U.S. patent application number 10/264639 was filed with the patent office on 2003-08-07 for combination therapy of angiotensin converting enzyme inhibitor and side-effect-reduced amount of aldosterone antagonist for treatment of cardiovascular disease.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to MacLaughlan, Todd E., Perez, Alfonso T..
Application Number | 20030148960 10/264639 |
Document ID | / |
Family ID | 23526204 |
Filed Date | 2003-08-07 |
United States Patent
Application |
20030148960 |
Kind Code |
A1 |
MacLaughlan, Todd E. ; et
al. |
August 7, 2003 |
Combination therapy of angiotensin converting enzyme inhibitor and
side-effect-reduced amount of aldosterone antagonist for treatment
of cardiovascular disease
Abstract
Combinations of an ACE inhibitor and an aldosterone receptor
antagonist are described for use in treatment of circulatory
disorders. Of particular interest are therapies using captopril or
enalapril co-administered with a low-dose of spironolactone. This
co-therapy would be particularly useful to treat or prevent the
progression of congestive heart failure while avoiding or reducing
aldosterone-antagonist-induced side effects such as
hyperkalemia.
Inventors: |
MacLaughlan, Todd E.;
(Grayslake, IL) ; Perez, Alfonso T.; (Lake Forest,
IL) |
Correspondence
Address: |
JOSEPH R. SCHUH
PHARMACIA CORPORATION
Corporate Patent Department
P.O. Box 5110
Chicago
IL
60680
US
|
Assignee: |
G.D. Searle & Co.
Chicago
IL
|
Family ID: |
23526204 |
Appl. No.: |
10/264639 |
Filed: |
October 4, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10264639 |
Oct 4, 2002 |
|
|
|
08727201 |
Oct 8, 1996 |
|
|
|
08727201 |
Oct 8, 1996 |
|
|
|
08386582 |
Feb 10, 1995 |
|
|
|
5537534 |
|
|
|
|
Current U.S.
Class: |
514/16.3 ;
514/16.4; 514/21.7; 714/E11.034 |
Current CPC
Class: |
G06F 11/1076 20130101;
A61P 9/00 20180101; G06F 2211/1009 20130101; G06F 2211/1059
20130101 |
Class at
Publication: |
514/16 |
International
Class: |
A61K 038/00 |
Claims
What is claimed is:
1. A combination comprising a therapeutically-effective amount of
an angiotensin converting enzyme inhibitor and an aldosterone
receptor antagonist, said aldosterone receptor antagonist being
present in an amount which is therapeutically effective to
antagonize a physiological effect of aldosterone but which amount
is not sufficient for said aldosterone receptor antagonist to cause
a substantial diurectic effect.
2. The combination of claim 1 wherein said aldosterone receptor
antagonist is a spirolactone-type compound.
3. The combination of claim 2 wherein said spirolactone-type
compound is spironolactone.
4. The combination of claim 1 wherein angiotensin converting enzyme
inhibitor is selected from the group consisting of alacepril,
benazepril, captopril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,
perindopril, quinapril, ramipril, saralasin acetate, temocapril,
trandolapril, ceranapril, moexipril, quinaprilat, spirapril,
Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril,
Marion Merrell Dow MDL-100240, perindoprilat and Servier
S-5590.
5. The combination of claim 4 wherein said angiotensin converting
enzyme inhibitor is selected from the group consisting of
alacepril, benazepril, captopril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,
perindopril, quinapril, ramipril, saralasin acetate, temocapril,
trandolapril, ceranapril, moexipril, quinaprilat and spirapril.
6. The combination of claim 1 further characterized by said
angiotensin converting enzyme inhibitor and said aldosterone
receptor antagonist being present in said combination in a weight
ratio range from about 0.1-to-one to about twenty-five-to-one of
said angiotensin converting enzyme inhibitor to said aldosterone
receptor antagonist.
7. The combination of claim 6 wherein said weight ratio range is
from about 0.5-to-one to about fifteen-to-one.
8. The combination of claim 7 wherein said weight ratio range is
from about 0.5-to-one to about five-to-one.
9. A co-therapy for treating a cardiovascular disorder in a subject
afflicted with or susceptible to multiple cardiovascular disorders,
wherein said co-therapy comprises administering a
therapeutically-effecti- ve amount of an angiotensin converting
enzyme inhibitor and administering an aldosterone receptor
antagonist in an amount therapeutically effective to antagonize
aldosterone but insufficient to cause substantial diuretic
effect.
10. The co-therapy of claim 9 wherein said subject is afflicted
with or susceptible to hypertension and said subject further
requires avoidance of the incidence of hyperkalemia.
11. The co-therapy of claim 10 wherein said subject is further
susceptible to congestive heart failure.
12. The co-therapy of claim 10 wherein said subject is further
susceptible to ventricular hypertrophy.
13. The co-therapy of claim 10 further characterized by
administering said angiotensin converting enzyme inhibitor and said
aldosterone receptor antagonist in a sequential manner.
14. The co-therapy of claim 10 further characterized by
administering said angiotensin converting enzyme inhibitor and said
aldosterone receptor antagonist in a substantially simultaneous
manner.
15. The co-therapy of claim 9 wherein said aldosterone receptor
antagonist is a spirolactone-type compound.
16. The co-therapy of claim 15 wherein said spirolactone-type
compound is spironolactone.
17. The co-therapy of claim 9 wherein said amgiotensin converting
enzyme inhibitor is selected from the group consisting of
alacepril, benazepril, captopril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,
perindopril, quinapril, ramipril, saralasin acetate, temocapril,
trandolapril, ceranapril, moexipril, quinaprilat, spirapril,
Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril,
Marion Merrell Dow MDL-100240, perindoprilat and Servier
S-5590.
18. The co-therapy of claim 17 wherein said angiotensin converting
enzyme inhibitor is selected from the group consisting of
alacepril, benazepril, captopril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,
perindopril, quinapril, ramipril, saralasin acetate, temocapril,
trandolapril, ceranapril, moexipril, quinaprilat and spirapril.
19. The co-therapy of claim 9 further characterized by said
angiotensin converting enzyme inhibitor and said aldosterone
receptor antagonist being used in said co-therapy in a weight ratio
range from about 0.1-to-one to about twenty-five-to-one of said
angiotensin converting enzyme inhibitor to said aldosterone
receptor antagonist.
20. The co-therapy of claim 19 wherein said weight ratio range is
from about 0.5-to-one to about fifteen-to-one.
21. The co-therapy of claim 20 wherein said weight ratio range is
from about 0.5-to-one to about five-to-one.
22. The co-therapy of claim 9 wherein said angiotensin converting
enzyme inhibitor is captopril, in a daily dose range from about 30
mg to about 80 mg per dose, or is enalapril in a dose range from
about 5 mg to about 25 mg per dose.
23. The co-therapy of claim 22 wherein said aldosterone receptor
antagonist is spironolactone in a daily dose range from about 1 mg
to about 23 mg per dose.
24. The co-therapy of claim 23 wherein said spironolactone daily
dose is in a range from about 5 mg to about 20 mg.
25. The co-therapy of claim 23 wherein said spironolactone daily
dose is in a range from about 5 mg to about 15 mg.
26. A pharmaceutically-acceptable dosage form comprising one or
more excipients and a fixed combination consisting of two
cardiovascular drug components, wherein said first drug component
is an ACE inhibitor and said second component is spironolactone,
wherein said first and second components are present in the dosage
form in a weight ratio of said-first-component-to-said-component in
a range from about 0.1-to-one to about 25-to-one.
27. The dosage form of claim 26 wherein said weight ratio range is
0.5-to-one to about 15-to-one.
28. The dosage form of claim 27 wherein said ACE inhibitor is
selected from the group consisting of alacepril, benazepril,
captopril, cilazapril, delapril, enalapril, enalaprilat,
fosinopril, fosinoprilat, imidapril, lisinopril, perindopril,
quinapril, ramipril, saralasin acetate, temocapril, trandolapril,
ceranapril, moexipril, quinaprilat and spirapril.
29. The dosage form of claim 28 wherein said ACE inhibitor is
enalapril.
30. The dosage form of claim 29 wherein enalapril is present in an
amount selected from a range from about 5 mg to about 20 mg and
spironolactone is present in an amount selected from a range from
about 5 mg to about 22.5 mg.
Description
FIELD OF THE INVENTION
[0001] Combinations of an angiotensin converting enzyme inhibitor
and an aldosterone receptor antagonist are described for use in
treatment of circulatory disorders, including cardiovascular
diseases such as heart failure, hypertension and congestive heart
failure. Of particular interest are therapies using a
spirolactone-type aldosterone receptor antagonist compound in
combination with an angiotensin converting enzyme inhibitor, using
a side-effect-reduced amount of the aldosterone receptor
antagonist.
BACKGROUND OF THE INVENTION
[0002] Myocardial (or cardiac) failure, that is, heart failure
("HF"), whether a consequence of previous myocardial infarction(s),
heart disease associated with hypertension, or primary
cardiomyopathy, is a major health problem of worldwide proportions.
The incidence of symptomatic heart failure has risen steadily over
the past several decades.
[0003] In clinical terms, decompensated cardiac failure consists of
a constellation of signs and symptoms that arise from congested
organs and hypoperfused tissues to form congestive heart failure
(CHF) syndrome. Congestion is caused largely by increased venous
pressure and by inadequate sodium (Na.sup.+) excretion, relative to
dietary Na.sup.+ intake, and is importantly related to circulating
levels of aldosterone (ALDO). An abnormal retention of Na.sup.+
occurs via tubular epithelial cells throughout the nephron,
including the later portion of the distal tubule and cortical
collecting ducts, where ALDO receptor sites are present.
[0004] ALDO is the body's most potent mineralocorticoid hormone. As
connoted by the term mineralocorticoid, this steroid hormone has
mineral-regulating activity. It promotes Na.sup.+ reabsorption not
only in the kidney, but also from the lower gastrointestinal tract
and salivary and sweat glands, each of which represents classic
ALDO-responsive tissues. ALDO regulates Na.sup.+ and water
resorption at the expense of potassium (K.sup.+) and magnesium
(Mg.sup.2+) excretion.
[0005] ALDO can also provoke responses in non-epithelial cells.
Elicited by a chronic elevation in plasma ALDO level that is
inappropriate relative to dietary Na.sup.+ intake, these responses
can have adverse consequences on the structure of the
cardiovascular system. Hence, ALDO can contribute to the
progressive nature of myocardial failure for multiple reasons.
[0006] Multiple factors regulate ALDO synthesis and metabolism,
many of which are operative in the patient with myocardial failure.
These include renin as well as non-renin-dependent factors (such as
K.sup.+, ACTH) that promote ALDO synthesis. Hepatic blood flow, by
regulating the clearance of circulating ALDO, helps determine ALDO
plasma concentration, an important factor in heart failure
characterized by reduction in cardiac output and hepatic blood
flow.
[0007] The renin-angiotensin-aldosterone system ("RAAS") is one of
the hormonal mechanisms involved in regulating pressure/volume
homeostasis and also in the development of hypertension, a
precursor condition implicated in the progression of more serious
cardiovascular diseases such as congestive heart failure.
Activation of the renin-angiotensin-aldosterone system begins with
secretion of the enzyme renin from the juxtaglomerular cells in the
kidney. The enzyme renin acts on a naturally-occurring substrate,
angiotensinogen, to release a decapeptide, Angiotensin I. This
decapeptide is cleaved by angiotensin converting enzyme ("ACE") to
provide an octapeptide, Angiotensin II, the primary active species
of this system. This octapeptide, angiotensin II, is a potent
vasoconstrictor and also produces other physiological effects such
as stimulating aldosterone secretion, promoting sodium and fluid
retention, inhibiting renin secretion, increasing sympathetic
nervous system activity, stimulating vasopressin secretion, causing
positive cardiac inotropic effect and modulating other hormonal
systems.
[0008] Emphasis has been placed on minimizing hyperaldosteronism as
a basis for optimizing patient treatment. This includes the
importance of ALDO-receptor antagonism both in patients treated
with conventional diuretic programs and in patients treated with
angiotensin-converting enzyme (ACE) inhibitors, who are often
constrained to small doses of ACE inhibitor because of orthostatic
hypotension. Such patients may demonstrate a recurrence of heart
failure symptoms likely related to elevations in plasma ALDO
levels.
[0009] Many aldosterone receptor blocking drugs and their effects
in humans are known. For example, spironolactone is a drug which
acts at the mineralocorticoid receptor level by competitively
inhibiting aldosterone binding. This steroidal compound has been
used for blocking aldosterone-dependent sodium transport in the
distal tubule of the kidney in order to reduce edema and to treat
essential hypertension and primary hyperaldosteronism [F. Mantero
et al, Clin. Sci. Mol. Med., 45 (Suppl 1), 219s-224s (1973)].
Spironolactone is also used commonly in the treatment of other
hyperaldosterone-related diseases such as liver cirrhosis and
congestive heart failure [F. J. Saunders et al, Aldactone;
Spironolactone: A Comprehensive Review, Searle, N.Y. (1978)].
Progressively-increasing doses of spironolactone from 1 mg to 400
mg per day [i.e., 1 mg/day, 5 mg/day, 20 mg/day] was administered
to a spironolactone-intolerant patient to treat cirrhosis-related
ascites [P. A. Greenberger et al, N. Eng. Reg. Allergy Proc., 7(4),
343-345 (July-August, 1986)]. It has been recognized that
development of myocardial fibrosis is sensitive to circulating
levels of both Angiotensin II and aldosterone, and that the
aldosterone antagonist spironolactone prevents myocardial fibrosis
in animal models, thereby linking aldosterone to excessive collagen
deposition [D. Klug et al, Am. J. Cardiol., 71(3), 46A-54A (1993)].
Spironolactone has been shown to prevent fibrosis in animal models
irrespective of the development of left ventricular hypertrophy and
the presence of hypertension [C. G. Brilla et al, J. Mol. Cell.
Cardiol., 25(5), 563-575 (1993)]. Spironolactone at a dosage
ranging from 25 mg to 100 mg daily is used to treat
diuretic-induced hypokalemia, when orally-administered potassium
supplements or other potassium-sparing regimens are considered
inappropriate [Physicians' Desk Reference, 46th Edn., p. 2153,
Medical Economics Company Inc., Montvale, N.J. (1992)].
[0010] Previous studies have shown that inhibiting ACE inhibits the
renin-angiotensin system by substantially complete blockade of the
formation of Angiotensin II. Many ACE inhibitors have been used
clinically to control hypertension. While ACE inhibitors may
effectively control hypertension, side effects are common including
chronic cough, skin rash, loss of taste sense, proteinuria and
neutropenia.
[0011] Moreover, although ACE inhibitors effectively block the
formation of Angiotensin II, aldosterone levels are not well
controlled in certain patients having cardiovascular diseases. For
example, despite continued ACE inhibition in hypertensive patients
receiving captopril, there has been observed a gradual return of
plasma aldosterone to baseline levels [J. Staessen et al, J.
Endocrinol., 91, 457-465 (1981)]. A similar effect has been
observed for patients with myocardial infarction receiving
zofenopril [C. Borghi et al, J. Clin. Pharmacol., 33, 40-45
(1993)]. This phenomenon has been termed "aldosterone escape".
[0012] Combinations of an aldosterone antagonist and an ACE
inhibitor have been investigated for treatment of heart failure. It
is known that mortality is higher in patients with elevated levels
of plasma aldosterone and that aldosterone levels increase as CHF
progresses from RAAS activation. Routine use of a diuretic may
further elevate aldosterone levels. ACE inhibitors consistently
inhibit angiotensin II production but exert only a mild and
transient antialdosterone effect.
[0013] Combining an ACE inhibitor and spironolactone has been
suggested to provide substantial inhibition of the entire RAAS. For
example, a combination of enalapril and a 25 mg daily dose of
spironolactone has been administered to ambulatory patients with
monitoring of blood pressure [P. Poncelet et al, Am. J. Cardiol.,
65(2), 33K-35K (1990)]. In a 90-patient study, a combination of
spironolactone at a dose in a range from 50 mg/day to 100 mg/day
(average 73 mg/day) and captopril was administered and found
effective to control refractory CHF without serious incidents of
hyperkalemia [U. Dahlstrom et al, Am. J. Cardiol., 71, 29A-33A
(Jan. 21, 1993)]. Spironolactone dosage at 100 mg/day
coadministered with an ACE inhibitor was reported to be highly
effective in 13 of 16 patients afflicted with congestive heart
failure, with a 25 mg/day to 50 mg/day spironolactone maintenance
dosage given at trial completion to compensated patients being
treated with an ACE inhibitor and loop diuretic [A. A. van Vliet et
al, Am. J. Cardiol., 71, 21A-28A (Jan. 21, 1993)]. Clinical
improvements have been reported for patients receiving a co-therapy
of spironolactone and the ACE inhibitor enalapril, although this
report mentions that controlled trials are needed to determine the
lowest effective doses and to identify which patients would benefit
most from combined therapy [F. Zannad, Am. J. Cardiol., 71 (3),
34A-39A (1993)].
SUMMARY OF DRAWING FIGURES
[0014] FIG. 1 shows urinary aldosterone levels at different rates
of spironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), as
compared to placebo, co-administered with stable doses of ACE
inhibitor and loop diuretic.
[0015] FIG. 2 shows plasma renin activity at different rates of
spironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), as
compared to placebo, co-administered with stable doses of ACE
inhibitor and loop diuretic.
[0016] FIG. 3 shows N-Terminal ANF levels at different rates of
spironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), as
compared to placebo, co-administered with stable doses of ACE
inhibitor and loop diuretic.
[0017] FIG. 4 shows changes in supine blood pressure at different
rates of spironolactone administration (12.5 mg, 25 mg, 50 mg, 75
mg), as compared to placebo, co-administered with stable doses of
ACE inhibitor and loop diuretic.
[0018] FIG. 5 shows changes in supine heart rate at different rates
of spironolactone administration(12.5 mg, 25 mg, 50 mg, 75 mg), as
compared to placebo co-administered with stable doses of ACE
inhibitor and loop diuretic.
DESCRIPTION OF THE INVENTION
[0019] Treatment or prevention of circulatory disorders, including
cardiovascular disorders such as heart failure, hypertension and
congestive heart failure, is provided by a combination therapy
comprising a therapeutically-effective amount of an angiotensin
converting enzyme ("ACE") inhibitor along with a
therapeutically-effective amount of a spirolactone-type aldosterone
receptor antagonist. Preferably, the spirolactone-type aldosterone
receptor antagonist is administered in the combination therapy at a
low dose, that is, at a dose lower than has been conventionally
used in clinical situations.
[0020] The combination therapy of the invention would be useful,
for example, to prevent or retard, in a subject, the development of
congestive heart failure which typically arises from essential
hypertension or from heart conditions following myocardial infarct.
Such subject would not typically be suffering from an edematous
condition and thus would not gain benefit from treatment with
conventional diuretic therapy as with loop diuretics which can
alter electrolyte balance and cause hypokalemic or hypomagnesia
conditions.
[0021] The phrase "angiotensin converting enzyme inhibitor" ("ACE
inhibitor") is intended to embrace an agent or compound, or a
combination of two or more agents or compounds, having the ability
to block, partially or completely, the rapid enzymatic conversion
of the physiologically inactive decapeptide form of angiotensin
("Angiotensin I") to the vasoconstrictive octapeptide form of
angiotensin ("Angiotensin II"). Blocking the formation of
Angiotensin II can quickly affect the regulation of fluid and
electrolyte balance, blood pressure and blood volume, by removing
the primary actions of Angiotensin II. Included in these primary
actions of Angiotensin II are stimulation of the synthesis and
secretion of aldosterone by the adrenal cortex and raising blood
pressure by direct constriction of the smooth muscle of the
arterioles.
[0022] The phrase "aldosterone receptor antagonist" embraces an
agent or compound, or a combination of two or more of such agents
or compounds, which agent or compound binds to the aldosterone
receptor as a competitive inhibitor of the action of aldosterone
itself at an aldosterone receptor site, such as typically found in
the renal tubules, so as to modulate the receptor-mediated activity
of aldosterone. Typical of such aldosterone receptor antagonists
are spirolactone-type compounds. The term "spirolactone-type" is
intended to characterize a steroidal structure comprising a lactone
moiety attached to a steroid nucleus, typically at the steroid "D"
ring, through a spiro bond configuration.
[0023] The phrase "combination therapy" (or "co-therapy"), in
defining use of an ACE inhibitor agent and an aldosterone receptor
antagonist agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[0024] The phrase "therapeutically-effective" is intended to
qualify the amount of each agent for use in the combination therapy
which will achieve the goal of improvement in cardiac sufficiency
by reducing or preventing, for example, the progression of
congestive heart failure, while avoiding adverse side effects
typically associated with each agent.
[0025] The phrase "low-dose amount", in characterizing a
therapeutically-effective amount of the aldosterone receptor
antagonist agent in the combination therapy, is intended to define
a quantity of such agent, or a range of quantity of such agent,
that is capable of improving cardiac sufficiency while reducing or
avoiding one or more aldosterone-antagonist-induced side effects,
such as hyperkalemia. A dosage of spironolactone which would
accomplish the therapic goal of favorably enhancing cardiac
sufficiency, while reducing or avoiding side effects, would be a
dosage that substantially avoids inducing diuresis, that is, a
substantially non-diuresis-effective dosage.
[0026] A preferred combination therapy would consist essentially of
two active agents, namely, an ACE inhibitor agent and aldosterone
receptor antagonist agent. The agents would be used in combination
in a weight ratio range from about 0.5-to-one to about
twenty-to-one of the angiotensin converting enzyme agent to the
aldosterone receptor antagonist agent. A preferred range of these
two agents (ACE inhibitor-to-ALDO antagonist) would be from about
one-to-one to about fifteen-to-one, while a more preferred range
would be from about one-to-one to about five-to-one, depending
ultimately on the selection of the ACE inhibitor and ALDO
antagonist.
[0027] Examples of ACE inhibitors which may be used in the
combination therapy are shown in the following four categories.
[0028] A first group of ACE inhibitors consists of the following
compounds: AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C,
CGS-13928C, CL-242817, CV-5975, Equaten, EU-4865, EU-4867, EU-5476,
foroxymithine, FPL 66564, FR-900456, Hoe-065, I5B2, indolapril,
ketomethylureas, KRI-1177, KRI-1230, L-681176, libenzapril, MCD,
MDL-27088, MDL-27467A, moveltipril, MS-41, nicotianamine,
pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134,
RG-6207, RGH-0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS
86127, RU-44403, S-8308, SA-291, spiraprilat, SQ-26900, SQ-28084,
SQ-28370, SQ-28940, SQ-31440, Synecor, utibapril, WF-10129,
Wy-44221, Wy-44655, Y-23785, Yissum P-0154, zabicipril and.
[0029] A second group of ACE inhibitors of interest consists of the
following compounds: Asahi Brewery AB-47, alatriopril, BMS 182657,
Asahi Chemical C-111, Asahi Chemical C-112, Dainippon DU-1777,
mixanpril, Prentyl, zofenoprilat and
1-(-(1-carboxy-6-(4-piperidinyl)hexyl) amino)-1-oxopropyl
octahydro-1H-indole-2-carboxylic acid.
[0030] A third group of ACE inhibitors of greater interest consists
of the following compounds: Bioproject BP1.137, Chiesi CHF 1514,
Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240,
perindoprilat and Servier S-5590.
[0031] A fourth group of ACE inhibitors of highest interest
consists of the following compounds: alacepril, benazepril,
captopril, cilazapril, delapril, enalapril, enalaprilat,
fosinopril, fosinoprilat, imidapril, lisinopril, perindopril,
quinapril, ramipril, saralasin acetate, temocapril, trandolapril,
ceranapril, moexipril, quinaprilat and spirapril.
[0032] Many of these ACE inhibitors are commercially available,
especially those listed in the fourth group, above. For example, a
highly preferred ACE inhibitor, captopril, is sold by E. R. Squibb
& Sons, Inc., Princeton, N.J., now part of
Bristol-Myers-Squibb, under the trademark "CAPOTEN", in tablet
dosage form at doses of 12.5 mg, 50 mg and 100 mg per tablet.
Enalapril or Enalapril Maleate, and Lisinopril are two more highly
preferred ACE inhibitors sold by Merck & Co, West Point, Pa.
Enalapril is sold under the trademark "VASOTEC" in tablet dosage
form at doses of 2.5 mg 5 mg, 10 mg and 20 mg per tablet.
Lisinopril is sold under the trademark "PRINIVIL" in tablet dosage
form at doses of 5 mg, 10 mg, 20 mg and 40 mg per tablet.
[0033] A family of spirolactone-type compounds of interest is
defined by Formula I 1
[0034] wherein R is lower alkyl of up to 5 carbon atoms, and 2
[0035] Lower alkyl residues include branched and un-branched
groups, preferably methyl, ethyl and n-propyl.
[0036] Specific compounds of interest within Formula I are the
following:
[0037]
7.alpha.-Acetylthio-3-oxo-4,15-androstadiene-[17((.beta.-1')-spiro--
5']perhydrofuran-2'-one;
[0038]
3-Oxo-7.alpha.-propionylthio-4,15-androstadiene-[17((.beta.-1')-spi-
ro-5']perhydrofuran-2'-one;
[0039]
6.beta.,7.beta.-Methylene-3-oxo4,15-androstadiene-[17((.beta.-1')-s-
piro-5']perhydrofuran-2'-one;
[0040]
15.alpha.,16.alpha.-Methylene-3-oxo-4,7.alpha.-propionylthio-4-andr-
ostene[17(.beta.-1')-spiro-5']perhydrofuran-2'-one;
[0041]
6.beta.,7.beta.,15.alpha.,16.alpha.-Dimethylene-3-oxo-4-androstene
[17(.beta.-1')-spiro-5']perhydrofuran-2'-one;
[0042]
7.alpha.-Acetylthio-15.beta.,16.beta.-Methylene-3-oxo-4-androstene--
[17(.beta.-1')-spiro-5']perhydrofuran-2'-one;
[0043]
15.beta.,16.beta.-Methylene-3-oxo-7.beta.-propionylthio-4-androsten-
e-[17(.beta.-1')-spiro-5']perhydrofuran-2'-one; and
[0044]
6.beta.,7.beta.,15.beta.,16.beta.-Dimethylene-3-oxo-4-androstene-[1-
7(.beta.-1')-spiro-5']perhydrofuran-2'-one.
[0045] Methods to make compounds of Formula I are described in U.S.
Pat. No. 4,129,564 to Wiechart et al issued on Dec. 12, 1978.
[0046] A second family of spirolactone-type compounds of interest
is defined by Formula II: 3
[0047] wherein R.sup.1 is C.sub.1-3-alkyl or C.sub.1-3 acyl and
R.sup.2 is H or C.sub.1-3-alkyl.
[0048] Specific compounds of interest within Formula II are the
following:
[0049]
1.alpha.-Acetylthio-15.beta.,16.beta.-methylene-7.alpha.-methylthio-
-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolactone; and
[0050]
15.beta.,16.beta.-Methylene-1.alpha.,7.alpha.-dimethylthio-3-oxo-17-
.alpha.-pregn-4-ene-21,17-carbolactone.
[0051] Methods to make the compounds of Formula II are described in
U.S. Pat. No. 4,789,668 to Nickisch et al which issued Dec. 6,
1988.
[0052] A third family of spirolactone-type compounds of interest is
defined by a structure of Formula III: 4
[0053] wherein R is lower alkyl, with preferred lower alkyl groups
being methyl, ethyl, propyl and butyl. Specific compounds of
interest include:
[0054]
3.beta.,21-dihydroxy-17.alpha.-pregna-5,15-diene-17-carboxylic acid
.gamma.-lactone;
[0055]
3.beta.,21-dihydroxy-17.alpha.-pregna-5,15-diene-17-carboxylic acid
.gamma.-lactone 3-acetate;
[0056] 3.beta.,21-dihydroxy-17.alpha.-pregn-5-ene-17-carboxylic
acid .gamma.-lactone;
[0057] 3.beta.,21-dihydroxy-17.alpha.-pregn-5-ene-17-carboxylic
acid .gamma.-lactone 3-acetate;
[0058] 21-hydroxy-3-oxo-17.alpha.-pregn-4-ene-17-carboxylic acid
.gamma.-lactone;
[0059] 21-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-17-carboxylic
acid .gamma.-lactone;
[0060] 21-hydroxy-3-oxo-17.alpha.-pregna-1,4-diene-17-carboxylic
acid .gamma.-lactone;
[0061]
7.alpha.-acylthio-21-hydroxy-3-oxo-17.alpha.-pregn-4-ene-17-carboxy-
lic acid .gamma.-lactones; and
[0062]
7.alpha.-acetylthio-21-hydroxy-3-oxo-17.alpha.-pregn-4-ene-17-carbo-
xylic acid .gamma.-lactone.
[0063] Methods to make the compounds of Formula III are described
in U.S. Pat. No. 3,257,390 to Patchett which issued Jun. 21,
1966.
[0064] A fourth family of compounds of interest is represented by
Formula IV: 5
[0065] wherein E' is selected from the group consisting of
ethylene, vinylene and (lower alkanoyl)thioethylene radicals, E" is
selected from the group consisting of ethylene, vinylene, (lower
alkanoyl)thioethylene and (lower alkanoyl)thiopropylene radicals; R
is a methyl radical except when E' and E" are ethylene and (lower
alkanoyl) thioethylene radicals, respectively, in which case R is
selected from the group consisting of hydrogen and methyl radicals;
and the selection of E' and E" is such that at least one (lower
alkanoyl)thio radical is present.
[0066] A preferred family of compounds within Formula IV is
represented by Formula V: 6
[0067] A more preferred compound of Formula V is
1-acetylthio-17.alpha.-(2-
-carboxyethyl)-17.beta.-hydroxy-androst-4-en-3-one lactone.
[0068] Another preferred family of compounds within Formula IV is
represented by Formula VI: 7
[0069] More preferred compounds within Formula VI include the
following:
[0070]
7.alpha.-acetylthio-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxy-and-
rost-4-en-3-one lactone;
[0071]
7.beta.-acetylthio-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxy-andr-
ost-4-en-3-one lactone;
[0072]
1.alpha.,7.alpha.-diacetylthio-17.alpha.-(2-carboxyethyl)-17.beta.--
hydroxy-androsta-4,6-dien-3-one lactone;
[0073]
7.alpha.-acetylthio-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxy-and-
rosta-1,4-dien-3-one lactone;
[0074]
7.alpha.-acetylthio-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxy-19--
norandrost-4-en-3-one lactone; and
[0075]
7.alpha.-acetylthio-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxy-6.a-
lpha.-methylandrost-4-en-3-one lactone;
[0076] In Formula IV-VI, the term "alkyl" is intended to embrace
linear and branched alkyl radicals containing one to about eight
carbons. The term "(lower alkanoyl)thio" embraces radicals of the
formula lower alkyl 8
[0077] Of particular interest is the compound spironolactone having
the following structure and formal name: 9
[0078] "spironolactone":
17-hydroxy-7.alpha.-mercapto-3-oxo-17.alpha.-preg-
n-4-ene-21-carboxylic acid .gamma.-lactone acetate
[0079] Methods to make compounds of Formula IV-VI are described in
U.S. Pat. No. 3,013,012 to Cella et al which issued Dec. 12, 1961.
Spironolactone is sold by G. D. Searle & Co., Skokie, Ill.,
under the trademark "ALDACTONE", in tablet dosage form at doses of
25 mg, 50 mg and 100 mg per tablet.
[0080] A diuretic agent may be used with the combination of ACE
inhibitor and aldosterone receptor antagonist. Such diuretic agent
may be selected from several known classes, such as thiazides and
related sulfonamides, potassium-sparing diuretics, loop diuretics
and organic mercurial diuretics.
[0081] Examples of thiazides are bendroflumethiazide, benzthiazide,
chlorothiazide, cyclothiazide, hydrochlorotthiazide,
hydroflumethiazode, methyclothiazide, polythiazide and
trichlormethiazide.
[0082] Examples of related sulfonamides are chlorthalidone,
quinethazone and metolazone.
[0083] An example of a non-thiazide sulfonamide diuretic is
metolazone.
[0084] Examples of potassium-sparing diuretics are triameterene and
amiloride.
[0085] Examples of loop diuretics, i.e., diuretics acting in the
ascending limb of the loop of Henle of the kidney, are furosemide
and ethynacrylic acid.
[0086] Examples of organic mercurial diuretics are mercaptomerin
sodium, merethoxylline procaine and mersalyl with theophylline.
BIOLOGICAL EVALUATION
Human Clinical Trials
[0087] A combination therapy of ACE inhibitor and spironolactone
was evaluated in humans as described in the following clinical
trials.
[0088] Patients: Two-hundred fourteen (214) patients with
symptomatic heart failure had an ejection fraction .ltoreq.35%, a
history of New York Heart Association (NYHA) functional
classification III-IV six months prior to enrollment, and current
classification II-IV were randomized among five treatment groups.
Patients were assigned to receive either spironolactone 12.5 mg (41
patients), 25 mg (45 patients), 50 mg (47 patients), 75 mg (41
patients), or placebo (40 patients) once a day for 12 weeks. Two
patients that were randomized failed to take the study medication
and were excluded from the analysis. All patients were taking a
stable dose of ACE inhibitor, loop diuretic, and optional digitalis
for 30 days prior to the first dose of study medication. Potassium
supplement therapy that was stable for 14 days prior to the first
dose of study medication was also allowed. Informed consent was
obtained from all patients, and the protocol was approved by each
ethical committee. At enrollment all patients had normal serum
potassium values (<5.5 mmol/L) and creatinine values of
.ltoreq.2.0 mg/dL or .ltoreq.180 mmol/L. Patients were excluded
from enrollment if they: (1) were diagnosed with either an acute
life-threatening disease (included patients with automatic
implantable cardioverter/defibrillator), valvular disease, unstable
angina, insulin-dependent diabetes, cancer (without a reoccurrence
within the last five years), or primary hepatic failure; (2) were
on a waiting list for a heart transplant or experienced a
myocardial infarction 30 days prior to the first dose of study
medication; (3) had laboratory values for hematology or
biochemistry considered abnormal and clinically significant prior
to the first dose of study medication; (4) received a potassium
spacing diuretic within 30 days prior to the first dose of study
medication.; (5) were receiving, on a regular basis, either
non-steroidal anti-inflammatory drugs or aspirin >325 mg/day,
steroids, dopamine agonists or antagonists, insulin or heparin; (6)
were on any investigational medication within 30 days of the first
dose of medication.
[0089] Study Design: This was a multinational, double-blind,
randomized, parallel group study.
[0090] Laboratory Measurements: The following information was
obtained from each patient at baseline:
[0091] 1. Concurrent medication within the past 30 days.
[0092] 2. 12-lead ECG
[0093] 3. Cardiac assessments that included blood pressure, pulse,
sodium retention score (general assessment of a patient's edematous
state was derived from the summation of scores obtained from Table
I), NYHA classification, and
[0094] 4. Signs and symptoms within the past 30 days.
1TABLE I Sodium Retention Score Parameters Grade Assessment Rales 0
Absent 1 In lower 1/3 of lungs 2 In lower 2/3 of lungs 3 In all
lung fields Peripheral 0 Absent Pitting Edema 1 Trace 2 Limited to
ankles 3 Not limited to ankles 4 Anasarca Weight Change -1
Decreased 0 Unchanged 1 Increased Hepatomegaly 0 Absent 1 Present
S3 Gallop 0 Absent 1 Present Increased Jugular 0 Absent Venous
Pressure 1 Present
[0095] The following laboratory values were obtained at the
pretreatment visit:
2 Hematology: White blood cell count (WBC), hematocrit, hemoglobin,
platelet count . Biochemistry: Creatinine, potassium, AST, SGOT,
urinary sodium/potassium ratio, bicarbonate, calcium, chloride,
creatinine, creatinine clearance, magnesium, glucose, urea, uric
acid. Neurohormones: Plasma renin activity, pro-atrial natriuretic
factor, urinary aldosterone.
[0096] Blood and urine samples were centrally analyzed at SciCor
Laboratories. Laboratory values for urinary aldosterone and renin
levels were done at the Ohio State University Laboratory in
Columbus, Ohio. Pro-atrial natriuretic factor samples were
evaluated at the University of Oslo Laboratory in Oslo, Norway.
Patients were evaluated 9 days after beginning study medication.
Documented changes in concurrent medications, signs and symptoms
and drug compliance were recorded. These procedures were repeated
at Week 4 and Week 8 visits. Patient information and procedures on
the final visit (Week 12) was identical to the pre-treatment
visit.
[0097] Statistical Analysis: Analysis of cardiac assessment changes
in patient therapy and vital signs were performed for both the
Intent-to-Treat (ITT) and evaluable patient groups. Analysis of
demographic variables, adverse events and clinical laboratory
values were performed in the ITT group. For each efficacy variable,
results of each visit were examined separately. An appropriate
trend test was used to test for overall dose-response. Pair-wise
comparisons were made for each active dose to placebo. Significant
levels for pair-wise comparisons were adjusted using the
Hochberg-Bonferromi method to maintain the overall Type I error
rate. All statistical methods were two-sided.
[0098] Recruitment: Two-hundred and fourteen patients were
recruited from 22 study sites in eleven countries.
[0099] Patient Characteristics: Patient demographic, vital signs,
and cardiac status at baseline are summarized in Table II.
3TABLE II Patient Demographics Spironolactone Spironolactone
Spironolactone Spironolactone 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d
Placebo P-Value Demographic Age (years) 63 .+-. 12 61 .+-. 9 62
.+-. 13 62 .+-. 13 61 .+-. 12 N.S. Caucasian/other (%) 93/7 98/2
93/7 88/12 97/3 N.S. Male/female (%) 78/22 82/18 74/26 88/12 83/18
N.S. Vital Signs Weight (kg) 74 75 73 78 73 N.S. Blood pressure
(mmHg) Systolic 121 120 121 125 121 N.S. Diastolic 76 76 75 81 74
N.S. Pulse (bpm) 76 74 76 74 71 N.S. Cardiac Status NYHA (%) II 63
60 43 49 38 III 34 38 55 49 60 IV 2 2 2 2 2 N.S. Sodium retention
score Mean value 1.54 1.62 1.64 1.61 1.78 N.S. ACE-I (Mean dose)
Captopril (mg) 57.3 57.5 69.7 59.4 65.4 N.S. Enalapril (mg) 16.4
13.4 14.5 16.3 10.8 N.S. Loop Diuretic (Mean dose) Furosemide (mg)
58.8 82.8 76.9 84.9 63.2 N.S. Digoxin (%) 78.0 77.8 76.6 80.5 77.5
N.S. Potassium supplement 43.9 37.8 34.0 39.0 30.0 N.S. (%)
[0100] Patients ranged in age from 26 to 83 years (mean=60), 81%
were male, 94% were Caucasian. At baseline 51% of the patients were
NYHA Class II, 47% were Class III. With respect to sodium retention
score, a statistically significant dose response was seen at Day 9
with higher doses showing more reduction in sodium retention score
(p=0.019). However, this effect was not seen at later visits
(p>0.20). There was an improvement in NYHA Class placebo group
and in all the spironolactone groups. Although a trend toward
improvement in the spironolactone group was observed, the
difference was not statistically significant.
[0101] Changes in Patient Therapy: The treatment groups did not
differ significantly with respect to changes in dose of ACE
inhibitor, digitalis or potassium supplements at any visit
(p.gtoreq.0.11). The treatment groups did differ significantly with
respect to changes in loop diuretic therapy only at Week 8
(p=0.004) in that more patients on the higher doses of
spironolactone had decreases in the loop diuretic dose compared to
the placebo group. This pattern was not observed at Week 12.
[0102] Chances in Vital Signs: Changes from baseline in vital signs
at Week 12 are summarized in Table III.
4TABLE III Mean Change in Weight and Vital Signs from Baseline to
Week 12 Spironolactone Spironolactone Spironolactone Spironolactone
P- 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d Placebo Value Weight 0.59
(3.00) -0.16 (3.02) .sup. 0.62 (2.05) -0.81 (2.70) 0.11 (2.46)
0.109 Supine systolic BP 1.84 (11.82) -4.46 (13.97) -7.04 (15.83)
-5.68 (15.62) 0.22 (13.45) 0.036 Supine diastolic BP -0.19 (9.13)
-2.74 (9.57) -5.11 (11.11) -5.91 (9.05) 1.78 (7.84) 0.014 Supine
pulse (BPM) -3.70 (9.56) -1.40 (10.00) -3.21 (11.27) -1.07 (13.79)
1.42 (9.69) 0.422
[0103] At all visits the 25 mg, 50 mg, and 75 mg groups had
decreases in mean systolic and diastolic blood pressure, while the
placebo group had increases in mean systolic and diastolic blood
pressure (both standing and supine). Dose response with respect to
standing and supine diastolic blood pressure was statistically
significant for all visits (p.ltoreq.0.002). Dose response with
respect to standing and supine blood pressure was statistically
significant at Week 4, Week 8, and Week 12 (p.ltoreq.0.033), but
not at Day 9 (p.gtoreq.0.12). No significant between-treatment
differences in change from baseline in pulse were observed at any
visit (p-values.gtoreq.0.136). A statistically significant dose,
response with greater decreases in pulse in the supine position at
higher doses was observed at Week 4 (p-value=0.045). Spironolactone
doses of 25 and 50 mg were also significantly different from
placebo (p-values.ltoreq.0.043) (See FIG. 1). At Day 9 and Week 4
visits, there was a statistically significant dose response with
respect to changes from baseline in body weight in that patients in
the 75 mg dose group experienced more weight loss than other
patients. This dose response was not observed at later visits
(p.gtoreq.0.062).
[0104] Clinical Laboratory Values: Table IV contains details of the
different clinical laboratory values that showed statistically
significant treatment differences with respect to mean changes at
Week 12 visit compared with their respective baseline value.
5TABLE IV Week 12 Mean Change Spironolactone Spironolactone
Spironolactone Spironolactone P- 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d
Placebo Value Urinary aldosterone (nmol/D) 4.21 4.27 8.11 11.13
0.76 0.002 N-Terminal ANF (pmol/L) -287.30 -294.60 -351.30 -370.60
54.50 0.022 PRA (NgAngl/L/s) 9.90 9.33 13.18 10.23 0.50 0.002
Hematocrit (%) 0.00 -0.02 -0.02 -0.03 0.00 0.002 Hemoglobin
(mmol/L/Fe) 0.12 -0.20 -0.31 -0.46 0.00 0.005 Potassium (mmol/L)
0.18 0.37 0.51 0.58 -0.10 0.001 Creatinine (umol/L) 6.83 9.30 14.06
21.90 -1.96 0.001 Sodium (mmol/L) -1.61 -1.85 -2.52 -3.37 -0.03
0.001
[0105] Urinary Aldosterone (See FIG. 1): Urinary aldosterone was
determined only for baseline and the 12 week visit. Urinary
aldosterone excretion showed mean increases from baseline in all
treatment groups (P.ltoreq.0.012). Greater increases were seen at
higher doses of spironolactone (p=0.002). All pair-wise comparisons
between active treatment and placebo were statistically significant
(p.ltoreq.0.009).
[0106] Plasma Renin Activity (PRA) (See FIG. 2): A statistically
significant dose-response with respect to change from baseline in
PRA was seen at Day 9, Week 4 and Week 12 (P.ltoreq.0.001) with
higher doses of spironolactone associated with greater increases in
PRA. PRA was not measured at Week 8.
[0107] N-Terminal Atrial Natriuretic Factor (ANF) (See FIG. 3): All
active treatments showed decreases from baseline at all treatment
visits. Dose-response was statistically significant at Day 9
(p=0.048), Week 4 (p=0.005), and Week 12 (p=0.008). ANF was not
measured at Week 8. In comparisons the 50 mg dose group differed
significantly from placebo at Week 4 (p=0.009) and Week 12
(p=0.006), while the 75 mg dose group differed significantly from
placebo at Week 12 only (p=0.007).
[0108] Hematocrit and Hemoglobin: At Day 9 visit a statistically
significant mean value difference between placebo and the different
active treatments was observed with lower values for the placebo
group than the active treatments (p<0.001). At Week 12 a reverse
statistically significant difference was observed with lower levels
for the active treatment groups for hematocrit (p=0.002) and
hemoglobin (0.005).
[0109] Serum Potassium: A statistically significant dose-response
with respect to change from baseline in serum potassium was seen at
all treatment period visits (p<0.001). Higher doses of
spironolactone were associated with larger increases in potassium.
All doses of active treatment had significantly higher serum
potassium levels relative to baseline than placebo
(p.ltoreq.0.034)
6 Incidence of Hyperkalemia Spironolactone Spironolactone
Spironolactone Spironolactone Treatment: Placebo 12.5 mg/d 25 mg/d
50 mg/d 75 mg/d Patients (%) 2 (5%) 2 (5%) 6 (13%) 9 (20%) 10
(24%)
[0110] Predictors of Hyperkalemia: Seven possible predictors of
hyperkalemia (potassium.gtoreq.5.5 mmol/L) were included in a
step-wise Cox regression analysis: randomized treatment (treated as
a categorical variable), age, baseline NYHA class, baseline serum
potassium, baseline PRA, baseline creatinine, baseline urinary
aldosterone, and type and dose of ACE-I. Besides the dose of
spironolactone, the following predictors of hyperkalemia were
statistically significant in the step-wise regression analysis:
type of ACE-I (captopril versus other), baseline serum creatinine,
and baseline serum potassium. Results are summarized as
follows:
7 Factor p-value Risk Ratio Captopril vs other ACE-I 0.013 0.318
Serum Creatinine > normal 0.038 2.72 Baseline Potassium >
median 0.040 2.32
[0111] In this, analysis, the risk ratio can be thought of as the
probability that the patient with the risk factor will develop
hyperkalemia, relative to the probability that a patient without
the risk factor will develop it. (For example, patients on
captopril are about one-third as likely to develop hyperkalemia as
a patient on another ACE-I.)
[0112] Risk ratios relative to placebo for the various doses of
spironolactone are:
8 Dose p-value Risk Ratio Spironolactone 12.5 mg 0.98 1.02
Spironolactone 25 mg 0.19 2.91 Spironolactone 50 mg 0.034 5.32
Spironolactone 75 mg 0.016 6.66
[0113] After adjusting for the above factors, other predictors
included in the step-wise regression analysis were not significant
(p-values.gtoreq.0.07). However, the following additional factor
was significantly related to the development of hyperkalemia when
considered apart from other predictors except the dose of
spironolactone.
9 Factor p-value Risk Ratio High ACE-I Dose 0.050 2.93
[0114] Serum Magnesium: Change from baseline in serum magnesium
showed a statistically significant dose-response at Day 9 and Week
4 (p.ltoreq.0.048), with more patients in the placebo group showing
decreases in serum magnesium. However, this effect was not seen at
later visits (p.gtoreq.0.083).
[0115] Adverse Effects: Table V summarizes the twelve most common
adverse events by different treatment groups. Only one symptom,
hyperkalemia, showed a clear dose-response in term of incidence
(p=0.001).
10TABLE V Incidence of Adverse Events Spironolactone Dose-Ranging
Study Intent-to-Treat Cohort (Top Twelve Events) Treatment Group
(Percentage of Patients) Spironolactone Spironolactone
Spironolactone Spironolactone Adverse Events 12.5 mg 25 mg 50 mg 75
mg Placebo Total Dyspnea 22.0 15.6 26.1 24.4 30.0 23.5 Angina
Pectoris 19.5 20.0 8.7 14.6 17.5 16.0 Dizziness 12.2 13.3 13.0 17.1
15.0 14.1 Fatigue 12.2 13.3 15.2 14.6 15.0 14.1 Nausea 2.4 17.8 6.5
19.5 12.5 11.7 Diarrhea 4.9 22.2 8.7 14.6 5.0 11.3 Abdominal Pain
7.3 8.9 13.0 7.3 17.5 10.8 Headache 9.8 2.2 15.2 7.3 20.0 10.8
Hyperkalemia 2.4 8.9 15.2 19.5 2.5 9.9 URT Infection 4.9 11.1 8.7
2.4 12.5 8.0 Arthralgia 4.9 4.4 8.7 4.9 7.5 6.1 Coughing 4.9 2.2
4.3 2.4 12.5 5.2
[0116] A breakdown of the hospitalizations is as follows:
11 Treat- ment Placebo 12.5 mg 25 mg 50 mg 75 mg P Patients 5 3 3
13 6 N.S. (%) (12.5%) (7.3%) (6.6%) (27.6%) (14.6%)
[0117] No deaths were reported during the drug treatment period.
Three patients died within 30 days after the study was completed.
These three patients were previously at the 50 mg dose.
[0118] Administration of the angiotensin converting enzyme
inhibitor and the aldosterone receptor antagonist may take place
sequentially in separate formulations, or may be accomplished by
simultaneous administration in a single formulation or separate
formulations. Administration may be accomplished by oral route, or
by intravenous, intramuscular or subcutaneous injections. The
formulation may be in the form of a bolus, or in the form of
aqueous or non-aqueous isotonic sterile injection solutions or
suspensions. These solutions and suspensions may be prepared from
sterile powders or granules having one or more
pharmaceutically-acceptable carriers or diluents, or a binder such
as gelatin or hydroxypropyl-methyl cellulose, together with one or
more of a lubricant, preservative, surface-active or dispersing
agent.
[0119] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
The ACE inhibitor may be present in an amount from about 1 to 200
mg, preferably from about 2 to 150 mg, depending upon the specific
ACE inhibitor selected. A suitable daily dose for a mammal may vary
widely depending on the condition of the patient and other factors.
The ALDO antagonist may be present in an amount of from about 1 to
400 mg, preferably from about 2 to 150 mg, depending upon the
specific ALDO antagonist compound selected and the specific disease
state being targeted for the combination therapy.
[0120] For disease states which require prevention, reduction or
treatment of a cardiovascular disease state without incidence of
hyperkalemia, for example, the ALDO antagonist component, typically
spironolactone, will be present in the combination therapy in an
amount in a range from about 1 mg to about 25 mg per dose. A
preferred range for spirolactone would be from about 5 mg to 15 mg
per dose. More preferably would be a range from about 10 mg to 15
mg per dose per day.
[0121] Examples of various fixed combinations of ACE inhibitor and
ALDO antagonist representing a "double therapy" of the invention
are as follow:
12 ACE Inhibitor ALDO Antagonist Captopril (mg).sup.1 Enalapril
(mg).sup.2 Spironolactone (mg).sup.2 12.5 to 25 5 to 15 5 12.5 to
25 5 to 15 7.5 12.5 to 25 5 to 15 10 12.5 to 25 5 to 15 12.5 12.5
to 25 5 to 15 15 12.5 to 25 5 to 15 17.5 12.5 to 25 5 to 15 20 12.5
to 25 5 to 15 22.5 .sup.1Dose given 1, 2 or 3 times per day
.sup.2Dose given once per day
[0122] The active ingredients may also be administered by injection
as a composition wherein, for example, saline, dextrose or water
may be used as a suitable carrier.
[0123] The dosage regimen for treating a disease condition with the
combination therapy of this invention is selected in accordance
with a variety of factors, including the type, age, weight, sex and
medical condition of the patient, the severity of the disease, the
route of administration, and the particular compound employed, and
thus may vary widely.
[0124] For therapeutic purposes, the active components of this
combination therapy invention are ordinarily combined with one or
more adjuvants appropriate to the indicated route of
administration. If administered per os, the components may be
admixed with lactose, sucrose, starch powder, cellulose esters of
alkanoic acids, cellulose alkyl esters, talc, stearic acid,
magnesium stearate, magnesium oxide, sodium and calcium salts of
phosphoric and sulfuric acids, gelatin, acacia gum, sodium
alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then
tableted or encapsulated for convenient administration. Such
capsules or tablets may contain a controlled-release formulation as
may be provided in a dispersion of active compound in
hydroxypropylmethyl cellulose. Formulations for parenteral
administration may be in the form of aqueous or non-aqueous
isotonic sterile injection solutions or suspensions. These
solutions and suspensions may be prepared from sterile powders or
granules having one or more of the carriers or diluents mentioned
for use in the formulations for oral administration. The components
may be dissolved in water, polyethylene glycol, propylene glycol,
ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl
alcohol, sodium chloride, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art.
[0125] Pharmaceutical compositions for use in the treatment methods
of the invention may be administered in oral form or by intravenous
administration. Oral administration of the combination therapy is
preferred. Dosing for oral administration may be with a regimen
calling for single daily dose, or for a single dose every other
day, or for multiple, spaced doses throughout the day. The active
agents which make up the combination therapy may be administered
simultaneously, either in a combined dosage form or in separate
dosage forms intended for substantially simultaneous oral
administration. The active agents which make up the combination
therapy may also be administered sequentially, with either active
component being administered by a regimen calling for two-step
ingestion. Thus, a regimen may call for sequential administration
of the active agents with spaced-apart ingestion of the separate,
active agents. The time period between the multiple ingestion steps
may range from a few minutes to several hours, depending upon the
properties of each active agent such a potency, solubility,
bioavailability, plasma half-life and kinetic profile of the agent,
as well as depending upon the age and condition of the patient. The
active agents of the combined therapy whether administered
simultaneously, substantially simultaneously, or sequentially, may
involve a regimen calling for administration of one active agent by
oral route and the other active agent by intravenous route. Whether
the active agents of the combined therapy are administered by oral
or intravenous route, separately or together, each such active
agent will be contained in a suitable pharmaceutical formulation of
pharmaceutically-acceptable excipients, diluents or other
formulations components. Examples of suitable
pharmaceutically-acceptable formulations containing the active
components for oral administration are given below. Even though
such formulations list both active agents together in the same
recipe, it is appropriate for such recipe to be utilized for a
formulation containing one of the active components.
EXAMPLE 1
[0126] An oral dosage may be prepared by screening and then mixing
together the following list of ingredients in the amounts
indicated. The dosage may then be placed in a hard gelatin
capsule.
13 Ingredients Amounts captopril 62.0 mg spironolactone 12.5 mg
magnesium stearate 10 mg lactose 100 mg
EXAMPLE 2
[0127] An oral dosage may be prepared by mixing together
granulating with a 10% gelatin solution. The wet granules are
screened, dried, mixed with starch, talc and stearic acid, screened
and compressed into a tablet.
14 Ingredients Amounts captopril 62.0 mg spironolactone 12.5 mg
calcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4
mg stearic acid 2 mg
EXAMPLE 3
[0128] An oral dosage may be prepared by screening and then mixing
together the following list of ingredients in the amounts
indicated. The dosage may then be placed in a hard gelatin
capsule.
15 Ingredients Amounts enalapril 14.3 mg spironolactone 12.5 mg
magnesium stearate 10 mg lactose 100 mg
EXAMPLE 4
[0129] An oral dosage may be prepared by mixing together
granulating with a 10% gelatin solution. The wet granules are
screened, dried, mixed with starch, talc and stearic acid, screened
and compressed into a tablet.
16 Ingredients Amounts enalapril 14.3 mg spironolactone 12.5 mg
calcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4
mg stearic acid 2 mg
[0130] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *