in the definition of "cardiovascular events" is a
restenosis effect
associated with coronary intervention.
By the term "prevention or reduction" of cardiovascular events as used herein,
is
meant that the incidence of myocardial infarction and/or death and/or the need
for
revascularization procedures associated with coronary intervention in Trailast
treated
patients are prevented or reduced in comparison to untreated patients. Also,
the incidence of
a restenosis effect is prevented or reduced in Trailast treated patients in
comparison to
untreated patients.
By the term "in association with coronary intervention" as used herein, is
meant that
the treatment with Tranilast can commence immediately, for example within 4 to
8 hours,
after coronary intervention, within a few days, for example 2 days, after
coronary
intervention or for a period of several days, for example about 7 days, prior
to coronary
intervention. Also contemplated within the term "in association with coronary
intervention"
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is a dosing protocol in which a dose or several doses are skipped, for example
in the
morning of or on the day of coronary invention.
By the term " collected over the observation period" as used herein, means a
period
of up to 12 months.
The present invention relates to a method for the prevention or reduction of
cardiovascular events associated with coronary intervention in a mammal,
particularly a
human, which comprises administering to the subject N-(3',4'-
dimethoxycinnamoyl)anthranilic acid (N-5') (Tranilast) or a pharmaceutically
acceptable
salt thereof in a daily dose of from greater than 300 mg to about 1,200 mg for
a treatment
period of up to 89 days in association with coronary intervention.
A preferred daily dosage amount of Tranilast for use in the present invention
is
about 400 mg to about 1,200 mg. A more preferred daily dosage amount of
Tranilast for
use in the present invention is from about 500 mg to about 1,000 mg. The most
preferred
daily dosage amount of Tranilast for use in the present invention is from
about 600 mg to
about 900 mg. Particularly preferred is a daily dosage amount of about 600 mg
of Tranilast
for use in the present invention. Particularly preferred is a daily dosage
amount of about
900 mg of Tranilast for use in the present invention.
A preferred treatment period for use in the present invention is about 60 days
in
association with coronary intervention. A more preferred treatment period for
use in the
present invention is about 45 days in association with coronary intervention.
The most
preferred treatment period for use in the present invention is about 30 days
in association
with coronary intervention. A preferred treatment period for use in the
present invention is
14 days in association with coronary intervention.
A preferred method of use in the current invention is a method for preventing
or
reducing myocardial infarction associated with coronary intervention.
A preferred method of use in the current invention is a method for preventing
or
reducing death associated with coronary intervention.
A preferred method of use in the current invention is a method for preventing
or
reducing the need for revascularization procedures associated with coronary
intervention.
A preferred method of use in the current invention is a method for preventing
or
reducing restenosis associated with coronary intervention.
The efficacy of the presently invented method is demonstrated by the Examples
below.
The present invention therefor provides a method for the prevention or
reduction of
cardiovascular events associated with coronary intervention in a mammal,
particularly a
human, which comprises administering to the subject N-(3',4'-
dimethoxycinnamoyl)anthranilic acid (N-5') (Tranilast) or a pharmaceutically
acceptable
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salt thereof in a daily dose of from greater than 300 mg to about 1,200 mg for
a treatment
period of up to 89 days in association with coronary intervention.
The invention also provides for the use of Tranilast or a pharmaceutically
acceptable salt thereof in the prevention or reduction of cardiovascular
events associated
with coronary intervention in a mammal, particularly a human, in a daily dose
of from
greater than 300 mg to about 1,200 mg for a treatment period of up to 89 days
in association
with coronary intervention.
The invention also provides for a pharmaceutical composition for use in the
prevention or reduction of cardiovascular events associated with coronary
intervention in a
mammal, particularly a human, which comprises Tranilast or a pharmaceutically
acceptable
salt thereof in a daily dose of from greater than 300 mg to about 1,200 mg for
a treatment
period of up to 89 days in association with coronary intervention.
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 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 dosage of Tranilast or a pharmaceutically
acceptable salt thereof as
an active ingredient will be an efficacious, nontoxic quantity selected from
the range of
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from above 300 mg to about 1,200 mg of active compound, preferably from about
500 mg
to about 1,000 mg of active compound, particularly preferred is a dosage of
about 600 mg,
particularly preferred is a dosage of about 900 mg, per adult patient
preferably by oral
administration for a treatment period of up to 89 days, preferably for about
60 days and
most preferably for about 30 days in association with coronary intervention.
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 treatment of cardiovascular events
associated with coronary intervention, the above indicated dose may be split
and
administered preferably from 1-6 times daily, preferably about 2 times a day,
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.
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 treatment of restenosis associated with
the
PCTA procedure is demonstrated by the following.
One hundred forty nine lesions with a partial occlusion, which undergo
successful
PTCA procedures with smooth dilation, are selected for study. These lesions
are divided
into two groups, and both groups do not differ significantly with sex,
distribution of
coronary artery or ratio of lesions restenosed after PTCA; One group (about 49
lesions)
receives Tranilast in a daily dose of 600 mg, preferably in two 300 mg tablets
administered
12 hours apart (hereinafter identified as group I), and another group (about
100 lesions) 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
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administered for 30 consecutive days after PTCA, and follow-up coronary
angiography is
performed within one year after PTCA.
The measurements are made in two projections and all measurements (before and
immediately after PTCA and at final follow-up) are made in the same projection
for more
accurate comparisons.
Diameter stenosis is calculated as the mean of measurements, and restenosis is
defined as a loss of at least 50% of the initial gain in luminal diameter
accomplished by
dilation or by 50% stenosis of a dilated vessel.
The comparative clinical data collected over the observation period
demonstrate the
efficacy of 30 days Tranilast treatment for the prevention or reduction of
restenosis in
patients after PTCA procedures.
EXAMPLE II
Efficacy of the invented method for preventing or reducing incidence of
myocardial
infarction associated with the PCTA procedure is demonstrated by the
following.
One hundred forty nine lesions with a partial occlusion, which undergo
successful
PTCA procedures with smooth dilation, are selected for study. These lesions
are divided
into two groups, and both groups do not differ significantly with sex,
distribution of
coronary artery or ratio of lesions restenosed after PTCA; One group (about 49
lesions)
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 lesions)
does not receive Tranilast (hereinafter identified as group IV). 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 PTCA.
The comparative clinical data collected over the observation period
demonstrate the
efficacy of 30 days Tranilast treatment for the prevention or reduction of
incidence of
myocardial infarction in patients after the PTCA procedure.
EXAMPLE III
Efficacy of the invented method for preventing or reducing incidence of death
associated with the PCTA procedure is demonstrated by the following.
One hundred forty nine lesions with a partial occlusion, which undergo
successful
PTCA procedures with smooth dilation, are selected for study. These lesions
are divided
into two groups, and both groups do not differ significantly with sex,
distribution of
coronary artery or ratio of lesions restenosed after PTCA; One group (about 49
lesions)
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receives Tranilast in a daily dose of 600 mg, preferably in two 300 mg tablets
administered
12 hours apart (hereinafter identified as group V), and another group (about
100 lesions)
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 30 consecutive days after PTCA.
The comparative clinical data collected over the observation period
demonstrate the
efficacy of 30 days Tranilast treatment for the prevention or reduction of
incidence of death
in patients after PTCA procedures.
EXAMPLE IV
Efficacy of the invented method for preventing or reducing the need for
revascularization procedures associated with PCTA procedure is demonstrated by
the
following.
One hundred forty nine lesions with a partial occlusion, which undergo
successful
PTCA procedures with smooth dilation, are selected for study. These lesions
are divided
into two groups, and both groups do not differ significantly with sex,
distribution of
coronary artery or ratio of lesions restenosed after PTCA; One group (about 49
lesions)
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 lesions)
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 PTCA.
The comparative clinical data collected over the observation period
demonstrate the
efficacy of 30 days Tranilast treatment for the prevention or reduction for
the need for
revascularization procedures in patients after PTCA procedures.
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.
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