U.S. patent application number 11/941519 was filed with the patent office on 2009-05-21 for method of treating bone pain caused by osteoarthritis.
Invention is credited to Joseph Bernstein.
Application Number | 20090131442 11/941519 |
Document ID | / |
Family ID | 39789307 |
Filed Date | 2009-05-21 |
United States Patent
Application |
20090131442 |
Kind Code |
A1 |
Bernstein; Joseph |
May 21, 2009 |
Method of Treating Bone Pain Caused by Osteoarthritis
Abstract
A method of treating bone pain caused by osteoarthritis by
administering to a patient an effective amount of a composition
containing a bone edema medication, such as a vasoactive medication
or phosphodiesterase inhibitor, including a PDE-5 inhibitor.
Inventors: |
Bernstein; Joseph;
(Haverford, PA) |
Correspondence
Address: |
CAESAR, RIVISE, BERNSTEIN,;COHEN & POKOTILOW, LTD.
11TH FLOOR, SEVEN PENN CENTER, 1635 MARKET STREET
PHILADELPHIA
PA
19103-2212
US
|
Family ID: |
39789307 |
Appl. No.: |
11/941519 |
Filed: |
November 16, 2007 |
Current U.S.
Class: |
514/243 ;
514/250; 514/252.16; 514/262.1; 514/275 |
Current CPC
Class: |
A61K 31/495 20130101;
A61P 29/02 20180101; A61K 31/519 20130101; A61K 31/53 20130101;
A61P 19/02 20180101; A61K 31/4985 20130101; A61K 31/506 20130101;
A61K 31/497 20130101; A61P 19/08 20180101; A61P 19/00 20180101 |
Class at
Publication: |
514/243 ;
514/275; 514/262.1; 514/252.16; 514/250 |
International
Class: |
A61K 31/53 20060101
A61K031/53; A61K 31/495 20060101 A61K031/495; A61K 31/519 20060101
A61K031/519; A61K 31/497 20060101 A61K031/497; A61K 31/4985
20060101 A61K031/4985 |
Claims
1. A method of treating pain comprising administering to a patient
a therapeutically effective amount of a pharmaceutically acceptable
bone edema medication.
2. The method of claim 1, wherein the pain is caused by joint
disease.
3. The method of claim 2, wherein the joint disease is
osteoarthritis.
4. The method of claim 1, wherein the pharmaceutically acceptable
bone edema medication is a vasoactive medication.
5. The method of claim 1, wherein the pharmaceutically acceptable
bone edema medication is a phosphodiesterase inhibitor.
6. The method of claim 5, wherein the phosphodiesterase inhibitor
is a subtype 5 phosphodiesterase enzyme (PDE5) selective
inhibitor.
7. The method of claim 6, wherein the PDE5 selective inhibitor is
selected from the group consisting of avanafil, sildenafil,
tadalafil, udenafil, vardenafil and zaprinast.
8. The method of claim 1, wherein the step of administering is via
an intramuscular route.
9. The method of claim 1, wherein the step of administering is via
an oral route.
10. The method of claim 1, wherein the step of administering is via
an intravenous route.
11. The method of claim 1, wherein the patient is a human.
12. The method of claim 1, wherein the patient is a non-human
mammal.
13. The method of claim 1, wherein the therapeutically effective
amount is a dose normally administered for known uses of the bone
edema medication.
14. The method of claim 1, wherein 50 mg or less of the bone edema
medication is administered.
15. A method of reducing intraosseous hypertension comprising
administering to a patient a therapeutically effective amount of a
pharmaceutically acceptable bone edema medication.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to the fields of
orthopedics and rheumatology and, in particular, to a treatment for
bone pain associated with osteoarthritis and related conditions.
More specifically, the present invention relates to a method of
treating pain caused by osteoarthritis with bone edema medications.
Medications that may be used according to the present invention
include vasoactive medications, such as phosphodiesterase
inhibitors, which modulate blood flow to bone of a patient in the
vicinity of an arthritic joint to affect the physiology of the bone
in a manner that leads to a reduction in the pain associated with
osteoarthritis.
BACKGROUND OF THE INVENTION
[0002] Osteoarthritis is the most common musculoskeletal and joint
diseases in the world. Because medical advances have increased the
average lifespan, yet have not devised an effective means of
preventing wear and tear of the joints, osteoarthritis is rapidly
becoming a significant medical and financial burden to the world
(Pelletier et al. 2006) and is a leading cause of impaired mobility
in the elderly. (Felson 2006). Osteoarthritis is a condition of
primary failure of articular cartilage, which is accompanied by
subchondral hardening of bone, osteophytes (bone spurs) at the
joint margin, juxtaarticular bone cysts, and joint space narrowing.
Pain is the most prominent and disabling symptom of osteoarthritis.
(Felson 2005). Osteoarthritis usually develops in the smaller
joints of the fingers, the weight-bearing joints of the leg, and
the movable portions of the spine, although any diarthrodial joint
can be affected.
[0003] Osteoarthritis was long thought to reflect the aging
process, in which repetitive use of joints results in cartilage
erosion. And whereas it is true that osteoarthritis is
characterized by cartilage loss, cartilage damage cannot be the
source of the pain, as there are no pain fibers in articular
cartilage, and in some patients cartilage loss may occur without
any accompanying symptoms. (Felson 2005). As more is understood
about the molecular structure and function of cartilage, the pain
associated with osteoarthritis appears to be the result of a
complex interplay between mechanical, cellular, and biochemical
forces.
[0004] At present, there are no means to effectively restore
damaged articular cartilage to its healthy state, i.e., once
damaged, human adult cartilage remains damaged for life. Thus, the
primary goals of treatment of osteoarthritis are to help patients
understand their disease, relieve their pain, minimize their
disability, and limit the progression of their disease. Medical
treatment of osteoarthritis often involves administration of pain
relievers such as acetaminophen or aspirin. Alternatively,
nonsteriodal anti-inflammatory drugs (NSAIDs), such as ibuprofen,
nabumetone or naproxen, amongst others, may be administered.
Although these drugs act to "block" the pain and/or reduce
inflammation, they do not affect the physiology underscoring and
producing the pain. Such an approach is suggested by the instant
invention.
[0005] Articular cartilage itself is relatively avascular, and
lacks pain receptors. Thus, although osteoarthritis represents a
failure of cartilage, the pain cannot and does not originate from
the damaged cartilage itself. Rather, the pain can be mediated by
the only peri-articular structures which possess the neural
apparatus for sensing pain (i.e., nociceptors): namely, the
synovium and the bone underlying the cartilage. It is only those
structures (alone or in combination) that can be responsible for
the sensation of pain experienced by patients suffering from
osteoarthritis.
[0006] There is clinical evidence suggesting that pressure within
the bone may contribute, at least in part, to joint pain. For
example, the medical literature has discussed a case in which Dr.
Scott Dye of San Francisco injected his own bone with saline under
pressure, in the name of science. He experienced pain which lasted
for a year.
[0007] Also, more than 30 years ago, it was observed that pain due
to severe osteoarthritis may be associated with "intraosseous
hypertension," i.e., pressure within the bone. (Arnoldi et al.
1975). Intraosseous hypertension is the manifestation of edema
within the bone. Thus, it has been proposed that local vascular
changes may be important in the pathogenesis of degenerative
arthritis and the production of its associated symptoms. (Arnoldi
et al. 1972). It has been further observed that surgical
decompression of bone (specifically in the case of osteonecrosis)
can relieve bone pain. Use of surgery, however, to alleviate
pressure within the bone is not ideal. For one thing, surgery can
produce myriad side effects and complications, but more to the
point, the problem with surgical decompression is that its benefit
will be transient. The fenestrations created during so-called
decompressive procedures are bound to fill with fibrocartilage.
Thus, there is an ongoing need for a safe and effective method for
alleviating pressure in bone causing joint pain, most typically
found in patients suffering from osteoarthritis.
SUMMARY OF THE INVENTION
[0008] It is an object of this invention to provide a method of
treating pain associated with osteoarthritis. It is another object
of this invention to provide a method of treating intraosseous
hypertension associated with osteoarthritis. It is a further object
of this invention to provide a method of treating osteoarthritis.
The present invention includes a method of treating bone pain
associated with osteoarthritis and other conditions by
administering to a patient a therapeutically effective amount of a
pharmaceutically acceptable bone edema medication. Bone edema
medications used according to the present invention include
vasoactive medications such as phosphodiesterase inhibitors.
According to an aspect of the present invention, a therapeutically
effective amount of a subtype 5 phosphodiesterase enzyme (PDE5)
selective inhibitor, such as avanafil, sildenafil, tadalafil,
udenafil, vardenafil and zaprinast, may be administered. The
medication is administered in an amount sufficient to reduce pain
associated with osteoarthritis and may be administered, for
example, via intravenous, transdermal or oral routes. Further, the
medication may be administered in combination with other
medications. The patient may be a human or a non-human mammal.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
[0009] The invention will be described in conjunction with the
following figures in which like reference numerals designate like
elements and wherein:
[0010] FIG. 1 is a coronal view of a magnetic resonance image (MRI)
scan of a patient's arthritic knee prior to routine administration
of a phosphodiesterase inhibitor.
[0011] FIG. 2 is a coronal view of an MRI of the same patient's
knee as in FIG. 1, after routine administration of a
phosphodiesterase inhibitor.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention provides methods of treating bone pain
by administering to a patient an effective amount of a
pharmaceutically acceptable bone edema medication. In accordance
with the present invention, bone edema medications, including
vasoactive medications and phosphodiesterase inhibitors, are
administered to a patient suffering from pain, e.g. joint pain from
osteoarthritis. Bone edema medications of the present invention
reduce or eliminate intraosseous hypertension in the bone, within
the vicinity of the affected joint, by altering vascular profusion
(blood flow in and out of the bone), thereby reducing bone edema.
By reducing or eliminating intraosseous hypertension, the method of
the present invention reduces or eliminates a source of pain for
osteoarthritis sufferers.
[0013] Phosphodiesterases (PDE) are a diverse family of enzymes
that hydrolyze cyclic nucleotides and thus play a key role in
regulating intracellular levels of second messangers--adenosine
monophosphate (cAMP) and guanosine monophosphate (cGMP)--and hence
cell function. (Boswell-Smith et al. 2006). PDE activity is found
in every cell in the body, although there is distinct cellular and
subcellular distribution of eleven isoenzymes, which has provided
many possibilities for selective therapeutic targets. Isoenzyme
selective targets have been identified for specific diseases. For
example, the subtype 3 phosphodiesterase enzyme PDE-3 selective
inhibitors have been used to treat cardiovascular disease, asthma,
congestive heart failure, to relax vascular and airway smooth
muscle, inhibit platelet aggregation, and induce lipolysis.
(Boswell-Smith et al. 2006). PDE-4, a cAMP-specific PDE, is the
predominant isoenzyme in the majority of inflammatory cells, with
the exception of platelets, implicated in inflammatory airways
disease. There is a current resurgence underway in the development
of PDE-4 inhibitors to treat central nervous system indications
such as memory enhancement. The PDE-5 enzyme catalyzes the
breakdown of the smooth muscle relaxing agent cGMP (U.S. Pat. No.
7,091,207) making it a cGMP-specific PDE. Those of ordinary skill
in the art will recognize that many compounds exist which are
inhibitors of PDE-5 including, sildenafil (marketed as
Viagra.RTM.), vardenafil (marketed as Levitra.RTM.), tadalafil
(marketed as Cialis.RTM.), ananafil, udenafil, zaprinast, and the
like.
[0014] The inventor has discovered that exposure to a PDE-5
inhibitor reduces or eliminates the pain associated with
osteoarthritis. Accordingly, in one embodiment of the present
invention, the PDE-5 inhibitor that is employed in the practice of
the present invention is sildenafil (Viagra.RTM.). Sildenfil is the
first oral agent approved for treatment of erectile function in
men. (U.S. Pat. No. 7,091,207). Its method of action is understood
to be as follows: Sexual stimulation results in the release of
nitric oxide from nerves and endothelial cells in the corpus
cavernosum of the penis, which in turn stimulates guanylate cyclase
with subsequent formation of cGMP. Accumulation of cGMP leads to
smooth muscle cell relaxation in the arteries, arterioles and
sinusoids in the corpus cavemosum, allowing this erectile tissue to
fill with blood and causing erection. Men with erectile dysfunction
may be unable to maintain adequate amounts of cGMP because it is
broken down by PDE-5, which is found in high levels in the
genetalia. By inhibiting PDE-5, sildenafil allows an increase in
cGMP concentration and improved vasodilation, thus facilitating
erection.
[0015] Without being bound by theory, in the practice of the
present invention, the vasodilatory action of PDE-5 inhibitors such
as sildenafil may function by affecting the muscle tone of blood
vessels, thereby altering blood flow. By modulating the blood flow
to bone of a patient suffering from joint pain with a PDE-5
inhibitor, the intraosseous pressure resulting from the buildup of
bone edema will be alleviated, thereby palliating joint pain.
[0016] In other embodiments of the invention, the PDE-5 inhibitors
are vardenafil and tadalafil, which are also used for treatment of
erectile dysfunction in men. However, the present invention is not
limited to phosphodiesterase inhibitors specifically recited herein
but also includes other phosphodiesterase inhibitors and vasoactive
medications which cause alterations in the inflow and outflow of
blood to bone. The broad concept of the present invention includes
the administration of any bone edema medication which reduces or
eliminates intraosseous hypertension, including those not yet
discovered, such as, but not limited to, injectable dosage forms
and solid dosage forms such as tablets, capsules, and the like.
[0017] The medications used in the practice of the present
invention may be administered as a pharmaceutical preparation
comprising a pharmaceutically acceptable carrier. Such a
pharmaceutical preparation may be in any of many forms known to be
suitable for administration of drugs. The medications may be
administered in the pure form or in a pharmaceutically acceptable
formulations including suitable elixirs, binders, and the like, or
as pharmaceutically acceptable salts or other derivatives (e.g.,
sildenafil citrate). It should be understood that the
pharmaceutically acceptable formulations and salts include liquid
and solid materials conventionally utilized to prepare injectable
dosage forms and solid dosage forms such as tablets and capsules.
Water may be used for the preparation of injectable compositions
which may also include conventional buffers and agents to render
the injectable composition isotonic. Other potential additives
include colorants, surfactants, binders and encapsulants, diluents,
excipients, disintegrating agents, coatings, preservatives and the
like.
[0018] Depending on the formulation, it is expected that the active
agent (e.g., PDE-5 inhibitor) will comprise 1-99% of the
composition and carrier will constitute 1-99% of the composition.
Such pharmaceutical compositions may include any suitable
pharmaceutically acceptable additives or adjuncts to the extent
that they do not hinder or interfere with the desired therapeutic
effect of the medication.
[0019] Those of ordinary skill in the art will recognize that the
exact dosage of the medication to be administered may vary
depending on factors such as the age, gender, weight and health
status of the individual patient, as well as on the precise nature
of the condition being treated. Similarly, the length of duration
of the treatment with the medication will vary from patient to
patient, and will depend on the application of the medication. In
all cases, the amount of medication to be administered and the
precise treatment protocol should be determined by a skilled
practitioner such as a physician.
[0020] The preferred dosage of medication required to practice
methods of the present invention, i.e., the quantity sufficient to
carry out the method, is about the same as or less than that which
is normally or typically administered for previously known uses or
applications of the medication, i.e., PDE-5 inhibitors for treating
male erectile dysfunction. For example, to elicit a reduction in
pain associated with osteoarthritis, a regular dose of 50 mg or
less of Viagra.RTM. is expected to be at least temporarily
effective for most patients.
[0021] The medication may be administered by any of a wide variety
of means which are well known to those of ordinary skill in the art
including, but not limited to, intravenously, intramuscularly,
orally, rectally, and the like, or by other routes including, but
not limited to, transdermal, sublingual, aerosol, etc., which is
suitable for the particular means of administration.
[0022] Further, the medications of the present invention may be
administered either alone or together with other medications in a
treatment protocol. For example, a PDE-5 inhibitor may be
administered either separately or in combination with other
osteoarthritis drugs.
[0023] While in some embodiments, the patient that is treated by
the methods of the present invention are human in origin, this need
not be the case. Those of ordinary skill in the art will recognize
that other mammals may also benefit from the methods of the present
invention. Thus, veterinarian applications are also contemplated.
Further, patients treated with medications according to the methods
of the present invention may be in any stage of life, e.g.,
new-born, adult or aging, although as previously mentioned,
osteoarthritis is considered to be primarily a disease of the
elderly.
[0024] The invention will be illustrated in more detail with
reference to the following Example, but it should be understood
that the present invention is not deemed to be limited thereto.
EXAMPLE
[0025] A physician, who is also the inventor of the present
invention, performed an arthroscopic surgical procedure on a male
patient suffering from a loose cartilage body in the setting of
severe arthritis in his knee. The patient was a competitive senior
tennis player and declined knee replacement for that reason. The
purpose of the procedure was merely to remove a loose body and
abate the mechanical symptoms it caused. Prior to the procedure, an
MRI of a coronal view of the patient's knee was taken, as shown in
FIG. 1.
[0026] Approximately one year later, the patient returned to his
physician for evaluation of what was believed to be an unrelated
ganglion cyst on the same knee. To evaluate this cystic mass,
another MRI of a coronal view of the patient's knee was taken, as
shown in FIG. 2. The patient had reported that over the few months
prior to the second MRI but well past the surgical procedures, his
pain from his knee arthritis had significantly improved. He
inquired whether the more recent MRI (FIG. 2) revealed why this was
so. The patient's physician and a senior radiologist compared the
earlier MRI (FIG. 1) to the later MRI (FIG. 2), and observed that
the earlier MRI (FIG. 1) showed white spots on the patient's tibial
spines, whereas the later MRI (FIG. 2) revealed that the white
spots had dissipated or resolved. The physician and a radiologist
noted that the high signal shown in the MRI of FIG. 1 represents
bone edema, and hence, intraosseous hypertension. They further
noted that the MRI of FIG. 2, as compared with that of FIG. 1,
showed a resolution of the edema, and that although the radiographs
were otherwise unchanged, the patient's symptoms were markedly
reduced. The physician therefore concluded that the patient had
intraosseous hypertension which was shown to have dissipated or
have been resolved by the time of the MRI of FIG. 2.
[0027] Upon questioning by his physician, the patient explained
that the only difference in his medical history (including
lifestyle, activity, new illness and medications) between the time
of the first and second MRIs was that he started using a
phosphodiesterase inhibitor. Specifically, the patient started
using Viagra.RTM. (50 mg of sildenafil, once per day). There were
no other changes in the interval medical history. The physician
inferred that reduction in knee pain experienced by the patient was
the result of the dissipation of the intraosseous hypertension
which, in turn, was the result of using a phosphodiesterase
inhibitor.
[0028] While the invention has been described in detail in terms of
its preferred embodiments and with reference to the above example,
it will be apparent to those skilled in the art that the invention
can be practiced with modification within the spirit and scope of
the appended claims. Accordingly, the present invention should not
be limited to the embodiments as described above, but should
further include all changes, modifications and equivalents thereof
within the spirit and scope of the description provided herein.
* * * * *