Note: Descriptions are shown in the official language in which they were submitted.
CA 02361578 2001-08-O1
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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, stem 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
3ournal 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 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 20010. As
reported in the
'935 patent, the incidence of restenosis associated with the PTCA procedure
usually is about
40°Io. The '935 patent does not contain any disclosure regarding the
ability of Tranilast to
effect cardiovascular events as defined 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 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 coronary intervention.
Numerous advantages would be realized if Tranilast could be efficaciously
administered for the prevention or reduction of cardiovascular events
associated with
coronary intervention.
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It has now surprisingly been discovered that Tranilast can be suitably
administered
in the prevention or reduction of cardiovascular events associated with
coronary
intervention.
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 about
300 mg to about
1,100 mg in association with coronary intervention.
This invention further 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 about 300 mg to about 1,100 mg for a treatment period of
at least three
consecutive months 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 phrase "cardiovascular events" as used herein, is preferably meant
myocardial infarction and death associated with coronary intervention. Also
included in the
term cardiovascular events is the need for revascularization procedures
associated with
coronary intervention.
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By the phrase "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.
By the phrase "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 phrase "in association with
coronary
intervention" 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 about 300 mg to about 1,100 mg in
association with
coronary intervention.
The present invention further 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 about 300 mg to about 1,100 mg for a
treatment period of
at least three consecutive months in association with coronary intervention.
A preferred daily dosage amount of Tranilast for use in the present invention
is
about 400 mg to about 1,000 mg. A more preferred daily dosage amount of
Tranilast for
use in the present invention is from about 500 mg to about 900 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 contemplated treatment period for use in the present invention is about 60
days in
association with coronary intervention. An additional contemplated treatment
period for use
in the present invention is about 45 days in association with coronary
intervention. A
preferred treatment period for use in the present invention is about 30 days
in association
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with coronary intervention. An additional contemplated 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.
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
salt thereof in a daily dose of from about 300 mg to about 1,100 mg in
association with
coronary intervention.
The present invention further 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
salt thereof in a daily dose of from about 300 mg to about 1,100 mg for a
treatment period of
at least three consecutive months 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 about
300 mg to about 1,100 mg in association with coronary intervention.
The invention further 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 about
300 mg to about 1,100 mg for a treatment period of at least three consecutive
months 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 about 300 mg to about 1,100 mg in association
with coronary
intervention.
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The invention further 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 about 300 mg to about 1,100 mg for a treatment
period of at
least three consecutive months 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 of
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
about 300 mg to about 1,100 mg of active compound, preferably from about 500
mg to
about 900 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 in association with coronary intervention. A treatment period
of at least three
consecutive months 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.
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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 preventing or reducing incidence of
myocardial
infarction associated with PCTA surgery 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
administered for 3 consecutive months after PTCA.
The comparative clinical data collected over the obsrevation period
demonstrate the
efficacy of 3 month Tranilast treatment for the prevention or reduction of
incidence of
myocardial infarction in patients after the PTCA procedure.
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EXAMPLE II
Efficacy of the invented method for preventing or reducing incidence of death
associated with PCTA surgery 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 3 consecutive months after PTCA.
The comparative clinical data collected over the observation period
demonstrate the
efficacy of 3 month Tranilast treatment for the prevention or reduction of
incidence of death
in patients after the PTCA procedure.
EXAMPLE III
Efficacy of the invented method for preventing or reducing the need for
revascularization procedures associated with PCTA surgery 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 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 3 consecutive months after PTCA.
The comparative clinical data collected over the observation period
demonstrate the
efficacy of 3 month Tranilast treatment for the prevention or reduction the
need for
revascularization procedures in patients after the PTCA procedure.
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EXAMPLE IV
Efficacy of the invented method for preventing or reducing incidence of
myocardial
infarction associated with PCTA surgery 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 of
incidence of
myocardial infarction in patients after the PTCA procedure.
EXAMPLE V
Efficacy of the invented method for preventing or reducing incidence of death
associated with PCTA surgery 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 IX), and another group (about
100 lesions)
does not receive Tranilast (hereinafter identified as group X). In addition,
patients may also
be given a calcium antagonist, nitrates and/or anti-platelet agentss. 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 the PTCA procedure.
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EXAMPLE VI
Efficacy of the invented method for preventing or reducing the need for
revascularization procedures associated with PCTA surgery 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 XI), and another group (about
100 lesions)
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 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 the
need for
revascularization procedures in patients after the PTCA procedure.
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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