U.S. patent application number 15/864327 was filed with the patent office on 2018-05-10 for bisphosphonate compositions and methods for treating heart failure.
The applicant listed for this patent is DUKE UNIVERSITY. Invention is credited to CATHLEEN S. COLON-EMERIC, KENNETH W. LYLES, CHRISTOPHER M. O'CONNOR, COLLEEN STACK, RICHARD S. STACK.
Application Number | 20180125869 15/864327 |
Document ID | / |
Family ID | 43649931 |
Filed Date | 2018-05-10 |
United States Patent
Application |
20180125869 |
Kind Code |
A1 |
LYLES; KENNETH W. ; et
al. |
May 10, 2018 |
BISPHOSPHONATE COMPOSITIONS AND METHODS FOR TREATING HEART
FAILURE
Abstract
The present invention provides for methods and compositions for
treating and/or preventing cardiac dysfunction by administering to
subject a therapeutically effective amount of a bisphosphonate,
functional analogue or a pharmaceutically effective salt
thereof.
Inventors: |
LYLES; KENNETH W.; (DURHAM,
NC) ; COLON-EMERIC; CATHLEEN S.; (DURHAM, NC)
; O'CONNOR; CHRISTOPHER M.; (DURHAM, NC) ; STACK;
RICHARD S.; (CHAPEL HILL, NC) ; STACK; COLLEEN;
(CHAPEL HILL, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DUKE UNIVERSITY |
Durham |
NC |
US |
|
|
Family ID: |
43649931 |
Appl. No.: |
15/864327 |
Filed: |
January 8, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13393248 |
Apr 27, 2012 |
9867838 |
|
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PCT/US2010/047417 |
Sep 1, 2010 |
|
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15864327 |
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61238797 |
Sep 1, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/66 20130101;
A61P 9/00 20180101; A61P 9/04 20180101; A61K 31/663 20130101 |
International
Class: |
A61K 31/663 20060101
A61K031/663; A61K 31/66 20060101 A61K031/66 |
Claims
1. An oral or liquid composition comprising zoledronic acid in a
therapeutically effective amount to increase ejection fraction in a
treated subject, wherein the therapeutically effective amount is
formulated to deliver from about 40 ug/kg to about 125 ug/kg to a
subject.
2. The composition of claim 1, wherein the amount of zoledronic
acid is about 100 ug/mg.
3. The composition of claim 1, wherein the ejection fraction is
increased in the left ventricle.
4. The composition of claim 1, further comprising at least one
other therapeutic agent selected from the group consisting of
nitrates, beta-adrenergic blockers, angiotensin converting enzyme
inhibitors, calcium channel antagonists, antihypertensive agents,
cholesterol lowering agents, diuretics, ACE inhibitors, cardiac
glycosides, non-peptide angiotensin II antagonists, IIb/IIIa
antagonists and aspirin.
5. The composition of claim 1, further comprising Vitamin D.
6. A kit for treatment or prevention of heart failure and negative
side-effects thereof, the kit comprising at least one dose of a
bisphosphonate in an therapeutically effective amount to treat or
prevent the symptoms of heart failure, wherein the therapeutically
effective amount is formulated to deliver from about 40 ug/kg to
about 125 ug/kg to a subject.
7. The kit of claim 6, further comprising a dosage of Vitamin D for
consumption from 1 day to one month.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/393,248, filed on Apr. 27, 2012, now U.S. Pat. No.
9,867,838, which in turn claims the priority of PCT International
Application NO. PCT/US2010/047417, filed on Sep. 1, 2010 and which
in turn claims priority to U.S. Provisional Application No.
61/238,797 filed on Sep. 1, 2009, the contents of which are
incorporated by reference herein for all purposes.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to reducing or inhibiting
cardiac dysfunction due to heart failure by administering a
bisphosphonate compound.
Related Art in the Field
[0003] The prevalence of heart failure ("HF") has grown to epidemic
proportions as the population ages and as cardiologists have become
more successful at reducing mortality from ischemic heart disease,
the most common prelude to HF. Specifically, more than 5.7 million
Americans suffer from heart failure, and an estimated 550,000 new
cases are diagnosed each year (Lloyd-Jones et al. 2009). Despite
current treatment options, patients with stage II or III heart
failure face a 2-year mortality rate of 25%, poor quality of life,
and repeated hospitalizations to manage acute decompensations. The
American Heart Association estimates the direct and indirect cost
of heart failure in the United States to be $37.2 billion dollars
in 2009 alone (Lloyd-Jones et al. 2009).
[0004] HF may be caused by many forms of heart disease. Common
causes of heart failure include: narrowing of the arteries
supplying blood to the heart muscle (coronary heart disease); prior
heart attack (myocardial infarction) resulting in scar tissue large
enough to interfere with normal function of the heart; high blood
pressure; heart valve disease due to past rheumatic fever or an
abnormality present at birth; primary disease of the heart muscle
itself (cardiomyopathy); and infection of the heart valves and/or
muscle itself (endocarditis and/or myocarditis). Each of these
disease processes can lead to heart failure by reducing the
strength of the heart muscle contraction, by limiting the ability
of the heart's pumping chambers to fill with blood due to
mechanical problems or impaired diastolic relaxation, or by filling
the heart's chambers with too much blood.
[0005] Cardiac dysfunction due to cardiotoxicity can also be caused
by radiation-induced heart disease (RIHD) and chemotherapeutic
agents which are caused by therapeutic interventions to treat
malignancies. Cardiotoxicity renders the heart unable to
efficiently pump blood throughout the body. Symptoms of this effect
include shortness of breath, fatigue, and anemia. These signals
indicate that the heart is having difficulty maintaining its
essential function. It has also been found that radiation therapy
(RT) can cause injury to all the components of the heart, including
the damage of small vessels that supply the blood to the heart. It
may cause scarring in the heart muscle. Further, the coronary
arteries are more prone to clotting after being treated with
radiation. The radiation may damage the endothelial lining of the
vessels making them form clots more readily. As stated above, the
chemotherapeutic agent used in cancer treatment, such as
anthracyclines, alkylating agents, antimetabolites,
antimicrotubules and etc. can also cause cardiotoxicity.
[0006] The dominant pathophysiology associated with HF is systolic
dysfunction, an impairment of cardiac contractility (with a
consequent reduction in the amount of blood ejected with each
heartbeat). Systolic dysfunction with compensatory dilation of the
ventricular cavities results in the most common form of heart
failure, "dilated cardiomyopathy." The counterpoint to systolic
dysfunction is diastolic dysfunction, an impairment of the ability
to fill the ventricles with blood, which can also result in heart
failure even with preserved left ventricular function. Heart
failure is ultimately associated with improper function of the
cardiac muscle cells involving a decrease in the ability to
effectively contract and relax.
[0007] Many of the same underlying conditions can give rise to
systolic and/or diastolic dysfunction, such as atherosclerosis,
hypertension, viral infection, valvular dysfunction, and genetic
disorders. Patients with these conditions typically present with
the same classical symptoms: shortness of breath, edema and
overwhelming fatigue. In approximately half of the patients with
dilated cardiomyopathy, the cause of their heart dysfunction is
ischemic heart disease due to coronary atherosclerosis. These
patients have had either a single myocardial infarction or multiple
myocardial infarctions and the consequent scarring and remodeling
results in the development of a dilated and hypocontractile
heart.
[0008] A more recent finding is that inflammatory cytokines are
elevated in patients with heart failure. Indeed, there is a direct
relationship between elevated levels of TNF-.alpha. and IL-6 and
the degree of hemodynamic abnormalities. Similarly, the higher the
TNF-.alpha. level the more severe the heart failure symptoms.
Interestingly, it has been found that TNF-.alpha. is not expressed
by normal human heart but is expressed in abundant amounts by human
failing heart. Furthermore, TNF-.alpha. can induce the expression
of other inflammatory cytokines.
[0009] Numerous compounds are known to be useful for the prevention
and treatment of heart failure, including alpha-adrenergic
antagonists, angiotensin II antagonists, angiotensin-converting
enzyme (ACE) inhibitors, beta-adrenergic antagonists,
antihypertensives, calcium channel blockers, diuretics, potassium
channel opening vasodilators, renin inhibitors, and serotonin
antagonists. However, in view of the high prevalence of heart
failure in the general population and the poor prognosis of these
patients, there remains a great need for agents that exploit new
mechanisms of action and may have better outcomes in terms of
relief of symptoms, safety, and patient mortality, both short-term
and long-term. New agents may provide a means to achieve better
clinical outcomes for those who have or are at risk for heart
failure.
SUMMARY OF THE INVENTION
[0010] The present invention includes methods and compositions for
treating cardiac dysfunctions and diseases related thereto.
[0011] In one aspect, the invention includes a method for treating
hypertrophy, hypertension, heart failure, ischemic heart disease,
ischemia reperfusion injury and acute heart failure of inflammatory
etiology, i.e., myocarditis and acute cardiac rejection associated
with cardiac transplantation in mammals that includes administering
to the mammal a therapeutically effective amount of a
bisphosphonate, functional analogue thereof or a pharmaceutically
effective salt thereof.
[0012] Another aspect of the present invention relates to
pharmaceutical compositions comprising a bisphosphonate and a
pharmaceutically acceptable carrier or diluent. The bisphosphonate
compound may include but is not limited to zoledronic acid,
risedronate, alendronate, cimadronate, clodronate, tiludronate,
etidronate, ibandronate, piridronate or pamidronate and functional
analogues thereof. Preferably the compound is zoledronic acid or
ibandronate.
[0013] Yet another aspect of the present invention relates to a
method for administering to a subject in need thereof an effective
amount of a bisphosphonate compound according to the invention and
subsequent to the diagnosis of heart failure, the occurrence of a
vascular injury, subsequent to a vascular surgical operation or in
combination with therapeutic interventions to treat malignancies
including radiation therapy and use of anthracycline compounds.
[0014] A still further aspect of the present invention relates to
use of a bisphosphonate and preferably, zoledronic acid to treat
systolic and/or diastolic dysfunction, wherein the zoledronic acid
is administered in a therapeutically effective amount to increase
the ability of the cardiac muscle cells to contract and relax
thereby increasing the filling and emptying of both the right and
left ventricle.
[0015] A further aspect of the present invention relates to
administration of the bisphosphonate compound at least annually,
either after the diagnosis of heart failure or after the occurrence
of a vascular injury or surgical operation. The amount of the
bisphosphonate compound administered is an amount effective to
treat or prevent a patient's heart failure. Preferably the
effective amount is from about 40 ug/kg to about 125 ug/kg, more
preferably from about 50 ug/kg to 100 ug/kg.
[0016] Effective treatment can be exhibited by an increase of
ejection fraction, increase in diastolic and/or systolic function,
improvement in hemodynamics, reduction in inflammatory cytokine
levels and neurohormone levels, reduction in markers of
inflammation, reduction in injury markers, inhibition of platelet
aggregation, improvement in endothelial function, reductions in
arrhythmias, and improvement in heart rate variability, improvement
in QRS dispersion and QTC prolongation, and improved immune
responsiveness, all of which can be tested by skilled artisans with
known and available testing regimes.
[0017] A still further aspect of the present invention relates to
the use of a bisphosphonate compound alone or together with other
cardiac therapeutic agents including, but not limited to nitrates,
beta-adrenergic blockers, calcium channel antagonists,
antihypertensive agents, cholesterol lowering agents, diuretics,
ACE inhibitors, non-peptide angiotensin II antagonists, IIb/IIIa
antagonists and aspirin in the manufacture of a medicament for the
prevention of cardiovascular events, for example stroke, heart
failure, cardiovascular death, myocardial infarction, worsening of
angina, cardiac arrest, or need for revascularization
procedures.
[0018] Another aspect of the present invention relates to a method
of treating cardiovascular diseases and diseases related thereto,
wherein a subject is administered Vitamin D (cholecalciferol or
egrocalciferol) in dosages ranging from about 50,000-125,000 IU in
a single or multiple dosages and a subsequent administration of a
bisphosphonate in an effective amount to treat or prevent heart
failure in the subject.
[0019] Yet another aspect of the present invention relates to a
method of delivering a bisphosphonate compound in a local or
targeted fashion using interventional techniques. This could be
accomplished by direct coronary injection in multiple clinical
contexts. In one preferred embodiment, the bisphosphonate could be
directly infused into a coronary artery of a patient undergoing an
emergency intervention for reperfusion during acute myocardial
infarction (AMI). In this scenario, direct intracoronary infusion
of the bisphosphonate compound may have a significant effect on
inflammation associated with reperfusion and healing or reperfusion
injury, on infarct size, on development of sequelae such as heart
failure, or on clinical outcomes. In an alternative embodiment, the
bisphosphonate compound could be injected into all coronary
arteries (for example via the left main and right coronary
arteries) after heart transplantation. It is anticipated that
timing, dosage, and dosage intervals would be determined based on
the disease the bisphosphonate is intended to treat or prevent, as
well as the clinical context in which the bisphosphonate is
administered.
[0020] Additional aspects of the present invention which may be
used with local or targeted drug delivery methods include coupling
of the bisphosphonate compound to a carrier such as a nanoparticle,
microsphere, or another type of particle of appropriate size,
shape, and other characteristics to effect targeted, local delivery
of the therapy. Associated devices or delivery vehicles are
preferably designed for intravascular or intracardiac placement.
These methods may include those in which devices or delivery
vehicles are designed to promote delivery of the bisphosphonate
compound over time. Such methods may include but are not limited to
intravascular or intracardiac prostheses that are coupled to or
constructed entirely out of bioabsorbable polymer. Alternatively,
the bisphosphonate could be eluted from another material that may
be durable or bioabsorbable.
[0021] In another aspect, the bisphosphonate compound may be
released over time through a membrane or other barrier from a patch
residing in the heart or the vasculature. Further, the
bisphosphonate compound may be delivered by elution from vascular
paving or hydrogel, including by way of deployment of a
hydrogel-coated or other drug-eluting balloon.
[0022] In a further aspect, the present invention provides for a
method wherein the bisphosphonate compound may be combined with a
device that is currently used to treat cardiovascular disorders.
For example, the bisphosphonate compound could be eluted, in
combination with an anti-restenosis drug or alone, from a
drug-eluting stent placed in the treatment of acute myocardial
infarction (AMI).
[0023] In a still further aspect, the present invention provides
administering a bisphosphonate, preferably zoledronic acid, in
combination with therapeutic interventions to treat malignancies,
wherein such interventions include radiation therapy and/or the use
of an antineoplastic agent used in chemotherapy.
[0024] A final aspect of the present invention relates to a kit for
treatment or prevention of heart failure and negative side-effects
thereof, the kit comprising at least one dose of a bisphosphonate
in an therapeutically effective amount to treat or prevent the
symptoms of heart failure. The kit may optionally include a
sufficient daily dosage of Vitamin D for consumption from 7 days to
one month.
[0025] Other aspects, objects, features and advantages of the
present invention would be apparent to one of ordinary skill in the
art from the following detailed description illustrating the
preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0026] FIG. 1 shows the compilation of the results of test swine
over the testing period.
[0027] FIG. 2 is a graph showing the average values of testing
swine administered the zoledronic acid or placebo.
[0028] FIG. 3 is a graph showing the absolute value of the increase
of ejection fraction
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention is directed to compositions and
methods for treatment of heart failure including treating any one
or more of the conditions underlying heart failure, including,
without limitation, decreased cardiac contractility, abnormal
diastolic or systolic compliance, reduced stroke volume, pulmonary
congestion, and decreased cardiac output, while minimizing or
attenuating deleterious effects commonly associated with previously
used compounds.
[0030] Bisphosphonates, a class of compounds that are pyrophosphate
analogues, have been used for thirty (30) years to treat skeletal
disorders caused by increased osteoclastic bone resorption (Rosen,
2005). The first compound approved for use in treating Paget's
disease of bone was etidronate. This was followed by more potent
nitrogen-containing bisphosphonates: alendronate, risedronate and
ibandronate; that have become the first line of therapy for
postmenopausal osteoporosis. However, until recently, these agents
had to be administered orally, requiring weekly to monthly dosing.
Now two bisphosphonates: ibandronate and zoledronic acid, are
efficacious in the treatment of osteoporosis when administered
intravenously, either quarterly each year (ibandronate), or
annually (zoledronic acid).
[0031] Bisphosphonates are the current drug of choice for
osteoporosis because they reduce fracture rates as well as the
attendant disability (Rosen, 2005). Although two types of
osteoporotic fractures (vertebral and hip) are associated with
increased mortality, until recently no clinical trial using
bisphosphonates to treat this disease has shown a reduction in
mortality. Recently, a clinical study was conducted wherein
patients who were within 90 days of surgical repair of a hip
fracture were randomized to receive either zoledronic acid or
placebo at baseline and yearly thereafter, with the primary
response variable being the rate of new clinical fractures
(Colon-Emeric et al. 2004). The trial had a positive outcome with a
35% reduction in the risk of all clinical fractures (Lyles et al.
2007). Further, a 28% reduction in mortality was observed in those
patients who received zoledronic acid compared to the placebo
subjects.
[0032] Another study of interest described the use of genetically
engineered mice exhibiting the effects of having Hutchinson-Gilford
Progeria Syndrome (HGPS). The people diagnosed with this disease
usually have small, fragile bodies, like those of elderly people.
Later, the condition causes wrinkled skin, atherosclerosis and
cardiovascular problems. The mice were treated with pravastatin and
zoledronic acid in an attempt to slow premature aging, growth
retardation, vascular disease, hair loss, and osteoporosis. (Varela
2008) In combination, these therapies were reported to increase the
median lifespan from 101 to 179 days.
[0033] Upon seeing the results of these studies, it was theorized
by the present inventors that the bisphosphonate could be
responsible for the reduction in mortality. Specifically, this
hypothesis was based on epidemiologic evidence linking
cardiovascular disease and osteoporosis, and overlapping patterns
of elevated inflammatory cytokines associated with disability and
death in both hip fracture patients and heart failure patients. The
testing results, as discussed herein, provide evidence that
administration of the bisphosphonate can positively impact a mammal
in heart failure.
Definitions
[0034] The term "bisphosphonate," as used herein, means any
compound which is an analog of endogenous pyrophosphate whereby the
central oxygen is replaced by carbon. Bisphosphonates include
aminobisphosphonates. Bisphosphonates include, but are not limited
to the following compounds: zoledronic acid, risedronate,
alendronate, cimadronate, clodronate, tiludronate, etidronate,
ibandronate, piridronate, or pamidronate and functional analogues
thereof.
[0035] The term "zoledronic acid," as used herein, means to include
the free acid itself, i.e.,
1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, as well as
any pharmaceutically acceptable salts and hydrates thereof and
solvates thereof formed from other solvents used for its
crystallization. 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic
acid and its pharmacologically acceptable salts, hydrates and
solvates are well-known from the literature. They can be prepared
by procedures known in the art, such as described, e.g., in U.S.
Pat. No. 4,939,130. See also U.S. Pat. Nos. 4,777,163 and
4,687,767. The contents of the latter three patents are hereby
incorporated by reference in their entirety.
[0036] The term "heart failure," as used herein, means impaired
cardiac function that renders the heart unable to maintain the
normal blood output at rest or with exercise, or to maintain a
normal cardiac output in the setting of normal cardiac filling
pressure. A left ventricular ejection fraction of about 40% or less
is indicative of heart failure (by way of comparison, an ejection
fraction of about 55% to 60% percent is normal). Patients with
heart failure display well-known clinical symptoms and signs, such
as tachypnea, pleural effusions, fatigue at rest or with exercise,
contractile dysfunction, and edema. Relative severity and disease
progression are assessed using well known methods, such as physical
examination, echocardiography, radionuclide imaging, invasive
hemodynamic monitoring, magnetic resonance angiography, and
exercise treadmill testing coupled with oxygen uptake studies.
[0037] The term, "ischemic heart disease," as used herein, means
any disorder resulting from an imbalance between the myocardial
need for oxygen and the adequacy of the oxygen supply. Most cases
of ischemic heart disease result from narrowing of the coronary
arteries, as occurs in atherosclerosis or other vascular
disorders.
[0038] The term "atherosclerotic cardiovascular disease," as used
herein, means a cardiovascular disease that is associated with or
secondary to an atherosclerotic condition, e.g. a diseased state of
the arteries characterized by an accumulation of intimal smooth
muscle cells, accumulation of macrophages and T-lymphocytes,
formation of large amounts of connective tissue matrix, and
accumulation of lipid, primarily in the form of cholesterol or
cholesterol esters within the cells and the surrounding connective
tissue, and accumulation of necrotic debris.
[0039] The term "myocardial infarction," as used herein, means a
process by which ischemic disease results in a region of the
myocardium being replaced by scar tissue.
[0040] The term "cardiotoxic compound," as used herein, means
chemotherapeutic agents including but not limited to
anthracyclines, such as, Doxorubicin, Daunorubicin, Epirubicin,
Idarubicin, and Mitoxantrone; alkylating agents, such as, Vusulfan,
Cisplatin, Cyclophosphamide, Ifosfamide and Mitomycin;
Antimetabolites, such as, Capecitabine, Cytarabine and Flurouracil;
Antimicrotubules, such as, Paclitazel and Vinca alkaloids;
Biological agents, such as, Alemtazumab, Bevacizumab, Cetuximab,
Rituximab, Trastuzumab, IL-2 and Interferon-.alpha.; and
miscellaneous, such as, Imatnib, Arsenic trioxide and
Etoposide.
[0041] The term "hypertension," as used herein, means blood
pressure that is considered by a medical professional (e.g., a
physician or a nurse) to be higher than normal and to carry an
increased risk for developing congestive heart failure.
[0042] The term "treating," as used herein, means that the
administration of a bisphosphonate compound slows or inhibits the
progression of heart failure during the treatment, relative to the
disease progression that would occur in the absence of treatment,
in a statistically significant manner. Well known indicia such as
left ventricular ejection fraction, exercise performance, and other
clinical tests as enumerated above, as well as survival rates and
hospitalization rates, event rates or composite endpoints may be
used to assess disease progression. Whether or not a treatment
slows or prevents disease progression in a statistically
significant manner may be determined by methods that are well known
in the art.
[0043] The term "preventing," as used herein, means minimizing or
partially or completely inhibiting the development of heart failure
in a mammal at risk for developing congestive heart failure.
Determination of whether heart failure is minimized or prevented by
administration of a bisphosphonate is made by known methods.
[0044] The term "at risk for heart failure", as used herein, means
an individual who smokes, is obese (i.e., 20% or more over their
ideal weight), has (or had) high blood pressure, ischemic heart
disease, a myocardial infarct, a genetic defect known to increase
the risk of heart failure, a family history of heart failure,
myocardial hypertrophy, hypertrophic cardiomyopathy, left
ventricular systolic dysfunction, coronary bypass surgery, vascular
disease, atherosclerosis, alcoholism, periocarditis, a viral
infection, gingivitis, an eating disorder (e.g., anorexia nervosa
or bulimia), is an alcoholic or cocaine addict, and/or has been
treated with radiation therapy or chemotherapy for treat
malignancies.
[0045] The term "therapeutically effective amount," as used herein,
means an amount of a compound or combination of compounds that
ameliorates, attenuates, or eliminates one or more symptoms of
heart failure or prevents or delays the onset of one or more
symptoms of heart failure as defined herein.
[0046] The term "pharmaceutically acceptable," as used herein,
means that the carrier, diluent, excipients, and/or salt must be
compatible with the other ingredients of the formulation, and not
deleterious to the patient. Examples of pharmaceutically acceptable
salts of the compounds include salts derived from an appropriate
base, such as an alkali metal (for example, sodium, potassium), an
alkaline earth metal (for example, calcium, magnesium), ammonium
and NR'.sub.4.sup.+ (wherein R' is C.sub.1-C.sub.4 alkyl).
Pharmaceutically acceptable salts of an amino group include salts
of: organic carboxylic acids such as acetic, lactic, tartaric,
malic, lactobionic, fumaric, and succinic acids; organic sulfonic
acids such as methanesulfonic, ethanesulfonic, isethionic,
benzenesulfonic and p-toluenesulfonic acids; and inorganic acids
such as hydrochloric, hydrobromic, sulfuric, phosphoric and
sulfamic acids. Pharmaceutically acceptable salts of a compound
having a hydroxyl group consist of the anion of said compound in
combination with a suitable cation such as Na.sup.+,
NH.sub.4.sup.+, or NR'.sub.4.sup.+ (wherein R' is for example a
C.sub.1-4 alkyl group).
[0047] The term "a form of Vitamin D," as used herein, means any
from of Vitamin D and functionally active analogue including
Vitamin D2 (ergocalciferol or calciferol) and Vitamin D3
(cholecalciferol); hormones including calcidiol, dihydrotachysterol
and calcitriol; Vitamin D analogues or metabolites including
doxercalciferol and paricalcitol.
[0048] The term "functionally active analog," as used herein, means
compounds derived from a particular parent compound by
straightforward substitutions that do not result in a substantial
(i.e. more than 100.times.) loss in the biological activity of the
parent compound, where such substitutions are modifications
well-known to those skilled in the art, e.g., esterification,
replacement of hydrogen by halogen, replacement of alkoxy by alkyl,
replacement of alkyl by alkoxy, etc.
[0049] As used herein, the term "heart tissue" includes, without
limitation, the myocardium of the heart (including cardiac muscle
fibers, connective tissue (endomysium), nerve fibers, capillaries,
and lymphatics); the endocardium of the heart (including
endothelium, connective tissue, and fat cells); the epicardium of
the heart (including fibroelastic connective tissue, blood vessels,
lymphatics, nerve fibers, fat tissue, and a mesothelial membrane
consisting of squamous epithelial cells); and any additional
connective tissue (including the pericardium), blood vessels,
lymphatics, fat cells, progenitor cells (e.g., side-population
progenitor cells), and nervous tissue found in the heart.
[0050] The bisphosphonate, and specifically zoledronic acid, is
preferably used in the form of pharmaceutical compositions that
contain a therapeutically effective amount of the bisphosphonate
active ingredient optionally together with or in admixture with
inorganic or organic, solid or liquid, pharmaceutically acceptable
carriers which are suitable for administration.
[0051] The pharmaceutical compositions may be, for example,
compositions for enteral, such as oral, rectal, aerosol inhalation
or nasal administration, compositions for parenteral, such as
intravenous or subcutaneous administration, or compositions for
transdermal administration, e.g., passive or iontophoretic.
Preferably, the pharmaceutical compositions are for intravenous
administration. The pharmaceutical compositions may also be for
direct intracoronary injection or elution from an intravascular or
intracardiac device.
[0052] The particular mode of administration and the dosage may be
selected by the attending physician taking into account the
particulars of the patient, especially age, weight, life style,
activity level, hormonal status, e.g., post-menopausal, and bone
mineral density as appropriate. Most preferably, however,
zoledronic acid is administered intravenously and the dosage of the
zoledronic acid may depend on various factors, including sex, age,
weight and/or individual condition of the subject.
[0053] Normally the dosage is such that a single dose of a
bisphosphonate, such as zoledronic acid or salt or hydrate thereof
is from about 0.002 to about 20.0 mg/kg, preferably from 0.01 to 1
mg/kg, and more preferably from about 0.04 mg/kg to about 0.125
mg/kg. The term "mg/kg" means mg of drug per kg body weight of the
subject. The dosage will be determined to correspond with the
frequency of administering the compound.
[0054] In accordance with the present invention, the
bisphosphonate, and preferably zoledronic acid or ibandronate, is
dosed at intervals of at least about once a month, every three
months, six months, e.g., once every 180 days, or less frequently,
conveniently once a year, or at any interval in between, e.g., once
every 7, 8, 9, 10 or 11 months. The dose mentioned above, either
administered as a single dose (which is preferred) or in several
partial doses, is preferably administered once per year
(understanding, of course, that it may not be exactly one year to
date but rather at yearly check-ups).
[0055] Timing and location for direct intracoronary injection or
targeted intravascular or intracardiac delivery of the
bisphosphonate compound may depend on the disorder being treated.
In one preferred embodiment, bisphosphonate treatment during an
acute myocardial infarction (AMI) would preferably include at least
one acute direct injection into the coronary supplying the
jeopardized myocardium at the time of interventional reperfusion.
In an alternative embodiment, bisphosphonate treatment after heart
transplant may include direct injection into all coronary arteries
after cardiac transplantation and periodically thereafter. Such
patients are frequently catheterized for biopsies and other
diagnostic or therapeutic procedures; these catheterizations may
provide a natural opportunity for targeted delivery of
bisphosphonate therapy in these disorders. In another alternative
embodiment, bisphosphonate treatment of myocarditis may be
performed by intracoronary injection at the time of diagnosis and
periodically thereafter. In yet another alternative embodiment,
bisphosphonate therapy for cardiomyopathy and various causes of HF
may be administered as either a single (one-time) or periodic
treatment.
[0056] Formulations in single dose unit form contain preferably
from about 1% to about 90%, and formulations not in single dose
unit form contain preferably from about 0.1% to about 20%, of the
zoledronic acid active ingredient. Pharmaceutical preparations for
enteral and parenteral administration are, for example, those in
dosage unit forms, such as drages, tablets or capsules and also
ampoules. They are prepared in a manner known per se, for example,
by means of conventional mixing, granulating, confectioning,
dissolving or lyophilizing processes.
[0057] For example, pharmaceutical preparations for oral
administration can be obtained by combining the active ingredient
with solid carriers, where appropriate granulating a resulting
mixture, and processing the mixture or granulate, if desired or
necessary after the addition of suitable adjuncts, into tablets or
drage cores. Suitable carriers are especially fillers, such as
sugars, for example, lactose, saccharose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, and also
binders, such as starch pastes, using, for example, corn, wheat,
rice or potato starch, gelatin, tragacanth, methylcellulose and/or
polyvinylpyrrolidone and, if desired, disintegrators, such as the
above-mentioned starches, also carboxymethyl starch, cross-linked
polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such
as sodium alginate. Adjuncts are especially flow-regulating agents
and lubricants, for example, silicic acid, talc, stearic acid or
salts thereof, such as magnesium or calcium stearate, and/or
polyethylene glycol. Drage cores are provided with suitable
coatings that may be resistant to gastric juices, there being used,
inter alia, concentrated sugar solutions that optionally contain
gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or
titanium dioxide, or lacquer solutions in suitable organic solvents
or solvent mixtures or, to produce coatings that are resistant to
gastric juices, solutions of suitable cellulose preparations, such
as acetylcellulose phthalate or hydroxypropylmethylcellulose
phthalate. Coloring substances or pigments may be added to the
tablets or drage coatings, for example for the purpose of
identification or to indicate different doses of active
ingredient.
[0058] Other orally administrable pharmaceutical preparations are
dry-filled capsules made of gelatin, and also soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The dry-filled capsules may contain the active ingredient in the
form of a granulate, for example, in admixture with fillers, such
as lactose; binders, such as starches; and/or glidants, such as
talc or magnesium stearate, and, where appropriate, stabilizers. In
soft capsules, the active ingredient is preferably dissolved or
suspended in suitable liquids, such as fatty oils, paraffin oil or
liquid polyethylene glycols, it being possible also for stabilizers
to be added.
[0059] Parenteral formulations are especially injectable fluids
that are effective in various manners, such as intra-arterially,
intramuscularly, intraperitoneally, intranasally, intradermally,
subcutaneously or preferably intravenously. Such fluids are
preferably isotonic aqueous solutions or suspensions which can be
prepared before use, for example, from lyophilized preparations
which contain the active ingredient alone or together with a
pharmaceutically acceptable carrier. The pharmaceutical
preparations may be sterilized and/or contain adjuncts, for example
preservatives, stabilizers, wetting agents and/or emulsifiers,
solubilizers, salts for regulating the osmotic pressure and/or
buffers.
[0060] Suitable formulations for transdermal application include an
effective amount of the zoledronic acid active ingredient with
carrier. Advantageous carriers include absorbable pharmacologically
acceptable solvents to assist passage through the skin of the host.
Characteristically, transdermal devices are in the form of a
bandage comprising a backing member, a reservoir containing the
compound optionally with carriers, optionally a rate controlling
barrier to deliver the active ingredient of the skin of the host at
a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[0061] In another embodiment, the present invention relates to
ensuring that the subject has an adequate level of Vitamin D before
the administration of the bisphosphonate compound and specifically
zoledronic acid. The level of Vitamin D can be easy determined by a
simple blood test that determines the level of Calcidiol
(25-hydroxyvitamin D). The unit dose of Vitamin D will be
determined by the specific form, the number of day of
administration, age and condition of patient, and level of
determined Vitamin D deficiency. For example, cholecalciferol may
in a unit tablet dose of from about 400 to 5000 IU or in
intramuscular form from about 50,000 units/cc to 100,000 units/cc;
egocalciferol in unit capsule dose of from about 400 to 50,000 IU;
oral calcitriol in a dose from about 0.10 to about 1 mcg which can
be administered at least once a day or in multiple administrations;
calcidiol or doxercalciferol, both of which are vitamin D analogues
may be administered in dose units of from about 300 to 2000 IU.
[0062] In yet another embodiment, the present invention relates to
a formulation that includes zoledronic acid, a form of Vitamin D
and optionally calcium in an essentially homogeneous mixture,
wherein a solution or solid unit dose can be administered in a
single dose. The single dose can be administered daily, monthly or
yearly, or at some intermediate interval depending on the
bisphosphonate compound.
[0063] In some applications, it may be advantageous to utilize the
active agent in a "vectorized" form, such as by encapsulation of
the bisphosphonate active agent in a liposome or other encapsulant
medium, or by fixation of the active agent, e.g., by covalent
bonding, chelation, or associative coordination, on a suitable
biomolecule, such as those selected from proteins, lipoproteins,
glycoproteins, and polysaccharides.
EXAMPLES
Material and Methods
Bisphosphonate Compound
[0064] Zoledronic acid (Zometa.RTM., Reclast.RTM.) bone density
conservation agent
IUPAC: (1-hydroxy-2-imidazol-1-yl-1-phosphoethyl)phosphonic acid
MF: C.sub.5H.sub.10N.sub.2O.sub.7P.sub.2/Entrez PCCompound CID:
68740
[0065] Zoledronic acid is FDA approved for the treatment of
postmenopausal osteoporosis, Paget's Disease of bone, and for the
prevention of skeletal complications in patients with certain
cancers such as multiple myeloma and prostate cancer.
Testing Animals
[0066] Gottingen miniswine were obtained from Marshall BioResources
in New York. The miniswine heart failure model created by Synecor
(N'diaye, 2008) manifests numerous sequelae of heart failure seen
in humans including significant systolic dysfunction, reduced
cardiac output, and LV dilatation and hypertrophy. Miniswine is an
ideal subspecies in which to create this model of heart failure for
numerous reasons. The coronary artery anatomy and distribution in
miniswine are remarkably similar to those in humans, as are their
heart-to-body size and weight ratios. Porcine and human hearts have
only a sparse collateral network, an essential quality when seeking
to reproduce the overall physiologic profile and clinical syndrome
associated with HF. The swine subject facilitates the creation of a
consistent and reproducible model. Miniswine in particular were
selected for their smaller size at sexual maturity, ease in
handling, and docile nature. Furthermore, the Gottingen miniswine
have been extensively used to model human metabolic bone disease,
especially osteoporosis.
[0067] All animal husbandry was done in accordance to The Guide for
the Care and Use of Laboratory Animals published by the Institute
of Laboratory Animal Resources Commission on Life Science National
Research Council, NATIONAL ACADEMY PRESS, 1996, and applicable USDA
regulations without exception. Animals were housed on site for a
minimum of 1 week prior to study assignment. Appropriate SOPs and
protocols were followed for housing conditions, health status
review, diet, pre-op instructions, and post operative care. All
animals remained on site for the duration of the study. Prior to
transport, the animals were inspected by the veterinarian and
cleared for transport and for use in the research study. The
animals were transported in a climate controlled truck and have
access to water at all times. During transport the animals were
checked every four hours to assure their safety and ensure that
water was available. All Synecor animals were identified by a
unique number which was either tattooed in ear or by ear tag.
Description of Experimental Design and Identification of Animal
Procedures.
[0068] Experimental Design:
[0069] The miniswine underwent sequential coronary embolization
procedures to induce irreversible heart failure. Two to four weeks
before the study, each animal was given 20,000 to 40,000 IU of
cholecalciferol orally. Sequential coronary embolization procedures
were performed on each animal in the manner described in IACUC
Protocol No. 014-12-06 until EF.ltoreq.35% or at least 20% less
than the original reading. Specifically, each animal underwent
sequential cardiac catheterizations for embolization of the LAD
with gelatin sponge particles. All interventional procedures were
performed using sterile technique under general anesthesia with
adequate post-operative pain control. Embolization procedures were
performed every 1-2 weeks until EF (measured
pre-embolization).ltoreq.35% or at least 20% less than the original
reading. This technique eventually exhausted the ability of the
myocardium to compensate for ischemic injury, leading to HF
characterized by decreased ejection fraction, increased SVR, LV
hypertrophy and increased LV end-diastolic volume, increased PCWP,
increased ANF and norepinephrine secretion, and patchy myocardial
fibrosis on histologic examination (Sabbah et al. 1991, Sakaguchi
et al. 2003, Li et al. 2005).
[0070] After a 2 week stabilization period followed by
documentation of persistent HF by cardiac catheterization, animals
were randomly assigned to a standard dose drug group or control
group. Baseline studies in addition to the echocardiogram included
24 hr Holter monitoring and measurement of serum, plasma, and
cellular biomarkers. The animals were treated with the study drug
or placebo 24 hours after acquisition of the baseline studies. Over
the next 12 weeks the miniswine were maintained as described below
and studies were performed at intervals as summarized in Table
1.
TABLE-US-00001 Baseline - Documented HF 24 Hrs 1 Week 2 Weeks 6
Weeks 12 Weeks Procedure (Day 1) (Day 2) (Day 7) (Day 14) (Day 42)
(Day 84) Echocardiogram X X X X 24 Hour Holter X X X X X X (0-24
hrs) (24-48 hrs (24 hrs prior post-drug) to endpoint study) Blood X
X X X X X Draw/Markers Study Drug Infusion X 15 min infusion
[0071] Study Drug:
[0072] zoledronic acid (bone density conservation agent) to be
administered as follows: [0073] a. Group 1 (Control) animals
received a 15-30 cc saline placebo infusion. [0074] b. Group 2
(Standard Dose) animals received an intravenous infusion of 100
microgram/kilogram body weight of zoledronic acid in 15 cc of 0.5
normal saline over 15 minutes.
[0075] Interventional Procedures:
[0076] Coronary Embolization:
[0077] Each animal underwent .gtoreq.2 cardiac catheterizations for
embolization of the LAD with gelatin sponge particles. Embolization
procedures were performed every 2 weeks until EF (measured
pre-embolization)<35% or at least 20% less then the original
reading. A 20 mg piece of gelatin sponge (Gelfoam; Pharmacia &
Upjohn, Peapack, N.J.) was cut into 1 mm.sup.3 pieces) and mixed
with 2 ml contrast media and 2 ml heparinized saline. 1.0 ml of the
gelatin-sponge mixture was injected over 90 seconds into the LAD
between the first and second diagonal branches. Embolization was
repeated every 30 minutes until significant impairment of LAD fill
time or malignant arrhythmia occurs. Bretylium tosylate (5 mg/kg)
was administered prior to embolization to reduce the risk of
arrhythmia. (Schumann 1993). EKG was monitored continuously
throughout the procedure.
[0078] Hemodynamic Assessment:
[0079] The hemodynamic assessments described here were performed
during each interventional procedure. Aortic and LV end-diastolic
pressures were measured at baseline, throughout, and up to 1 hour
after each microembolization procedure via catheter-tip
micromanometers (Millar Instruments, Houston, Tex.). PCWP, PA, RA,
and RV pressures were measured during the same timeframe using a
Swan-Ganz catheter with coupled pressure transducer. Triplicate
cardiac output measurements were performed using the thermodilution
technique. Arterial pressure was measured continuously via the
femoral arterial sheath.
[0080] Coronary Angiography:
[0081] Cineangiography and ventriculography was performed before
and after each embolization procedure to assess LV volumes and LAD
fill time.
[0082] Continuous Holter Monitoring was performed for 24 hrs pre-
and post-drug infusion, and also for 24 hrs each at 1 week, 2
weeks, 6 weeks, and 12 weeks.
[0083] Biomarkers:
[0084] The following biomarkers were assessed at baseline, 24 hrs,
1 week, 2 weeks, 6 weeks, and 12 weeks: CRP, IL6, IL-1, IL-18, BNP,
TNF alpha, ESR, osteoprotogerin, cardiac specific troponins,
dendritic cell proliferation assay (flow cytometry), gamma-delta T
cell assay (flow cytometry), granzyme release (measuring activity
of CD8 lymphocytes), interferon gamma assay (activity of CD4
lymphocytes/Th1 helper response), quantative immunoglobulin levels
(B cell function), 25-hydroxyvitamin D, PTH, CTX-1, CTX-2, P1NP,
and osteocalcin. Alternatively or in addition, blood was banked at
these time points for analysis at a later date.
[0085] Necropsy and histology was performed after each animal is
euthanized under anesthesia at 12 weeks. Animals initiate the study
3 at a time, staggered at 6 week intervals.
Example 1
[0086] The utility of the a bisphosphonate compound of the present
invention as medical agents in the treatment or prevention of HF in
animals, particularly mammals (e.g. humans) was demonstrated by the
activity of the compounds in in vivo testing described below.
[0087] This example describes the treatment of a miniswine for
induced heart failure. Approximately 1 week before the procedure to
create heart failure, the swine was given 10-15,000 IU of
cholecalciferol orally. The miniswine underwent sequential coronary
embolizations to create heart failure in the manner described
above. Catheterizations were performed under general anesthesia and
the microembolization procedures were discontinued when ejection
fraction (EF) was approximately .gtoreq.20% relative to the initial
testing baseline.
[0088] After the swine developed heart failure as evidenced by the
reduction in EF value, the swine was then treated with zoledronic
acid. Swine 1 (2514), 2 (4997) 3 (5272) and 4 (6928) received an
intravenous infusion of 100 microgram/kilogram body weight of
zoledronic acid in 15 cc of 0.5 normal saline over 15 minutes.
Swine 5 (6167), 6 (7479), 7 (5760) and 8 (0492) received a 15 cc
saline placebo infusion.
[0089] After the administration of the drug and placebo, the EF was
tested approximately every 2 weeks. The results for both the
control and zoledronic acid group are shown in FIG. 1. As evidenced
by the results set forth in FIG. 1, the swine 2514 had an ejection
fraction at baseline that was at least 70% and during the series of
embolizations, the swine 2514 had a reduction to 40% (a value
consistent with heart failure). Notably on day 42, swine 2514 was
embolized for a final time that effected the reduction to 40% EF.
100 ug/kg of zoledronic acid was then administered in this test
animal (2514) and 14 days after the zoledronic acid was
administered to the test animal, the ejection fraction had
increased almost to 57.8% which was held for approximately 12
weeks. Test swine 2, 3 and 4, also exhibited an increase in EF.
Notably, the control swine did not exhibit an increase in the
ejection fraction and stay at essentially the same level of
ejection fraction after completion of embolization.
[0090] FIG. 2 graphically illustrates the average values of the
control and zoledronic treated swine as set forth in FIG. 1 and it
is evident that after treatment with zoledronic acid, the ejection
fraction slowly increased over the six week period. Notably the
effect was statically significant. The control group did not see a
similar effect. This result indicates that the zoledronic acid
compound reduced the effects of heart failure.
[0091] FIG. 3 graphically illustrates that at the end of six weeks
there was almost a 12% increase in the ejection fraction, which is
time-dependent and statistically significant. In the control the
increase in the control group of swine showed approximately a 1%
increase. Based on the above data, it may be concluded that
treatment with a bisphosphonate is effective and can be proposed as
a therapy for improvement of cardiac function in a variety of
disease states, including HF.
[0092] Although the invention has been described with reference to
specific preferred embodiments, it will be appreciated that many
variations may be made to the invention without departing from the
spirit or scope thereof. All such modifications are intended to be
included within the scope of the following claims.
REFERENCES
[0093] All references cited herein are hereby incorporated by
reference herein for all purposes. [0094] Colon-Emeric C, Caminis
J, Suh T T, Pieper C F, Janning C, Magaziner J, Adachi J,
Rosario-Jansen T, Mesenbrink P, Horowitz Z D, Lyles K W The HORIZON
Recurent Fracture Trial: Design of a clinical trial in the
prevention of subsequestn fractures in elders after low trauma hip
fracture repair. Curr Med Opin Res., 2004; 20:903-910. [0095]
N'diaye C S, O'Connor C M. Progressive myocardial dysfunction
induced in porcine model by two-stage coronary embolization with
gelatin sponge. Poster presented at Alpha Omega Alpha Research
Symposium Duke University Medical Center, Aug. 8, 2008. [0096] Li H
H, Shen Z Y, Hui J, Li K, Zheng L, Jiao P, Teng X M, Zhu J Z, Gao W
D, Yang J H, Zhou B Y. 2005. A pig model of myocardial infarction
by intracoronary embolization with gelatin sponge [abstract in
English; article in Chinese]. Zhonghua Yi Xue Za Zh, 85(9):599-601.
[0097] Lloyd-Jones D, Adams R, Carnethon M, et al. Heart Disease
and Stroke Statistics--2009 Update: A Report From the American
Heart Association Statistics Committee and Stroke Statistics
Subcommittee. Circulatio., Jan. 27, 2009 2009; 119(3):e21-181.
[0098] Lyles K W, Colon-Emeric C S, Magaziner J S, Adachi J D,
Pieper C F, Mautalen C, Hylstrup L, Recknor C, Nordsletten L, Moore
K A, Lavecchia C, Zhang J, Mesenbrink P, Hodgson P K, Abrams K,
Orloff J J, Horowitz Z, Eriksen E F, Boonen S. Zoledronic acid and
clinical Fractures and Mortality after Hip Fracture. N Engl J Med.,
2007; 357:1799-1809. [0099] Reinwald S, Burr D. Review of
Nonprimate Large Animal Models for Osteoporosis Research. J Bone
Miner Res 2008 23:1353-13468. [0100] Rosen, C J. Postmenopausal
Osteoporosis. N Engl J Med., 2005 353:595-603. [0101] Sabbah H N,
Stern P D, Kono T, Gheorgiade M, Levine T B, Jafri S, Hawkins E T,
Goldstein S. A canine model of chronic heart failure produced by
multiple sequential microembolizations. Am J Physiol Heart Circ
Physio., 1991; 260(4):H1379-84. [0102] Sakaguchi G, Sakakibara Y,
Tambara K, Lu F, Premaratne G, Nishimura K, Komeda M. 2003. A pig
model of chronic heart failure by intracoronary embolization with
gelatin sponge. Ann Thorac Surg., 75:1942-7. [0103] Schumann R E,
Harold M E, Gillette P C, Swindle M M, Gaymes C H. Prophylactic
treatment of miniswine with bretylium for experimental cardiac
catheterization. Lab Anim Sci., 1993 June; 43(3):244-6. [0104]
Swindle, M M. Technical bulletin: anesthesia and analgesia in
mimiswine http://www.sinclairresearch.com/PDF Files/anesthesia and
analgesia in miniswine.pdf [0105] Swindle M M, Horneffer P J,
Gardner T J, Gott V L, Hall T S, Stuart R S, Baumgartner W A,
Borkon A M, Galloway E, Reitz B A. Anatomic and anesthetic
considerations in experimental cardiopulmonary surgery in
miniswine. Lab Anim Sci., 1986 August; 36(4):357-61. [0106] Varela
I, Pereira S, Ugalde A P, Navarro C L, Suarez M F, Cau P, Cadinanos
J, Osorio F G, Foray N, Cobo J, de Carlos F, Levy N, Freije J M P,
Lopez-Otin C. Combined treatment with statins and
aminobisphosphonates extends longevity in a mouse model of human
premature aging. Nature Medicine, 2008; 14:767-772.
* * * * *
References