U.S. patent application number 14/489127 was filed with the patent office on 2015-01-01 for nitroxyl progenitors in the treatment of heart failure.
The applicant listed for this patent is The Board of Supervisors of Louisiana State University and Agricultural and Mechanical College, The Government of the United States of America as Represented by the Secretary of the Department of, The Johns Hopkins University, The Regents of the University of California. Invention is credited to Martin Feelisch, Jon Fukuto, David A. Kass, Tatsuo Katori, Katrina Miranda, Nazareno Paolocci, David A. Wink.
Application Number | 20150004259 14/489127 |
Document ID | / |
Family ID | 31887216 |
Filed Date | 2015-01-01 |
United States Patent
Application |
20150004259 |
Kind Code |
A1 |
Wink; David A. ; et
al. |
January 1, 2015 |
NITROXYL PROGENITORS IN THE TREATMENT OF HEART FAILURE
Abstract
Administration of an HNO/NO.sup.+ donating compound, such as
Angeli's salt, increases myocardial contractility while
concomitantly lowering left ventricular preload in subjects
experiencing heart failure. Moreover, administration of the
HNO/NO.sup.- donating compound isopropylamine (IPA)/NO
(Na(CH.sub.3).sub.2CHNHN(O)NO) surprisingly exhibited positive
inotropic effects in subjects experiencing heart failure that were
superior to those caused by the HNO/NO.sup.- donating compound
Angeli's salt. Additionally, in contrast to the effects observed
with NO.sup.- donors, administration of an HNO/NO.sup.- donor in
combination with a positive inotropic agent did not impair the
positive inotropic effect of the positive inotropic agent. Further,
HNO/NO.sup.- exerts its positive inotropic effect independent of
the adrenergic system, increasing contractility even in subjects
receiving beta-antagonist therapy.
Inventors: |
Wink; David A.; (Hagerstown,
MD) ; Feelisch; Martin; (Shreveport, LA) ;
Kass; David A.; (Columbia, MD) ; Paolocci;
Nazareno; (Baltimore, MD) ; Miranda; Katrina;
(Tuscon, AZ) ; Fukuto; Jon; (Agoura, CA) ;
Katori; Tatsuo; (Baltimore, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Board of Supervisors of Louisiana State University and
Agricultural and Mechanical College
The Government of the United States of America as Represented by
the Secretary of the Department of
The Regents of the University of California
The Johns Hopkins University |
Shreveport
Rockville
Oakland
Baltimore |
LA
MD
CA
MD |
US
US
US
US |
|
|
Family ID: |
31887216 |
Appl. No.: |
14/489127 |
Filed: |
September 17, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13446700 |
Apr 13, 2012 |
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14489127 |
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12949533 |
Nov 18, 2010 |
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13446700 |
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11096924 |
Mar 31, 2005 |
7863262 |
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12949533 |
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10226412 |
Aug 21, 2002 |
6936639 |
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11096924 |
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Current U.S.
Class: |
424/718 |
Current CPC
Class: |
A61K 31/13 20130101;
A61P 9/04 20180101; A61K 31/655 20130101; A61K 31/16 20130101; A61K
31/16 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
33/00 20130101; A61K 31/13 20130101 |
Class at
Publication: |
424/718 |
International
Class: |
A61K 33/00 20060101
A61K033/00 |
Claims
1-25. (canceled)
26. A method of treating heart failure comprising: delivering to a
subject experiencing heart failure, a positively inotropic amount
of nitroxyl, wherein said positively inotropic amount increases
myocardial contractility.
27. The method of claim 26, wherein the heart failure is acute
heart failure.
Description
FIELD
[0001] Pharmaceutical compounds and compositions are disclosed that
are useful to treat heart failure.
BACKGROUND
[0002] Congestive heart failure (CHF) is a generally progressive,
life threatening condition in which myocardial contractility is
depressed such that the heart is unable to adequately pump the
blood returning to it, also referred to as decompensation. Symptoms
include breathlessness, fatigue, weakness, leg swelling, and
exercise intolerance. On physical examination, patients with heart
failure often have elevated heart and respiratory rates (an
indication of fluid in the lungs), edema, jugular venous
distension, and enlarged hearts. The most common cause of CHF is
atherosclerosis, which causes blockages in the coronary arteries
that provide blood flow to the heart muscle. Ultimately, such
blockages may cause myocardial infarction with subsequent decline
in heart function and resultant heart failure. Other causes of CHF
include valvular heart disease, hypertension, viral infections of
the heart, alcohol consumption, and diabetes. Some cases of CHF
occur without clear etiology and are called idiopathic. The effects
of CHF on a subject experiencing the condition can be fatal.
[0003] There are several types of CHF. Two types of CHF are
identified according to which phase of the cardiac pumping cycle is
more affected. Systolic heart failure occurs when the heart's
ability to contract decreases. The heart cannot pump with enough
force to push a sufficient amount of blood into the circulation
leading to a reduced left ventricular ejection fraction. Lung
congestion is a typical symptom of systolic heart failure.
Diastolic heart failure refers to the heart's inability to relax
between contractions and allow enough blood to enter the
ventricles. Higher filling pressures are required to maintain
cardiac output, but contractility as measured by left ventricular
ejection fraction is typically normal. Swelling (edema) in the
abdomen and legs is a typical symptom of diastolic heart
failure.
[0004] CHF is also classified according to its severity. The New
York Heart Association classification classifies CHF into four
classes:
[0005] Class I--no obvious symptoms, with no limitations on
physical activity;
[0006] Class II--some symptoms during or after normal activity,
with mild physical activity limitations;
[0007] Class III--symptoms with less than ordinary activity, with
moderate to significant physical activity limitations;
[0008] Class IV--significant symptoms at rest, with severe to total
physical activity limitations.
Typically, a subject progresses through the classes as the subject
lives with the condition.
[0009] Although CHF is generally thought of as a chronic,
progressive condition, it can also develop suddenly. This type of
CHF is called acute CHF, and it is a medical emergency. Acute CHF
can be caused by acute myocardial injury that affects either
myocardial performance, such as myocardial infarction, or
valvular/chamber integrity, such as mitral regurgitation or
ventricular septal rupture, which leads to an acute rise in left
ventricular and diastolic pressure resulting in pulmonary edema,
and dyspnea.
[0010] Common treatment agents for CHF include, vasodilators (drugs
that dilate blood vessels), positive inotropes (drugs that increase
the heart's ability to contract), and diuretics (drugs to reduce
fluid). Additionally, beta-antagonists (drugs that antagonize
beta-adrenergic receptors) have recently become standard agents for
treating mild to moderate heart failure. Lowes et al., Clin.
Cardiol., 23:11111-6 (2000).
[0011] Positive inotropic agents include beta-adrenergic agonists,
such as dopamine, dobutamine, dopexamine, and isoproterenol.
Dobutamine is commonly given to subjects experiencing late-stage
heart failure characterized by severely reduced ventricular
ejection fraction or the inability of the subject to undertake
physical activity without discomfort. Dobutamine is particularly
effective for treating this type of heart failure because of its
cardio-selectivity. U.S. Pat. No. 4,562,206 describes dobutamine's
cardio-selectivity for the beta-1 adrenergic receptor relative to
its activity at the vascular alpha and beta-2 adrenergic receptors.
This cardio-selectivity results in a desired positive inotropic
effect without a substantial, concomitant increase or decrease in
blood pressure. Such blood pressure changes in subjects
experiencing heart failure could cause further deterioration in
heart function.
[0012] However, the use of beta-agonists has potential
complications, such as arrhythmogenesis and increased oxygen demand
by the heart. Additionally, the initial short-lived improvement of
myocardial contractility afforded by these drugs is followed by an
accelerated mortality rate resulting largely from a greater
frequency of sudden death. Katz, HEART FAILURE: PATHOPHYSIOLOGY,
MOLECULAR BIOLOGY AND CLINICAL MANAGEMENT, Lippincott, Williams
& Wilkins (1999).
[0013] Beta-antagonists antagonize beta-adrenergic receptor
function. While initially contra-indicated in heart failure, they
have been found to provide a marked reduction in mortality and
morbidity in clinical trials. Bouzamondo et al., Fundam. Clin.
Pharmacol., 15:95-109 (2001). Accordingly, they have become an
established therapy for heart failure. Bouzamondo, supra. However,
even subjects that improve under beta-antagonist therapy may
subsequently decompensate and require acute treatment with a
positive inotropic agent. Unfortunately, as their name suggests,
beta-antagonists block the mechanism of action of the positive
inotropic beta-agonists that are used in emergency care centers.
Bristow et al., J. Card. Fail., 7:8-12 (2001).
[0014] Additionally, vasodilating agents are also used to treat
heart failure. Vasodilators, such as nitroglycerin, have been used
for a long period of time to treat heart failure. However, the
cause of nitroglycerin's therapeutic effect was not known until
late in the last century when it was discovered that the nitric
oxide molecule (NO.) was responsible for nitroglycerin's beneficial
effects. In fact, the Nobel Prize was awarded in 1998 to three
researchers who discovered NO.'s beneficial effects. Opie &
White in NITRATES IN DRUGS FOR THE HEART, W.B. Saunder,
Philadephia, 33-53 (2001), explain that such compounds are useful
for treating heart failure due to their balanced venous and
arterial vasorelaxant effects. U.S. Pat. No. 5,212,204 describes a
group of NO. donating compounds containing the NONO group. The
patent discloses that NO. donated from such compounds has
vasodilative properties and can be useful to treat cardiac diseases
that would respond favorably to a decrease in blood pressure,
including acute congestive heart failure. The patent identifies
Angeli's salt (sodium trioxodinitrate or Na.sub.2N.sub.2O.sub.3) as
such a compound. Angeli's salt is a compound that can decompose to
donate either NO.sup.- or NO. depending on the oxidation state of
the environment. Fitzhugh & Keefer, Free Radical Biology &
Medicine, 28(10):1463-1469 (2000). For example, in the presence of
oxidants such as ferricyanide, Angeli's salt decomposes to donate
NO. Fitzhugh & Keefer, supra.
[0015] In some subjects experiencing heart failure, a nitric oxide
donor is administered in combination with a positive inotropic
agent to both cause vasodilation and to increase myocardial
contractility. However, this combined administration can impair the
effectiveness of positive inotropic treatment agents. For example,
Hart et al., Am. J. Physiol. Heart Circ. Pyhsiol., 281:146-54
(2001) reported that administration of the nitric oxide donor
sodium nitroprusside, in combination with the positive inotropic,
beta-adrenergic agonist dobutamine, impaired the positive
intotropic effect of dobutamine. Hare et al., Circulation,
92:2198-203 (1995) also disclosed the inhibitory effect of NO on
the effectiveness of dobutamine.
[0016] Researchers have also investigated other forms of nitric
oxide to determine their effects on the heart. The nitroxyl species
includes the nitroxyl anion (NO.sup.-), which is the one-electron
reduction product of NO. Depending on the pH of the environment,
the nitroxyl anion may be protenated to HNO. Experiments testing
the effects of NO donors in cardiac diseases have demonstrated that
NO.sup.- can have a deleterious effect on the myocardium when given
to reperfused myocardium. In fact, Ma et al., Proc. Nat'l Acad
Sci., 96(25):14617-14622 (1999) reported that administration of
Angeli's salt as an NO.sup.- donor to anesthetized rabbits 5
minutes prior to reperfusion (after ischemia) increased myocardial
ischemia/reperfusion injury. Also, Takahira et al., Free Radical
Biology & Medicine, 31(6):809-815 (2001) reported that
administration of Angeli's salt as an NO.sup.- donor during
ischemia and 5 minutes before reperfusion of rat renal tissue
contributed to neutrophil infiltration into the tissue, which is
believed to cause ischemia/reperfusion injury.
[0017] Patent Cooperation Treaty (PCT) international application
PCT/US00/12957 discloses administering a charged nitric oxide
species to offset the adverse effects of a potassium channel
activator in a method of administering a potassium channel
activator to prevent or treat cardiovascular disorders including,
among others, congestive heart failure. The only NO.sup.- donors
described in the application are thionitrates that form disulfide
species.
SUMMARY
[0018] The inventors discovered that administration of a nitroxyl
(HNO/NO.sup.-) donating compound, such as Angeli's salt, increased
myocardial contractility while it concomitantly lowered left
ventricular preload in subjects experiencing heart failure.
Moreover, administration of the HNO/NO.sup.- donating compound
isopropylamine (IPA)/NO (Na(CH.sub.3).sub.2CHNHN(O)NO) surprisingly
exhibited positive inotropic effects in subjects experiencing heart
failure that were superior to those caused by the HNO/NO.sup.-
donating compound Angeli's salt. Additionally, in contrast to the
effects observed with NO donors, administration of an HNO/NO.sup.-
donor in combination with a positive inotropic agent did not impair
the positive inotropic effect of the positive inotropic agent.
Further, the inventors discovered that HNO/NO.sup.- exerts its
positive inotropic effect independent of the adrenergic system,
increasing contractility even in subjects receiving beta-antagonist
therapy.
[0019] Accordingly, due to their concomitant positive
inotropic/lusotropic action and unloading effects, HNO/NO.sup.-
donors are helpful in treating cardiovascular diseases
characterized by high resistive load and poor contractile
performance. In particular, HNO/NO.sup.- donating compounds such as
IPA/NO are useful treatment agents for heart failure. Moreover,
these agents are useful when used in combination with other
positive inotropic agents, such as beta-adrenergic agonists for
example, dobutamine. Additionally, HNO/NO.sup.- donors are useful
for treating heart failure in subjects receiving beta-antagonist
therapy.
[0020] Provided herein are methods of treating heart failure by
administering a therapeutically effective dose at least one
HNO/NO.sup.- donating compound to a subject experiencing heart
failure. Also provided are methods of administering a
therapeutically effective dose of at least one HNO/NO.sup.-
donating compound in combination with at least one other positive
inotropic agent to a subject experiencing heart failure. Further
provided are methods of administering a therapeutically effective
dose of at least one HNO/NO.sup.- donating compound to a subject
who is receiving beta-antagonist therapy and who is experiencing
heart failure.
[0021] More particularly, methods are provided herein for
administering compounds containing the N-oxy-N-nitroso group
(diazeniumdolates), which donate HNO/NO.sup.-, to treat heart
failure. Such compounds include Angeli's salt, IPA/NO, and analogs
and derivatives of such compounds. Additionally, methods are
provided herein for administering such compounds in combination
with beta-adrenergic agonists to treat heart failure. Such agonists
include dopamine, dobutamine, and isoproterenol, and analogs and
derivatives of such compounds. Also provided are methods of
administering HNO/NO.sup.- donors to subjects receiving treatment
with beta-antagonizing agents such as propranolol, metoprolol,
bisoprolol, bucindolol, and carvedilol. Further, methods are
provided herein for treating specific classifications of heart
failure, such as Class III heart failure and acute heart
failure.
[0022] These and other features and aspects of the disclosed
methods will become more apparent and better understood with regard
to the following figures and description.
BRIEF DESCRIPTION OF THE FIGURES
[0023] FIG. 1 shows the percentage change from a baseline for
several diagnostic tests of hearts of conscious dogs experiencing
congestive heart failure (CHF) resulting from administration of the
HNO/NO.sup.- donating compounds Angeli's salt (AS) and
isoproylamine/NO (IPA/NO), as well as the NO donors diethylamine/NO
(DEA/NO) and nitroglycerin (NTG). The diagnostic tests included
end-systolic elastance (Ees), preload-normalized maximal change in
pressure over change in time dP/dt (D.sub.EDV), pre-load
recruitable stroke work (PRSW), the time constant of ventricular
relaxation (tau), end systolic pressure (Pes), end diastolic volume
(Edv), arterial resistance (Ea), and end diastolic pressure
(Edp).
[0024] FIG. 2 shows the percentage change from a baseline for
several diagnostic tests of hearts of conscious dogs experiencing
CHF resulting from the administration of the HNO/NO.sup.- donating
compound Angeli's salt (AS), and the administration of AS when the
dog hearts were under loading conditions (AS+volume). The
diagnostic tests included Ees, preload-normalized maximal change in
pressure over change in time dP/dt (dPdt-EDV), PRSW, tau, end
systolic pressure (ESP), end systolic volume (ESV), end diastolic
volume (EDV), Ea, and end diastolic pressure (EDP).
[0025] FIG. 3 shows the percentage change from a baseline for
several diagnostic tests of hearts of conscious dogs experiencing
CHF resulting from the administration of the NO. donating compound
DEA/NO and the administration of DEA/NO when the dog hearts were
under a load (DEA/NO with volume). The diagnostic tests included
Ees, D.sub.EDV, PRSW, tau, ESP, ESV, EDV, Ea, and EDP.
[0026] FIG. 4 shows the percentage change from a baseline for
several diagnostic tests of hearts of conscious dogs experiencing
CHF resulting from the administration of the NO. donating compound
nitroglycerin (NTG) and the administration of NTG when the dog
hearts were under a load (volume loading). The diagnostic tests
included Ees, D.sub.EDV, PRSW, tau, ESP, ESV, EDV, Ea, and EDP.
[0027] FIG. 5 shows the percentage change from a baseline for
several diagnostic tests of hearts of conscious dogs experiencing
CHF resulting from the administration of the positive inotropic
agent dobutamine (DOB) in combination with the HNO/NO.sup.-
donating compounds AS and IPA/NO and the NO. donating compounds
DEA/NO and NTG. The diagnostic tests included Ees, D.sub.EDV, PRSW,
tau, Pes, ESV, EDV, arterial resistance (EA), and EDP.
[0028] FIG. 6 shows the percentage change from a baseline for
several diagnostic tests of hearts of conscious dogs experiencing
heart failure (HF) resulting from the administration of calcitonin
gene-related peptide.sub.8-37 (CGRP.sub.8-37), administration of
CGRP.sub.8-37 in combination with AS, and administration of AS
alone. The diagnostic tests included Ees, D.sub.EDV, PRSW, tau,
Pes, end diastolic pressure (Ped), end diastolic volume (Ved), and
Ea.
[0029] FIG. 7 shows the blood plasma CGRP levels in picomoles
(pmol) per milliliter (ml) in the artery, vein, and coronary sinus
of normal conscious dogs (controls) and conscious dogs experiencing
heart failure.
[0030] FIG. 8 shows the percentage change from a baseline for
several diagnostic tests of hearts of normal conscious dogs, which
dogs were under beta-antagonist therapy with propranolol, resulting
from administration of the HNO/NO.sup.- donating compound AS. The
tests included Ees, D.sub.ERV, and PRSW.
DETAILED DESCRIPTION
[0031] Disclosed herein is a method of treating CHF by
administering a therapeutically effective dose of at least one
nitroxyl (HNO/NO.sup.-) donating compound to a subject experiencing
heart failure. In particular embodiments the HNO/NO.sup.- donating
compound is IPA/NO. In other particular embodiments the
HNO/NO.sup.- donating compound is Piloty's acid. Also disclosed
herein is a method of treating CHF by administering a
therapeutically effective dose of at least one HNO/NO.sup.-
donating compound in combination with a therapeutically effective
dose of at least one positive inotropic agent to a subject
experiencing heart failure. In particular embodiments the
HNO/NO.sup.- donating compound is a diazeniumdolate, such as
IPA/NO, and the positive inotrope is a beta-adrenergic agonist,
such as dobutamine. Additionally, in particular embodiments of the
methods described above, the HNO/NO.sup.- donating compound or the
combination of the HNO/NO.sup.- donating compound and the positive
inotropic compound are used to treat Class III CHF, or other
non-acute CHF. In still other embodiments the methods are used to
treat acute CHF. Also disclosed is a method of treating CHF in a
subject receiving beta-antagonist therapy by administering a
therapeutically effective dose of at least one HNO/NO.sup.-
donating compound. In particular embodiments the HNO/NO.sup.-
donating compound is a diazeniumdolate, such as Angeli's salt.
[0032] A nitroxyl donor is an agent or compound that provides a
physiologically effective amount of HNO or NO.sup.- (HNO/NO.sup.-).
The HNO/NO.sup.- donating compound is any compound that donates
HNO/NO.sup.- and has a safety profile indicating the compound would
be tolerated by a subject in the amount necessary to achieve a
therapeutic effect. One of ordinary skill in the art would be able
to determine the safety of administering particular compounds and
dosages to live subjects. Such a compound includes any compound
having the formula
##STR00001##
wherein J is an organic or inorganic moiety, M.sup.+x is a
pharmaceutically acceptable cation, wherein x is the valence of the
cation, a is 1 or 2, b and c are the smallest integers that result
in a neutral compound, and wherein the compound is administered
under conditions that cause it to release HNO/NO.sup.-. The
compounds of Formula I are known generally as diazeniumdolates
because they contain the N-oxy-N-nitroso complex. Angeli's salt is
a compound of formula I that disassociates under physiological
conditions to donate HNO/NO.sup.-. Other diazeniumdolates that
disassociate under physiological conditions to generate
HNO/NO.sup.-, such as IPA/NO or Sulfi/NO
(N-nitrosohydroxylamine-N-sulfonate/ammonium salt), are also used
in performing the method. Additionally, analogs and derivatives of
such compounds can be used. Moreover, conditions, such as the
oxidation state of the environment, can be altered to cause such
compounds to donate HNO/NO.sup.-.
[0033] An analog is a molecule that differs in chemical structure
from a parent compound, for example a homolog (differing by an
increment in the chemical structure, such as a difference in the
length of an alykl chain), a molecular fragment, a structure that
differs by one or more functional groups, or a change in
ionization. Structural analogs are often found using quantitative
structure activity relationships (QSAR), with technologies such as
those disclosed in Remington: The Science and Practice of
Pharmacology, 19.sup.th Edition (1995), chapter 28. A derivative is
a biologically active molecule derived from the base structure.
[0034] Wang et al., "New chemical and biological aspects of
S-nitrosothiols," Curr. Med. Chem., 7(8):821-34 (2000), describes
NO.sup.- formation from heterolytic decomposition of S-nitrosothiol
compounds. Thus, S-nitrosothiol compounds such as
S-nitroso-L-cystine ethyl ester, S-nitroso-L-cystine,
S-nitroso-glutathione, S-nitroso-N-acetyl-cystine,
S-nitroso-3-mercaptoetanol, S-nitroso-3-mercaptopropanoic acid,
S-nitroso-2-aimonethanethiol, S-nitroso-N-acetyl penicillamine
(SNAP), S-nitrosocaptopril, as well as others are also used in
performing the provided method. In particular, S-nitrosoglutathione
(GNSO) has been reported as capable of being reduced to
HNO/NO.sup.- in the presence of thiols. Hogg et al., Biochem. J.,
323:477-481 (1997).
[0035] Piloty's acid (benzenesulfohydroxamic acid) is a hydroxamic
acid (X(.dbd.O)NHOH) that donates HNO/NO.sup.- and is useful in
performing the provided methods. Other hydroxamic acids that donate
HNO/NO.sup.-, in particular, other sulfohyrdroxamic acids and their
derivatives are also useful.
[0036] Thionitrates (R--(S)--NO.sub.2, wherein R is a polypeptide,
an amino acid, a sugar, a modified or unmodified oligonucleotide, a
straight or branched, saturated or unsaturated, aliphatic or
aromatic, substituted or unsubstituted hydrocarbon, or a
heterocylclic group) that donate HNO/NO.sup.- are useful in
performing the methods provided. In particular, such compounds that
form disulfide species are useful.
[0037] One of ordinary skill in the art would be able to determine
these and other compounds capable of donating HNO/NO.sup.-. Also
included in this term is direct administration of HNO/NO.sup.-.
[0038] Compositions comprising more than one HNO/NO.sup.- donating
compound are also used. For example, IPA/NO and another compound
that dissociates to generate HNO/NO.sup.- for example, Piloty's
acid, are used to treat heart failure.
[0039] In particular embodiments the HNO/NO.sup.- donating compound
is administered in the form of a pharmaceutical composition. A
pharmaceutical composition comprising an effective amount of the
HNO/NO.sup.- donating compound as an active ingredient could be
easily prepared by standard procedures well known in the art, with
pharmaceutically acceptable non-toxic solvents and/or sterile
carriers, if necessary. Such preparations are administered orally
or in injectable form, or directly to myocardial tissue. In other
embodiments the HNO/NO.sup.- donor is administered without a
pharmaceutical carrier. In particular embodiments the HNO/NO.sup.-
donor is administered by a short-term infusion, such as for 5 to 20
minutes. In other embodiments the HNO/NO.sup.- donor is
administered by a long-term infusion, such as from 3-4 hours. The
HNO/NO.sup.- donated by Angeli's salt retains its beneficial
effects during 3-4 hours of perfusion.
[0040] The dose of the HNO/NO.sup.- donating compound is a
therapeutically effective dose. A therapeutically effective dose of
an HNO/NO.sup.- donating compound comprises a dose effective to
increase contractility in a subject experiencing heart failure.
Optimizing therapy to be effective across a broad population can be
performed with a careful understanding of various factors to
determine the appropriate therapeutic dose, in view of the
inventors' disclosure that these agents cause a positive inotropic
effect as well as venous dilation. In particular embodiments, an
infusion of 10 micrograms (.mu.g)/kilogram of body weight
(kg)/minute (min) is administered for 5-20 min to treat acute heart
failure. In one example, the agent administered at this dose is
Angeli's salt. In other embodiments an infusion of 2.5 .mu.g/kg/min
is administered for 5-20 min to treat acute heart failure. In one
example, the agent administered at this dose is IPA/NO.
[0041] A positive inotrope is an agent or compound that causes an
increase in myocardial contractile function. Such an agent includes
a beta-adrenergic receptor agonist, an inhibitor of
phophodiesterase activity, and calcium-sensitizers. Beta-adrenergic
receptor agonists include, among others, dopamine, dobutamine,
terbutaline, and isoproterenol. Analogs and derivatives of such
compounds are also used. For example, U.S. Pat. No. 4,663,351
describes a dobutamine prodrug that can be administered orally. One
of ordinary skill in the art would be able to determine these and
other compounds that are capable of causing positive inotropic
effects and also additional beta-agonist compounds. In particular
embodiments the beta-receptor agonist is selective for the beta-1
receptor. However, in other embodiments the beta-agonist is
selective for the beta-2 receptor, or is not selective for any
particular receptor. Additionally, compositions comprising more
than one positive inotropic agent are used. For example, dobutamine
and isoproterenol are used to treat heart failure.
[0042] In particular embodiments the positive inotropic agent is
administered in combination with the HNO/NO.sup.- donor. The
combined administration of the HNO/NO.sup.- donor and the positive
inotropic agent comprises administering the HNO/NO.sup.- donor
either sequentially with the positive inotropic agent for example,
the treatment with one agent first and then the second agent, or
administering both agents at substantially the same time, wherein
there is an overlap in performing the administration. With
sequential administration a subject is exposed to the agents at
different times, so long as some amount of the first agent, which
is sufficient to be therapeutically effective in combination with
the second agent, remains in the subject when the other agent is
administered. Treatment with both agents at the same time can be in
the same dose, such as a physically mixed dose, or in separate
doses administered at the same time.
[0043] In particular embodiments the positive inotropic agent is
administered in the form of a pharmaceutical composition. A
pharmaceutical composition comprising an effective amount of the
positive inotropic agent as an active ingredient could be easily
prepared by standard procedures well known in the art, with
pharmaceutically acceptable non-toxic solvents and/or sterile
carriers, if necessary. Such preparations are administered orally
or in injectable form, or directly to myocardial tissue. In other
embodiments the positive inotropic agent is administered without a
pharmaceutical carrier.
[0044] The dose of the positive inotropic agent is a
therapeutically effective dose. In particular embodiments positive
inotropic agent is administered at a dose of between 2 and 20
.mu.g/kg/min. In certain examples dobutamine is administered at
this dose. However, in other embodiments, higher and lower dosages
are administered to subjects experiencing heart failure. For
example, a dose of 0.5 .mu.g/kg/min is administered, or a dose of
40 .mu.g/kg/min is administered. Optimizing therapy to be effective
across a broad population can be performed with a careful
understanding of various factors to determine the appropriate
therapeutic dose, in view of the inventors' disclosure that the
positive inotropic agent is administered in combination with an
HNO/NO.sup.- donor.
[0045] In particular embodiments an HNO/NO.sup.- donor is
administered to a subject experiencing heart failure that is
receiving beta-antagonist therapy. A beta-antagonist (also known as
a beta-blocker) includes any compound that effectively acts as an
antagonist at a subject's beta-adrenergic receptors, and provides
desired therapeutic or pharmaceutical results, such as diminished
vascular tone and/or heart rate. In particular embodiments the
beta-antagonist is selective for a particular receptor, such as the
beta-1 receptor. In other embodiments the beta-antagonist is not
selective for any particular beta receptor. Beta-antagonizing
agents include metoprolol, bisoprolol, bucindolol, carvedilol,
timolol, propranolol, pindolol, and atenolol. One of ordinary skill
in the art would be able to identify these and other compounds that
are capable of acting as beta-adrenergic antagonists at a subject's
beta-adrenergic receptors.
[0046] A subject who is receiving beta-antagonist therapy is any
subject to whom a beta-antagonist has been administered, and in
whom the beta-antagonist continues to act as an antagonist at the
subject's beta-adrenergic receptors. In particular embodiments a
determination of whether a subject is receiving beta-blocking
therapy is made by examination of the subject's medical history. In
other embodiments the subject is screened for the presence of
beta-blocking agents by chemical tests, such as high-speed liquid
chromatography as described in Thevis et al., Biomed. Chromatogr.,
15:393-402 (2001).
[0047] The administration of an HNO/NO.sup.- donating compound
either alone, in combination with a positive inotropic agent, or to
a subject receiving beta-antagonist therapy, is used to treat heart
failure of all classifications. In particular embodiments an
HNO/NO.sup.- donating compound is used to treat early-stage chronic
heart failure, such as Class II heart failure. In other embodiments
an HNO/NO.sup.- donating compound is used in combination with a
positive inotropic agent, such as isoproterenol to treat Class IV
heart failure. In still other embodiments an HNO/NO.sup.- donating
compound is used in combination with a positive inotropic agent,
such as isoproterenol to treat acute heart failure. In some
embodiments, when HNO/NO.sup.- is used to treat early stage heart
failure, the dose administered is lower than that used to treat
acute heart failure. In other embodiments the dose is the same as
is used to treat acute heart failure.
[0048] The following are non-limiting examples of particular
embodiments of the methods provided herein.
Example 1
[0049] This example demonstrates that infusion of an HNO/NO.sup.-
donor caused positive inotropic effects in failing myocardium.
Further, infusion of an HNO/NO.sup.- donor complemented the
positive inotropic effect of dobutamine, as opposed to the
impairment of dobutamine's positive inotropic effect observed with
NO donors. Additionally, when compared with an infusion of Angeli's
salt designed to cause a systemic blood pressure decrease nearly
equivalent to that caused by IPA/NO, the HNO/NO.sup.- donor IPA/NO
exerted a stronger positive inotropic effect.
[0050] The effect of HNO/NO.sup.- donated by AS (10 micrograms
(.mu.g)/kilogram (kg)/minute (min) for 5-20 min) and IPA/NO
(2.5-5.0 .mu.g/kg/min for 5-20 min) on basal cardiovascular
function was tested in mongrel dogs. Studies were performed at a
constant heart rate during atrial pacing (130-160 beats per
minute). Myocardial effects produced by HNO/NO.sup.- donating
compounds were compared to those produced by the NO. donors DEA/NO
and nitroglycerin at doses titrated to achieve the same decline in
systolic pressure (a measure of systemic blood pressure) as the
HNO/NO.sup.- donors.
[0051] Hemodynamic data was sampled at 250 Hertz (Hz) and
steady-state and pressure-dimension parameters were derived. Since
in vivo cardiac contractility assessment requires separation of the
effects of chamber loading, pressure-volume relation indexes,
specifically, the end-systolic elastance (Ees), and the slope of
dP/dt.sub.max-end-diastolic dimension (D.sub.EDV) relations were
employed. Isovolumic relaxation was derived from pressure decay
waveforms assuming a nonzero decay asymptote.
[0052] Serum concentrations of nitrite and nitrate were determined
by a modified Griess assay, with and without prior chemical
reduction of nitrate to nitrite using VCl.sub.3. Serum stored at
-70.degree. C. was deproteinized by ultrafiltration (30 kilodalton
(kD) cut-off, Centricon, Sartorius) at 4.degree. C., and absorbance
at 540 nanometer (nm) read using a plate reader (Perkin Elmer HTS
7000 BioAssay Reader controlled by TECAN WinSelect software) after
a 37.degree. C. incubation with Griess reagents for 30-45 min.
[0053] With reference to FIG. 1, each compound tested was
administered in doses titrated to achieve nearly equivalent end
systolic pressures (Pes) in order to allow comparison between
equivalent levels of dilation. Angeli's salt and IPA/NO caused
significant increases in contractility during heart failure as
measured by Ees, D.sub.EDV, and PRSW. These increases were much
greater than the small increases observed with DEA/NO and were
opposite of the negative inotropic effects observed with
nitroglycerin. Additionally, both Angeli's salt and IPA/NO reduced
the cardiac load as measured by Edv (preload) and Ea (afterload).
Surprisingly, IPA/NO caused a greater increase in cardiac
contractility than Angeli's salt as measured by Ees, which, being
load-independent, is a good parameter for assessing myocardial
contractility. This is especially surprising because the doses of
IPA/NO were one-half to one-quarter the doses of Angeli's salt.
[0054] With reference to FIG. 2, the administration of HNO/NO.sup.-
exhibited a positive inotropic effect, which was not dependent on
cardiac load. As illustrated by the measurements of Ees and PRSW
for both loaded and unloaded states, HNO/NO.sup.- exerted a nearly
equivalent positive inotropic effect regardless of cardiac load.
This indicates that the contractility increases caused by
HNO/NO.sup.- are primary as opposed to secondary effects. In
contrast, with reference to FIG. 3, the minor positive inotropic
effects observed with the administration of NO. (DEA/NO) were
reversed when the heart was under cardiac load conditions, that is
at matched end-diastolic volume. Moreover, FIG. 4 illustrates that
administration of the NO donor nitroglycerin caused contractility
to decrease when administered alone, and caused an even greater
negative inotropic effect under loading conditions. This indicates
that the minor contractility increase observed with DEA/NO is
merely secondary to the vasodilatory effects of the compound. That
is, NO. has no direct positive inotropic effects because any
increases in contractility were abolished upon volume
repletion.
[0055] With reference to FIG. 5, administration of AS and IPA/NO
resulted in a greater positive inotropic effect than administration
of dobutamine alone. For example, administration of AS resulted in
a more than doubling of Ees over administration of dobutamine
alone. In contrast, administration of DEA/NO and nitroglycerin
reduced the positive inotropic effect of dobutamine, as illustrated
by the decrease in Ees when the dobutamine was administered with
DEA/NO and NTG.
Example 2
[0056] This example demonstrates that the positive inotropic effect
of HNO/NO.sup.- is a function of its stimulation of calcitonin
gene-related peptide (CGRP) signaling rather than a function of
beta-agonism.
[0057] To test the relation between the inotropic action of
HNO/NO.sup.- and calcitonin gene-related peptide (CGRP) signaling,
CGRP receptors in mongrel dogs were antagonized using the selective
antagonist CGRP.sub.8-37 (400 .mu.g in 30 milliliters (ml) of
saline bolus, then 2.6 .mu.g/kg/min for 15 min). Plasma CGRP levels
measurements were performed by sampling the blood of the dogs.
Blood samples (2.5 ml) were withdrawn from arterial, venous, and
coronary sinus catheters. After sampling, catheters were flushed
with heparanized saline. Samples were centrifuged at 1600 times
gravity (g) for 20 minutes at 4.degree. Celcius (C). Plasma was
then separated and stored at -20.degree. C. until analysis. Plasma
(0.5 ml) was used to extract CGRP by addition of 0.8 ml of ethanol.
The mixture was centrifuged at 1600 g for 20 minutes. After
removing the supernatant, the extracted samples were air dried at
room temperature overnight and then stored at 4.degree. C.
Immediately prior to assay, dried samples were reconstituted with
assay buffer following manufacturer's instructions (Peninsula Labs)
and assayed for CGRP by radioimmunoassay (RIA). CGRP antiserum,
code RAS 6012, was used. The dynamic assay range was 1-128
picograms (pg) per 300 microliters (.mu.L) of sample. Stimulation
with HNO/NO.sup.- donors and diagnostic tests were performed as
described above in Example 1.
[0058] With reference to FIG. 6, administration of the selective
CGRP antagonist CGRP.sub.8-37 resulted in a modest negative
inotropic effect during heart failure as measured by Ees. This
result was not unexpected given that CGRP is known positive
inotrope. Doggrell, Expert Opin. Investig. Drugs, 10:1131-8 (2001).
More interestingly, CGRP.sub.8-37 effectively prevented the
HNO/NO.sup.--mediated, positive inotropic effect of Angeles salt as
is illustrated by a comparison of the Ees data resulting from the
combined administration of CGRP.sub.8-37 and Angeli's salt with the
results observed from administration of Angeli's salt alone. These
results illustrate that the positive inotropy of HNO/NO.sup.- is
caused by stimulating release of CGRP, which is a
nonadrenergic/noncholinergic (NANC) neuromodulator.
[0059] This is supported by the data illustrated in FIG. 7, which
show that blood plasma CGRP levels were increased by administration
of the HNO/NO.sup.- donor Angeli's salt in both normal and heart
failure conditions. A sensitive and specific radioimmunoassay (RIA)
was used to study blood plasma levels of CGRP in normal and in CHF
dogs, both in basal and stimulated conditions (after administration
of AS, DEA/NO and nitroglycerin). The basal mean plasma levels of
CGRP were 23, 24.5 and 27 pg/ml in the artery, vein, and coronary
sinus of normal dogs, respectively. These levels were significantly
reduced in all vascular compartments in CHF dogs: 13.3.+-.0.7,
14.3.+-.1.4, and 14.+-.0.6 pg/ml in artery, vein, and sinus,
respectively. When stimulated with the HNO/NO.sup.- donor AS,
plasma CGRP levels increased substantially in both normal and CHF
dogs (FIG. 7). In contrast, stimulation with DEA/NO and
nitroglycerin failed to significantly increased CGRP levels. These
data clearly show that HNO/NO.sup.- directly stimulates the release
of CGRP.
Example 3
[0060] This example demonstrates that HNO/NO.sup.- effectively
increases contractility even when administered to a subject
receiving beta-antagonist therapy.
[0061] As illustrated in FIG. 8, administration of the HNO/NO.sup.-
donor Angeli's salt (as described in Example 1) to a normal subject
that is receiving beta-antagonist therapy (propranolol, 2
milligrams/kg in bolus) caused an increase in contractility as
indexed by Ees and D.sub.EDV. This increase was observed despite
the propranolol-induced reduction in myocardial performance.
Similar results were obtained in one heart failure subject (data
not shown).
[0062] The above-described examples merely provide particular
embodiments of the provided method. They are not intended to be
limiting in any way. Moreover, although embodiments of the method
provided have been described herein in detail, it will be
understood by those of skill in the art that variations may be made
thereto without departing from the spirit of the invention or scope
of the appended claims.
* * * * *