Note: Descriptions are shown in the official language in which they were submitted.
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PCTIUS98I23480
AN'I~iYPERL~DBMIC STATW-LP(a) I1~THIBITOR COMBINATIONS
FIELD OF THE INVENTION
This invention concerns a combination of a statin compound, which is
known to cause a reduction in plasma levels of low-density lipoproteins (LDL)
cholesterol, and a compound which inhibits the formation of lipoprotein (a),
Lp(a), which is a modified form of LDL, but which are unaffected by statins.
The
combination is useful for treating vascular disorders and diabetes mellitus.
BACKGROUND OF THE INVENTION
Several clinical studies have established that lowering certain forms of
cholesterol in a mammal is an effective way to treat and prevent heart
attacks,
sudden death, and angina, both in subjects having higher than normal levels of
circulating cholesterol, as well as those having normal levels of cholesterol.
Lowering LDL, the bad form of cholesterol, is now one of the primary
objectives
of physicians treating patients who have, or who have a high risk of
developing,
cardiovascular diseases such as coronary heart disease, atherosclerosis,
myocardial infarction, stroke, cerebral infarction, and even restenosis
following
balloon angioplasty. Many physicians are now utilizing cholesterol lowering
agents purely as a prophylactic treatment in healthy subjects whose
cholesterol
levels are normal, thereby guarding against development of cardiovascular
diseases.
The most commonly used cholesterol lowering agents are the statins,
which are compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase, the enzyme responsible for catalyzing the
conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step
in the cholesterol biosynthetic pathway.
There are several forms of circulating blood cholesterol which occur
naturally in mammals. Some forms are considered "bad" cholesterol, while other
forms are considered "good" cholesterol and are essential for good health. The
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good form of cholesterol has been established to be high density lipoprotein
(HDL). Low density lipoprotein (LDL) is a "bad" cholesterol. Another form of
LDL cholesterol, the primary bad form, is a modified form of LDL called
lipoprotein(a), or "Lp(a)". High levels of Lp(a) are now believed to be
detrimental
and can lead to cardiovascular diseases, and is one of the major risk factors
leading to death from heart disease.
Because vascular diseases such as coronary heart disease, stroke, and even
peripheral vascular disease, remain a leading cause of death and disability
throughout the world, the need continues to develop new and improved
treatments, as well as agents that will actually prevent the formation of
these
diseases.
We have now discovered that treatment and prevention of vascular
diseases can be effected by administering a combination of a statin with an
Lp(a)
inhibitor. Typical Lp(a) inhibitors are the retinoids, as described in U.S.
Patent
5,489,611 incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention provides a pharmaceutical composition comprised of an
effective amount of a statin and an effective amount of an Lp(a) inhibitor.
More
particularly, one embodiment of the invention is a combination of a statin
with an
Lp(a) inhibitor which is a retinoid.
The combinations of this invention can also employ the pharmaceutically
acceptable salts of the respective active components.
Preferred retinoids are those described in U.S. Patent 5,489,611. Especially
preferred compositions employ 9-cis-retinoic acid or 13-cis-retinoic acid.
Also
preferred are trans-retinal and trans-retinol, as well as 13-cis-retinol, 13-
cis-
retinal, 9-cis-retinol, and 9-cis-retinal.
Another class of preferred Lp(a) inhibitors to be employed are
aminophosphonates of the Formula I
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' 1
~/OR 2
OR
X3 (B)n ~ H I
~--N-A
wherein:
X1 and X2 independently are hydrogen, straight or branched C1-Cg alkyl
and C 1-Cg alkoxy, hydroxy, or nitro;
X3 is hydrogen or Cl-C4 alkyl; or X30, together with one of XI or X2 is
an alkylidene dioxy ring having from 1 to 4 carbon atoms;
Rl and R2 independently are hydrogen, or straight or branched C1-C6
alkyl;
B is CH2, -CH2CH2-, or CH=CH-;
nis0orl;
Z is hydrogen, straight or branched C1-Cg alkyl, an aryl group Ar, or
R3C0, where R3 is C1-C4 alkyl or perfluoro C1-C4 alkyl;
A is hydrogen, CH2CH=CH2, straight or branched C1-Cg alkyl or
x4 \ x4
- (CH2)m ~ 5 - (CH2)m / x4 - (CH2)~p~
wX , ,
X6
N \
- (CH2)k~ -.<~ I / ~ -~H- (CH2)~ ~
' S ~ CH '
3
CH3
\ \
H- (CHZ)m ~ ~ -(CH2)~ ~H ~ ~ - H
\ ' CH ' ~ '
3
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X7
X~
~ _H ,
' X7
X~
O
\ 4
__~~- ~CH2Im ~ ~ ~ / X ~ ~ ~ N I ~ X4
J ~. ,
X4 O
X4
iJ -COO-R, where k is an integer from 2 to 4, m is 0 or an integer
i
from 1 to 5, X4, X5, X6, identical or different, are H, a straight or branched
alkyl
or alkoxy groups from 1 to 8 carbon atoms, a hydroxy, trifluoromethyl, nitro,
amino, dimethylamino, diethylamino group, a halogen atom (F, Cl, Br, I), X4
and
X5 may form an alkylidendioxy ring having from 1 to 4 carbon atoms, X~ is H or
CH3, R is a straight or branched alkyl group having from 1 to 6 carbon atoms,
an
aryl or aryIalkyl group from b to 9 carbon atoms;
or a pharmaceutically acceptable salt thereof.
These compounds are disclosed in U.S. Patent 5,424,303 incorporated
herein by reference.
A preferred composition employs an aminophosphonate of the Formula II
O
I I
i - OCH3
HO ~ ~ CH NH I ~ II
i
Another class of Lp(a) inhibitors are diazo aniline derivatives, compounds
of Formula III
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R3
R1
\ III
N=N-Ar
R
where
Rl and R2 independently are hydrogen or straight or branched Cl-C6
alkyl, or taken together with the nitrogen to which they are attached complete
a 5-
to 7-membered ring, optionally substituted with Cl-C6 alkyl or Cl-C6 alkoxy;
R3 is C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halo, nitro, perfluoroalkyl,
amino, C1-C6 alkyl or di-C1-C6 alkyl amino, or cyano; and
Ar is phenyl optionally substituted by carboxyl, Cl-C6 alkoxycarbonyl,
cyano, CONH2, S02NH2, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halo, nitro,
amino, C1-C6 alkyl or di-C1-C6 alkylamino, or C1-C6 arylamino.
The compositions preferably will contain compounds of Formula III such
as:
4-[(4-(N,N-diethylamino)phenyl)azo]-benzonitrile;
4-[(2-Chloro-4-N,N-dimethylamino)phenyl)azo]-benzonitrile;
4-[(4-(N,N-diethylamino)phenyl)azo]-benzoic acid ethyl ester;
3-[(4-(N-piperidyl)phenyl)azo]-benzonitrile;
4-[(4-(N,N-dimethylamino)phenyl)azo]-benzamide; and
4-[(4-(N,N-dimethylamino)phenyl)azo]-benzsulfonamide.
Such phenylazo compounds are described in U.S. Patent 4,397,944, 3,978,201,
and in WO 97/26890, all incorporated herein by reference.
Typical statins to be employed in combination with the compound of
Formula I include atorvastatin, simvastatin, pravastatin, cerivastatin,
mevastatin,
velostatin, fluvastatin, lovastatin, dalvastatin, and fluindostatin. The
statins can be
employed as pharmaceutically acceptable salts, for example, atorvastatin
calcium.
A particularly preferred composition of this invention utilizes a retinoid
together with a statin selected from atorvastatin calcium, pravastatin sodium,
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simvastatin, lovastatin, and cerivastatin. The most preferred composition
employs
the compound of Formula III with atorvastatin calcium.
Also provided by the invention are methods for treating vascular diseases
such as peripheral vascular disease, coronary heart disease, stroke, and
restenosis.
The invention provides a method for lowering Lp(a), plasma triglycerides, very
low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, and
apolipoprotein B. The invention additionally provides a method for elevating
plasma HDL cholesterol, apolipoprotein A-I, and apolipoprotein E. The
invention
also provides a method for treating and preventing noninsulin-dependent
diabetes
mellitus by increasing insulin sensitivity comprising administering a
combination
of this invention.
DETAILED DESCRIPTION OF THE INVENTION
We have discovered that combining a statin with an Lp(a) inhibitor
provides a surprisingly effective composition for treating and preventing
vascular
diseases, as well as diabetes mellitus. An Lp(a) inhibitor is any compound
which
is effective at reducing Lp(a) in a mammal. As noted above, the Lp(a)
inhibitors
as used herein are compounds such as those described in U.S. Patent 5,489,611
and 5,424,303, both incorporated herein by reference. The compounds can be the
free acid or a salt form.
The other active component of the combinations of this invention is a
statin. The term "statin", where used in the specification and the appendant
claims, is synonymous with the terms "3-hydroxy-3-methylglutaryl-Coenzyme A
reductase inhibitor" and "HMG-CoA reductase inhibitor." These three terms are
used interchangeably throughout the specification and appendant claims. As the
synonyms suggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl-
Coenzyme A reductase and, as such, are effective in lowering the level of
blood
plasma cholesterol. Statins and pharmaceutically acceptable salts thereof are
particularly useful in lowering low-density lipoprotein cholesterol {LDL-C)
levels
in mammals, and particularly in humans.
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The HMG-CoA reductase inhibitors suitable for use herein include, but are
not limited to, simvastatin, pravastatin, rivastatin, mevastatin,
fluindostatin,
cerivastatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin,
compactin, or
lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin,
rivastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin,
dalvastatin, dihydrocompactin, compactin, lovastatin, or pharmaceutically
acceptable salts thereof. However, it is to be noted that atorvastatin calcium
is a
particularly preferred statin to be employed in the present combination. See
U.S.
Patent 5,273,995 incorporated herein by reference.
The statins disclosed herein are prepared by methods well-known to those
skilled in the art. Specifically, simvastatin may be prepared according to the
method disclosed in U.S. Patent 4,444,784, which is incorporated herein by
reference. Pravastatin may be prepared according to the method disclosed in
U.S.
Patent 4,346,227, which is incorporated herein by reference. Cerivastatin may
be
IS prepared according to the method disclosed in U.S. Patent 5,502,199, which
is
incorporated herein by reference. Cerivastatin may alternatively be prepared
according to the method disclosed in European Patent Application Publication
No.
EP617019. Mevastatin may be prepared according to the method disclosed in U.S.
Patent 3,983,140, which is incorporated herein by reference. Velostatin may be
prepared according to the methods disclosed in U.S. Patent 4,448,784 and U.S.
Patent 4,450,171, both of which are incorporated herein by reference.
Fluvastatin
may be prepared according to the method disclosed in U.S. Patent 4,739,073,
which is incorporated herein by reference. Compactin may be prepared according
to the method disclosed in U.S. Patent 4,804,770, which is incorporated herein
by
reference. Lovastatin may be prepared according to the method disclosed in
U.S.
Patent 4,231,938, which is incorporated herein by reference. Dalvastatin maybe
prepared according to the method disclosed in European Patent Application
Publication No. 738510 A2. Fluindostatin may be prepared according to the
method disclosed in European Patent Application Publication No. 363934 A1.
Dihydrocompactin may be prepared according to the method disclosed in U.S.
Patent 4,450,171, which is incorporated herein by reference.
It will be recognized that certain of the above statins contain either a free
carboxylic acid or a free amine group as part of the chemical structure.
Further,
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certain statins within the scope of this invention contain lactone moieties,
which
exist in equilibrium with the free carboxylic acid form. These lactones can be
maintained as carboxylates by preparing pharmaceutically acceptable salts of
the
lactone. Thus, this invention includes pharmaceutically acceptable salts of
those
S carboxylic acids or amine groups. The expression "pharmaceutically
acceptable
salts" includes both pharmaceutically acceptable acid addition salts and
pharmaceutically acceptable cationic salts. The expression "pharmaceutically
acceptable cationic salts" is intended to define but is not limited to such
salts as
the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal
salts (e.g.,
calcium and magnesium}, aluminum salts, ammonium salts, and salts with organic
amines such as benzathine (N,N'-dibenzylethylenediamine), choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucarnine), benethamine
(N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-
2-hydroxymethyl-1,3-propanediol} and procaine. The expression
"pharmaceutically acceptable add addition salts" is intended to define but is
not
limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen
sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate,
succinate,
citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
The pharmaceutically acceptable cationic salts of statins containing free
carboxylic acids may be readily prepared by reacting the free acid form of the
statin with an appropriate base, usually one equivalent, in a co-solvent.
Typical
bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium
hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide,
benzathine, choline, diethanolamine, piperazine, and tromethamine. The salt is
isolated by concentration to dryness or by addition of a non-solvent. In many
cases, salts are preferably prepared by mixing a solution of the acid with a
solution of a different salt of the cation (sodium or potassium
ethylhexanoate,
magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the
desired cationic salt precipitates, or can be otherwise isolated by
concentration
and/or addition of a non-solvent.
The pharmaceutically acceptable acid addition salts of statins containing
free amine groups may be readily prepared by reacting the free base form of
the
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statin with the appropriate acid. When the salt is of a monobasic acid (e.g.,
the
hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the
hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate),
or the
dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the
citrate), at
least one molar equivalent and usually a molar excess of the acid is employed.
However, when such salts as the sulfate, the hemisuccinate, the hydrogen
phosphate, or the phosphate are desired, the appropriate and exact chemical
equivalents of acid will generally be used. The free base and the acid are
usually
combined in a co-solvent from which the desired salt precipitates, or can be
otherwise isolated by concentration and/or addition of a non-solvent.
Further, the statins of the instant invention and the pharmaceutically
acceptable salts of the statins of the instant invention may also occur as
hydrates
or solvates. Said hydrates and solvates are also within the scope of the
invention.
The same holds true for the Lp(a) inhibitors, for example, the retinoids.
The pharmaceutical combinations and methods of this invention are all
adapted to therapeutic use as agents in the prevention and treatment of
atherosclerosis, angina pectoris, and a condition characterized by the
presence of
both hypertension and hyperlipidemia in mammals, particularly humans. Further,
since these diseases and conditions are closely related to the development of
cardiac disease and adverse cardiac conditions, these combinations and
methods,
by virtue of their action as antiatherosclerotics, antianginals,
antihypertensives,
and antihyperlipidemics are useful in the management of cardiac risk in
subjects at
risk of developing adverse cardiac conditions and in subjects at risk of
suffering
adverse cardiac events.
The utility of the compositions of the present invention as medical agents
in the treatment of atherosclerosis in mammals (e.g., humans) is demonstrated
by
the activity of the compounds of this invention in conventional assays and in
a
clinical protocol such as that described below.
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Effect of an Lp(a) Inhibitor and a Statin, Alone and in Combination,
on the Treatment of Atherosclerosis
This study is a prospective randomized evaluation of the effect of a
combination of 9-cis-retinoic acid or a pharmaceutically acceptable salt
thereof
and a statin on the progression/regression of coronary and carotid artery
disease.
The study is used to show that a combination of 9-cis-retinoic acid or a
pharmaceutically acceptable acid addition salt and a statin is effective in
slowing
or arresting the progression or causing regression of existing coronary artery
disease (CAD) as evidenced by changes in coronary angiography or carotid
ultrasound, in subjects with established disease.
This study is an angiographic documentation of coronary artery disease
carned out as a double-blind, placebo-controlled trial of a minimum of about
500 subjects and preferably of about 780 to about 1200 subjects. It is
especially
preferred to study about 1200 subjects in this study. Subjects are admitted
into the
study after satisfying certain entry criteria set forth below.
Entry criteria: Subjects accepted for entry into this trial must satisfy
certain criteria. Thus, the subject must be an adult, either male or female,
aged
18 to 80 years of age in whom coronary angiography is clinically indicated.
Subjects will have angiographic presence of a significant focal lesion such as
30%
to 50% on subsequent evaluation by quantitative coronary angiography (QCA) in
a minimum of one segment (non-PTCA, non-bypassed, or non-MI vessel) that is
judged not likely to require intervention over the next 3 years. It is
required that
the segments undergoing analysis have not been interfered with. Since
percutaneous transluminal cardiac angioplasty (PTCA) interferes with segments
by the insertion of a balloon catheter, non-PTCA segments are required for
analysis. It is also required that the segments to be analyzed have not
suffered a
thrombotic event, such as a myocardial infarct (MI). Thus, the requirement for
non-MI vessels. Segments that will be analyzed include: left main, proximal,
mid
and distal left anterior descending, first and second diagonal branch,
proximal and
distal left circumflex, first or largest space obtuse marginal, proximal, mid
and
distal right coronary artery. Subjects will have an ejection fraction of
greater than
30% determined by catheterization or radionuclide ventriculography or ECHO
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cardiogram at the time of the qualifying angiogram or within the previous
3 months of the acceptance of the qualifying angiogram provided no intervening
event such as a thrombotic event or procedure such as PTCA has occurred.
Generally, due to the number of patients and the physical limitations of
any one facility, the study is carried out at multiple sites. At entry into
the study,
subjects undergo quantitative coronary angiography as well as B-mode carotid
artery ultrasonography and assessment of carotid arterial compliance at
designated
testing centers. This establishes baselines for each subject. Once admitted
into the
test, subjects are randomised to receive the compound of 9-cis-retinoic acid
(200 mg) and placebo or a statin (dose is dependent upon the particular statin
used; however, generally 80 mg will be used at first) and placebo or 9-cis-
retinoic
acid (200~mg) and a statin (80 mg). It will be recognized by a skilled person
that
the free base form or other salt forms of 9-cis-retinoic acid or the free base
form or
other salt farms of the statin may be used in this invention. Calculation of
the
dosage amount for these other forms of the statin and 9-cis-retinoic acid is
easily
accomplished by performing a simple ratio relative to the molecular weights of
the
species involved. The amount of 9-cis-retinoic acid may be varied as required.
Generally, a subject will start out taking 200 mg, and the amount will be
titrated
down to as little as 50 mg as determined by the clinical physician. The amount
of
the statin will similarly be titrated down from 80 mg if it is determined by
the
physician to be in the best interests of the subject. The subjects are
monitored for a
1- to 3-year period, generally 3 years being preferred. B-mode carotid
ultrasound
assessment of carotid artery atherosclerosis and compliance are performed at
regular intervals throughout the study.
Generally, 6-month intervals are suitable. Typically this assessment is
performed using B-mode ultrasound equipment. However, a person skilled in the
art may use other methods of performing this assessment. Coronary angiography
is performed at the conclusion of the 1- to 3-year treatment period. The
baseline
and posttreatment angiograms and the intervening carotid artery B-mode
ultrasonograms are evaluated for new lesions or progression of existing
atherosclerotic lesions. Arterial compliance measurements are assessed for
changes from baseline and over the 6-month evaluation periods.
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The primary objective of this study is to show that the combination of
carboxyalkylether or a pharmaceutically acceptable acid addition salt and a
statin
reduces the progression of atherosclerotic lesions as measured by quantitative
coronary angiography (QCA) in subjects with clinical coronary artery disease.
QCA measures the opening in the lumen of the arteries measured.
The primary endpoint of the study is the change in the average mean
segment diameter of the coronary artery tree. Thus, the diameter of an
arterial
segment is measured at various portions along the length of that segment. The
average diameter of that segment is then determined. After the average segment
diameter of many segments has been determined, the average of all segment
averages is determined to arnve at the average mean segment diameter. The mean
segment diameter of subjects taking a statin and 9-cis-retinoic acid or a
pharmaceutically acceptable acid addition salt will decline more slowly, will
be
halted completely, or there will be an increase in the mean segment diameter.
These results represent slowed progression of atherosclerosis, no change in
the
progression of atherosclerosis, and regression of atherosclerosis,
respectively.
The secondary objective of this study is that the combination of
carboxyalkylether or a pharmaceutically acceptable acid addition salt and a
statin
reduces the rate of progression of atherosclerosis in the carotid arteries as
measured by the slope of the maximum intimal-medial thickness measurements
averaged over 12 separate wall segments (Mean Max) as a function of time, more
than does compound III or a pharmaceutically acceptable acid addition salt or
a
statin alone. The intimal-medial thickness of subjects taking a statin and
compound III or a pharmaceutically acceptable salt thereof will increase more
slowly, will cease to increase, or will decrease. These results represent
slowed
progression of atherosclerosis, halted progression of atherosclerosis, and
regression of atherosclerosis, respectively. Further, these results may be
used to
facilitate dosage determinations.
The utility of the compounds of the present invention as medical agents in
the treatment of angina pectoris in mammals (e.g., humans) is demonstrated by
the
activity of the compounds of this invention in conventional assays and the
clinical
protocol described below.
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Effect of 9-Cis-Retinoic Acid and a Statin, Alone and in Combination,
on the Treatment of Angina
This study is a double-blind, parallel-arm, randomized study to show the
effectiveness of 9-cis-retinoic acid or a pharmaceutically acceptable acid
addition
salt thereof and a statin given in combination in the treatment of symptomatic
angina.
Entry criteria: Subjects are males or females between 18 and 80 years of
age with a history of typical chest pain associated with one of the following
objective evidences of cardiac ischemia: (1 ) stress test segment elevation of
about
one millimeter or more from the ECG; (2) positive treadmill stress test; (3)
new
wall motion abnormality on ultrasound; or (4) coronary angiogram with a
significant qualifying stenosis. Generally a stenosis of about 30% to 50% is
considered to be significant.
Each subject is evaluated for about 10 to 32 weeks. At least IO weeks are
generally required to complete the study. Sufficient subjects are used in this
screen to ensure that about 200 to 800 subjects and preferably about 400
subjects
are evaluated to complete the study. Subjects are screened for compliance with
the
entry criteria, set forth below, during a 4-week run-in phase. After the
screening
criteria are met, subjects are washed out from their current anti-anginai
medication
and stabilized on a long acting nitrate such as nitroglycerine, isosorbide-
S-mononitrate or isosorbide dinitrate. The term "washed out", when used in
connection with this screen, means the withdrawal of current anti-anginal
medication so that substantially all of said medication is eliminated from the
body
of the subject. A period of 8 weeks is preferably allowed for both the washout
period and for the establishment of the subject on stable doses of said
nitrate.
Subjects having one or two attacks of angina per week while on stable doses of
long acting nitrate are generally permitted to skip the washout phase. After
subjects are stabilized on nitrates, the subjects enter the randomization
phase
provided the subjects continue to have either one or two angina attacks per
week.
In the randomization phase, the subjects are randomly placed into one of the
four
arms of the study set forth below. After completing the washout phase,
subjects in
compliance with the entry criteria undergo 24-hour ambulatory
electrocardiogram
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(ECG) such as Holter monitoring, exercise stress testing such as a treadmill,
and
evaluation of myocardial perfusion using photon emission tomography (PET)
scanning to establish a baseline for each subject. When conducting a stress
test,
the speed of the treadmill and the gradient of the treadmill can be controlled
by a
technician. The speed of the treadmill and the angle of the gradient are
generally
increased during the test. The time intervals between each speed and gradient
increase is generally determined using a modified Bruce Protocol.
After the baseline investigations have been completed, subjects are
initiated on one of the following four arms of the study: (1) placebo; (2) a
statin
(about 2.5 mg to about 160 mg); (3) 9-cis-retinoic acid (about 25 mg to about
200 mg); or (4) a combination of the above doses of 9-cis-retinoic acid and a
statin together. The subjects are then monitored for 2 to 24 weeks. It will be
recognized by a skilled person that the free base form or other salt forms of
compound III or the free base form or other salt forms of the statin may be
used in
this invention. Calculation of the dosage amount for these other forms of the
statin
and compound III is easily accomplished by performing a simple ratio relative
to
the molecular weights of the species involved.
After the monitoring period has ended, subjects will undergo the following
investigations: (1) 24-hour ambulatory ECG, such as Holter monitoring;
(2) exercise stress testing (e.g., treadmill using said modified Bruce
Protocol); and
(3) evaluation of myocardial perfusion using PET scanning. Patients keep a
diary
of painful ischemic events and nitroglycerine consumption. It is generally
desirable to have an accurate record of the number of anginal attacks suffered
by
the patient during the duration of the test. Since a patient generally takes
nitroglycerin to ease the pain of an anginal attack, the number of times that
the
patient administers nitroglycerine provides a reasonably accurate record of
the
number of anginal attacks.
To demonstrate the effectiveness and dosage of the drug combination of
this invention, the person conducting the test will evaluate the subject using
the
tests described. Successful treatment will yield fewer instances of ischemic
events
as detected by ECG, will allow the subject to exercise longer or at a higher
intensity level on the treadmill or to exercise without pain on the treadmill,
or will
yield better perfusion or fewer perfusion defects on PET.
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The utility of the compounds of the present invention as medical agents in
the treatment of hypertension and hyperlipidemia in mammals (e.g., humans)
suffering from a combination of hypertension and hyperlipidemia is
demonstrated
by the activity of the compounds of this invention in conventional assays and
the
clinical protocol described below.
Effects of an Lp(a) Inhibitor and a Statin, Alone and in Combination, on the
Treatment of Subjects Having Both Hypertension and Hyperlipidemia
This study is a double-blind, parallel-arm, randomized study to show the
effectiveness of carboxyalkylether or a pharmaceutically acceptable acid
addition
salt thereof and a statin given in combination in controlling both
hypertension and
hyperlipidemia in subjects who have mild, moderate, or severe hypertension and
hyperlipidemia.
Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks.
Sufficient subjects are used in this screen to ensure that about 400 to 800
subjects
are evaluated to complete the study.
Entry criteria: Subjects are male or female adults between 18 and 80 years
of age having both hyperlipidemia and hypertension. The presence of
hyperlipidemia is evidenced by evaluation of the LDL cholesterol level of the
subject relative to certain positive risk factors. If the subject has no
coronary heart
disease (CHD) and has less than two positive risk factors, then the subject is
considered to have hyperlipidemia, which requires drug therapy if the LDL of
the
subject is >_190 mgldL. If the subject has no CHD and has two or more positive
risk factors, then the subject is considered to have hyperlipidemia, which
requires
drug therapy if the LDL of the subject is >_160 mg/dL. If the subject has CHD,
then the subject is considered to have hyperlipidemia if the LDL of the
subject is
?I30 mg/dL.
Positive risk factors include: (1 ) male over 45, (2) female over SS wherein
said female is not undergoing hormone replacement therapy (HRT), (3) family
history of premature cardiovascular disease, (4} the subject is a current
smoker,
(5) the subject has diabetes, (6) an HDL of less than 45 mg/dL, and (7) the
subject
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has hypertension. An HDL of >60 mg/dL is considered a negative risk factor and
will offset one of the above mentioned positive risk factors.
The presence of hypertension is evidenced by a sitting diastolic blood
pressure (BP) of >90 mmHg or sitting systolic BP of >140 mmHg. All blood
pressures are generally determined as the average of three measurements taken
5 minutes apart.
Subjects are screened for compliance with the entry criteria set forth
above. After all screening criteria are met, subjects are washed out from
their
current antihypertensive and lipid lowering medication and are placed on the
NCEP ATP II Step 1 diet. The NCEP ATP II {adult treatment panel, 2nd revision)
Step 1 diet sets forth the amount of saturated and unsaturated fat which can
be
consumed as a proportion of the total caloric intake. The term "washed out",
where used in connection with this screen, means the withdrawal of current
antihypertensive and lipid lowering medication so that substantially all of
said
medication is eliminated from the body of the subject. Newly diagnosed
subjects
generally remain untreated until the test begins. These subjects are also
placed on
the NCEP Step 1 diet. After the 4-week washout and diet stabilization period,
subjects undergo the following baseline investigations: (1) blood pressure and
(2) fasting lipid screen. The fasting lipid screen determines baseline lipid
levels in
the fasting state of a subject. Generally, the subject abstains from food for
12 hours, at which time lipid levels are measured.
After the baseline investigations are performed, subjects are started on one
of the following: (1) a fixed dose of 9-cis-retinoic acid, generally about 25
to
200 mg; (2) a fixed dose of a statin, generally about 2.5 mg to about I60 mg;
or
(3) a combination of the above doses of 9-cis-retinoic acid and a statin
together. It
will be recognized by a skilled person that the free base form or other salt
forms of
9-cis-retinoic acid or the free base form or other salt forms of the statin
may be
used in this invention. Calculation of the dosage amount for these other forms
of
the statin and 9-cis-retinoic acid is easily accomplished by performing a
simple
ratio relative to the molecular weights of the species involved. Subjects
remain on
these doses for a minimum of 6 weeks, and generally for no more than 8 weeks.
The subjects return to the testing center at the conclusion of the 6 to 8
weeks so
that the baseline evaluations can be repeated. The blood pressure of the
subject at
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the conclusion of the study is compared with the blood pressure of the subject
upon entry. The lipid screen measures the total cholesterol, LDL-cholesterol,
HDL-cholesterol, triglycerides, apoB, very low-density lipoprotein (VLDL) and
other components of the lipid profile of the subject. Improvements in the
values
obtained after treatment relative to pretreatment values indicate the utility
of the
drug combination.
The utility of the compounds of the present invention as medical agents in
the management of cardiac risk in mammals (e.g., humans) at risk for an
adverse
cardiac event is demonstrated by the activity of the compounds of this
inventian in
conventional assays and the clinical protocol described below.
Effects of an Lp(a) Inhibitor and a Statin, Alone and in Combination,
on Subjects at Risk of Future Cardiovascular Events
This study is a double-blind, parallel-arm, randomized study to
demonstrate the effectiveness of carboxyalkylether or a pharmaceutically
acceptable acid addition salt and a statin given in combination in reducing
the
overall calculated risk of future events in subjects who are at risk for
having future
cardiovascular events. This risk is calculated by using the Framingham Risk
Equation. A subject is considered to be at risk of having a future
cardiovascular
event if that subject is more than one standard deviation above the mean as
calculated by the Framingham Risk Equation. The study is used to evaluate the
efficacy of a fixed combination of carboxylalkylether or a pharmaceutically
acceptable acid addition salt and a statin in controlling cardiovascular risk
by
controlling both hypertension and hyperlipidemia in patients who have both
mild
to moderate hypertension and hyperlipidemia.
Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks.
Su~cient subjects are recruited to ensure that about 400 to 800 subjects are
evaluated to complete the study.
Entry criteria: Subjects included in the study are male or female adult
subjects between 18 and 80 years of age with a baseline 5-year risk, which
risk is
above the median for said subject's age and sex, as defined by the Framingham
Heart Study, which is an ongoing prospective study of adult men and women
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showing that certain risk factors can be used to predict the development of
coronary heart disease. The age, sex, systolic and diastolic blood presswe,
smoking habit, presence or absence of carbohydrate intolerance, presence or
absence of left ventricular hypertrophy, serum cholesterol, and HDL of more
than
one standard deviation above the norm for the Framingham Population are all
evaluated in determining whether a patient is at risk for adverse cardiac
event. The
values for the risk factors are inserted into the Framingham Risk Equation and
calculated to determine whether a subject is at risk for a futwe
cardiovascular
event.
Subjects are screened for compliance with the entry criteria set forth
above. After all screening criteria are met, patients are washed out from
their
current antihypertensive and lipid lowering medication and any other
medication
which will impact the results of the screen. The patients are then placed on
the
NCEP ATP II Step 1 diet, as described above. Newly diagnosed subjects
generally
remain untreated until the test begins. These subjects are also placed on the
NCEP
ATP II Step 1 diet. After the 4-week washout and diet stabilization period,
subjects undergo the following baseline investigations: (1) blood presswe;
(2) fasting; (3) lipid screen; (4) glucose tolerance test; (S) ECG; and (6)
cardiac
ultrasound. These tests are carried out using standard procedwes well-known to
persons skilled in the art. The ECG and the cardiac ultrasound are generally
used
to measwe the presence or absence of left ventricular hypertrophy.
After the baseline investigations are performed, patients will be started on
one of the following: (1 ) a fixed dose of 9-cis-retinoic acid (about 25 to
200 mg);
(2) a fixed dose of a statin (about 2.5 mg to about 160 mg); or (3) the
combination
of the above doses of 9-cis-retinoic acid and a stadn. Patients are kept on
these
doses and are asked to return in 6 to 8 weeks so that the baseline evaluations
can
be repeated. At this time, the new values are entered into the Framingham Risk
Equation to determine whether the subject has a lower, greater, or no change
in
the risk of future cardiovascular event.
The above assays demonstrating the effectiveness of a retinoid or
pharmaceutically acceptable acid addition salts thereof and atorvastatin or
pharmaceutically acceptable salts thereof in the treatment of angina pectoris,
atherosclerosis, hypertension and hyperlipidemia together, and the management
of
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cardiac risk, also provide a means whereby the activities of the compounds of
this
invention can be compared between themselves and with the activities of other
known compounds. The results of these comparisons are useful for determining
synergistic dosage levels in mammals, including humans, for the treatment of
such
diseases.
The following dosage amounts and other dosage amounts set forth
elsewhere in this specification and in the appendant claims are for an average
human subject having a weight of about 65 kg to about 70 g. The skilled
practitioner will readily be able to determine the dosage amount required for
a
subject whose weight falls outside the 65 to 70 kg range, based upon the
medical
history of the subject and the presence of diseases, e.g., diabetes, in the
subject.
All doses set forth herein; and in the appendant claims, are daily doses.
In general, in accordance with this invention, the Lp{a) inhibitor is
generally administered in a dosage of about 25 mg to about 500 mg. Preferably,
9-cis-retinoic acid is administered in a dosage of about 5 mg to about 100 mg.
It
will be recognized by a skilled person that the free base form or other salt
forms of
9-cis-retinoic acid may be used in this invention. Calculation of the dosage
amount for these other forms of or the free base form or other salt forms of
La(a)
inhibitors is easily accomplished by performing a simple ratio relative to the
molecular weights of the species involved.
In general, in accordance with this invention, the above statins are
administered in the following dosage amounts:
Simvastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 40 mg;
Pravastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 40 mg;
Cerivastatin, generally about 25 ~,g to about 5 mg and preferably about
1 mg to about 3.2 mg;
Fluvastatin, generally about 2.5 mg to about 160 mg and preferably about
20 mg to about 80 mg;
Lovastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 80 mg; and
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Atorvastatin, generally about 2.5 mg to about 160 mg and preferably about
mg to about 80 mg.
It will be recognized by a skilled person that the free base form or other
salt forms of the above statins may be used in this invention. Calculation of
the
dosage amount for these other forms of or the free base form or other salt
forms
said statins is easily accomplished by performing a simple ratio relative to
the
molecular weights of the species involved.
The compounds of the present invention are generally administered in the
form of a pharmaceutical composition comprising at least one of the compounds
10 of this invention together with a pharmaceutically acceptable carrier or
diluent.
Thus, the compounds of this invention can be administered either individually
or
together in any conventional oral, parenteral, or transdermal dosage form.
For oral administration, a pharmaceutical composition can take the form of
solutions, suspensions, tablets, pills, capsules, powders, and the like.
Tablets
t 5 containing various excipients such as sodium citrate, calcium carbonate,
and
calcium phosphate are employed along with various disintegrants such as starch
and preferably potato or tapioca starch and certain complex silicates,
together with
binding agents such as polyvinylpyrrolidone, sucrose, gelatin, and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl
sulfate, and talc are often very useful for tableting purposes. Solid
compositions of
a similar type are also employed as fillers in soft- and hard-filled gelatin
capsules;
preferred materials in this connection also include lactose or milk sugar, as
well as
high molecular weight polyethylene glycols. When aqueous suspensions and/or
elixirs are desired for oral administration, the compounds of this invention
can be
combined with various sweetening agents, flavoring agents, coloring agents,
emulsifying agents, and/or suspending agents, as well as such diluents as
water,
ethanol, propylene glycol, glycerin, and various like combinations thereof.
The combinations of this invention may also be administered in a
controlled release formulation such as a slow release or a fast release
formulation.
Such controlled release formulations of the combination of this invention may
be
prepared using methods well-known to those skilled in the art. The method of
administration will be determined by the attendant physician or other person
skilled in the art after an evaluation of the subject's condition and
requirements.
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The generally preferred formulation of atorvastatin calcium is LipitorO as
described in U.S. Patent 5,686,104, incorporated herein by reference.
For purposes of parenteral administration. solutions in sesame or peanut
oil or in aqueous propylene glycol can be employed, as well as sterile aqueous
solutions of the corresponding water-soluble salts. Such aqueous solutions may
be
suitably buffered, if necessary, and the liquid diluent first rendered
isotonic with
sufficient saline or glucose. These aqueous solutions are especially suitable
for
intravenous, intramuscular, subcutaneous, and intraperitoneal injection
purposes.
In this connection, the sterile aqueous media employed are all readily
obtainable
by standard techniques well-known to those skilled in the art.
Methods of preparing various pharmaceutical compositions with a certain
amount of active ingredient are known, or will be apparent in light of this
disclosure, to those skilled in this art. For examples, see Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easter, Pennsylvania., 15th
Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1%
to 95% of the compounds) of this invention, preferably 1 % to 70%. In any
event,
the composition or formulation to be administered will contain a quantity of a
compounds) according to the invention in an amount effective to treat the
condition or disease of the subject being treated.
Since the present invention relates to the treatment of diseases and
conditions with a combination of active ingredients which may be administered
separately, the invention also relates to combining separate pharmaceutical
compositions in kit form. The kit includes two separate pharmaceutical
compositions: a carboxyalkylether or a pharmaceutically acceptable acid
addition
salt thereof and a statin or a pharmaceutically acceptable salt thereof. The
kit
includes container means for containing the separate compositions such as a
divided bottle or a divided foil packet; however, the separate compositions
may
also be contained within a single, undivided container. Typically, the kit
includes
directions for the administration of the separate components. The kit form is
particularly advantageous when the separate components are preferably
administered in different dosage forms (e.g., oral and parenteral), are
administered
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at different dosage intervals, or when titration of the individual components
of the
combination is desired by the prescribing physician.
It should be understood that the invention is not limited to the particular
embodiments described herein, but that various changes and modifications may
be
made without departing from the spirit and scope of this novel concept as
defined
by the following claims.
