U.S. patent application number 16/050798 was filed with the patent office on 2018-12-13 for compositions and methods of treating muscular dystrophy with thromboxane-a2 receptor antagonists.
The applicant listed for this patent is Cumberland Pharmaceuticals Inc., Vanderbilt University. Invention is credited to Erica Carrier, Ines Macias-Perez, Leo PAVLIV, James WEST.
Application Number | 20180353481 16/050798 |
Document ID | / |
Family ID | 60267383 |
Filed Date | 2018-12-13 |
United States Patent
Application |
20180353481 |
Kind Code |
A1 |
PAVLIV; Leo ; et
al. |
December 13, 2018 |
Compositions and Methods of Treating Muscular Dystrophy with
Thromboxane-A2 Receptor Antagonists
Abstract
The present invention is directed to methods of treating and/or
ameliorating muscular dystrophy and/or treating cardiomyopathy in
muscular dystrophy patients by administration of a therapeutically
effective amount of a thromboxane A.sub.2 receptor antagonist.
Inventors: |
PAVLIV; Leo; (Cary, NC)
; WEST; James; (Nashville, TN) ; Macias-Perez;
Ines; (Mt. Juliet, TN) ; Carrier; Erica;
(Nashville, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cumberland Pharmaceuticals Inc.
Vanderbilt University |
Nashville
Nashville |
TN
TN |
US
US |
|
|
Family ID: |
60267383 |
Appl. No.: |
16/050798 |
Filed: |
July 31, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15592727 |
May 11, 2017 |
10064845 |
|
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16050798 |
|
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62334748 |
May 11, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 21/04 20180101;
A61P 1/00 20180101; A61P 21/00 20180101; A61P 9/00 20180101; A61K
31/422 20130101; A61P 9/10 20180101; A61P 1/04 20180101 |
International
Class: |
A61K 31/422 20060101
A61K031/422 |
Goverment Interests
[0001] This invention was made with government support under grant
numbers R01HL095797 and P01HL108800 awarded by the National
Institutes of Health. The government has certain rights in the
invention.
Claims
1. A method of treating or ameliorating muscular dystrophy in a
subject in need of treatment thereof, comprising administering a
therapeutically effective amount of a thromboxane A.sub.2 receptor
antagonist to the patient.
2. The method of claim 1, wherein the muscular dystrophy is
fibrosis is selected from the group consisting of Duchenne MD
(DMD), Becker MD, and Limb-Girdle MD.
3. The method of claim 1, further comprising administering the
thromboxane A.sub.2 antagonist to the patient on a chronic
basis.
4. The method of claim 3, wherein the cardiac function of the
patient is maintained or improved.
5. The method of claim 3, wherein the thromboxane A.sub.2 receptor
antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid (Ifetroban), and pharmaceutically acceptable salts
thereof.
6. The method of claim 3, wherein the thromboxane A.sub.2 receptor
antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt (Ifetroban Sodium).
7. The method of claim 1, wherein the thromboxane A.sub.2 receptor
antagonist is administered orally, intranasally, rectally,
vaginally, sublingually, buccally, parenterally, or
transdermally.
8. The method of claim 1, wherein the thromboxane A.sub.2 receptor
antagonist is administered parenterally.
9. The method of claim 1, wherein the thromboxane A.sub.2 receptor
antagonist is administered orally.
10. The method of claim 3, wherein the thromboxane A.sub.2 receptor
antagonist is administered prophylactically to prevent
cardiomyopathy in the patient.
11. The method of claim 3, wherein the thromboxane A.sub.2 receptor
antagonist is administered prophylactically to prevent
gastrointestinal dysfunction in the patient.
12. The method of claim 3, wherein the therapeutically effective
amount is from about 50 mg to about 500 mg.
13. The method of claim 5, wherein the therapeutically effective
amount is from about 150 mg to about 350 mg per day and the
ifetroban is administered orally.
14. A method of treating cardiac and/or gastrointestinal
dysfunction in a human patient suffering from muscular dystrophy,
comprising chronically administering a therapeutically effective
amount of a thromboxane A.sub.2 receptor antagonist to the human
patient.
15. The method of claim 14, wherein the therapeutically effective
amount is from about 100 mg to about 500 mg.
16. The method of claim 14, wherein the thromboxane A.sub.2
receptor antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid (Ifetroban), and pharmaceutically acceptable salts
thereof.
17. The method of claim 16, wherein the thromboxane A.sub.2
receptor antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt (Ifetroban Sodium).
18. The method of claim 16, wherein the therapeutically effective
amount is from about, 150 mg to about 350 mg per day and the
ifetroban is administered orally.
19. The method of claim 13, wherein the gastrointestinal
dysfunction is smooth muscle dysfunction.
20. The method of claim 16, wherein the therapeutically effective
amount of ifetroban provides improved ventricular function to the
heart of the patient.
Description
FIELD OF THE INVENTION
[0002] The present invention is related to the use of thromboxane
A.sub.2 receptor antagonists (e.g., Ifetroban) in the treatment of
muscular dystrophy in mammals, e.g., humans, and pharmaceutical
compositions for the same comprising thromboxane A.sub.2 receptor
antagonists (e.g., Ifetroban) in an effective amount to treat these
diseases.
BACKGROUND OF THE INVENTION
[0003] Muscular Dystrophy (MD) is a group of 30+ diseases that
causes progressive weakness and loss of muscle mass due to
mutations in dystrophin, a protein needed to form healthy muscle.
Duchenne MD (DMD) comprises half of MD; affects 1 in 3,500 boys and
1/3 have no family history. Onset is between ages 2 and 3 and
progresses rapidly. Becker MD (BMD) is the 2nd most common form of
MD; 1 in 30,000 boys; BMD is milder and slowly progresses compared
to DMD; symptoms may not be seen until teens, mid-20s or later.
Limb-Girdle MD (LGMD) can affects as many as 1 in 14,500 and causes
weakness and wasting of the muscles in the proximal arms and
legs.
[0004] Complications of muscular dystrophy include inability to
walk, breathing problems, scoliosis, cardiomyopathy and swallowing
problems. There is no cure. Treatment to-date is to manage symptoms
or slow progression.
[0005] Delta-sarcoglycan (DSG) is a transmembrane glycoprotein
which forms as a complex, the dystrophin-associated glycoprotein
complex (DGC). The DGC plays a central role in maintaining
integrity of the cell membrane by linking the extracellular matrix
("ECM"; a substance containing collagen, elastin, proteoglycans,
glycosaminoglycans, and fluid, produced by cells and in which the
cells are embedded) and cytoskeleton (the inner structural
elements, or backbone, of a cell. It consists of microtubules and
various filaments that spread out through the cytoplasm, providing
both structural support and a means of transport within the
cell).
[0006] In both skeletal and cardiac muscle, the DGC consists of
dystrophin, the syntrophins, a- and b-dystroglycan (a-, b-DG), the
sarcoglycans (a-, b-, g-, d-SG), and sarcospan (SSPN).
[0007] Mutations in the dystrophin gene lead to high incidence of
cardiomyopathy in DMD and BMD. Mutations in sarcoglycans within DGC
are responsible for Limb-Girdle MD and associated with
cardiomyopathy. A major function of dystrophin is to strengthen the
sarcolemma by cross-linking the ECM with the cytoskeleton. Utrophin
and a7b1 integrin fulfil the same function. Dystrophin works to
connect sarcolemma to cytoplasmic actin cytoskeleton. Dysfunction
produces membrane instability, elevated [Ca2+]I and disrupted NO
signaling. .gamma.- and .delta.-SG form a core necessary for
delivery/retention of other SG to the membrane.
[0008] Patients with mutations in DSG (e.g., patients suffering
from muscular dystrophy) present with cardiomyopathy.
[0009] Absence of dystrophin in Duchenne muscular dystrophy (DMD)
causes progressive breakdown of muscle cells. In the heart, loss of
dystrophin leads to abnormally increased intracellular calcium,
degradation of contractile proteins, fibrosis, and myocardial
death. With advances in respiratory support, cardiomyopathy is now
a primary cause of death amongst DMD patients. DM D patients
develop an insidious decline in cardiac function leading to heart
failure and can also develop arrhythmias, with the potential for
sudden cardiac death, even with minimal decrease in cardiac
function by physical symptoms or echocardiography. Because of this,
cardiac magnetic resonance (CMR) is useful for detection of early
cardiac involvement in DMD patients. Increased myocardial fibrosis
and expanded extracellular volume in CMR predicts left ventricular
(LV) dysfunction, and are associated with an increased risk of
arrhythmia and hospitalization for heart failure or death.
[0010] While less severely affected than skeletal and cardiac
muscle, intestinal smooth muscle function can also be altered by
atrophy and fibrosis. In DMD patients, particularly when
wheelchair-bound, this can lead to poor gut motility,
gastroesophageal reflux, and chronic constipation, which negatively
affect patient quality of life. More critically, the possible
complications of dilatation, fecal impaction, or intestinal
pseudo-obstruction can be life-threatening.
[0011] The cellular damage characteristic of DMD is also associated
with increased formation of reactive oxygen species, or oxidative
stress. (Grosso, et al., Isoprostanes in dystrophinopathy: Evidence
of increased oxidative stress. Brain Dev. 2008; 30(6):391-5.
doi:10.1016/j.braindev.2007.11.005. PubMed PMID: 18180123). These
free radicals can react with membrane phospholipids to form
isoprostanes, which circulate freely after release by
phospholipase, and the relatively stable 15-F2t-isoprostane
(F2-IsoP) is a primary biomarker of in vivo oxidative stress.
(Montuschi, et al., Isoprostanes: markers and mediators of
oxidative stress. FASEB J. 2004; 18(15):1791-800.
doi:10.1096/fj.04-2330rev). Plasma F2-IsoP levels are increased in
DMD patients (Grosso, et al., cited above), and urinary F2-IsoP
levels are increased in heart failure patients, where they
correlate with the severity of the disease (Cracowski, et al.,
Increased formation of F(2)-isoprostanes in patients with severe
heart failure. Heart. 2000; 84(4):439-40. PubMed PMID:10995421;
PMCID: PMC172944614). In addition to heralding cellular stress,
isoprostanes can also be the source of damage via activation of the
thromboxane/prostanoid receptor (TPr), and F2-isoP signaling
through the TPr decreases angiogenesis and causes vasoconstriction
(Bauer, et al., Pathophysiology of isoprostanes in the
cardiovascular system: implications of isoprostane-mediated
thromboxane A2 receptor activation. Brit J Pharmacol. 2014;
171:3115-3115) and fibrosis (Acquaviva, et al. Signaling pathways
involved in isoprostane-mediated fibrogenic effects in rat hepatic
stellate cells. Free Radic Biol Med. 2013; 65:201-7,
doi:10.1016/j.freeradbiomed.2013.06.023. PubMed PMID: 23792773;
Comporti, et al. Isoprostanes and hepatic fibrosis, Mol Aspects
Med. 2008; 29(1-2):43-9. doi: 10.1016/j.mam.2007.09.011. PubMed
PMID: 18061254).
[0012] Fibrosis is the formation of excess fibrous connective
tissue in an organ or tissue in a reparative or reactive process.
This can be a reactive, benign, or pathological state, and
physiologically acts to deposit connective tissue, which can
obliterate the architecture and function of the underlying organ or
tissue. Fibrosis can be used to describe the pathological state of
excess deposition of fibrous tissue, as well as the process of
connective tissue deposition in healing. While the formation of
fibrous tissue is normal, and fibrous tissue is a normal
constituent of organs or tissues in the body, scarring caused by a
fibrotic condition may obliterate the architecture of the
underlying organ or tissue.
[0013] To date, there are no commercially available therapies that
are effective in treating or preventing fibrotic disease.
Conventional treatment frequently involves conicosteroids, such as
prednisone, and/or other medications that help improve muscle
strength and delay the progression of certain types of muscular
dystrophy. Also, heart medications, such as angiotensin-converting
enzyme (ACE) inhibitors or beta blockers may be administered to
muscular dystrophy patients, if the muscular dystrophy damages the
heart.
SUMMARY OF THE INVENTION
[0014] It is an object of the present invention to provide new
methods of treating muscular dystrophy in mammals, e.g.,
humans.
[0015] In accordance with the above objects, the present invention
provides for methods of treating muscular dystrophy by
administering a therapeutically effective amount of a thromboxane
A.sub.2 receptor antagonist to a patient in need thereof.
[0016] In accordance with the above objects and others, the present
invention is directed in part to a method of treating or
ameliorating muscular dystrophy in a subject in need of treatment
thereof, comprising administering a therapeutically effective
amount of a thromboxane A2 receptor antagonist to the patient. The
muscular dystrophy is fibrosis is selected from the group
consisting of Duchenne MD (DMD), Becker MD, and Limb-Girdle MD. The
thromboxane A2 receptor antagonist may be administered orally,
intranasally, rectally, vaginally, sublingually, buccally,
parenterally, or transdermally. In certain preferred embodiments,
the method further comprises administering the thromboxane A2
antagonist to the patient on a chronic basis. In certain
embodiments, the thromboxane A.sub.2 receptor antagonist comprises
a therapeutically effective amount of
[S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbonyl-
]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid (Ifetroban), and pharmaceutically acceptable salts thereof. In
certain embodiments, the thromboxane A.sub.2 receptor antagonist
comprises a therapeutically effective amount of
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt (Ifetroban Sodium). In certain preferred
embodiments, the cardiac function of the patient is maintained or
improved. Certain embodiments of the invention are directed to the
method, wherein the thromboxane A2 receptor antagonist is
administered prophylactically to prevent cardiomyopathy in the
patient, and/or to prophylactically to prevent gastrointestinal
dysfunction in the patient. In certain preferred embodiments, the
therapeutically effective amount is from about 50 mg to about 500
mg. In certain preferred embodiments, the thromboxane A2 receptor
antagonist is ifetroban and the therapeutically effective amount is
from about 150 mg to about 350 mg per day. In certain embodiments,
the ifetroban is administered orally. In certain embodiments, the
present invention is directed to a method of treating and/or
ameliorating muscular dystrophy in a patient in need thereof,
comprising administering to a patient in need thereof a
therapeutically effective amount of a thromboxane A.sub.2 receptor
antagonist to provide a desired plasma concentration of the
thromboxane A.sub.2 receptor antagonist of about 0.1 ng/ml to about
10,000 ng/ml.
[0017] The invention is also directed to a method of providing
cardioprotective effects to a human patient(s) suffering from
muscular dystrophyvia the administration of a thromboxane A.sub.2
receptor antagonist as described herein.
[0018] The invention is further directed to a method of improving
right heart adaptation to load stress in a human patient(s)
suffering from muscular dystrophy via the administration of a
thromboxane A.sub.2 receptor antagonist as described herein.
[0019] The invention is further directed to a method of treating
cardiac and/or gastrointestinal dysfunction in a human patient
suffering from muscular dystrophy, comprising chronically
administering a therapeutically effective amount of a thromboxane
A2 receptor antagonist to the human patient. In certain preferred
embodiments, the thromboxane A2 receptor antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid (Ifetroban), and pharmaceutically acceptable salts thereof,
and in certain most preferred embodiments the thromboxane A2
receptor antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carb-
onyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt (Ifetroban Sodium). The therapeutically
effective amount may be, e.g., from about 100 mg to about 500 mg.
The thromboxane A2 receptor antagonist may be administered, e.g.,
in an amount from about 50 or 100 mg to about 500 mg per day. In
certain embodiments, the thromboxane A2 receptor antagonist is
ifetroban or a pharmaceutically acceptable salt thereof and the
daily dose is from about 150 mg to about 350 mg per day. In certain
embodiments, the ifetroban is administered orally. In certain
embodiments, the gastrointestinal dysfunction is smooth muscle
dysfunction. In certain embodiments, the therapeutically effective
amount of ifetroban provides improved ventricular function to the
heart of the patient.
[0020] The present invention also relates to methods and
compositions for treating muscular dystrophy in a mammal(s) or
human(s) in need of treatment thereof, the method comprising
administering a therapeutically effective amount of a thromboxane
A.sub.2 receptor antagonist to a subject(s) or patient(s) in need
thereof. Preferably, the method of treatment comprises
administering a composition comprising administering a
therapeutically effective amount of a thromboxane A.sub.2 receptor
antagonist to a muscular dystrophy patient in need thereof in an
amount effective to improve heart function. Further provided is a
method of preventing fibrosis or sclerosis in a subject(s) or
patient(s) in need of such treatment, comprising administering a
composition comprising a thromboxane A.sub.2 receptor antagonist in
an amount effective to reduce the formation of fibrotic or
sclerotic tissue that would occur in the absence of such
treatment.
[0021] In a certain embodiment, the fibrosis is associated with a
fibroproliferative disease selected from the group consisting of
heart fibrosis, kidney fibrosis, liver fibrosis, lung fibrosis, and
systemic sclerosis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0023] FIG. 1A is a photograph of a vehicle-treated DKO (double
knockout) Mouse at 10 weeks;
[0024] FIG. 1B is a photograph of an ifetroban-treated DKO mouse at
10 weeks;
[0025] FIG. 2 is a graph showing plasma cTNI in dSG KO males at 3
months (vehicle-treated versus ifetroban-treated);
[0026] FIG. 3 is a graph showing 3 month Echo data in mice
(WT(wild-type), dSG-vehicle and dSG-ifetroban treated);
[0027] FIG. 4 is a graph providing cardiac output data for male
mice at 3 months (WT, dSG KO-vehicle and dSG KO-ifetroban
treated);
[0028] FIG. 5 is a graph providing spontaneous exercise data for 6
month old males (WT, dSG-vehicle and dSG-ifetroban treated);
[0029] FIG. 6 is a graph showing average wire hang time in male
mice at 6 months (WT, dSG-vehicle and dSG-ifetroban treated);
[0030] FIG. 7 is a graph showing the results of a wire hanging
experiment (average hang time) at 6 months (WT, dSG; vehicle versus
ifetroban-treated; P=0.0056 for genotype by 2-way ANOVA);
[0031] FIG. 8 is a graph showing 6 month wire hang time (longest
time) for male mice tested (WT, dSG-vehicle, dSG-ifetroban
treated);
[0032] FIGS. 9A (dSGKO-vehicle) and 9B (DsGKO-ifetroban) show
cardiac histology in dSG KO males. Less fibrosis seen in ifetroban
treated RV. Shown is Masson's trichrome at 4.times. for gross
histology. All tears/folds/red hotspots from slice preparation and
not pathology. Some RV may also be affected by slicing
(arrows).
[0033] FIGS. 10A(dSG-Veh), 10B(dSG-veh), 10C(dSG-ifetroban) and
10D(dSG-ifetroban) show cardiac histology in dSG KO males (using
Masson's trichrome, 2.times.). It can be seen that there is less
fibrosis in the ifetroban treated RV. RV=right ventricle.
[0034] FIGS. 11A1, 11A2, 11A3 and 11A4 shows cardiac histology in
dSG KO males (using Masson's trichrome, 10.times.) in the left
ventricle (11A1=mouse #1, dSG KO-vehicle; 11A2=mouse #2, dSG
KO-vehicle; 11A3=mouse #1, dSG KO-ifetroban; and 11A4=mouse #2, dSG
KO-ifetroban); FIGS. 11B1, 11B2, 11B3 and 11B4 shows cardiac
histology in the right ventricle (11B1=mouse #1, dSG KO-vehicle;
11B2=mouse #2, dSG KO-vehicle; 11B3=mouse #1, dSG KO-ifetroban; and
11B4=mouse #2, dSG KO-ifetroban). LV=left ventricle; RV=right
ventricle. Less fibrosis was seen in ifetroban-treated KO mice.
[0035] FIGS. 12A(WT1), 12B(dSG-KO-vehicle), 12C(WT2) and
12D(dSG-KO-ifetroban) shows skeletal muscle histology in WT and dSG
KO males (tibialis cross-section, using Masson's trichrome). Some
fibrosis may be due to specific section of muscle.
[0036] FIGS. 13A(WT-vehicle), 13B(WT-ifetroban), 13C(dSG
KO-vehicle) and 13D(dSG-KO-ifetroban) are cross-sections of
intestinal tissue showing that ifetroban may prevent the loss of
intestinal smooth muscle in the large intestine Muscularis. The DSG
KO mice were missing smooth muscle (especially missing longitudinal
smooth muscle) while ifetroban-treated mice have similar sections
to WT smooth muscle. "H&E"=Hematoxylin & eosin.
[0037] FIG. 13 shows that ifetroban-treated dSG KO mice have less
fibrosis than vehicle-treated dSG KO mice.
[0038] FIGS. 14A and 14B are graphs showing the percent survival of
dSG KO males (14A) and dSG females (14B) treated with ifetroban or
vehicle.
[0039] FIG. 15 are graphs showing wire hang in WT and DKO males at
10 weeks (ifetroban-treated ("ifr") versus vehicle);
[0040] FIG. 16 is a graph showing spontaneous running in WT and DKO
mice measured from 9-10 weeks (DKO-vehicle and DKO-ifetroban
treated); and
[0041] FIG. 17 is a graph showing survival for all DKO mice
(vehicle and ifetroban treated).
DETAILED DESCRIPTION OF THE INVENTION
[0042] In accordance with the above stated objects, it is believed
that administration of a therapeutically effective amount of a
thromboxane A.sub.2 receptor antagonist to a subject(s) or
patient(s) in need thereof can treat cardiomyopathy associated with
muscular dystrophy.
[0043] The phrase "therapeutically effective amount" refers to that
amount of a substance that produces some desired local or systemic
effect at a reasonable benefit/risk ratio applicable to any
treatment. The effective amount of such substance will vary
depending upon the subject and disease condition being treated, the
weight and age of the subject, the severity of the disease
condition, the manner of administration and the like, which can
readily be determined by one of ordinary skill in the art.
[0044] The TPr is a G protein-coupled receptor which is located in
platelets, immune cells, smooth muscle, and cardiomyocytes, and its
activation has deleterious consequences in the heart. We have
recently shown (in our U.S. Patent Application Publication No.
2015/0328190) that blockade of the TPr with the antagonist
ifetroban dramatically decreases right ventricular fibrosis and
improves cardiac function in a pressure-overload model of pulmonary
arterial hypertension. Although the TPr has multiple endogenous
ligands including F2-IsoP, thromboxane A2, prostaglandin H2, and
20-HETE, blockade of thromboxane synthase with ozagrel or
prostaglandin/thromboxane synthesis with aspirin had no effect on
fibrosis or cardiac function in our pressure-overload model. Thus,
F2-IsoP is an excellent candidate as an activating ligand of the
TPr in the stressed heart. Beyond the right ventricle, TPr
activation also contributes to LV hypertrophy and heart failure in
mouse models of systemic hypertension and Gh-overexpression. In
addition, TPr activation causes increased intracellular calcium,
arrhythmia, and cell death in ventricular cardiomyocytes, and
decreased peristalsis in the gut. Although the role of the TPr in
MD is unknown, these actions position the receptor to have an
impact on some of the most pressing concerns in DMD.
[0045] Applicants explored the possibility that TPr activity may
contribute to pathology in muscular dystrophy. In preliminary
studies, the effects of blocking TPr activity in a
.delta.-sarcoglycan knockout (dSG KO) mouse model of limb-girdle
muscular dystrophy (LGMD). We found that treatment with the
antagonist ifetroban, given in drinking water, limits the formation
of cardiac fibrosis and prevents a decline in cardiac function
while normalizing elevated plasma cardiac troponin I levels, a
clinically-used biomarker for cardiac injury. The inhibition of LV
epicardial fibrosis may have particular applicability to DMD
patients, where cardiac fibrosis typically begins in the
sub-epicardium of the left ventricular (LV) free wall and
progresses to include the remaining LV free wall and septum.
Ifetroban treatment also significantly improved survival in dSG KO
mice, and in utrophin/dystrophin double knockout (DKO) mice, a
model of severe DMD, TPr antagonism with ifetroban improved 10-week
survival from 56% to 100%. Therefore, it is believed that TPr
activity contributes to pathology in muscular dystrophy.
[0046] In accordance with the present invention, it is believed
that increased isoprostane signaling through the TPr contributes to
cardiomyopathy and smooth muscle dysfunction in DMD, and thus
treatment with ifetroban, an orally active TPr antagonist, will
improve cardiac and gut function and decrease spontaneous mortality
in mammals (as demonstrated in preclinical mouse models of DMD). It
is also believed that treatment with a thromboxane A.sub.2 receptor
antagonist (ifetroban) may contribute to cardioprotection by
increasing the regenerative capability of the heart, and therefore
may provide functional improvement of the heart (e.g., improved
ventricular function). Thus, the invention is directed in part to
the use of TPr antagonists as a treatment for cardiac and/or
gastrointestinal dysfunction in DMD. The invention is also directed
in part to the use of TPR antagonists for providing
cardioprotection by increasing the regenerative capability of the
heart and/or providing functional improvement of the heart of a
muscular dystrophy (human) patient.
[0047] The term "thromboxane A2 receptor antagonist" as used herein
refers to a compound that inhibits the expression or activity of a
thromboxane receptor by at least or at least about 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,
98%, 99%, or 100% in a standard bioassay or in vivo or when used in
a therapeutically effective dose. In certain embodiments, a
thromboxane A2 receptor antagonist inhibits binding of thromboxane
A.sub.2 to the receptor. Thromboxane A2 receptor antagonists
include competitive antagonists (i.e., antagonists that compete
with an agonist for the receptor) and non-competitive antagonists.
Thromboxane A2 receptor antagonists include antibodies to the
receptor. The antibodies may be monoclonal. They may be human or
humanized antibodies. Thromboxane A2 receptor antagonists also
include thromboxane synthase inhibitors, as well as compounds that
have both thromboxane A2 receptor antagonist activity and
thromboxane synthase inhibitor activity.
Thromboxane A.sub.2 Receptor Antagonist
[0048] The discovery and development of thromboxane A.sub.2
receptor antagonists has been an objective of many pharmaceutical
companies for approximately 30 years (see, Dogne J-M, et al., Exp.
Opin. Ther. Patents 11: 1663-1675 (2001)). Certain individual
compounds identified by these companies, either with or without
concomitant thromboxane A.sub.2 synthase inhibitory activity,
include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI),
UK-147535 (Pfizer), GR 32191 (Glaxo), and S-18886 (Servier).
Preclinical pharmacology has established that this class of
compounds has effective antithrombotic activity obtained by
inhibition of the thromboxane pathway. These compounds also prevent
vasoconstriction induced by thromboxane A.sub.2 and other
prostanoids that act on the thromboxane A.sub.2 receptor within the
vascular bed, and thus may be beneficial for use in preventing
and/or treating hepatorenal syndrome and/or hepatic
encephalopathy.
[0049] Suitable thromboxane A2 receptor antagonists for use in the
present invention may include, for example, but are not limited to
small molecules such as ifetroban (BMS; [1
S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(pentylamino)carbony-1-
]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2yl]methyl]benzenepropanoic
acid), as well as others described in U.S. Patent Application
Publication No. 2009/0012115, the disclosure of which is hereby
incorporated by reference in its entirety.
[0050] Additional thromboxane A2 receptor antagonists suitable for
use herein are also described in U.S. Pat. No. 4,839,384
(Ogletree); U.S. Pat. No. 5,066,480 (Ogletree, et al.); U.S. Pat.
No. 5,100,889 (Misra, et al.); U.S. Pat. No. 5,312,818 (Rubin, et
al.); U.S. Pat. No. 5,399,725 (Poss, et al.); and U.S. Pat. No.
6,509,348 (Ogletree), the disclosures of which are hereby
incorporated by reference in their entireties. These may include,
but are not limited to, interphenylene 7-oxabicyclo-heptyl
substituted heterocyclic amide prostaglandin analogs as disclosed
in U.S. Pat. No. 5,100,889, including:
[0051]
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[[(4-cyclo-hexy-
lbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]be-
nzenepropanoic acid (SQ 33,961), or esters or salts thereof;
[0052]
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[[[(4-chloro-ph-
enyl)-butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methy-
l]benzenepropanoic acid or esters, or salts thereof;
[0053]
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-3-[[3-[4-[[(4-cycloh-exy-
lbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo]2.2.1]hept-2-yl]benzene
acetic acid, or esters or salts thereof;
[0054]
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-[2-[[3-[4-[[(4-cyclohexy-
l-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]ph-
enoxy]acetic acid, or esters or salts thereof;
[0055]
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.]-2-[[3-[4-[[(7,7-dime-thyl-
octyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]be-
nzenepropanoic acid, or esters or salts thereof.
[0056] 7-oxabicycloheptyl substituted heterocyclic amide
prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889,
issued Mar. 31, 1992, including
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]-6-[3-[4-[[(4-cycl-
ohexylbutyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-h-
exenoic acid, or esters or salts thereof;
[0057]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-cyclohe-
xyl-butyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexe-
noic acid, or esters or salts thereof;
[0058]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[(4-cyclohex-
yl-buty)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-(2.2.1]hept-2-yl]-4-
-hexenoic acid, or esters or salts thereof;
[0059]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[(1-pyrrolid-
inyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid, or esters or salts thereof;
[0060]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-(cycloexylam-
ino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoic
acid or esters or salts thereof;
[0061]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(2-cyclohe-
xyl-ethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexe-
noic acid, or esters or salts thereof;
[0062]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[[2-(4-chlo-
ro-phenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-
-4-hexenoic acid, or esters or salts thereof;
[0063]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]-6-[3-[4-[[(4-chloroph-
enyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid, or esters or salts thereof;
[0064]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[[4-(4-clor-
o-phenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]--
4-hexenoic acid, or esters or salts thereof;
[0065]
[1S-[11.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4.alpha.-[[-(-
6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-y-
l]-4-hexenoic acid, or esters, or salts thereof;
[0066]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-L3-L4-[[(6-cyclohe-
xyl-hexyl)amino]carbonyl]-2-oxazoly]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexen-
oic acid, or esters or salts thereof;
[0067]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.]]-6-[3-[4-[(propylamino-
)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid, or esters or salts thereof
[0068]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-butylph-
enyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid, or esters or salts thereof;
[0069]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[(2,3-dihydr-
o-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo(2.2.1]hept-2-yl]-4-hexe-
noic acid, or esters or salts thereof;
[0070]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-cyclohe-
xyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(phe-
nylsulfonyl)-4-hexenamide;
[0071]
[1S-[11.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-cycloh-
exyl-butyl)amino]carbonyl]-2-oxazolyl]-N-(methylsulfonyl)-7-oxabicyclo[2-.-
2.1]hept-2-yl]-4-hexenamide;
[0072]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-7-[3-[4-[[(4-cyclohe-
xyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo
(2.2.1)hept-2-yl]-5-heptenoic acid, or esters or salts thereof;
[0073]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-cyclohe-
xyl-butyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2-yl]-
-4-hexenoic acid or esters or salts thereof:
[0074]
[1S-[1.alpha.,2.alpha.,3.alpha.,4.alpha.)]]-6-[3-[4-[[(7,7-dimethyl-
octyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoi-
c acid, or esters or salts thereof;
[0075]
[1S-[1.alpha.,2.alpha.(E),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-cyclohe-
xyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexe-
noic acid;
[0076]
[1S-[1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-3-[4-[[(4-(cyclohexylbut-
yl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoic
acid or esters or salts thereof;
[0077]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[4-[[(4-cyclohe-
xyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hex-
enoic acid, or esters or salts thereof;
[0078] 7-oxabicycloheptane and 7-oxabicycloheptene compounds
disclosed in U.S. Pat. No. 4,537,981 to Snitman et al, the
disclosure of which is hereby incorporated by reference in its
entirety, such as
[1S-(1.alpha.,2.alpha.(Z),3.alpha.(1E,3S*,4R*),4.alpha.)]]-7-[3-(3-hydrox-
y-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid (SQ 29,548); the 7-oxabicycloheptane substituted
aminoprostaglandin analogs disclosed in U.S. Pat. No. 4,416,896 to
Nakane et al, the disclosure of which is hereby incorporated by
reference in its entirety, such as
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-7-[3-[[2-(phenylamino)carb-
onyl]-hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid; the 7-oxabicycloheptane substituted diamide prostaglandin
analogs disclosed in U.S. Pat. No. 4,663,336 to Nakane et al, the
disclosure of which is hereby incorporated by reference in its
entirety, such as, [1S-[1.alpha.,
2.alpha.(Z),3.alpha.,4.alpha.)]]-7-[3-[[[[(1-oxoheptyl)amino]-acetyl]amin-
o]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid and the
corresponding tetrazole, and
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-7-[3-[[[[(4-cyclohexyl-1-o-
xobutyl)-amino]acetyl]amino]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-hepten-
oic acid;
[0079] 7-oxabicycloheptane imidazole prostaglandin analogs as
disclosed in U.S. Pat. No. 4,977,174, the disclosure of which is
hereby incorporated by reference in its entirety, such as
[S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[[4-(4-cyclohexyl-1-hy-
droxybutyl)-1H-imidazole-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexe-
noic acid or its methyl ester;
[0080]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[[4-(3-cyclohex-
yl-propyl)-1H]-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexen-
oic acid or its methyl ester;
[0081]
[1S-[1.alpha.,2.alpha.(X(Z),3.alpha.,4.alpha.)]]-6-[3-[[4-(4-cycloh-
exyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4--
hexenoic acid or its methyl ester;
[0082]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.]]-6-[3-(1H-imidazol-1-y-
lmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its
methyl ester; or
[0083]
[1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.)]]-6-[3-[[4-[[(4-cycloh-
exyl-butyl)amino]carbonyl]-1H-imidazol-1-yl]methyl-7-oxabicyclo-[2.2.1]-he-
pt-2-yl]-4-hexenoic acid, or its methyl ester;
[0084] The phenoxyalkyl carboxylic acids disclosed in U.S. Pat. No.
4,258,058 to Witte et al, the disclosure of which is hereby
incorporated by reference in its entirety, including
4-[2-(benzenesulfamido)ethyl]phenoxy-acetic acid (BM
13,177-Boehringer Mannheim), the sulphonamidophenyl carboxylic
acids disclosed in U.S. Pat. No. 4,443,477 to Witte et al, the
disclosure of which is hereby incorporated by reference in its
entirety, including
4-[2-(4-chlorobenzenesulfonamido)ethyl]-phenylacetic acid (BM
13,505, Boehringer Mannheim), the arylthioalkylphenyl carboxylic
acids disclosed in U.S. Pat. No. 4,752,616, the disclosure of which
is hereby incorporated by reference in its entirety, including
4-(3-((4-chlorophenyl)sulfonyl)propyl)benzene acetic acid.
[0085] Other examples of thromboxane A.sub.2 receptor antagonists
suitable for use herein include, but are not limited to vapiprost
(which is a preferred example),
(E)-5-[[[(pyridinyl)]3-(trifluoromethyl)phenyl]methylene]aminol-oxy]penta-
noic acid also referred to as R68,070-Janssen Research
Laboratories,
3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylindol-2-yl]-2,-2-dimethylpro-
panoic acid [(L-655240 Merck-Frosst) Eur. J. Pharmacol. 135(2):193,
March 17, 87],
5(Z)-7-([2,4,5-cis]-4-(2-hydroxyphenyl)-2-trifluoromethyl-1,3-di-
oxan-5-yl)heptenoic acid (ICI 185282, Brit. J. Pharmacol. 90 (Proc.
Suppl):228 P-Abs, March 87),
5(Z)-7-[2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl]heptenoic acid
(ICI 159995, Brit. J. Pharmacol. 86 (Proc. Suppl):808 P-Abs.,
December 85),
N,N'-bis[7-(3-chlorobenzeneamino-sulfony-1)-1,2,3,4-tetrahydro-isoquinoly-
l]disulfonylimide (SKF 88046, Pharmacologist 25(3):116 Abs., 117
Abs, August 83),
(1.alpha.(Z)-2.beta.,5.alpha.]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]-methoxy]--
2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (AH
23848-Glaxo, Circulation 72(6):1208, December 85, levallorphan
allyl bromide (CM 32,191 Sanofi, Life Sci. 31 (20-21):2261,
November 15, 82),
(Z,2-endo-3-oxo)-7-(3-acetyl-2-bicyclo[2.2.1]heptyl-5-hepta-3Z-enoic
acid, 4-phenyl-thiosemicarbazone (EP092-Univ. Edinburgh, Brit. J.
Pharmacol. 84(3):595, March 85); GR 32,191
(Vapiprost)-[1R-[1.alpha.(Z),2.beta.,3.beta.,5.alpha.]]-(+)-7-[5-([1,1'-b-
iphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic
acid; ICI
192,605-4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxypheny-
l)-1,3-dioxan-5-yl]hexenoic acid; BAY u 3405
(ramatroban)-3-[[(4-fluorophenyl)-sulfonyl]amino]-1,2,3,4-tetrahydro-9H-c-
arbazole-9-propanoic acid; or ONO
3708-7-[2.alpha.,4.alpha.-(dimethylmethano)-6.beta.-(2-cyclopentyl-2.beta-
.-hydroxyacetamido)-1.alpha.-cyclohexyl]-5(Z)-heptenoic acid;
(.+-.)(5Z)-7-[3-endo-((phenylsulfonyl)amino]-bicyclo[2.2.1]hept-2-exo-yl]-
-heptenoic acid (S-1452, Shionogi domitroban, Anboxan.RTM..);
(-)6,8-difluoro-9-p-methylsulfonylbenzyl-1,2,3,4-tetrahydrocarbazol-1-yl--
acetic acid (L670596. Merck) and
(3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoi-
c acid (L655240, Merck).
[0086] The preferred thromboxane A2 receptor antagonist of the
present invention is ifetroban or any pharmaceutically acceptable
salts thereof.
[0087] In certain preferred embodiments the preferred thromboxane
A2 receptor antagonist is ifetroban sodium (known chemically as
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt.
Methods of Treatment
[0088] In certain embodiments of the present invention there is
provided a method of treating and/or ameliorating cardiomyopathies
in a patient or patient population by administration of a
therapeutically effective amount of a thromboxane A.sub.2 receptor
antagonist to a patient(s) in need thereof.
[0089] The administration of a therapeutically effective amount of
a thromboxane A.sub.2 receptor antagonist may be accomplished via
any therapeutically useful route of administration, including but
not limited to orally, intranasally, rectally, vaginally,
sublingually, buccally, parenterally, or transdermally. In certain
preferred embodiments, the thromboxane A.sub.2 receptor antagonist
is administered parenterally. In certain further embodiments, the
thromboxane A.sub.2 receptor antagonist is administered by
intra-articular injection. In certain further embodiments, the
thromboxane A.sub.2 receptor antagonist is administered directly to
the affected anatomic site. In another embodiment, the thromboxane
A.sub.2 receptor antagonist is administered through the hepatic
artery.
[0090] In certain preferred embodiments, the plasma concentrations
of thromboxane A.sub.2 receptor antagonists range from about 0.1
ng/ml to about 10,000 ng/ml. Preferably, the plasma concentration
of thromboxane A.sub.2 receptor antagonists range from about 1
ng/ml to about 1,000 ng/ml.
[0091] When the thromboxane A.sub.2 receptor antagonists is
ifetroban, the desired plasma concentration for treatment of
cardiomyopathies in muscular dystrophies in certain embodiments
should be greater than about 10 ng/mL (ifetroban free acid). Some
therapeutic effects of thromboxane A.sub.2 receptor antagonist,
e.g., ifetroban, may be seen at concentrations of greater than
about 1 ng/mL.
[0092] The dose administered should be adjusted according to age,
weight and condition of the patient, as well as the route of
administration, dosage form and regimen and the desired result.
[0093] In order to obtain the desired plasma concentration of
thromboxane A.sub.2 receptor antagonists for the treatment of
cardiomyopathy in muscular dystrophy patients, daily doses of the
thromboxane A.sub.2 receptor antagonists preferably range from
about 0.1 mg to about 5000 mg. In certain preferred embodiments,
the thromboxane A.sub.2 receptor antagonist is administered on a
chronic basis. Daily doses may range from about 1 mg to about 1000
mg; about 10 mg to about 1000 mg; about 50 mg to about 500 mg;
about 100 mg to about 500 mg; about 200 mg to about 500 mg; about
300 mg to about 500 mg; or from about 400 mg to about 500 mg per
day. In certain preferred embodiments where the mammal is a human
patient, the therapeutically effective amount is from about 100 mg
to about 2000 mg per day, or from about 10 mg or about 100 mg to
about 1000 mg per day, and certain embodiments more preferably from
about 50 to about 500 mg per day, or from about 100 mg to about 500
mg per day. The daily dose may be administered in divided doses or
in one bolus or unit dose or in multiple dosages administered
concurrently. In this regard, the ifetroban may be administered
orally, intranasally, rectally, vaginally, sublingually, buccally,
parenterally, or transdermally. In certain preferred embodiments,
the pharmaceutical composition described above, the therapeutically
effective amount is from about 10 mg to about 1000 mg ifetroban (or
pharmaceutically acceptable salt thereof) per day. In certain
preferred embodiments, the therapeutically effective amount is from
about 100 to about 500 mg per day, and in certain embodiments from
about 150 mg to about 350 mg per day will produce therapeutically
effective plasma levels of ifetroban free acid for the treatment of
muscular dystrophy. In certain preferred embodiments, a daily dose
of ifetroban sodium from about 10 mg to about 250 mg (ifetroban
free acid amounts) will produce therapeutically effective plasma
levels of ifetroban free acid for the treatment of muscular
dystrophy.
[0094] Preferably, the therapeutically effective plasma
concentration of thromboxane A.sub.2 receptor antagonists ranges
from about 1 ng/ml to about 1,000 ng/ml for the treatment of
muscular dystrophy.
[0095] When the thromboxane A.sub.2 receptor antagonist is
ifetroban, the desired plasma concentration for providing an
inhibitory effect of A.sub.2/prostaglandin endoperoxide receptor
(TPr) activation, and thus a reduction of cerebral microvascular
activation should be greater than about 10 ng/mL (ifetroban free
acid). Some inhibitory effects of thromboxane A.sub.2 receptor
antagonist, e.g., ifetroban, may be seen at concentrations of
greater than about 1 ng/mL.
[0096] The dose administered must be carefully adjusted according
to age, weight and condition of the patient, as well as the route
of administration, dosage form and regimen and the desired
result.
[0097] However, in order to obtain the desired plasma concentration
of thromboxane A.sub.2 receptor antagonists, daily doses of the
thromboxane A.sub.2 receptor antagonists ranging from about 0.1 mg
to about 5000 mg should be administered. Preferably, the daily dose
of thromboxane A.sub.2 receptor antagonists ranges from about 1 mg
to about 1000 mg; about 10 mg to about 1000 mg; about 50 mg to
about 500 mg; about 100 mg to about 500 mg; about 200 mg to about
500 mg; about 300 mg to about 500 mg, and about 400 mg to about 500
mg per day.
[0098] In certain preferred embodiments, a daily dose of ifetroban
sodium from about 10 mg to about 250 mg (ifetroban free acid
amounts) will produce effective plasma levels of ifetroban free
acid.
Pharmaceutical Compositions
[0099] The thromboxane A.sub.2 receptor antagonists of the present
invention may be administered by any pharmaceutically effective
route. For example, the thromboxane A.sub.2 receptor antagonists
may be formulated in a manner such that they can be administered
orally, intranasally, rectally, vaginally, sublingually, buccally,
parenterally, or transdermally, and, thus, be formulated
accordingly.
[0100] In certain embodiments, the thromboxane A.sub.2 receptor
antagonists may be formulated in a pharmaceutically acceptable oral
dosage form. Oral dosage forms may include, but are not limited to,
oral solid dosage forms and oral liquid dosage forms.
[0101] Oral solid dosage forms may include, but are not limited to,
tablets, capsules, caplets, powders, pellets, multiparticulates,
beads, spheres and any combinations thereof. These oral solid
dosage forms may be formulated as immediate release, controlled
release, sustained (extended) release or modified release
formulations.
[0102] The oral solid dosage forms of the present invention may
also contain pharmaceutically acceptable excipients such as
fillers, diluents, lubricants, surfactants, glidants, binders,
dispersing agents, suspending agents, disintegrants,
viscosity-increasing agents, film-forming agents, granulation aid,
flavoring agents, sweetener, coating agents, solubilizing agents,
and combinations thereof.
[0103] Depending on the desired release profile, the oral solid
dosage forms of the present invention may contain a suitable amount
of controlled-release agents, extended-release agents,
modified-release agents.
[0104] Oral liquid dosage forms include, but are not limited to,
solutions, emulsions, suspensions, and syrups. These oral liquid
dosage forms may be formulated with any pharmaceutically acceptable
excipient known to those of skill in the art for the preparation of
liquid dosage forms. For example, water, glycerin, simple syrup,
alcohol and combinations thereof.
[0105] In certain embodiments of the present invention, the
thromboxane A.sub.2 receptor antagonists may be formulated into a
dosage form suitable for parenteral use. For example, the dosage
form may be a lyophilized powder, a solution, suspension (e.g.,
depot suspension).
[0106] In other embodiments, the thromboxane A.sub.2 receptor
antagonists may be formulated into a topical dosage form such as,
but not limited to, a patch, a gel, a paste, a cream, an emulsion,
liniment, balm, lotion, and ointment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0107] The following examples are not meant to be limiting and
represent certain embodiments of the present invention.
Example I
[0108] In this example, ifetroban sodium tablets are prepared with
the following ingredients listed in Table 1:
TABLE-US-00001 TABLE 1 Ingredients Percent by weight Na salt of
Ifetroban 35 Mannitol 50 Microcrystalline Cellulose 8 Crospovidone
3.0 Magnesium Oxide 2.0 Magnesium Stearate 1.5 Colloidal Silica
0.3
[0109] The sodium salt of ifetroban, magnesium oxide, mannitol,
microcrystalline cellulose, and crospovidone is mixed together for
about 2 to about 10 minutes employing a suitable mixer. The
resulting mixture is passed through a #12 to #40 mesh size screen.
Thereafter, magnesium stearate and colloidal silica are added and
mixing is continued for about 1 to about 3 minutes.
[0110] The resulting homogeneous mixture is then compressed into
tablets each containing 35 mg, ifetroban sodium salt.
Example II
[0111] In this example, 1000 tablets each containing 400 mg of
ifetroban sodium are produced from the following ingredients listed
in Table 2:
TABLE-US-00002 TABLE 2 Ingredients Amount Na salt of Ifetroban 400
gm Corn Starch 50 g Gelatin 7.5 g Microcrystalline Cellulose
(Avicel) 25 g Magnesium Stearate 2.5 g
Example III
[0112] An injectable solution of ifetroban sodium is prepared for
intravenous use with the following ingredients listed in Table
3:
TABLE-US-00003 TABLE 3 Ingredients Amount Ifetroban Sodium 2500 mg
Methyl Paraben 5 mg Propyl Paraben 1 mg Sodium Chloride 25,000 mg
Water for injection q.s. 5 liter
[0113] The sodium salt of ifetroban, preservatives and sodium
chloride are dissolved in 3 liters of water for injection and then
the volume is brought up to S liters. The solution is filtered
through a sterile filter and aseptically filled into pre-sterilized
vials which are then closed with pre-sterilized rubber closures.
Each vial contains a concentration of 75 mg of active ingredient
per 150 ml of solution.
Example IV
[0114] dSG KO mice, chosen for their cardiac phenotype, are a model
of LGMD, but DMD which occurs in approximately 1:3500 male births
(1), is liar more common a disease than LGMD. The mdx mouse model
of DMD poorly replicates the shortened life expectancy, cardiac
fibrosis, and cardiomyopathy seen in DMD patients. The
utrophin/dystrophin DKO model had significant mortality by 10
weeks, although treatment with the TPr antagonist ifetroban led to
100% survival to this predetermined timepoint. Although TPr
antagonism may prevent spontaneous death in DMD, due to severe
kyphosis and frailty we were not able to obtain much useful cardiac
data with the DKO model of DMD.
[0115] Example 4 utilized West/Carrier Muscular Dystrophy Animal
Models (Delta-sarcoglycan knock-out mice (sgcd-/-)). Mice devoid of
DSG develop cardiomyopathy and MD with signs of progressive disease
such as necrosis, muscular regeneration, inflammation and fibrosis
within the first 3 months of life. Mice that are homozygous for the
targeted mutation are viable, fertile and normal in size. No gene
product (protein) is immunodetected in skeletal muscle microsomal
preparations. At 8 weeks of age there is an onset of sudden
mortality, with a 50% survival rate at 28 weeks. Elevated creatine
kinase serum levels are indicative of striated muscle degeneration.
Histopathology of skeletal muscle tissue reveals degeneration and
regeneration of muscle fibers, inflammatory infiltrate,
perivascular fibrosis and calcification. At 12 weeks of age,
cardiac muscle tissue also begins to show degeneration,
inflammatory infiltration and perivascular fibrosis. Myofiber
membranes have permeability defects as assessed by Evans blue dye
uptake into myofiber cytoplasm. Skeletal muscle of mutant mice have
an enhanced sensitivity to mechanically induced sarcolemmal damage.
Dystrophin deficient mice have minimal clinical symptoms with
lifespan reduced by only 25% unlike humans with DMD reduced by 75%,
possibly due to compensatory mechanisms upregulated in mice. A
major function of dystrophin is to strengthen the sarcolemma by
cross-linking the ECM with the cytoskeleton. Utrophin and a7b1
integrin fulfil the same function and are upregulated in mdx mice.
They work to connect sarcolemma to cytoplasmic actin cytoskeleton.
Dysfunction produces membrane instability, elevated [Ca2+]I and
disrupted NO signaling. .gamma.- and .delta.-SG form a core
necessary for delivery/retention of other SG to the membrane.
[0116] While the DSG KO (sgcd-/-) mice lack functional
delta-sarcoglycan, the MD phenotype is milder than the human
disease. Since utrophin, a dystrophin-related protein, is able to
compensate for the loss of dystrophin, loss of utrophin and
dystrophin (DKO) results in a more severe phenotype. DKO are
significantly smaller and show more severe muscle disease (similar
or worse than that of humans with MD). The mice are difficult to
generate and care for, and often die prematurely. Ifetroban
treatment was started at 3 weeks upon weaning.
[0117] In Example IV, vehicle-treated mice were carefully cared for
to get them to reach 10 weeks of life (e.g., the mice were checked
on them constantly and a low dish of crushed food and water was
placed right next to where the mice huddled in the cage, in an
attempt to get them some nutrition without them needing to move
much).
[0118] FIG. 1 are photos of a vehicle-treated compared with an
ifetroban-treated DKO mouse. FIG. 1A is a photograph of a
vehicle-treated DKO Mouse at 10 weeks. FIG. 1B is a photograph of
an ifetroban-treated DKO mouse at 10 weeks. The ability to wrap the
tail around the wire is dependent on muscle function. A reason the
DKO mice are really hard to evaluate in the wire hang is that they
have such severe scoliosis that their hind paws are very close to
their front paws, so raising their hind paws to get a 4-limbed grip
is not difficult despite their affliction.
[0119] FIG. 2 shows plasma cTNI in dSG KO males at 3 months. The
term "cTNI" means plasma cardiac troponin I. The term "KO" means
knockout. The term "dSG" means Delta sarcoglycan. The term "WT"
means wildtype. Plasma cardiac troponin I (cTNI) is highly specific
and sensitive for myocardial tissue and can be measured rapidly. It
is a reliable biomarker for cardiac damage. In FIG. 2, it can be
seen that the plams cTNI levels are much higher in dSG KO mice than
in WT mice.
[0120] FIG. 3 provides 3 month Echo data. The results shown therein
demonstrate that at 3 months dSG KO males show cardiac dysfunction
and ifetroban prevents cardiac dysfunction.
[0121] FIG. 4 provides cardiac output data for male dSG KO mice at
3 months. FIG. 4 shows that the dSG KO mice treated with ifetroban
have improved cardiac dysfunction compared to vehicle. The cardiac
function improved similar to WT levels.
[0122] FIG. 5 provides spontaneous exercise date for 6 month old
males. The exercise was voluntary wheel running-free access to the
wheel for 10 days after 4.5M of treatment. Males demonstrate a
skeletal function deficit at 6M that is seen to a less extent in
ifetroban-treated DSG KO mice. No difference is seen in females who
run more compared to males regardless of genotype.
[0123] FIG. 6 shows wire hang in dSG mice at 6 months. An improved
wire hang time is apparent in the dSG mice treated with ifetroban.
*p<0.05 from WT by one-way ANOVA followed by Dunnett's multiple
comparison post-test. Veh and ife-treated groups were NS tested
against each other. N in parentheses. "ife"=ifetroban.
[0124] FIG. 7 shows the results of a wire hanging experiment at 6
months, with the average hang time plotted for dSG and WT mice.
[0125] FIG. 8 depicts wire hang time for mice tested. Male mice do
not hang for a long time compared to females. It was difficult to
measure any difference caused by ifetroban if any.
[0126] FIGS. 9A (dSGKO-vehicle) and 9B (DsGKO-ifetroban) show
cardiac histology in dSG KO males. Less fibrosis seen in ifetroban
treated RV. Shown is Masson's trichrome at 4.times. for gross
histology. All tears/folds/red hotspots from slice preparation and
not pathology. Some RV may also be affected by slicing
(arrows).
[0127] FIGS. 10A(dSG-Veh), 10B(dSG-veh), 10C(dSG-ifetroban) and
10D(dSG-ifetroban) show cardiac histology in dSG KO males (using
Masson's trichrome, 2.times.). It can be seen that there is less
fibrosis in the ifetroban treated RV. RV=right ventricle.
[0128] FIGS. 11A1, 11A2, 11A3 and 11A4 shows cardiac histology in
dSG KO males (using Masson's trichrome, 10.times.) in the left
ventricle (11A1=mouse #1, dSG KO-vehicle; 11A2=mouse #2, dSG
KO-vehicle; 11A3=mouse #1, dSG KO-ifetroban; and 11A4=mouse #2, dSG
KO-ifetroban); FIGS. 11B1, 11B2, 11B3 and 11B4 shows cardiac
histology in the right ventricle (11B1=mouse #1, dSG KO-vehicle;
11B2=mouse #2, dSG KO-vehicle; 11B3=mouse #1, dSG KO-ifetroban; and
11B4=mouse #2, dSG KO-ifetroban). LV=left ventricle; RV=right
ventricle. Less fibrosis was seen in ifetroban-treated KO mice.
[0129] FIGS. 12A(WT1), 12B(dSG-KO-vehicle), 12C(WT2) and
12D(dSG-KO-ifetroban) shows skeletal muscle histology in WT and dSG
KO males (tibialis cross-section, using Masson's trichrome). Some
fibrosis may be due to specific section of muscle.
[0130] FIGS. 13A(WT-vehicle), 13B(WT-ifetroban), 13C(dSG
KO-vehicle) and 13D(dSG-KO-ifetroban) are cross-sections of
intestinal tissue showing that ifetroban may prevent the loss of
intestinal smooth muscle in the large intestine Muscularis. The DSG
KO mice were missing smooth muscle (especially missing longitudinal
smooth muscle) while ifetroban-treated mice have similar sections
to WT smooth muscle. "H&E"=Hematoxylin & eosin.
[0131] FIG. 13 shows that ifetroban-treated dSG KO mice have less
fibrosis than vehicle-treated dSG KO mice.
[0132] FIGS. 14A and 14B are graphs showing the percent survival of
dSG KO males (14A) and dSG females (14B) treated with ifetroban or
vehicle.
[0133] FIG. 15 are graphs showing wire hang in DKO males at 10
weeks (ifetroban-treated ("ife") versus vehicle). The results show
that the ifetroban-treated mice had significantly longer average
hang times than mice treated with vehicle.
[0134] FIG. 16 shows spontaneous running in DKO mice: measured from
9-10 weeks.
[0135] FIG. 17 shows survival for all DKO mice. The
ifetroban-treated mice survived beyond 70 days, while the
vehicle-treated mice (both male and female) did not.
CONCLUSION
[0136] In the preceding specification, the invention has been
described with reference to specific exemplary embodiments and
examples thereof. It will, however, be evident that various
modifications and changes may be made thereto without departing
from the broader spirit and scope of the invention as set forth in
the claims that follow. The specification and drawings are
accordingly to be regarded in an illustrative manner rather than a
restrictive sense.
* * * * *