U.S. patent application number 10/324856 was filed with the patent office on 2003-06-05 for method of treatment for decreasing mortality resulting from congestive heart failure.
This patent application is currently assigned to Boehringer Mannheim Pharmaceuticals Corporation- SmithKline Beecham Corp. Limited Partnership No. 1. Invention is credited to Lukas-Laskey, Mary Ann, Ruffolo, Robert JR., Shusterman, Neil Howard, Sponer, Gisbert, Strein, Klaus.
Application Number | 20030105138 10/324856 |
Document ID | / |
Family ID | 26012210 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105138 |
Kind Code |
A1 |
Lukas-Laskey, Mary Ann ; et
al. |
June 5, 2003 |
Method of treatment for decreasing mortality resulting from
congestive heart failure
Abstract
A method of treatment using a compound of Formula I: 1 wherein:
R.sub.1 is hydrogen, lower alkanoyl of up to 6 carbon atoms or
aroyl selected from benzoyl and naphthoyl; R.sub.2 is hydrogen,
lower alkyl of up to 6 carbon atoms or arylalkyl selected from
benzyl, phenylethyl and phenylpropyl; R.sub.3 is hydrogen or lower
alkyl of up to 6 carbon atoms; R.sub.4 is hydrogen or lower alkyl
of up to 6 carbon atoms, or when X is oxygen, R.sub.4 together with
R.sub.5 can represent --CH.sub.2--0--; X is a valency bond,
--CH.sub.2, oxygen or sulfur; Ar is selected from phenyl, naphthyl,
indanyl and tetrahydronaphthyl; R.sub.5 and R.sub.6 are
individually selected from hydrogen, fluorine, chlorine, bromine,
hydroxyl, lower alkyl of up to 6 carbon atoms, a --CONH.sub.2--
group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower
alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6
carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
R.sub.5 and R.sub.6 together represent methylenedioxy; or a
pharmaceutically acceptable salt thereof, alone or in conjunction
with one or more other therapeutic agents, said agents being
selected from the group consisting of ACE inhibitors, diuretics,
and digoxin for decreasing mortality resulting from congestive
heart failure (CHF) in mammals, particularly humans.
Inventors: |
Lukas-Laskey, Mary Ann;
(Philadelphia, PA) ; Ruffolo, Robert JR.; (Spring
City, PA) ; Shusterman, Neil Howard; (Wynnewood,
PA) ; Sponer, Gisbert; (Laudenbach, DE) ;
Strein, Klaus; (Hemsbach, DE) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
Boehringer Mannheim Pharmaceuticals
Corporation- SmithKline Beecham Corp. Limited Partnership No.
1
|
Family ID: |
26012210 |
Appl. No.: |
10/324856 |
Filed: |
December 19, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10324856 |
Dec 19, 2002 |
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09863535 |
May 23, 2001 |
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09863535 |
May 23, 2001 |
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09616814 |
Jul 13, 2000 |
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09616814 |
Jul 13, 2000 |
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09351949 |
Jul 12, 1999 |
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09351949 |
Jul 12, 1999 |
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09037098 |
Mar 9, 1998 |
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09037098 |
Mar 9, 1998 |
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08483635 |
Jun 7, 1995 |
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5760069 |
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Current U.S.
Class: |
514/330 ;
514/411 |
Current CPC
Class: |
A61K 31/403 20130101;
A61P 9/00 20180101; A61K 31/7048 20130101; A61P 9/04 20180101; A61K
31/7048 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/330 ;
514/411 |
International
Class: |
A61K 031/454; A61K
031/403 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 8, 1995 |
DE |
19503.995.5 |
Claims
What is claimed is:
1. A method of treatment for decreasing mortality resulting from
congestive heart failure in mammals comprising internally
administering to a mammal in need thereof an effective amount of a
compound which is both a .beta.-adrenoceptor antagonist and a
.alpha..sub.1-adrenoceptor antagonist alone or in conjunction with
one or more other therapeutic agents, said agents being selected
from the group consisting of an angiotensin converting enzyme
inhibitor, a diuretic, and digoxin.
2. A method of treatment according to claim 1 wherein said mammal
is human.
3. A method of treatment according to claim 1 wherein said compound
is carvedilol.
4. A method of treatment according to claim 3 comprising
administering said carvedilol in a dosage range of from about 3.125
to about 50 mg given twice daily.
5. A method of treatment according to claim 4 comprising
administering said carvedilol in a maintenance dose of about 25 mg
given twice daily.
6. A method of treatment according to claim 4 fcomprising
administering said carvedilol in a maintenance dose of between
about 25 mg and about 50 mg given twice daily to patients whose
weight exceeds about 85 kg.
7. A method of treatment according to claim 6 wherein said
maintenance dose is about 50 mg given twice daily in patients whose
weight exceeds about 85 kg.
8. A method of treatment according to claim 3 wherein said ACE
inhibitor is captopril, lisinopril, or enalapril, or any
pharmaceutically acceptable salt thereof.
9. A method of treatment according to claim 3 wherein said diuretic
is hydrochlorothiazide or furosemide, or any pharmaceutically
acceptable salt thereof.
10. A method of treatment for decreasing mortality resulting from
congestive heart failure in mammals comprising internally
administering to a mammal in need thereof an effective amount of a
compound of Formula 1: 4wherein: R.sub.1 is hydrogen, lower
alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and
naphthoyl; R.sub.2 is hydrogen, lower alkyl of up to 6 carbon atoms
or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
R.sub.3 is hydrogen or lower alkyl of up to 6 carbon atoms; R.sub.4
is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is
oxygen, R.sub.4 together with R.sub.5 can represent
--CH.sub.2--0--; X is a valency bond, --CH.sub.2, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and
tetrahydronaphthyl; R.sub.5 and R.sub.6 are individually selected
from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl
of up to 6 carbon atoms, a --CONH.sub.2-- group, lower alkoxy of up
to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon
atoms, lower alkysulphinyl of up to 6 carbon atoms and lower
alkylsulphonyl of up to 6 carbon atoms; or or a pharmaceutically
acceptable salt thereof.
11. A method of treatment according to claim 10 wherein said mammal
is human.
12. A method of treatment according to claim 10 wherein said
compound is carvedilol.
13. A method of treatment according to claim 12 comprising
administering said carvedilol in a dosage range of from about 3.125
to about 50 mg given twice daily.
14. A method of treatment according to claim 13 comprising
administering said carvedilol in a maintenance dose of about 25 mg
given twice daily
15. A method of treatment according to claim 13 comprising
administering said carvedilol in a maintenance dose of between
about 25 mg and about 50 mg given twice daily to patients whose
weight exceeds about 85 kg.
16. A method of treatment according to claim 15 wherein said
maintenance dose is about 50 mg given twice daily in patients whose
weight exceeds about 85 kg.
17. A method of treatment for decreasing mortality resulting from
congestive heart failure in mammals comprising internally
administering to a mammal in need thereof an effective amount of a
therapeutic agent selected from the group consisting of an ACE
inhibitor, a diuretic, and digoxin in conjunction with a compound
of Formula I: 5wherein: R.sub.1 is hydrogen, lower alkanoyl of up
to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
R.sub.2 is hydrogen, lower alkyl of up to 6 carbon atoms or
arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
R.sub.3 is hydrogen or lower alkyl of up to 6 carbon atoms; R.sub.4
is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is
oxygen, R.sub.4 together with R.sub.5 can represent
--CH.sub.2--0--; X is a valency bond, --CH.sub.2, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and
tetrahydronaphthyl; R.sub.5 and R.sub.6 are individually selected
from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl
of up to 6 carbon atoms, a --CONH.sub.2-- group, lower alkoxy of up
to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon
atoms, lower alkysulphinyl of up to 6 carbon atoms and lower
alkylsulphonyl of up to 6 carbon atoms; or or a pharmaceutically
acceptable salt thereof.
18. A method of treatment according to claim 17 wherein said mammal
is human.
19. A method of treatment according to claim 17 wherein said
compound is carvedilol.
20. A method of treatment according to claim 19 comprising
administering said carvedilol in a dosage range of from about 3.125
to about 50 mg given twice daily.
21. A method of treatment according to claim 20 comprising
administering said carvedilol in a maintenance dose of about 25 mg
given twice daily.
22. A method of treatment according to claim 20 comprising
administering said carvedilol in a maintenance dose of between
about 25 mg and about 50 mg given twice daily to patients whose
weight exceeds about 85 kg.
23. A method of treatment according to claim 22 wherein said
maintenance dose is about 50 mg given twice daily in patients whose
weight exceeds about 85 kg.
24. A method of treatment according to claim 19 wherein said ACE
inhibitor is captopril, lisinopril, or enalapril, or any
pharmaceutically acceptable salt thereof.
25. A method of treatment according to claim 19 wherein said
diuretic is hydrochlorothiazide or furosemide, or any
pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a new method of treatment
using compounds which are dual non-selective .beta.-adrenoceptor
and .alpha..sub.1-adrenoceptor antagonists, in particular the
carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably
carvedilol, for decreasing the mortality of patients suffering from
congestive heart failure (CHF). The invention also relates to a
method of treatment using compounds which are dual non-selective
.beta.-adrenoceptor and .alpha..sub.1-adrenoceptor antagonists, in
particular the carbazolyl-(4)-oxypropanolamine compounds of Formula
I, preferably carvedilol, in conjunction with one or more other
therapeutic agents, said agents being selected from the group
consisting of angiotensin converting enzyme (ACE) inhibitors,
diuretics, and digoxin, for decreasing the mortality of patients
suffering from CHF.
BACKGROUND OF THE INVENTION
[0002] Congestive heart failure occurs as a result of impaired
pumping capability of the heart and is associated with abnormal
retention of water and sodium. Traditionally, treatment of chronic
mild failure has included limitation of physical activity,
restriction of salt intake, and the use of a diuretic. If these
measures are not sufficient, digoxin, which is an agent that
increases the force of mycardial contraction, is typically added to
the treatment regiment. Subsequently, angiotensin converting enzyme
inhibitors, which are compounds that prevent the conversion of
angiotensin I into the pressor-active angiotensin II, are
prescribed for chronic treatment of congestive heart failure, in
conjunction with a diuretic, digoxin, or both.
[0003] Congestive heart failure is a condition that is associated
with activation of both the renin-angiotensin system (RAS) and the
sympathetic nervous system (SNS). Modulation of the RAS by
angiotensin converting enzyme inhibitors has been shown to improve
the symptoms associated with CHF. Sharpe, D. N., Murphy, J., Coxon,
R. & Hannan S. F. (1984) Circulation, 70, 271-278. However, ACE
inhibitors appear to have little effect on the enhanced SNS in CHF.
Cohn, J. N., Johnson, G. & Ziesche, S., (1991) N. Engl. J.
Med., 325, 293-302 and Francis, G. S., Rector, T. S. & Cohn, J.
N. (1988) Am. Heart J., 116, 1464-1468. Therefore, there is a need
for an agent that would be effective in blocking the activation of
the SNS in CHF patients.
[0004] Also, congestive heart failure is a well-known cardiac
disorder which results in an annual mortality in excess of 50
percent. Applefeld, M. M., (1986) Am. J. Med., 80, Suppl. 2B,
73-77. Therefore, therapeutic agents that would decrease the
mortality resulting from CHF in patients suffering therefrom are
highly desirable.
SUMMARY OF THE INVENTION
[0005] The present invention provides a new method of treatment
using pharmaceutical compounds which are dual non-selective
.beta.-adrenoceptor and .alpha..sub.1-adrenoceptor antagonists and,
in particular, the carbazolyl-(4)-oxypropanolamine compounds of
Formula I, alone or in conjunction with one or more other
therapeutic agents, said agents being selected from the group
consisting of ACE inhibitors, diuretics, and digoxin, as
therapeutics for decreasing mortality resulting from congestive
heart failure in mammals, particularly humans. In particular, the
present invention preferably provides a method of treatment, alone
or in conjunction with one or more other therapeutic agents, said
agents being selected from the group consisting of ACE inhibitors,
diuretics, and digoxin, for the compound of Formula I wherein
R.sub.1 is --H, R.sub.2 is --H, R.sub.3 is --H, R.sub.4 is --H, X
is O, Ar is phenyl, R.sub.5 is ortho --OCH.sub.3, and R.sub.6 is
--H, said compound being better known as carvedilol, which is
(1-(carbazol-4-yloxy-3-[[2-(o-methox-
yphenoxy)ethyl]amino]-2-propanol), or a pharmaceutically acceptable
salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0006] U.S. Pat. No. 4,503,067 discloses
carbazolyl-(4)-oxypropanolamine compounds of Formula I: 2
[0007] wherein:
[0008] R.sub.1 is hydrogen, lower alkanoyl of up to 6 carbon atoms
or aroyl selected from benzoyl and naphthoyl;
[0009] R.sub.2 is hydrogen, lower alkyl of up to 6 carbon atoms or
arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
[0010] R.sub.3 is hydrogen or lower alkyl of up to 6 carbon
atoms;
[0011] R.sub.4 is hydrogen or lower alkyl of up to 6 carbon atoms,
or when X is oxygen, R.sub.4 together with R.sub.5 can represent
--CH.sub.2--0--;
[0012] X is a valency bond, --CH.sub.2, oxygen or sulfur;
[0013] Ar is selected from phenyl, naphthyl, indanyl and
tetrahydronaphthyl;
[0014] R.sub.5 and R.sub.6 are individually selected from hydrogen,
fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6
carbon atoms, a --CONH.sub.2-- group, lower alkoxy of up to 6
carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms,
lower alkysulphinyl of up to 6 carbon atoms and lower
alkylsulphonyl of up to 6 carbon atoms; or
[0015] R.sub.5 and R.sub.6 together represent methylenedioxy;
[0016] and pharmaceutically acceptable salts thereof.
[0017] This patent further discloses a compound of Formula I,
better known as carvedilol, which is
(1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethy-
l]amino]-2-propanol), having the structure shown in Formula II:
3
[0018] Formula I compounds, of which carvedilol is exemplary, are
novel multiple action drugs useful in the treatment of mild to
moderate hypertension. Carvedilol is known to be both a competitive
non-selective .beta.-adrenoceptor antagonist and a vasodilator, and
is also a calcium channel antagonist at higher concentrations. The
vasodilatory actions of carvedilol result primarily from
.alpha..sub.1-adrenoceptor blockade, whereas the
.beta.-adrenoceptor blocking activity of the drug prevents reflex
tachycardia when used in the treatment of hypertension. These
multiple actions of carvedilol are responsible for the
antihypertensive efficacy of the drug in animals, particularly in
humans. See Willette, R. N., Sauermelch, C. F. & Ruffolo, R.
R., Jr. (1990) Eur. J. Pharmacol., 176, 237-240; Nichols, A. J.,
Gellai, M. & Ruffolo, R. R., Jr. (1991) Fundam. Clin.
Pharmacol., 5, 25-38; Ruffolo, R. R., Jr., Gellai, M., Hieble, J.
P., Willette, R. N. & Nichols, A. J. (1990) Eur. J. Clin.
Pharmacol., 38, S82-S88; Ruffolo, R. R., Jr., Boyle, D. A., Venuti,
R. P. & Lukas, M. A. (1991) Drugs of Today, 27, 465-492; and
Yue, T.-L., Cheng, H., Lysko, P. G., Mckenna, P. J., Feuerstein,
R., Gu, J., Lysko, K. A., Davis, L. L. & Feuerstein, G. (1992)
J. Pharmacol. Exp. Ther., 263, 92-98.
[0019] The antihypertensive action of carvedilol is mediated
primarily by decreasing total peripheral vascular resistance
without causing the concomitant reflex changes in heart rate
commonly associated with other antihypertensive agents. Willette,
R. N., et al. supra; Nichols, A. J., et al. supra; Ruffolo, R. R.,
Jr., Gellai, M., Hieble, J. P., Willette, R. N. & Nichols, A.
J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88.. Carvedilol also
markedly reduces infarct size in rat, canine and porcine models of
acute myocardial infarction, Ruffolo, R. R., Jr., et al., Drugs of
Today, supra, possibly as a consequence of its antioxidant action
in attenuating oxygen free radical-initiated lipid peroxidation.
Yue, T.-L., et al. supra.
[0020] Recently, it has been discovered in clinical studies that
pharmaceutical compounds which are dual non-selective
.beta.-adrenoceptor and .alpha..sub.1-adrenoceptor antagonists, in
particular the compounds of Formula I, preferably carvedilol, alone
or in conjunction with conventional agents, said agents being ACE
inhibitors, diuretics, and digoxin, are effective therapeutic
agents for treating CHF. The use of agents, such as carvedilol in
treating CHF is surprising, since, in general, .beta.-blockers are
contraindicated in patients suffering from heart failure, because
.beta.-blockers are known to have undesirable cardiodepressive
effects. The most surprising observation from the studies in which
the instant compounds were used to treat CHF is that said
compounds, in particular carvedilol, are able to decrease the
mortality resulting from CHF in humans by about 67 percent.
Furthermore, this result is present across all classifications of
CHF and both etiologies (eschemic and non-eschemic). This result is
surprising since two recent mortality studies using the
.beta.-blockers metoprolol (Waagstein, et al., (1993) Lancet, 342,
1441-1446) and bisoprolol (CIBIS investigators and committees,
(1994) Circulation, 90, 1765-1773) in the treatment of CHF showed
no difference in mortality between drug-treated patients and
placebo-treated patients.
[0021] According to the method of treatment of the present
invention, the desirable therapeutic effect of the compounds of
Formula I, particularly carvedilol, may be augmented by using any
one of said compounds, or any pharmaceutically acceptable salt of
said compounds, in conjunction with ACE inhibitors, diuretics, and
digoxin, which are effective therapeutic agents for the treatment
of CHF. In particular, the preferred ACE inhibitors of the present
invention are selected from the group consisting of captopril,
lisinopril, and enalapril, or any pharmaceutically acceptable salts
thereof and the preferred diuretics of the present invention are
hydrochlorothiazide or furosemide, or any pharmaceutically
acceptable salts thereof. The desireable therapeutic benefits of
the compounds of Formula I, particularly carvedilol, are additive
with those of such ACE inhibitors, or diuretics, or digoxin when
administered in combination therewith. Captopril is commercially
available from E. R. Squibb & Sons, Inc. Lisinopril, enalapril
and hydrochloro-thiazide are commercially available from Merck
& Co. Furosemide is commercially available from Hoechst-Roussel
Pharmaceuticals, Inc. Digoxin is commercially available from
Burroughs Wellcome Co.
[0022] Compounds of Formula I may be conveniently prepared as
described in U.S. Pat. No. 4,503,067. Carvedilol is commercially
available from SmithKline Beecham Corporation and Boehringer
Mannheim GmbH (Germany).
[0023] Pharmaceutical compositions of the compounds of Formula I,
including carvedilol, alone or in combination with ACE inhibitors,
or diuretics, or digoxin may be administered to patients according
to the present invention in any medically acceptable manner,
preferably orally. For parenteral administration, the
pharmaceutical composition will be in the form of a sterile
injectable liquid stored in a suitable container such as an
ampoule, or in the form of an aqueous or nonaqueous liquid
suspension. The nature and composition of the pharmaceutical
carrier, diluent or excipient will, of course, depend on the
intended route of administration, for example whether by
intravenous or intramuscular injection
[0024] Pharmaceutical compositions of the compounds of Formula I
for use according to the present invention may be formulated as
solutions or lyophilized powders for parenteral administration.
Powders may be reconstituted by addition of a suitable diluent or
other pharmaceutically acceptable carrier prior to use. The liquid
formulation is generally a buffered, isotonic, aqueous solution.
Examples of suitable diluents are normal isotonic saline solution,
standard 5% dextrose in water or buffered sodium or ammonium
acetate solution. Such formulation is especially suitable for
parenteral administration, but may also be used for oral
administration or contained in a metered dose inhaler or nebulizer
for insufflation. It may be desirable to add excipients such as
ethanol, polyvinyl-pyrrolidone, gelatin, hydroxy cellulose, acacia,
polyethylene glycol, mannitol, sodium chloride or sodium
citrate.
[0025] Alternatively, these compounds may be encapsulated, tableted
or prepared in a emulsion or syrup for oral administration.
Pharmaceutically acceptable solid or liquid carriers may be added
to enhance or stabilize the composition, or to facilitate
preparation of the composition. Liquid carriers include syrup,
peanut oil, olive oil, glycerin, saline, ethanol, and water. Solid
carriers include starch, lactose, calcium sulfate dihydrate, terra
alba, magnesium stearate or stearic acid, talc, pectin, acacia,
agar or gelatin. The carrier may also include a sustained release
material such as glyceryl monostearate or glyceryl distearate,
alone or with a wax. The amount of solid carrier varies but,
preferably, will be between about 20 mg to about 1 g per dosage
unit. The pharmaceutical preparations are made following the
conventional techniques of pharmacy involving milling, mixing,
granulating, and compressing, when necessary, for tablet forms; or
milling, mixing and filling for hard gelatin capsule forms. When a
liquid carrier is used, the preparation will be in the form of a
syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
Such a liquid formulation may be administered directly p.o. or
filled into a soft gelatin capsule.
[0026] Dosing in humans for the treatment of disease according to
the present invention should not exceed a dosage range of from
about 3.125 to about 50 mg of the compounds of Formula I,
particularly carvedilol, preferably given twice daily. As one of
ordinary skill in the art will readily comprehend, the patient
should be started on a low dosage regimen of the desired compound
of Formula I, particularly carvedilol, and monitered for well-known
symptoms of intolerance, e.g., fainting, to such compound. Once the
patient is found to tolerate such compound, the patient should be
brought slowly and incrementally up to the maintenance dose. The
preferred course of treatment is to start the patient on a dosage
regimen of either 3.125 or 6.25 mg, preferably given twice daily,
for two weeks. The choice of initial dosage most appropriate for
the particular patient is determined by the practitioner using
well-known medical principles, including, but not limited to, body
weight. In the event that the patient exhibits medically acceptable
tolerance of the compound for two weeks, the dosage is doubled at
the end of the two weeks and the patient is maintained at the new,
higher dosage for two more weeks, and observed for signs of
intolerance. This course is continued until the patient is brought
to a maintenance dose. The preferred maintenance dose is 25 mg,
preferably given twice daily, for patients having a body weight of
up to 85 kg. For patients having a body weight of over 85 kg, the
maintenance dose is between about 25 mg and about 50 mg, preferably
given twice daily; preferably about 50 mg, preferably given twice
daily.
[0027] Dosing in humans for the treatment of disease according to
the present invention includes the combination of compounds of
Formula I with conventional agents. For example, the usual adult
dosage of hydrochlorothiazide is 25-100 mg daily as a single dose
or divided dose. The recommended starting dose for enalapril is 2.5
mg administered once or twice daily. The usual therapeutic dosing
range for enalapril is 5-20 mg daily, given as a single dose or two
divided doses. For most patients the usual initial daily dosage of
captopril is 25 mg tid, with most patients having a satisfactory
clinical improvement at 50 or 100 mg tid.
[0028] It will be appreciated that the actual preferred dosages of
the compounds being used in the compositions of this invention will
vary according to the particular composition formulated, the mode
of administration, the particular site of administration and the
host being treated.
[0029] No unacceptable toxicological effects are expected when the
compounds of Formula I, including the compound of Formula II, are
used according to the present invention.
[0030] The example which follows is intended in no way to limit the
scope of this invention, but is provided to illustrate how to use
the compounds of this invention. Many other embodiments will be
readily apparent to those skilled in the art.
Experimental
Mortality Studies in CHF Patients
[0031] Summary
[0032] To determine if .beta.-adrenergic blockade might inhibit the
deleterious effects of the sympathetic nervous system on survival
in heart failure (CHF), 1052 patients with CHF were prospectively
enrolled into a multicenter trial program, in which patients were
randomly assigned (double-blind) to 6-12 months' treatment with
placebo (PBO) or carvedilol (CRV),. After a common screening
period, patients with class II-IV CHF (see next paragraph for the
definitions of the classification of CHF) and an ejection fraction
.ltoreq.0.35 were assigned to one of four protocols based on
performance on a 6-minute walk test. PBO or CRV was added to
existing therapy with digoxin, diuretics and an ACE inhibitor.
All-cause mortality was monitored by a prospectively constituted
Data and Safety Monitoring Board (DSMB). After 25 months of
enrollment, the DSMB recommended termination of the program because
of a favorable effect of CRV on survival. By intention-to-treat,
mortality was 8.2% in the PBO group but only 2.9% in the CRV group
(P=0.0001, Cochran-Mantel-Haensel analysis). This represented a
reduction in risk of death by CRV of 67% (95% CI: 42% to 81%). The
treatment effect was similar in patients with class II and class
III-IV symptoms. Mortality was reduced in class II patients from
5.9% to 1.9%, a 68% reduction (95% CI: 20% to 97%) [P=0.015,], and
in class III-IV patients from 11.0% to 4.2%, a 67% reduction (95%
CI: 30% to 84%), [P=0.004, log-rank]. Importantly, the effect of
CRV was similar in ischemic heart disease (risk reduced by 67%,
P=0.003) and in non-ischemic dilated cardiomyopathy (risk reduced
by 67%, P=0.014). In conclusion, the addition of CRV to
conventional therapy is associated with a substantial (67%)
reduction in the mortality of patients with chronic CHF. The
treatment effect is seen across a broad range of severity and
etiology of disease.
[0033] As used herein, by "Class II CHF" is meant patients with
cardiac disease resulting in slight or moderate limitation of
physical activity. They are comfortable at rest. Ordinary physical
activity results in fatigue, palpitations, dyspnea, or anginal
pain. By "Class III CHF" is meant patients with cardiac disease
resulting in marked limitations of physical activity. They are
comfortable at rest. Less than ordinary physical activity results
in fatigue, palpitations, dyspnea, or anginal pain. By "Class IV
CHF" is meant patients with cardiac disease resulting in inability
to carry on any physical activity without discomfort, symptoms or
cardiac insufficiency, or of the anginal syndrome. By "less than
ordinary physical activity" is meant climbing one flight of stairs,
or walking two hundred yards.
[0034] Design of Study
[0035] Patients on background therapy with diuretics, ACE
inhibitors and/or digoxin were stratified on the basis of baseline
submaximal exercise performance, into one of four trials:
[0036] study 220, a dose response study in moderate (NYHA II-IV)
CHF with exercise testing as a primary endpoint
[0037] study 221, a dose titration study in moderate (NYHA II-IV)
CHF with exercise testing as a primary endpoint
[0038] study 239, a dose titration study in severe (NYHA III-IV)
CHF with quality of life as a primary endpoint
[0039] study 240, a dose titration study in mild (NYHA II-III) CHF
with progression of CHF as a primary endpoint
[0040] Sixty-four centers in the U.S. participated in the trial
program. All sites conducted protocols 239 and 240, while 33
performed protocol 220 and 31 performed protocol 221.
[0041] Although each trial had its own individual objectives, the
overall program objective defined prospectively was evaluation of
all-cause mortality. Based upon a projected enrollment of 1100
patients, the program had 90% power to detect a 50% reduction in
mortality (two-sided) between carvedilol and placebo, assuming a
mortality rate in the placebo group of 12% over the duration of the
trials (.alpha.=0.05).
[0042] Randomization was preceded by a screening and challenge
period common to the four protocols The purpose of the screening
period was to qualify patients for study entry, obtain reproducible
baseline measurements, and stratify patients into the appropriate
trial based on submaximal exercise testing. During the challenge
period, patients received low-dose open-label carvedilol (6.25 mg
b.i.d.) for two weeks. Patients unable to tolerate this dose did
not proceed to randomization. Patients tolerating low-dose
carvedilol were then randomized to blinded medication (carvedilol
or placebo) with the dose titrated over several weeks in the range
of 6.25 to 50 mg b.i.d. (or equivalent level of placebo). The
maintenance phase of each study ranged from six to 12 months, after
which patients had the option of receiving open-label carvedilol in
an extension study.
[0043] Results
[0044] The analysis presented below corresponds to the data set on
which the DSMB made the recommendation to terminate the trials.
Included in this intent-to-treat analysis are all patients enrolled
in the U.S. trials as of Jan. 20, 1995; 624 receiving carvedilol
and 356 placebo. An analysis of baseline patient characteristics
(Table 1) shows good balance between the randomized groups.
1TABLE 1 US Carvedilol Heart Failure Trials - Baseline
Characteristics Placebo Carvedilol Characteristic (n = 356) (n =
624) Age, mean .+-. SD (years) 59.9 .+-. 11.7 58.8 .+-. 11.8 Sex (%
men) 62% 62% Etiology (% isehemic) 43% 40% Severity of CHF Class II
41% 41% Class III-IV 40% 39% Unknown 19% 20% LV ejection fraction,
mean .+-. SD 0.22 .+-. 0.07 0.23 .+-. 0.08 6 Minute walk (m .+-.
SD) 373 .+-. 88 379 .+-. 81 Blood pressure (mmHg) 115/73 115/73
Heart rate (bpm .+-. SD) 85 .+-. 13 86 .+-. 13
[0045] The overall mortality results for the program are shown in
Table 2. All deaths that occurred during the intent-to-treat period
are included. Treatment with carvedilol resulted in a 67% reduction
in the risk of all-cause mortality. Analysis of mortality by
certain baseline characteristics shows this to be a broad effect
regardless of severity or etiology of CHF. The effect was uniform
in patients with mild heart failure or moderate to severe heart
failure. Similarly, the mortality reduction was equivalent in
patients with ischemic or non-ischemic heart failure.
2TABLE 2 Evaluation of Mortality in US Carvedilol CHF Studies Risk
Reduction Carvedilol Placebo (95% CI) p value* All Cause Mortality
18/624 29/356 67% <0.0001 (2.9%) (8.2%) (42-81) Class II CHF
7/361 12/202 68% 0.015 (1.9%) (5.9%) (20-97) Class III-IV CHF
11/263 17/154 66% 0.004 (4.2%) (11.0%) (30-84) Ischemic Etiology
10/311 16/178 67% 0.003 (3.2%) (8.9%) (32-85) Non-Isehemic 8/313
13/178 67% 0.014 Etiology (2.5%) (7.3%) (20-86)
*Cochran-Mantel-Haensel Analysis
[0046] Conclusion
[0047] The U.S. Phase III trials were prospectively designed to
evaluate the effects of carvedilol on the wellbeing and survival of
patients with congestive heart failure. Twenty-five months after
the program was initiated, the independent Data and Safety
Monitoring Board recommended that the trials be terminated because
of a 67% reduction in all-cause mortality. This effect was
independent of the underlying severity or etiology of heart
failure.
[0048] The foregoing is illustrative of the use of the compounds of
this invention. This invention, however, is not limited to the
precise embodiment described herein, but encompasses all
modifications within the scope of the claims which follow.
* * * * *