U.S. patent application number 10/863771 was filed with the patent office on 2005-01-27 for method of treating lower urinary tract disorders.
This patent application is currently assigned to Dynogen, Inc.. Invention is credited to Fraser, Matthew O., Landau, Steven B., Miller, Cheryl L..
Application Number | 20050020577 10/863771 |
Document ID | / |
Family ID | 33162987 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050020577 |
Kind Code |
A1 |
Landau, Steven B. ; et
al. |
January 27, 2005 |
Method of treating lower urinary tract disorders
Abstract
The invention relates to a method of treating at least one
symptom of a lower urinary tract disorder in a subject in need of
treatment wherein the symptom is selected from the group consisting
of urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis. The method comprises administering to a
subject in need of treatment a therapeutically effective amount of
a compound that has 5-HT.sub.3 receptor antagonist activity and
NorAdrenaline Reuptake Inhibitor (NARI) activity. The invention
further relates to a method of treating at least one symptom of a
lower urinary tract disorder in a subject in need of treatment
wherein the symptom is selected from the group consisting of
urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis, comprising coadministering to said subject a
first amount of a 5-HT.sub.3 antagonist and a second amount of a
NARI, wherein the first and second amounts together comprise a
therapeutically effective amount or are each present in a
therapeutically effective amount.
Inventors: |
Landau, Steven B.;
(Wellesley, MA) ; Miller, Cheryl L.; (Natick,
MA) ; Fraser, Matthew O.; (Apex, NC) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Assignee: |
Dynogen, Inc.
|
Family ID: |
33162987 |
Appl. No.: |
10/863771 |
Filed: |
June 7, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10863771 |
Jun 7, 2004 |
|
|
|
10817332 |
Apr 2, 2004 |
|
|
|
60536341 |
Jan 13, 2004 |
|
|
|
60496502 |
Aug 20, 2003 |
|
|
|
60461022 |
Apr 4, 2003 |
|
|
|
Current U.S.
Class: |
514/218 ;
514/252.16; 514/260.1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 31/5513 20130101; A61K 31/551 20130101; A61K 31/519 20130101;
A61P 13/02 20180101; A61P 29/00 20180101; A61P 43/00 20180101; A61P
13/08 20180101; A61K 31/5513 20130101; A61K 31/00 20130101; A61K
2300/00 20130101; A61K 45/06 20130101; A61P 13/10 20180101; A61K
2300/00 20130101 |
Class at
Publication: |
514/218 ;
514/252.16; 514/260.1 |
International
Class: |
A61K 031/551; A61K
031/519 |
Claims
1-70. (canceled)
71. A method of treating overactive bladder comprising
administering a compound of formula I: 8or a pharmaceutically
acceptable salt thereof to a human subject in need thereof on an
as-needed basis, wherein R.sub.1 and R.sub.2 independently
represent hydrogen, halogen or a C.sub.1-C.sub.6 alkyl group; or
R.sub.1 and R.sub.2 together with the carbon atom to which they are
attached form a cycloalkylene group having 5 to 6 carbon atoms;
R.sub.3 and R.sub.4 independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; R.sub.5 is hydrogen, C.sub.1-C.sub.6
alkyl, 9or --C(O)--NH--R.sub.6 wherein m is an integer from about 1
to about 3, X is halogen and R.sub.6 is a C.sub.1-C.sub.6 alkyl
group; and Ar is a substituted or unsubstituted phenyl, 2-thienyl
or 3-thienyl group; and n is 2 or 3.
72. The method of claim 71, wherein said as-needed basis is from
about 0 minutes to about 10 hours prior to commencement of an
activity wherein suppression of overactive bladder is desired.
73. The method of claim 71, wherein said as-needed basis is from
about 0 minutes to about 5 hours prior to commencement of an
activity wherein suppression of overactive bladder is desired.
74. The method of claim 71, wherein said as-needed basis is from
about 0 minutes to about 3 hours prior to commencement of an
activity wherein suppression of overactive bladder is desired.
75. The method of claim 71, wherein said as-needed basis is about
10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about
2 hours, about 3 hours, about 4 hours, about 5 hours, about 6
hours, about 7 hours, about 8 hours, about 9 hours, or about 10
hours prior to commencement of an activity wherein suppression of
overactive bladder is desired.
76. A method of treating overactive bladder comprising
administering a compound of formula II: 10or a pharmaceutically
acceptable salt thereof to a human subject in need thereof on an
as-needed basis.
77. The method of claim 76, wherein said as-needed basis is from
about 0 minutes to about 10 hours prior to commencement of an
activity wherein suppression of overactive bladder is desired.
78. The method of claim 76, wherein said as-needed basis is from
about 0 minutes to about 5 hours prior to commencement of an
activity wherein suppression of overactive bladder is desired.
79. The method of claim 76, wherein said as-needed basis is from
about 0 minutes to about 3 hours prior to commencement of an
activity wherein suppression of overactive bladder is desired.
80. The method of claim 76, wherein said as-needed basis is about
10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about
2 hours, about 3 hours, about 4 hours, about 5 hours, about 6
hours, about 7 hours, about 8 hours, about 9 hours, or about 10
hours prior to commencement of an activity wherein suppression of
overactive bladder is desired.
81. A method of treating a lower urinary tract disorder comprising
administering a compound of formula I: 11or a pharmaceutically
acceptable salt thereof to a human subject in need thereof on an
as-needed basis, wherein R.sub.1 and R.sub.2 independently
represent hydrogen, halogen or a C.sub.1-C.sub.6 alkyl group; or
R.sub.1 and R.sub.2 together with the carbon atom to which they are
attached form a cycloalkylene group having 5 to 6 carbon atoms;
R.sub.3 and R.sub.4 independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; R.sub.5 is hydrogen, C.sub.1-C.sub.6
alkyl, 12or --C(O)--NH--R.sub.6 wherein m is an integer from about
1 to about 3, X is halogen and R.sub.6 is a C.sub.1-C.sub.6 alkyl
group; and Ar is a substituted or unsubstituted phenyl, 2-thienyl
or 3-thienyl group; and n is 2 or 3.
82. The method of claim 81, wherein said as-needed basis is from
about 0 minutes to about 10 hours prior to commencement of an
activity wherein treatment of a lower urinary tract disorder is
desired.
83. The method of claim 81, wherein said as-needed basis is from
about 0 minutes to about 5 hours prior to commencement of an
activity wherein treatment of a lower urinary tract disorder is
desired.
84. The method of claim 81, wherein said as-needed basis is from
about 0 minutes to about 3 hours prior to commencement of an
activity wherein treatment of a lower urinary tract disorder is
desired.
85. The method of claim 81, wherein said as-needed basis is about
10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about
2 hours, about 3 hours, about 4 hours, about 5 hours, about 6
hours, about 7 hours, about 8 hours, about 9 hours, or about 10
hours prior to commencement of an activity wherein treatment of a
lower urinary tract disorder is desired.
86. A method of treating a lower urinary tract disorder comprising
administering a compound of formula II: 13or a pharmaceutically
acceptable salt thereof to a human subject in need thereof on an
as-needed basis.
87. The method of claim 86, wherein said as-needed basis is from
about 0 minutes to about 10 hours prior to commencement of an
activity wherein treatment of a lower urinary tract disorder is
desired.
88. The method of claim 86, wherein said as-needed basis is from
about 0 minutes to about 5 hours prior to commencement of an
activity wherein treatment of a lower urinary tract disorder is
desired.
89. The method of claim 86, wherein said as-needed basis is from
about 0 minutes to about 3 hours prior to commencement of an
activity wherein treatment of a lower urinary tract disorder is
desired.
90. The method of claim 86, wherein said as-needed basis is about
10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about
2 hours, about 3 hours, about 4 hours, about 5 hours, about 6
hours, about 7 hours, about 8 hours, about 9 hours, or about 10
hours prior to commencement of an activity wherein treatment of a
lower urinary tract disorder is desired.
91. Use of
4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D]pyrim-
idine or a salt thereof for the manufacture of a medicament for the
treatment of urinary incontinence.
92. Use according to claim 91, wherein the salt is the monohydrate
hydrochloride.
93. Use according to claim 91 or claim 92, wherein the urinary
incontinence is stress urinary incontinence.
94. A method for the treatment of urinary incontinence in a patient
suffering therefrom, comprising administering to the patient an
effective amount of
4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D]pyrim-
idine or a salt thereof.
95. The method according to claim 94, wherein the salt is the
monohydrate hydrochloride.
96. The method according to claim 94 or claim 95, wherein the
urinary incontinence is stress urinary incontinence.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/536,341,filed on Jan. 13, 2004, U.S. Provisional
Application No. 60/496,502 filed on Aug. 20, 2003 and U.S.
Provisional Application No. 60/461,022 filed on Apr. 4, 2003. The
entire teachings of the above applications are incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] Lower urinary tract disorders affect the quality of life of
millions of men and women in the United States every year. While
the kidneys filter blood and produce urine, the lower urinary tract
functions to store and periodically eliminate urine and includes
all other parts of the urinary tract except the kidneys. Generally,
the lower urinary tract includes the ureters, the urinary bladder,
sphincter and the urethra. Disorders of the lower urinary tract
include overactive bladder, interstitial cystitis, prostatitis,
prostadynia and benign prostatic hyperplasia.
[0003] Overactive bladder is a treatable medical condition that is
estimated to affect 17 to 20 million people in the United States.
Symptoms of overactive bladder can include urinary frequency,
urinary urgency, urinary urge incontinence (accidental loss of
urine) due to a sudden and unstoppable need to urinate, nocturia
(the disturbance of nighttime sleep because of the need to urinate)
or enuresis resulting from overactivity of the detrusor muscle (the
smooth muscle of the bladder which contracts and causes it to
empty).
[0004] Neurogenic overactive bladder (or neurogenic bladder) is a
type of overactive bladder which occurs as a result of detrusor
muscle overactivity referred to as detrusor hyperreflexia,
secondary to known neurologic disorders. Patients with neurologic
disorders, such as stroke, Parkinson's disease, diabetes, multiple
sclerosis, peripheral neuropathy, or spinal cord lesions often
suffer from neurogenic overactive bladder. In contrast,
non-neurogenic overactive bladder occurs as a result of detrusor
muscle overactivity referred to as detrusor muscle instability.
Detrusor muscle instability can arise from non-neurological
abnormalities, such as bladder stones, muscle disease, urinary
tract infection or drug side effects or can be idiopathic.
[0005] Due to the enormous complexity of micturition (the act of
urination) an exact mechanism which causes overactive bladder is
not known. Overactive bladder can result from hypersensitivity of
sensory neurons of the urinary bladder, arising from various
factors including inflammatory conditions, hormonal imbalances, and
prostate hypertrophy. Destruction of the sensory nerve fibers,
either from a crushing injury to the sacral region of the spinal
cord, or from a disease that causes damage to the dorsal root
fibers as they enter the spinal cord can also lead to overactive
bladder. In addition, damage to the spinal cord or brain stem
causing interruption of transmitted signals can lead to
abnormalities in micturition. Therefore, both peripheral and
central mechanisms can be involved in mediating the altered
activity in overactive bladder.
[0006] In spite of the uncertainty regarding whether central or
peripheral mechanisms, or both, are involved in overactive bladder,
many proposed mechanisms implicate neurons and pathways that
mediate non-painful visceral sensation. Somatosensory information
from the bladder is relayed by nociceptive A.delta. and C fibers
that enter the spinal cord via the dorsal root ganglion (DRG) and
project to the brainstem and thalamus via second or third order
neurons (Andersson (2002) Urology 59:18-24; Andersson (2002)
Urology 59:43-50; Morrison, J., Steers, W. D., Brading, A., Blok,
B., Fry, C., de Groat, W. C., Kakizaki, H., Levin, R., and Thor, K.
B., "Basic Urological Sciences" In: Incontinence (vol. 2) Abrams,
P. Khoury, S., and Wein, A. (Eds.) Health Publications, Ltd.,
Plymbridge Ditributors, Ltd., Plymouth, UK., (2002). A number of
different subtypes of sensory afferent neurons can be involved in
neurotransmission from the lower urinary tract. These can be
classified as, but not limited to, small diameter, medium diameter,
large diameter, myelinated, unmyelinated, sacral, lumbar,
peptidergic, non-peptidergic, IB4 positive, IB4 negative, C fiber,
A.delta. fiber, high threshold or low threshold neurons.
Nociceptive input to the DRG is thought to be conveyed to the brain
along several ascending pathways, including the spinothalamic,
spinoreticular, spinomesencephalic, spinocervical, and in some
cases dorsal column/medial lemniscal tracts (A. I. Basbaum and T.
M. Jessell (2000) The perception of pain. In Principles of Neural
Science, 4th. ed.).
[0007] Currently there are no clinically approved applications of
central nervous system oriented pharmacotherapies for treating
lower urinary tract disorders, such as overactive bladder. However,
recent animal studies have suggested potential targets in the
central nervous system for modulating urinary tract functions. For
example, in the raphe nucleus of the caudal brain stem,
5-hydroxytryptamine (serotonin, 5-HT) containing neurons send
projections to the dorsal horn as well as to the autonomic and
sphincter motor nuclei in the lumbosacral spinal cord. The
sympathetic and parasympathetic autonomic nuclei as well as the
sphincter motor nuclei receive prominent serotonergic input from
the raphe nuclei in the caudal brain stem. Activity in the
serotonergic pathway generally enhances urine storage by
facilitating the vesical sympathetic reflex pathway and inhibiting
the parasympathetic voiding pathway (Sharma, A. et al. (2000)
Pharmacokinetics and safety of duloxetine, a dual-serotonin and
norepinephrine reuptake inhibitor. J. Clin. Pharmacol. 40: 161 and
Thor, K. B. et al. (1995) Effects of duloxetine, a combined
serotonin and norephinephrine reuptake ihibitor, on central neural
control of lower urinary tract function in the
chloralose-anesthetized female cat. J. Pharmacol. Exp. Ther. 274:
1016.)
[0008] Among the various subtypes of 5-HT receptors, 5-HT.sub.2 and
5-HT.sub.3 receptors mediate excitatory effects on sympathetic and
somatic reflexes to increase outlet resistance. Moreover,
5-HT.sub.2C and 5-HT.sub.3 receptors have also been shown to be
involved in inhibition of the micturition reflex (Downie, J. W.
(1999) Pharmacological manipulation of central micturition
circuitry. Curr. Opin. SPNS Inves. Drugs 1:23). In fact, 5-HT.sub.3
receptor inhibition has been shown to diminish 5-HT mediated
contractions in rabbit detrusor (Khan, M. A. et al. (2000)
Doxazosin modifies serotonin-mediated rabbit urinary bladder
contraction. Potential clinical relevance. Urol. Res. 28:116).
[0009] Current treatments for overactive bladder include
medication, diet modification, programs in bladder training,
electrical stimulation, and surgery. Currently, antimuscarinics
(which are members of the general class of anticholinergics) are
the primary medication used for the treatment of overactive
bladder. The antimuscarinic, oxbutynin, has been the mainstay of
treatment for overactive bladder. However, treatment with
antimuscarinics suffers from limited efficacy and side effects such
as dry mouth, dry eyes, dry vagina, blurred vision, cardiac side
effects, such as palpitations and arrhythmia, drowsiness, urinary
retention, weight gain, hypertension and constipation, which have
proven difficult for some individuals to tolerate.
[0010] Interstitial cystitis is another lower urinary tract
disorder of unknown etiology that predominantly affects young and
middle-aged females, although men and children can also be
affected. Symptoms of interstitial cystitis can include irritative
voiding symptoms, urinary frequency, urinary urgency, nocturia or
suprapubic or pelvic pain related to and relieved by voiding. Many
interstitial cystitis patients also experience headaches as well as
gastrointestinal and skin problems. In some cases, interstitial
cystitis can also be associated with ulcers or scars of the
bladder. (Metts, J. F. (2001) Interstitial Cystitis: Urgency and
Frequency Syndrome. American Family Physician 64(7):
1199-1206).
[0011] Currently, the only FDA-approved oral medication for use in
interstitial cystitis is ELMIRON.RTM. (pentosan polysulfate
sodium). ELMIRON.RTM. was approved in 1996 and is thought to work
by restoring a damaged, thin or leaky bladder surface. However,
ELMIRON.RTM. must be taken continually for several months before
any improvements can be expected. As such, lack of patient
compliance often results in unsuccessful treatment. In addition,
treatment with ELMIRON.RTM. is not effective in a large percentage
of patients.
[0012] Other medications which have been used "off-label" for the
treatment of interstitial cystitis include, for example,
antidepressants, antihistamines and anticonvulsants (See,
Theoharides, T. C. (2001) New agents for the medical treatment of
interstitial cystitis. Exp. Opin. Invest. Drugs 10(3): 521-46).
However, in view of the unknown cause of interstitial cystitis and
the suggestion that the disorder is multifactorial in origin, these
additional therapies have not provided adequate relief of the
associated symptoms.
[0013] Prostatitis and prostadynia are other lower urinary tract
disorders that have been suggested to affect approximately 2-9% of
the adult male population (Collins M. M. et al., (1998) "How common
is prostatitis? A national survey of physician visits," Journal of
Urology, 159: 1224-1228). Prostatitis is an inflammation of the
prostate, and includes bacterial prostatitis (acute and chronic)
and non-bacterial prostatitis. Acute and chronic bacterial
prostatitis are characterized by inflammation of the prostate and
bacterial infection of the prostate gland, usually associated with
symptoms of pain, urinary frequency and/or urinary urgency. Chronic
bacterial prostatitis is distinguished from acute bacterial
prostatitis based on the recurrent nature of the disorder. Chronic
non-bacterial prostatitis is characterized by inflammation of the
prostate which is of unknown etiology accompanied by the presence
of an excessive amount of inflammatory cells in prostatic
secretions not currently associated with bacterial infection of the
prostate gland, and usually associated with symptoms of pain,
urinary frequency and/or urinary urgency. Prostadynia is a disorder
which mimics the symptoms of prostatitis absent inflammation of the
prostate, bacterial infection of the prostate and elevated levels
inflammatory cells in prostatic secretions. Prostadynia can be
associated with symptoms of pain, urinary frequency and/or urinary
urgency.
[0014] Currently, there are no established treatments for
prostatitis and prostadynia. Antibiotics are often prescribed, but
with little evidence of efficacy. COX-2 selective inhibitors and
.alpha.-adrenergic blockers and have been suggested as treatments,
but their efficacy has not been established. Hot sitz baths and
anticholinergic drugs have also been employed to provide some
symptomatic relief.
[0015] Benign prostatic hyperplasia (BPH) is a non-malignant
enlargement of the prostate that is very common in men over 40
years of age. BPH is thought to be due to excessive cellular growth
of both glandular and stromal elements of the prostate. Symptoms of
BPH can include urinary frequency, urinary urgency, urge
incontinence, nocturia, or reduced urinary force and speed of
flow.
[0016] Invasive treatments for BPH include transurethral resection
of the prostate, transurethral incision of the prostate, balloon
dilation of the prostate, prostatic stents, microwave therapy,
laser prostatectomy, transrectal high-intensity focused ultrasound
therapy and transurethral needle ablation of the prostate. However,
complications can arise through the use of some of these
treatments, including retrograde ejaculation, impotence,
postoperative urinary tract infection and some urinary
incontinence. Non-invasive treatments for BPH include androgen
deprivation therapy and the use of 5.alpha.-reductase inhibitors
and .alpha.-adrenergic blockers. However, these treatments have
proven only minimally to moderately effective for some
patients.
[0017] In view of the limitations associated with existing
therapies and treatments for lower urinary tract disorders, new
therapies and treatments are highly desirable.
SUMMARY OF THE INVENTION
[0018] The invention relates to a method of treating at least one
symptom of a lower urinary tract disorder in a subject in need of
treatment wherein the symptom is selected from the group consisting
of urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis. The method comprises administering to a
subject in need of treatment a therapeutically effective amount of
a compound that has 5-HT.sub.3 receptor antagonist activity and
NorAdrenaline Reuptake Inhibitor (NARI) activity.
[0019] In a particular embodiment, the compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity are
thieno[2,3-d]pyrimidine derivatives such as those described in U.S.
Pat. No. 4,695,568, the entire content of which is incorporated
herein by reference.
[0020] In a specific embodiment, the compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity are represented by
structural Formula I: 1
[0021] wherein, R.sub.1 and R.sub.2 independently represent
hydrogen, halogen or a C.sub.1-C.sub.6 alkyl group; or R.sub.1 and
R.sub.2 together with the carbon atoms to which they are attached
form a cycloalkylene group having 5 to 6 carbon atoms;
[0022] R.sub.3 and R4 independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group;
[0023] R.sub.5 is hydrogen, C.sub.1-C.sub.6 alkyl, 2
[0024] or --C(O)--NH--R.sub.6,
[0025] wherein m is an integer from about 1 to about 3, X is
halogen and R.sub.6 is a C.sub.1-C.sub.6 alkyl group;
[0026] Ar is a substituted or unsubstituted phenyl, 2-thienyl or
3-thienyl group; and
[0027] n is 2 or 3; or a pharmaceutically acceptable salt
thereof.
[0028] In a specific embodiment, the compound having 5-HT.sub.3
receptor antagonist activity and NARI activity is represented by
the formula: 3
[0029] or a pharmaceutically acceptable salt thereof. This compound
is commonly referred to as MCI-225, also referred to as DDP-225.
The chemical name of the structure set forth in the formula is:
4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine.
[0030] In as specific embodiment, the symptom is selected from the
group consisting of urinary frequency, urinary urgency, nocturia
and enuresis.
[0031] In one embodiment, the lower urinary tract disorder can be
selected from the group consisting of overactive bladder,
interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0032] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0033] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0034] The invention further relates to a method of treating at
least one symptom of a lower urinary tract disorder in a subject in
need of treatment wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urinary urge
incontinence, nocturia and enuresis comprising coadministering to
said subject a therapeutically effective amount of a 5-HT.sub.3
receptor antagonist and a therapeutically effective amount of a
NARI.
[0035] The invention further relates to a method of treating at
least one symptom of a lower urinary tract disorder in a subject in
need of treatment wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urinary urge
incontinence, nocturia and enuresis comprising coadministering to
said subject a first amount of a 5-HT.sub.3 receptor antagonist and
a second amount of a NARI, wherein the first and second amounts
together comprise a therapeutically effective amount.
[0036] In as specific embodiment, the symptom is selected from the
group consisting of urinary frequency, urinary urgency, nocturia
and enuresis.
[0037] In one embodiment, the lower urinary tract disorder can be
selected from the group consisting of overactive bladder,
interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0038] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0039] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0040] The invention further relates to pharmaceutical compositions
useful for the treatment of at least one symptom of a lower urinary
tract disorder in a subject in need of treatment wherein the
symptom is selected from the group consisting of urinary frequency,
urinary urgency, urinary urge incontinence, nocturia and enuresis.
The pharmaceutical composition comprises a first amount of a
5-HT.sub.3 receptor antagonist compound and a second amount of a
NARI compound. The pharmaceutical compositions of the present
invention can optionally contain a pharmaceutically acceptable
carrier. The 5-HT.sub.3 receptor antagonist and the NARI can each
be present in the pharmaceutical composition in a therapeutically
effective amount. In another aspect, said first and second amounts
can together comprise a therapeutically effective amount.
[0041] In as specific embodiment, the symptom is selected from the
group consisting of urinary frequency, urinary urgency, nocturia
and enuresis.
[0042] In one embodiment, the lower urinary tract disorder can be
selected from the group consisting of overactive bladder,
interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0043] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0044] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0045] The invention further relates to use of a compound that has
5-HT.sub.3 receptor antagonist activity and NARI activity for the
manufacture of a medicament for treating at least one symptom of a
lower urinary tract disorder in a subject in need of treatment
wherein the symptom is selected from the group consisting of
urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis. In addition, the invention also relates to
the use of a pharmaceutical composition comprising a first amount
of a 5-HT.sub.3 receptor antagonist compound and a second amount of
a NARI compound for the manufacture of a medicament for the
treatment of at least one symptom of a lower urinary tract disorder
in a subject in need of treatment wherein the symptom is selected
from the group consisting of urinary frequency, urinary urgency,
urinary urge incontinence, nocturia and enuresis. The
pharmaceutical composition used for the manufacture of a medicament
can optionally contain a pharmaceutically acceptable carrier. The
5-HT.sub.3 receptor antagonist and the NARI can each be present in
the pharmaceutical composition in a therapeutically effective
amount or said first and second amounts can together comprise a
therapeutically effective amount.
[0046] The foregoing and other objects, features and advantages of
the invention will be apparent from the following more particular
description of preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] FIG. 1 is a graph of bladder capacity (reported as % Bladder
Capacity normalized to the last vehicle treatment measurement of
the AA/Veh 3 treatment group) for the indicated treatment regimen
in female rats subjected to the dilute acetic acid model described
herein (Sal=saline).
[0048] FIG. 2 is a graph of bladder capacity (reported as % Bladder
Capacity normalized to the last vehicle treatment measurement of
the AA treatment group) for the indicated treatment regimen in cats
subjected to the dilute acetic acid model described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0049] The invention relates to a method of treating at least one
symptom of a lower urinary tract disorder in a subject in need of
treatment wherein the symptom is selected from the group consisting
of urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis. In one embodiment, the lower urinary tract
disorder can be selected from the group consisting of overactive
bladder, interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperlasia. In another embodiment, the lower urinary
tract disorder is overactive bladder. In yet another embodiment,
the lower urinary tract disorder is interstitial cystitis.
Monoamine Neurotransmitters
[0050] Monoamine neurotransmitters such as noradrenaline (also
referred to as norepinephrine), serotonin (5-hydroxytryptamine,
5-HT) and dopamine are known and disturbances in these
neurotransmitters have been indicated in many types of disorders,
such as depression. These neurotransmitters travel from the
terminal of a neuron across a small gap referred to as the synaptic
cleft and bind to receptor molecules on the surface of a second
neuron. This binding elicits intracellular changes that initiate or
activate a response or change in the postsynaptic neuron.
Inactivation occurs primarily by transport of the neurotransmitter
back into the presynaptic neuron, which is referred to as reuptake.
These neurons or neuroendocrine cells can be found both in the
Central Nervous System (CNS) and in the Peripheral Nervous System
(PNS).
Noradrenaline and Noradrenaline Reuptake Inhibitors
[0051] As used herein, the term NorAdrenaline Reuptake Inhibitor
(NARI) refers to an agent (e.g., a molecule, a compound) which can
inhibit noradrenaline transporter function. For example, a NARI can
inhibit binding of a ligand of a noradrenaline transporter to said
transporter and/or inhibit transport (e.g., uptake or reuptake of
noradrenaline). As such, inhibition of the noradrenaline transport
function in a subject, can result in an increase in the
concentration of physiologically active noradrenaline. It is
understood that NorAdrenergic Reuptake Inhibitor and NorEpinephrine
Reuptake Inhibitor (NERI) are synonymous with NorAdrenaline
Reuptake Inhibitor (NARI).
[0052] As used herein, noradrenaline transporter refers to
naturally occurring noradrenaline transporters (e.g., mammalian
noradrenaline transporters (e.g., human (Homo sapiens)
noradrenaline transporters, murine (e.g., rat, mouse) noradrenaline
transporters)) and to proteins having an amino acid sequence which
is the same as that of a corresponding naturally occurring
noradrenaline transporter (e.g., recombinant proteins). The term
includes naturally occurring variants, such as polymorphic or
allelic variants and splice variants.
[0053] In certain embodiments, the NARI can inhibit the binding of
a ligand (e.g., a natural ligand such as noradrenaline, or other
ligand such as nisoxetine) to a noradrenaline transporter. In other
embodiments, the NARI can bind to a noradrenaline transporter. For
example, in a preferred embodiment, the NARI can bind to a
noradrenaline transporter, thereby inhibiting binding of a ligand
to said transporter and inhibiting transport of said ligand. In
another preferred embodiment, the NARI can bind to a noradrenaline
transporter, and thereby inhibit transport.
[0054] The NARI activity of a compound can be determined employing
suitable assays. More specifically, to determine the inhibition
constant (Ki) for noradrenaline reuptake, an assay which monitors
inhibition of noradrenaline (NA) uptake can be used. For example,
radiolabelled noradrenaline, such as [.sup.3H]NA and the test
compound of interest can be incubated under conditions suitable for
uptake with brain tissue or a suitable fraction thereof, for
example, a synaptosomal fraction from rat brain tissue (harvested
and isolated in accordance with generally accepted techniques), and
the amount of uptake of [.sup.3H]NA in the tissue or fraction can
be determined (e.g., by liquid scintillation spectrometry).
IC.sub.50 values can be calculated by nonlinear regression
analysis. The inhibition constants, Ki values, can then be
calculated from the IC.sub.50 values using the Cheng-Prusoff
equation: 1 K i = IC 50 1 + ( [ L ] / K d )
[0055] wherein [L]=the concentration of free radioligand used in
the assay and K.sub.d=the equilibrium dissociation constant of the
radioligand. To determine the non-specific uptake, incubations can
be performed by following the same assay, but in the absence of
test compound at 4.degree. C. (i.e., under conditions not suitable
for uptake).
[0056] In a preferred embodiment, NARI activity is determined using
the radioligand uptake assay described above, according to the
procedure detailed in Eguchi et al., Arzneim.-Forschung/Drug Res.,
47(12): 1337-47 (1997).
[0057] Specifically, rats are decapitated and the cortical,
hypothalamic, hippocampal and striatal tissues are rapidly
dissected. The tissues are homogenized (Potter homogenizer with
Teflon pestle) in 10 volumes of ice cold 0.32 mol/L sucrose. The
P.sub.2 fraction is obtained by centrifugation at 1000.times.g for
10 minutes and 11500.times.g for 20 minutes and suspended in
Krebs-Ringer phosphate buffer, pH 7.4 (124 mmo/L NaCl, 5 mmol/L
KCl, 20 mmol/L Na.sub.2HPO.sub.4, 1.2 mmol/L KH.sub.2PO.sub.4, 1.3
mmol/L MgSO.sub.4, 0.75 mmol/L CaCl.sub.2, 10 mmol/L glucose). The
[.sup.3H]NA uptake assays are performed on the cortical and
hypothalamic synaptosomes.
[0058] The assay tubes contain radiolabled noradrenaline,
[.sup.3H]NA, in a volume of 0.2 mL, compounds at 5 or more
concentrations in a volume of 0.1 mL, and the oxygenated buffer
described above in a volume of 0.5 mL. After 5 minutes
preincubation at 37 .degree. C., uptake is initiated by the
addition of the synaptosomal fraction in volume of 0.2 mL. The
final concentration of [.sup.3H]NA in the incubation mixtures is
0.25 .mu.mol/L. The reaction is stopped after 5 minutes by
filtration through Whatman GF/B glass fiber filter under a vacuum
with a cell harvester. The filter is rinsed three times with 4 mL
of saline and placed in a scintillation vial containing 10 mL of
Atomlight (Du Pont/NEN Research Products). Radioactivity is
measured by liquid scintillation spectrometry. For determination of
non-specific uptake, incubations are performed at 4.degree. C.
without the addition of test compounds. IC.sub.50 values are
calculated by nonlinear regression analysis. Inihibitor constants,
Ki values, are calculated from the IC.sub.50 values using the
Cheng-Prusoff equation.
[0059] NARI compounds suitable for use in the invention have a Ki
value for NARI activity of about 500 nmol/L or less, such as about
250 nmol/L or less, for example, about 100 nmol/L or less. It is
preferred that the Ki value for NARI activity be about 100 nmol/L
or less. It is understood that the exact value of the Ki for a
particular compound can vary depending on the assay conditions
employed for determination (e.g., radioligand and tissue source).
As such, it is preferred that the NARI activity be assessed
essentially according to the radioligand binding assay described in
Eguchi et al., Arzneim.-Forschung/Drug Res., 47(12): 1337-47 (1997)
and discussed in detail above.
[0060] In addition, to possessing sufficient NARI activity, it is
preferred that the NARI compounds possess one or more
characteristics selected from the group consisting of:
[0061] a) the substantial absence of anticholinergic effects;
[0062] b) the selective inhibition of noradrenaline reuptake as
compared to inhibition of serotonin reuptake; and
[0063] c) the selective inhibition of noradrenaline reuptake as
compared to inhibition of dopamine reuptake.
[0064] Selective inhibition of noradrenaline reuptake as compared
to inhibition of serotonin or dopamine reuptake can be determined
by comparing the Ki values for the respective reuptake inhibitions.
The inhibition constants for serotonin and dopamine reuptake can be
determined as described above for nordrenaline, but employing the
appropriate radioligand and tissue for the activity being assessed
(e.g., [.sup.3H] 5-HT for serotonin, using e.g., hypothalamic or
cortical tissue and [.sup.3H]DA for dopamine (DA), using e.g.,
striatal tissue).
[0065] A preferred method of determining serotonin reuptake
inhibition and dopaminergic reuptake inhibition is described in
Eguchi et al., Arzneim.-Forschung/Drug Res., 47(12): 1337-47
(1997). Specifically, rats are decapitated and the cortical,
hypothalamic, hippocampal and striatal tissues are rapidly
dissected. The tissues are homogenized (Potter homogenizer with
Teflon pestle) in 10 volumes of ice cold 0.32 mol/L sucrose. The
P.sub.2 fraction is obtained by centrifugation at 1000.times.g for
10 minutes and 11500.times.g for 20 minutes and suspended in
Krebs-Ringer phosphate buffer, pH 7.4 (124 mmol/L NaCl, 5 mmol/L
KCl, 20 mmol/L Na.sub.2HPO.sub.4, 1.2 mmol/L KH.sub.2PO.sub.4, 1.3
mmol/L MgSO.sub.4, 0.75 mmol/L CaCl.sub.2, 10 mmol/L glucose). The
[.sup.3H]5-HT uptake assays are performed on the cortical,
hypothalamic and hippocampal synaptosomes, and the [.sup.3H]DA
uptake assays are performed on striatal synaptosomes.
[0066] The assay tubes contain the appropriate radiolabled ligand
(i.e., [.sup.3H]5-HT or [.sup.3H]DA), in a volume of 0.2 mL,
compounds at 5 or more concentrations in a volume of 0.1 mL, and
the oxygenated buffer described above in a volume of 0.5 mL. After
5 minutes preincubation at 37.degree. C., uptake is initiated by
the addition of the synaptosomal fraction in volume of 0.2 mL. The
final concentration of [.sup.3H]DA in the striatal incubation
mixtures is 0.4 .mu.mol/L. The final concentrations of
[.sup.3H]5-HT in the cortical, hypothalamic and hippocampal
synaptosome incubation mixtures are 0.02 .mu.mol/L, 0.04 .mu.mol/L
and 0.08 .mu.mol/L. The reaction is stopped after 5 minutes
([.sup.3H]5-HT) or 3 minutes [.sup.3H]DA by filtration through
Whatman GF/B glass fiber filter under a vacuum with a cell
harvester. The filter is rinsed three times with 4 mL of saline and
placed in a scintillation vial containing 10 mL of Atomlight (Du
Pont/NEN Research Products). Radioactivity is measured by liquid
scintillation spectrometry. For determination of non-specific
uptake incubations are performed at 4.degree. C. without the
addition of test compounds. IC.sub.50 values are calculated by
nonlinear regression analysis. Inhibition constants, Ki values, are
calculated from the IC.sub.50 values using the Cheng-Prusoff
equation.
[0067] Following determination of the Ki values for inhibition of
noradrenaline, serotonin and/or dopamine uptake, the ratio of the
activities can be determined. Selective inhibition of noradrenaline
reuptake as compared to inhibition of serotonin reuptake and/or
dopaminergic reuptake, refers to a compound having a Ki value for
inhibition of serotonin (re)uptake and/or dopamine (re)uptake which
is about 10 times or more than the Ki for inhibition of
noradrenaline (re)uptake. That is, the ratio, Ki inhibition of
serotonin (re)uptake/Ki inhibition of noradrenaline (re)uptake, is
about 10 or more, such as about 15 or more, about 20 or more, for
example, about 30, 40 or 50 or more. Likewise, the ratio, Ki
inhibition of dopamine (re)uptake/Ki inhibition noradrenaline
(re)uptake, is about 10 or more, such as about 15 or more, about 20
or more, for example, about 30, 40 or 50 or more.
[0068] It is preferred that the Ki values for comparison are
determined according to the method of Eguchi et al., discussed in
detail above. It is most preferred, that the Ki values for NARI
activity and inhibition of serotonin reuptake activity, which are
compared to determine selective inhibition are determined according
to the method of Eguchi et al. using a synaptosomal preparation
from rat hypothalamic tissue. Further, it is most preferred, that
the Ki values for NARI activity and inhibition of dopamine reuptake
activity, which are compared to determine selective inhibition are
determined according to the method of Eguchi et al. using a
synaptosomal preparation from rat hypothalamic tissue for
inhibition of noradrenaline uptake and from rat striatal tissue for
inhibition of dopamine uptake.
[0069] In another embodiment, the NARI is characterized by the
substantial absence of anticholinergic effects. As used herein,
substantial absence of anticholinergic effects, refers to a
compound which has an IC.sub.50 value for binding to muscarinic
receptors of about 1 .mu.mol/L or more. The IC.sub.50 value for
binding to muscarinic receptors can be determined using a suitable
assay, such as an assay which determines the ability of a compound
to inhibit the binding of suitable radioligand to muscarinic
receptors. A preferred assay for determination of the IC.sub.50
value for binding of a compound to muscarinic receptors is
described in Eguchi et al., Arzneim.-Forschung/Drug Res., 47(12):
1337-47 (1997).
[0070] Specifically, the binding assays for determination of
binding to muscarinic receptors can be performed on tissue isolated
from the rat cerebral cortex. The buffer is any suitable buffer,
for example, 50 mmol/L Tris-HCl, pH=7.4. The preferred radiolabeled
ligand is [.sup.3H]QNB (3-quinuclidinyl benzilate) which is present
in a final concentration of 0.2 nmol/L. The test compound is added
at various concentrations and the resulting mixtures are incubated
for 60 minutes at 37.degree. C. The reaction is terminated by rapid
vacuum filtration onto glass fiber filter. Radioactivity trapped on
the filter is measured by scintillation spectrometry. Non-specific
binding is determined using 100 .mu.mol/L atropine. IC.sub.50
values can be calculated by nonlinear regression analysis.
[0071] In a particular embodiment, the NARI compound can be
selected from venlafaxine, duloxetine, buproprion, milnacipran,
reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine,
maprotiline, oxaprotiline, levoprotiline, viloxazine and
atomoxetine.
[0072] In a preferred embodiment, the NARI compound can be selected
from reboxetine, lefepramine, desipramine, nortriptyline,
tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine
and atomoxetine.
Serotonin and 5-HT.sub.3 Receptor Antagonists
[0073] The neurotransmitter serotonin was first discovered in 1948
and has subsequently been the subject of substantial scientific
research. Serotonin, also referred to as 5-hydroxytryptamine
(5-HT), acts both centrally and peripherally on discrete 5-HT
receptors. Currently, fourteen subtypes of serotonin receptors are
recognized and delineated into seven families, 5-HT.sub.1 through
5-HT.sub.7. These subtypes share sequence homology and display some
similarities in their specificity for particular ligands. A review
of the nomenclature and classification of the 5-HT receptors can be
found in Neuropharm., 33: 261-273 (1994) and Pharm. Rev.,
46:157-203 (1994).
[0074] Recent animal studies have suggested that targeting specific
subtypes of 5-HT receptors could offer additional treatments for
lower urinary tract dysfunctions. For example, among the various
subtypes of 5-HT receptors, 5-HT.sub.2 and 5-HT.sub.3 receptors
mediate excitatory effects on sympathetic and somatic reflexes to
increase outlet resistance. Moreover, 5-HT.sub.2C and 5-HT.sub.3
receptors have also been shown to be involved in inhibition of the
micturition reflex (Downie, J. W. (1999) Pharmacological
manipulation of central micturition circuitry. Curr. Opin. SPNS
Inves. Drugs 1:23). In fact, 5-HT.sub.3 receptor inhibition has
been shown to diminish 5-HT mediated contractions in rabbit
detrusor (Khan, M. A. et al. (2000) Doxazosin modifies
serotonin-mediated rabbit urinary bladder contraction. Potential
clinical relevance. Urol. Res. 28:116).
[0075] As used herein, 5-HT.sub.3 receptor refers to naturally
occurring 5-HT.sub.3 receptors (e.g., mammalian 5-HT.sub.3
receptors (e.g., human (Homo sapiens) 5-HT.sub.3 receptors, murine
(e.g., rat, mouse) 5-HT.sub.3 receptors)) and to proteins having an
amino acid sequence which is the same as that of a corresponding
naturally occurring 5-HT.sub.3 receptor (e.g., recombinant
proteins). The term includes naturally occurring variants, such as
polymorphic or allelic variants and splice variants.
[0076] As used herein, the term 5-HT.sub.3 receptor antagonist
refers to an agent (e.g., a molecule, a compound) which can inhibit
5-HT.sub.3 receptor function. For example, a 5-HT.sub.3 receptor
antagonist can inhibit binding of a ligand of a 5-HT.sub.3 receptor
to said receptor and/or inhibit a 5-HT.sub.3 receptor-mediated
response (e.g., reduce the ability of 5-HT.sub.3 to evoke the von
Bezold-Jarisch reflex).
[0077] In certain embodiments, the 5-HT.sub.3 receptor antagonist
can inhibit binding of a ligand (e.g., a natural ligand, such as
serotonin (5-HT.sub.3), or other ligand such as GR65630) to a
5-HT.sub.3 receptor. In certain embodiments, the 5-HT.sub.3
receptor antagonist can bind to a 5-HT.sub.3 receptor. For example,
in a preferred embodiment, the 5-HT.sub.3 receptor antagonist can
bind to a 5-HT.sub.3 receptor, thereby inhibiting the binding of a
ligand to said receptor and a 5-HT.sub.3 receptor-mediated response
to ligand binding. In another preferred embodiment, the 5-HT.sub.3
receptor antagonist can bind to a 5-HT.sub.3 receptor, and thereby
inhibit a 5-HT.sub.3 receptor-mediated response.
[0078] 5-HT.sub.3 receptor antagonists can be identified and
activity assessed by any suitable method, for example, by a method
which assesses the ability of a compound to inhibit radioligand
binding to 5-HT.sub.3 receptor (see, for example, Eguchi et al.,
Arzneim.-Forschung/Drug Res., 47(12): 1337-47 (1997) and G.
Kilpatrick et al., Nature, 330: 746-748 (1987)) and/or by their
effect on the 5-HT.sub.3-induced von Bezold-Jarisch (B-J) reflex in
the cat or rat (following the general methods described by Butler
et al., Br. J. Pharmacol., 94: 397-412 (1988) and Ito et al., J.
Pharmacol. Exp. Ther., 280(1): 67-72 (1997), respectively).
[0079] In a preferred embodiment, 5-HT.sub.3 receptor antagonist
activity of a compound can be determined according to the method
described in Eguchi et al., Arzneim.-Forschung/Drug Res., 47(12):
1337-47 (1997). Specifically, the binding assays for determination
of binding to the 5-HT.sub.3 receptor can be performed on N1E-115
mouse neuroblastoma cells (American Type Culture Collection (ATCC)
Accession No. CRL-2263) in 20 mmol/L HEPES buffer (pH=7.4)
containing 150 mmol/L NaCl, 0.35 mmol/L of radiolabeled ligand
([.sup.3H]GR.sub.65630) and the test compound at 6 or more
concentrations at 25.degree. C. for 60 minutes. The reaction is
terminated by rapid vacuum filtration onto glass fiber filter.
Radioactivity trapped on the filter is measured by scintillation
spectrometry. Non-specific binding is determined using 1 .mu.mol/L
of MDL-7222 (endo-8-methyl-8-azabicyclo
[3.2.1]oct-3-yl-3,5-dichlorobenzoate- . IC.sub.50 values are
calculated by nonlinear regression analysis. The affinity
constants, Ki values, are calculated from the IC.sub.50 values
using the Cheng-Prusoff equation.
[0080] Compounds having 5-HT.sub.3 receptor antagonist activity
which are suitable for use in the invention have an affinity for
5-HT.sub.3 receptor (Ki) of not more than about 250 times the Ki of
ondansetron for 5-HT.sub.3 receptor. This relative activity to
ondansetron (Ki of test agent for 5-HT.sub.3 receptor/Ki of
ondansetron for 5-HT.sub.3 receptor), can be determined by assaying
the compound of interest and ondansetron using a suitable assay
under controlled conditions, for example, conditions which differ
primarily in the agent being tested. It is preferred that the
relative activity of the 5-HT.sub.3 receptor antagonist activity be
not more than about 200 times that of ondansetron, for example, not
more than about 150 times that of ondansetron, such as not more
than about 100 times that of ondansetron, for example, not more
than about 50 times that of ondansetron. In a particularly
preferred embodiment, the compound having 5-HT.sub.3 receptor
antagonist activity has a relative activity to ondansetron of not
more than about 10.
[0081] In certain embodiments, the 5-HT.sub.3 receptor antagonist
can be selected from indisetron, YM-114
((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro--
1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron,
talipexole, azasetron, bemesetron, tropisetron, ramosetron,
ondansetron, palonosetron, lerisetron, alosetron, N-3389,
zacopride, cilansetron, E-3620
([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-
-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393,
itasetron, zatosetron, dolasetron, (.+-.)-zacopride,
(.+-.)-renzapride, (-)-YM-060, DAU-6236, BIMU-8 and GK-128
([2-[2-methylimidazol-1-yl)methyl]-benzo[f]th- iochromen-1-one
monohydrochloride hemihydrate]).
[0082] In preferred embodiments, the 5-HT.sub.3 receptor antagonist
can be selected from indisetron, granisetron, azasetron,
bemesetron, tropisetron, ramosetron, ondansetron, palonosetron,
lerisetron, alosetron, cilansetron, itasetron, zatosetron, and
dolasetron.
[0083] As used herein, lower urinary tract refers to all parts of
the urinary tract except the kidneys.
[0084] As used herein, lower urinary tract disorder refers to any
disorder involving the lower urinary tract, including but not
limited to overactive bladder, interstitial cystitis, prostatitis,
prostadynia and benign prostatic hyperplasia.
[0085] As used herein, bladder disorder refers to any condition
involving the urinary bladder.
[0086] As used herein, overactive bladder refers to a chronic
condition resulting from overactivity of the detrusor muscle,
wherein the bladder initiates contraction too early while filling
with urine, manifesting with one or more symptoms of urinary
frequency, urinary urgency, urinary urge incontinence, nocturia or
enuresis. Overactive bladder can be neurogenic or
non-neurogenic.
[0087] Neurogenic overactive bladder (or neurogenic bladder) is a
type of overactive bladder which occurs as a result of detrusor
muscle overactivity referred to as detrusor hyperreflexia,
secondary to neurologic disorders.
[0088] Non-neurogenic overactive bladder occurs as a result of
detrusor muscle overactivity referred to as detrusor muscle
instability. Detrusor muscle instability can arise from
non-neurological abnormalities, such as bladder stones, muscle
disease, urinary tract infection or drug side effects or can be
idiopathic.
[0089] Interstitial cystitis is used herein in its conventional
sense to refer to a disorder associated with symptoms that can
include irritative voiding symptoms, urinary frequency, urgency,
nocturia, suprapubic pain and/or pelvic pain related to and
relieved by voiding.
[0090] As used herein, urinary frequency refers to urinating more
frequently than the patient desires. As there is considerable
interpersonal variation in the number of times in a day that an
individual would normally expect to urinate, "more frequently than
the patient desires" is further defined as a greater number of
times per day than that patient's historical baseline. "Historical
baseline" is further defined as the median number of times the
patient urinated per day during a normal or desirable time
period.
[0091] As used herein, urinary urgency refers to sudden strong
urges to urinate with little or no chance to postpone the
urination.
[0092] As used herein, urinary urge incontinence (also referred to
as urge incontinence) refers to the involuntary loss of urine
associated with urinary urgency.
[0093] As used herein, nocturia refers to being awakened from sleep
to urinate more frequently than the patient desires.
[0094] As used herein, enuresis refers to involuntary voiding of
urine which can be complete or incomplete. Nocturnal enuresis
refers to enuresis which occurs during sleep. Diurnal enuresis
refers to enuresis which occurs while awake.
[0095] As used herein, stress incontinence or urinary stress
incontinence refers to a medical condition in which urine leaks
when a person coughs, sneezes, laughs, exercises, lifts heavy
objects, or does anything that puts pressure on the bladder.
[0096] As used herein, prostatitis refers to any type of disorder
associated with inflammation of the prostate, including chronic and
acute bacterial prostatitis and chronic non-bacterial prostatitis,
and which is usually associated with symptoms of urinary frequency
and/or urinary urgency.
[0097] Acute and chronic bacterial prostatitis are used herein in
the conventional sense to refer to a disorder characterized by
inflammation of the prostate and bacterial infection of the
prostate gland, usually associated with symptoms of pain, urinary
frequency and/or urinary urgency. Chronic bacterial prostatitis is
distinguished from acute bacterial prostatitis based on the
recurrent nature of the disorder. Chronic non-bacterial prostatitis
is used herein in its conventional sense to refer to a disorder
characterized by inflammation of the prostate which is of unknown
etiology accompanied by the presence of an excessive amount of
inflammatory cells in prostatic secretions not currently associated
with bacterial infection of the prostate gland, and usually
associated with symptoms of pain, urinary frequency and/or urinary
urgency.
[0098] Prostadynia is a disorder which mimics the symptoms of
prostatitis absent inflammation of the prostate, bacterial
infection of the prostate and elevated levels inflammatory cells in
prostatic secretions. Prostadynia can be associated with symptoms
of pain, urinary frequency and/or urinary urgency.
[0099] Benign prostatic hyperplasia is used herein in its
conventional sense to refer to a disorder associated with benign
enlargement of the prostate gland which can be associated with
urinary frequency, urinary urgency, urge incontinence, nocturia,
and/or reduced urinary force and speed of flow.
[0100] The invention relates to a method of treating at least one
symptom of a lower urinary tract disorder in a subject in need of
treatment wherein the symptom is selected from the group consisting
of urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis. The method comprises administering to a
subject in need of treatment a therapeutically effective amount of
a compound that has 5-HT.sub.3 receptor antagonist activity and
NorAdrenaline Reuptake Inhibitor (NARI) activity.
[0101] In a particular embodiment, the compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity are
thieno[2,3-d]pyrimidine derivatives such as those described in U.S.
Pat. No. 4,695,568, the entire content of which is incorporated
herein by reference.
[0102] In a specific embodiment, the compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity are represented by
Formula I: 4
[0103] wherein, R.sub.1 and R.sub.2 independently represent
hydrogen, halogen or a C.sub.1-C.sub.6 alkyl group; or R.sub.1 and
R.sub.2 together with the carbon atoms to which they are attached
form a cycloalkylene group having 5 to 6 carbon atoms;
[0104] R.sub.3 and R.sub.4 independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group;
[0105] R.sub.5 is hydrogen, C.sub.1-C.sub.6 alkyl, 5
[0106] or --C(O)--NH--R.sub.6,
[0107] wherein m is an integer from about 1 to about 3, X is
halogen and R.sub.6 is a C.sub.1-C.sub.6 alkyl group;
[0108] Ar is a substituted or unsubstituted phenyl, 2-thienyl or
3-thienyl group; and n is 2 or 3; or a pharmaceutically acceptable
salt thereof.
[0109] Substituted phenyl, 2-thienyl or 3-thienyl group refers to a
phenyl, 2-thienyl or 3-thienyl group in which at least one of the
hydrogen atoms available for substitution has been replaced with a
group other than hydrogen (i.e., a substituent group). Multiple
substituent groups can be present on the phenyl, 2-thienyl or
3-thienyl ring. When multiple substituents are present, the
substituents can be the same or different and substitution can be
at any of the substitutable sites on the ring. Substituent groups
can be, for example, a halogen atom (fluorine, chlorine, bromine or
iodine); an alkyl group, for example, a C.sub.1-C.sub.6 alkyl group
such as a methyl, ethyl, propyl, butyl, pentyl or hexyl group; an
alkoxy group, for example, a C.sub.1-C.sub.6 alkoxy group such as
methoxy, ethoxy, propoxy, butoxy; a hydroxy group; a nitro group;
an amino group; a cyano group; or an alkyl substituted amino group
such as methylamino, ethylamino, dimethylamino or diethylamino
group.
[0110] C.sub.1-C.sub.6 alkyl group refers to a straight-chain or
branched alkyl group having from one to six carbon atoms. For
example, the C.sub.1-C.sub.6 alkyl group can be a strain-chain
alkyl such as methyl, ethyl, propyl, etc. Alternatively, the alkyl
group can be branched for example, an isopropyl or t-butyl
group.
[0111] Halogen refers to fluorine, chlorine, bromine or iodine.
[0112] In a particular embodiment, the compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity are represented by
Formula I, wherein R.sub.1 is a C.sub.1-C.sub.6 alkyl group and Ar
is a substituted phenyl. In this embodiment, it is preferred that
the phenyl group is substituted with a halogen.
[0113] In a particularly preferred embodiment, the compounds having
5-HT.sub.3 receptor antagonist activity and NARI activity are
represented by Formula I, wherein n is 2, R.sub.1 is a
C.sub.1-C.sub.6 alkyl group and Ar is a substituted phenyl.
Preferably, the phenyl group is substituted with a halogen and the
alkyl group of R.sub.1 is a methyl group.
[0114] In yet another embodiment, the compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity are represented by
Formula I, wherein R.sub.1 is a C.sub.1-C.sub.6 alkyl group or a
halogen and Ar is an unsubstituted phenyl. Further, when R.sub.1 is
an alkyl group and Ar is an unsubstituted phenyl, R.sub.2 can also
be a hydrogen or a C.sub.1-C.sub.6 alkyl group.
[0115] In a particularly preferred embodiment, the compounds having
5-HT.sub.3 receptor antagonist activity and NARI activity are
represented by Formula I, wherein n is 2, R.sub.1 is a
C.sub.1-C.sub.6 alkyl group and Ar is an unsubstituted phenyl. In a
specific embodiment, wherein n is 2, R.sub.1 is a C.sub.1-C.sub.6
alkyl group and Ar is an unsubstituted phenyl, R.sub.2 can be
hydrogen or a C.sub.1-C.sub.6 alkyl group.
[0116] In a particularly preferred embodiment, the compound having
5-HT.sub.3 receptor antagonist activity and NARI activity is
represented by structural Formula II: 6
[0117] or a pharmaceutically acceptable salt thereof. This compound
is commonly referred to in the art as MCI-225, also referred to as
DDP-225. The chemical name of the structure set forth in the
formula is:
4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine.
[0118] In one embodiment, the lower urinary tract disorder can be
selected from the group consisting of overactive bladder,
interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0119] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0120] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0121] In another embodiment, the method further comprises
administering a therapeutically effective amount of an (i.e., one
or more) additional therapeutic agent.
[0122] Compounds having 5-HT.sub.3 receptor antagonist activity and
NARI activity, such as the compounds represented by structural
Formulas I and II are useful for treating at least one symptom of a
lower urinary tract disorder selected from the group consisting of
urinary frequency, urinary urgency, urinary urge incontinence,
nocturia and enuresis, by virtue of the dual therapeutic modes of
action which they can exhibit. That is, the unique ability to
modulate the function of both the 5-HT.sub.3 receptor and the
noradrenaline reuptake mechanism can provide an enhanced treatment
regimen for the subject undergoing treatment. For example, the
ability to treat at least one symptom of a lower urinary tract
disorder by modulating both peripheral and central effects can
provide enhanced treatment.
[0123] In a preferred embodiment, compounds having 5-HT.sub.3
receptor antagonist activity and NARI activity, such as the
compounds of Formula I and II possess one or more characteristics
selected from the group consisting of:
[0124] a) the substantial absence of anticholinergic effects;
[0125] b) the selective inhibition of noradrenaline reuptake as
compared to inhibition of serotonin reuptake; and
[0126] c) the selective inhibition of noradrenaline reuptake as
compared to inhibition of dopamine reuptake.
[0127] For example, the specific compound MCI-225 has been shown to
be a selective NARI and a 5-HT.sub.3 receptor antagonist with
substantially no anticholinergic activity. Eguchi et al.,
Arzneim.-Forschung/Drug Res., 47(12): 1337-47 (1997), reported
inhibition constants for MCI-225 for the uptake the
[.sup.3H]monoamine neurotransmitters noradrenaline, serotonin and
dopamine in various rat brain tissues. More specifically, MCI-225
inhibited the uptake of [.sup.3H]NA and [.sup.3H]5-HT by
synaptosomes from rat hypothalamic tissue with inhibition constants
of Ki=35.0 nmol/L and Ki=491 nmol/L, respectively. In addition,
MCI-225 inhibited the uptake of [.sup.3H]NA and [.sup.3H]5-HT by
synaptosomes from rat cortical tissue with inhibition constants of
Ki=0.696 nmol/L and Ki=1070 nmol/L, respectively. MCI-225 was also
reported to inhibit the uptake of serotonin by synaptosomes from
rat hippocampal tissue with an inhibition constant of Ki=244
nmol/L. Further, the MCI-225 inhibition constant for the uptake of
[.sup.3H]DA by synaptosomes from rat striatal tissue was reported
as Ki=14,800. MCI-225 did not inhibit Monoamine Oxidase-A (MAO-A)
and Monoamine Oxidase-B (MAO-B) activities.
[0128] With regard to 5-HT.sub.3 receptor antagonist activity,
Eguchi et al. reported that MCI-225 showed high affinity for the
5-HT.sub.3 receptor (Ki less than 100 nmol/L) in comparison to the
other receptors tested. In addition, MCI-225 showed affinity for
the 5-HT.sub.3 receptor similar to that reported for ondansetron in
the same radioligand binding assay. Briefly, the inhibition of
radiolabeled ligand binding by MCI-225, using a suitable
radioligand and tissue combination for the receptor of interest was
determined. The receptors tested included, .alpha..sub.1,
.alpha..sub.2, .beta..sub.1, .beta..sub.2, 5-HT.sub.1, 5-HT.sub.1A,
5-HT.sub.1c, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.6,
5-HT.sub.7, D.sub.1, D.sub.2, Muscarinic, M.sub.1, M.sub.2,
M.sub.3, Nicotonic, H.sub.1, H.sub.2, GABA-A, GABA-B, BZP, Opiate
non-selective, Opiate .kappa., Opiate .mu., Opiate .delta., CRF
(Corticotropin Releasing Factor) and glucocorticoid. The IC.sub.50
values determined for MCI-225, for these additional receptors were
all greater than 1 .mu.mol/L.
[0129] The invention further relates to a method of treating at
least one symptom of a lower urinary tract disorder in a subject in
need of treatment wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urinary urge
incontinence, nocturia and enuresis, comprising coadministering to
said subject a therapeutically effective amount of a 5-HT.sub.3
receptor antagonist and a therapeutically effective amount of a
NARI.
[0130] The invention further relates to a method of treating at
least one symptom of a lower urinary tract disorder in a subject in
need of treatment wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urinary urge
incontinence, nocturia and enuresis comprising coadministering to
said subject a first amount of a 5-HT.sub.3 receptor antagonist and
a second amount of a NARI, wherein the first and second amounts
together comprise a therapeutically effective amount.
[0131] In one embodiment, the lower urinary tract disorder can be
selected from the group consisting of overactive bladder,
interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0132] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0133] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0134] In another embodiment, the coadministration methods further
comprise administering a therapeutically effective amount of an
(i.e., one or more) additional therapeutic agent.
[0135] In certain embodiments of the coadministration method, the
5-HT.sub.3 receptor antagonist can be selected from indisetron,
YM-114
((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1-
H-indole), granisetron, talipexole, azasetron, bemesetron,
tropisetron, ramosetron, ondansetron, palonosetron, lerisetron,
alosetron, N-3389, zacopride, cilansetron, E-3620
([3(S)-endo]-4-amino-5-chloro-N-(8-methyl--
8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide),
lintopride, KAE-393, itasetron, zatosetron, dolasetron,
(.+-.)-zacopride, (.+-.)-renzapride, (-)-YM-060, DAU-6236, BIMU-8
and GK-128
([2-[2-methylimidazol-1-yl)methyl]-benzo[f]thiochromen-1-one
monohydrochloride hemihydrate]).
[0136] In preferred embodiments, the 5-HT.sub.3 receptor antagonist
can be selected from indisetron, granisetron, azasetron,
bemesetron, tropisetron, ramosetron, ondansetron, palonosetron,
lerisetron, alosetron, cilansetron, itasetron, zatosetron, and
dolasetron.
[0137] In certain embodiments, the NARI compound can be selected
from venlafaxine, duloxetine, buproprion, milnacipran, reboxetine,
lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline,
oxaprotiline, levoprotiline, viloxazine and atomoxetine.
[0138] In a preferred embodiment, the NARI compound can be selected
from reboxetine, lefepramine, desipramine, nortriptyline,
tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine
and atomoxetine.
[0139] In a preferred embodiment, the NARI compound possesses one
or more characteristics selected from the group consisting of:
[0140] a) the substantial absence of anticholinergic effects;
[0141] b) the selective inhibition of noradrenaline reuptake as
compared to inhibition of serotonin reuptake; and
[0142] c) the selective inhibition of noradrenaline reuptake as
compared to inhibition of dopamine reuptake.
[0143] The invention further relates to pharmaceutical compositions
useful for the treatment of at least one symptom of a lower urinary
tract disorder in a subject in need of treatment wherein the
symptom is selected from the group consisting of urinary frequency,
urinary urgency, urinary urge incontinence, nocturia and enuresis.
The pharmaceutical composition comprises a first amount of a
5-HT.sub.3 receptor antagonist compound and a second amount of a
NARI compound. The pharmaceutical compositions of the present
invention can optionally contain a pharmaceutically acceptable
carrier. The 5-HT.sub.3 receptor antagonist and the NARI can each
be present in the pharmaceutical composition in a therapeutically
effective amount. In another aspect, said first and second amounts
can together comprise a therapeutically effective amount.
[0144] In one embodiment, the lower urinary tract disorder can be
selected from the group consisting of overactive bladder,
interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0145] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0146] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0147] In a further embodiment, the pharmaceutical composition
further comprises an (i.e., one or more) additional therapeutic
agent.
[0148] An additional therapeutic agent suitable for use in the
methods and pharmaceutical compositions described herein, can be,
but is not limited to, for example: an antimuscarinic (e.g.,
oxybutynin, DITROPAN.RTM., tolterodine, flavoxate, propiverine,
trospium); a muscosal surface protectant (e.g., ELMIRON.RTM.); an
antihistamine (e.g., hydroxyzine hydrochloride or pamoate); an
anticonvulsant (e.g., NEURONTIN.RTM. and KLONOPIN.RTM.); a muscle
relaxant (e.g., VALIUM.RTM.); a bladder antispasmodic (e.g.,
URIMAX.RTM.); a tricyclic antidepressant (e.g., imipramine); a
nitric oxide donor (e.g., nitroprusside), a .beta..sub.3-adrenergic
receptor agonist, a bradykinin receptor antagonist, a neurokinin
receptor antagonist, a sodium channel modulator, such as TTX-R
sodium channel modulator and/or activity dependent sodium channel
modulator and a Cav2.2 subunit calcium channel modulator.
Generally, the additional therapeutic agent will be one that is
useful for treating the disorder of interest. Preferably, the
additional therapeutic agent does not diminish the effects of the
primary agent(s) and/or potentiates the effect of the primary
agent(s).
[0149] Use of an additional therapeutic agent in combination with
the primary agent(s) (i.e., a compound having 5-HT.sub.3 receptor
antagonist activity and NARI activity or a combination of a first
compound having 5-HT.sub.3 receptor antagonist activity and a
second compound having NARI activity) can result in less of any of
the primary agent(s) and/or less of the additional agent being
needed to achieve therapeutic efficacy. In some instances, use of
less of an agent can be advantageous in that it provides a
reduction in undesirable side effects.
[0150] By the term "antimuscarinic agent" as used herein is
intended any muscarinic acetylcholine receptor antagonist. Unless
otherwise indicated, the terms "anticholinergic agent,"
"antinicotinic agent," and "antimuscarinic agent" are intended to
include anticholinergic, antinicotinic, and antimuscarinic agents
as disclosed further herein, as well as acids, salts, esters,
amides, prodrugs, active metabolites, and other derivatives
thereof. Further, it is understood that any salts, esters, amides,
prodrugs, active metabolites or other derivatives are
pharmaceutically acceptable as well as pharmacologically
active.
[0151] More specifically, oxybutynin, also known as
4-diethylaminio-2-butynyl phenylcyclohexyglycolate is a preferred
antimuscarinic agent. It has the following structure: 7
[0152] Ditropan.RTM.(oxybutynin chloride) is the d,l racemic
mixture of the above compound, which is known to exert
antispasmodic effect on smooth muscle and inhibit the muscarinic
action of acetylcholine on smooth muscle. Metabolites and isomers
of oxybutynin have also been shown to have activity useful
according to the present invention. Examples include, but are not
limited to N-desethyl-oxybutynin and S-oxybutynin (see, e.g., U.S.
Pat. Nos. 5,736,577 and 5,532,278). Additional compounds that have
been identified as antimuscarinic agents and are useful in the
present invention include, but are not limited to:
[0153] a. Darifenacin (Daryon.RTM.) or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0154] b. Solifenacin or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0155] c. YM-905 (solifenacin succinate) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0156] d. Solifenacin monohydrochloride or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0157] e. Tolterodine (Detrol.RTM.) or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0158] f. Propiverine (Detrunorm.RTM.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0159] g. Propantheline bromide (Pro-Banthine.RTM.) or acids,
salts, enantiomers, analogs, esters, amides, prodrugs, active
metabolites, and derivatives thereof;
[0160] h. Hyoscyamine sulfate (Levsin.RTM., Cystospaz.RTM.) or
acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof;
[0161] i. Dicyclomine hydrochloride (Bentyl.RTM.) or acids, salts,
enantiomers, a nalogs, esters, amides, prodrugs, active
metabolites, and derivatives thereof;
[0162] j. Flavoxate hydrochloride (Urispas.RTM.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0163] k. d,l (racemic) 4-diethylamino-2-butynyl
phenylcyclohexylglycolate or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0164] l.
(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropana-
mine L-hydrogen tartrate or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0165] m.
(+)-(1S,3'R)-quinuclidin-3'-yl-1-phenyl-1,2,3,4-tetrahydro-isoqu-
inoline-2-carboxylate monosuccinate or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0166] n.
alpha(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol
proprionate or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0167] o. 1-methyl-4-piperidyl diphenylpropoxyacetate or acids,
salts, enantiomers, analogs, esters, amides, prodrugs, active
metabolites, and derivatives thereof;
[0168] p. 3-hydroxyspiro[1H,5H-nortropane-8,1'-pyrrolidinium
benzilate or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0169] q. 4 amino-piperidine containing compounds as disclosed in
Diouf et al. (2002) Bioorg. Med. Chem. Lett. 12: 2535-9;
[0170] r. pirenzipine or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0171] s. methoctramine or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0172] t. 4-diphenylacetoxy-N-methyl piperidine methiodide;
[0173] u. tropicamide or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0174] v.
(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-
-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0175] w. PNU-200577
((R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphen-
yl)-3-phenylpropanamine) or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0176] x. KRP-197 (4-(2-methylimidazolyl)-2,2-diphenylbutyramide)
or acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof;
[0177] y. Fesoterodine or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof; and
[0178] z. SPM 7605 (the active metabolite of Fesoterodine), or
acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof.
[0179] The identification of further compounds that have
antimuscarinic activity and would therefore be useful in the
present invention can be determined by performing muscarinic
receptor binding specificity studies as described by Nilvebrant
(2002) Pharmacol. Toxicol. 90: 260-7 or cystometry studies as
described by Modiri et al. (2002) Urology 59: 963-8.
[0180] The term ".beta..sub.3 adrenergic receptor agonist" is used
in its conventional sense to refer to a compound that binds to and
agonizes .beta..sub.3 adrenergic receptors. Unless otherwise
indicated, the term .beta..sub.3 adrenergic agonist" is intended to
include .beta..sub.3 adrenergic agonist agents as disclosed further
herein, as well as acids, salts, esters, amides, prodrugs, active
metabolites, and other derivatives thereof. Further, it is
understood that any salts, esters, amides, prodrugs, active
metabolites or other derivatives are pharmaceutically acceptable as
well as pharmacologically active.
[0181] Compounds that have been identified as .beta..sub.3
adrenergic agonist agents and are useful in the present invention
include, but are not limited to:
[0182] a. TT-138 and phenylethanolamine compounds as disclosed in
U.S. Pat. No. 6,069,176, PCT Publication No. WO 97/15549 and
available from Mitsubishi Pharma Corp., or acids, salts, esters,
amides, prodrugs, active metabolites, and other derivatives
thereof;
[0183] b. FR-149174 and propanolamine derivatives as disclosed in
U.S. Pat. Nos. 6,495,546 and 6,391,915 and available from Fujisawa
Pharmaceutical Co., or acids, salts, esters, amides, prodrugs,
active metabolites, and other derivatives thereof;
[0184] c. KUC-7483, available from Kissei Pharmaceutical Co., or
acids, salts, esters, amides, prodrugs, active metabolites, and
other derivatives thereof,
[0185] d. 4'-hydroxynorephedrine derivatives such as
2-2-chloro-4-(2-((1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino-
)ethyl)-phenoxy acetic acid as disclosed in Tanaka et al. (2003) J.
Med. Chem. 46: 105-12 or acids, salts, esters, amides, prodrugs,
active metabolites, and other derivatives thereof;
[0186] e. 2-amino-1-phenylethanol compounds, such as BRL35135
((R*R*)-(.+-.)-[4-[2-[2-(3-chlorophenyl)-2-ydroxyethylamino]propyl]phe
noxy]acetic acid methyl ester hydrobromide salt as disclosed in
Japanese Patent Publication No. 26744 of 1988 and European Patent
Publication No. 23385), and SR58611A
[0187]
((RS)-N-(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)-2--
(3-chlorophenyl)-2-hydroxyethanamine hydrochloride as disclosed in
Japanese Laid-open Patent Publication No. 66152 of 1989 and
European Laid-open Patent Publication No. 255415) or acids, salts,
esters, amides, prodrugs, active metabolites, and other derivatives
thereof;
[0188] f. GS 332 (Sodium (2R)-[3-[3-[2-(3
Chlorophenyl)-2-hydroxyethylamin- o]cyclohexyl]phenoxy]acetate) as
disclosed in lizuka et al. (1998) J. Smooth Muscle Res. 34: 139-49
or acids, salts, esters, amides, prodrugs, active metabolites, and
other derivatives thereof;
[0189] g. BRL-37,344 (4-[-[(2-hydroxy-(3-chlorophenyl)
ethyl)-amino]propyl]phenoxyacetate) as disclosed in Tsujii et al.
(1998) Physiol. Behav. 63: 723-8 and available from GlaxoSmithKline
or acids, salts, esters, amides, prodrugs, active metabolites, and
other derivatives thereof;
[0190] h. BRL-26830A as disclosed in Takahashi et al. (1992) Jpn
Circ. J. 56: 936-42 and available from GlaxoSmithKline or acids,
salts, esters, amides, prodrugs, active metabolites, and other
derivatives thereof;
[0191] i. CGP 12177
(4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2-one- ) (a 1/2
adrenergic antagonist reported to act as an agonist for the 3
adrenergic receptor) as described in Tavernier et al. (1992) J.
Pharmacol. Exp. Ther. 263: 1083-90 and available from Ciba-Geigy or
acids, salts, esters, amides, prodrugs, active metabolites, and
other derivatives thereof;
[0192] j. CL 316243
(R,R-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]pr-
opyl]-1,3-benzodioxole-2,2-dicarboxylate) as disclosed in Berlan et
al. (1994) J. Pharmacol. Exp. Ther. 268: 1444-51 or acids, salts,
esters, amides, prodrugs, active metabolites, and other derivatives
thereof;
[0193] k. Compounds having 3 adrenergic agonist activity as
disclosed in U.S. Patent Application 20030018061 or acids, salts,
esters, amides, prodrugs, active metabolites, and other derivatives
thereof;
[0194] l. ICI 215,001 HCl
((S)-4-[2-Hydroxy-3-phenoxypropyl-aminoethoxy]ph- enoxyacetic acid
hydrochloride) as disclosed in Howe (1993) Drugs Future 18: 529 and
available from AstraZeneca/ICI Labs or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0195] m. ZD 7114 HCl (ICI D7114;
(S)-4-[2-Hydroxy-3-phenoxypropyl-aminoet-
hoxy]-N-(2-methoxyethyl)phenoxyacetamide HCl) as disclosed in Howe
(1993) Drugs Future 18: 529 and available from AstraZeneca/ICI Labs
or acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof;
[0196] n. Pindolol
(1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propan- ol) as
disclosed in Blin et al (1994) Mol.Pharmacol. 44: 1094 or acids,
salts, enantiomers, analogs, esters, amides, prodrugs, active
metabolites, and derivatives thereof;
[0197] o. (S)-(-)-Pindolol
((S)-1-(1H-indol-4-yloxy)-3-[(1-methylethyl)ami- no]-2-propanol) as
disclosed in Walter et al (1984) Naunyn-Schmied.Arch.Pharmacol.
327: 159 and Kalkman (1989) Eur.J.Pharmacol. 173: 121 or acids,
salts, enantiomers, analogs, esters, amides, prodrugs, active
metabolites, and derivatives thereof;
[0198] p. SR 59230A HCl
(1-(2-Ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1--
naphthalenyl]amino]-(2S)-2-propanol hydrochloride) as disclosed in
Manara et al. (1995) Pharmacol. Comm. 6: 253 and Manara et al.
(1996) Br. J. Pharmacol. 117: 435 and available from Sanofi-Midy or
acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof;
[0199] q. SR 58611
(N[2s)7-carb-ethoxymethoxy-1,2,3,4-tetra-hydronaphth]-(-
2r)-2-hydroxy-2(3-chlorophenyl) ethamine hydrochloride) as
disclosed in Gauthier et al. (1999) J. Pharmacol. Exp. Ther. 290:
687-693 and available from Sanofi Research; and
[0200] r. YM178 available from Yamanouchi Pharmaceutical Co. or
acids, salts, esters, amides, prodrugs, active metabolites, and
other derivatives thereof.
[0201] The identification of further compounds that have
.beta..sub.3 adrenergic agonist activity and would therefore be
useful in the present invention can be determined by performing
radioligand binding assays and/or contractility studies as
described by Zilberfarb et al. (1997) J. Cell Sci. 110: 801-807;
Takeda et al. (1999) J. Pharmacol. Exp. Ther. 288: 1367-1373; and
Gauthier et al. (1999) J. Pharmacol. Exp. Ther. 290: 687-693.
[0202] Further, agents for use as additional therapeutic agents
include sodium channel modulators, such as TTX-R sodium channel
modulators and/or activity dependent sodium channel modulators.
TTX-R sodium channel modulators for use in the present invention
include but are not limited to compounds that modulate or interact
with Nav1.8 and/or Nav1.9 channels.
[0203] Sodium channel modulators suitable for use as in the
practice of the invention include, but are not limited to
propionamides such as Ralfinamide (NW-1029) (as disclosed in U.S.
Pat. No. 5,236,957 and U.S. Pat. No. 5,391,577), which is also
known as (+)-2(S)-[4-(2-Fluorobenzylox- y)benzylamino]propionamide
and safinamide (as disclosed in U.S. Pat. No. 5,236,957 and U.S.
Pat. No. 5,391,577), which is also known as
2(S)-[4-(3-Fluorobenzyloxy)benzylamino]propionamide
methanesulfonate
[0204] Further sodium channel modulators include for example,
N-phenylalkyl substituted .alpha.-amino carboxamide derivatives in
addition to Ralfinamide and Salfinamide as disclosed in U.S. Pat.
No. 5,236,957; Other N-phenylalkyl substituted .alpha.-amino
carboxamide derivatives in addition to Ralfinamide and Salfinamide
as disclosed in U.S. Pat. No. 5,391,577; Substituted
2-benzylamino-2-phenyl-acetamide compounds as disclosed in U.S.
Pat. No. 6,303,819; aryldiazines and aryltriazines such as:
sipatrigine (BW-619C; as disclosed in U.S. Pat. No. 5,684,005),
which is also known as 4-Amino-2-(4-methylpiperazin-1-yl)-
-5-(2,3,5-trichlorophenyl)pyrimidine;
2-(4-Methylpiperazin-1-yl)-5-(2,3,5--
trichlorophenyl)pyrimidine-4-amine; lamotrigine (as disclosed in
U.S. Pat. No. 4,602,017), which is also known as
6-(2,3-Dichlorophenyl)-1,2,4-triaz- ine-3,5-diamine; GW-273293 (as
disclosed in U.S. Pat. No. 6,599,905), which is also known as
3-(2,3,5-Trichlorophenyl)pyrazine-2,6-diamine; 4030W92 (as
disclosed in U.S. Pat. No. 6,124,308), which is also known as
5-(2,3-Dichlorophenyl)-6-(fluoromethyl)pyrimidine-2,4-diamine;
Carbamazepine (as disclosed in U.S. Pat. No. 2,948,718), which is
also known as 5H-Dibenz[d,f]azepine-5-carboxamide; Oxcarbazepine
(as disclosed in U.S. Pat. No. 3,642,775), which is also known as
10-Oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide;
licarbazepine (as disclosed in DE 2011045), which is also known as
(.+-.)-10-Hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide;
BIA-2-093 (as disclosed in U.S. Pat. No. 5,753,646), which is also
known as Acetic acid
5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10(S)-yl ester;
ADCI (as disclosed in U.S. Pat. No. 5,196,415), which is also known
as
(.+-.)-5,10-Imino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ca-
rboxamide; Phenytoin sodium (as disclosed in U.S. 2,409,754) and
OROS.RTM.-Phenytoin (as disclosed in U.S. Pat. No. 4,260,769),
which are also known as 5,5-Diphenylhydantoin sodium salt and
5,5-Diphenyl-2,4-imidazolidinedione salt; Fosphenytoin sodium (as
disclosed in U.S. Pat. No. 4,260,769) and phosphenytoin sodium,
which are also known as 3-(Hydroxymethyl)-5,5-diphenylhydantoin
phosphate ester disodium salt and
5,5-Diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidine- dione
disodium salt; Pilsicainide hydrochloride and analogs thereof (as
disclosed in U.S. Pat. No. 4,564,624), which is also known as
N-(2,6-Dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride;
N-(2,6-Dimethylphenyl)-1-azabicyclo[3.3.0]octane-5-acetamide
hydrochloride; Tocainide (as disclosed in DE 2235745), which is
also known as 2-Amino-N-(2,6-dimethylphenyl)propanamide
hydrochloride; Flecainide (as disclosed in U.S. Pat. No.
3,900,481), which is also known as
N-(2-Piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
monoacetate; mexiletine hydrochloride (as disclosed in U.S. Pat.
No. 3,954,872), which is also known as
1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride; Ropivacaine
hydrochloride (as disclosed in PCT Publication No. WO 85/00599),
which is also known as (-)-(S)-N-(n-Propyl)piperidine-2-
-carboxylic acid 2,6-xylidide hydrochloride monohydrate;
(-)-(S)-N-(2,6-Dimethylphenyl)-1-propylpiperidine-2-carboxamide
hydrochloride monohydrate; (-)-(S)-1-Propyl-2',6'-pipecoloxylidide
hydrochloride monohydrate; Lidocaine (as disclosed in U.S. Pat. No.
2,441,498), which is also known as
2-(diethylamino)-N-(2,6-dimethylphenyl- )acetamide; mepivacaine (as
disclosed in U.S. Pat. No. 2,799,679), which is also known as
N-(2,6-dimethylphenyl)-1-methyl-2-piperidinecarboxamide;
bupivacaine (as disclosed in U.S. Pat. No. 2,955,111), which is
also known as
1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide; Prilocaine
(as disclosed in U.S. Pat. No. 3,160,662), also known as
N-(2-methylphenyl)-2-(propylamino)propanamide; etidocaine (as
disclosed in U.S. Pat. No. 3,812,147), which is also known as
N-(2,6-dimethylphenyl)-1-methyl-2-piperidinecarboxamide; tetracaine
(as disclosed in U.S. Pat. No. 1,889,645), which is also known as
4-(butylamino)benzoic acid 2-(diethylamino)ethyl ester; dibucaine
(as disclosed in U.S. Pat. No. 1,825,623), which is also known as
2-butoxy-N-[2-(diethylamino)-ethyl]-4-quinolinecarboxamide;
Soretolide, which is also known as
2,6-Dimethyl-N-(5-methylisozaxol-3-yl)benzamide; RS-132943 (as
disclosed in U.S. Pat. No. 6,110,937), which is also known as
3(S)-(4-Bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine
hydrochloride
[0205] The identification of other agents that have affinity for
TTX-R sodium channels or proteins associated with TTX-R sodium
channels and would be useful in the present invention can be
determined by methods that measure functional TTX-R channel
activity such as sodium flux as disclosed in Stallcup, W B (1979)
J. Physiol. 286: 525-40 or electrophysiological approaches as
disclosed in Weiser and Wilson (2002) Mol. Pharmacol. 62: 433-438.
The identification of other agents that exhibit activity-dependent
modulation of sodium channels and would be useful in the present
invention can be determined by methods as disclosed in Li et al.,
(1999) Molecular Pharmacology 55:134-141.
[0206] Further, agents for use as additional therapeutic agents
include "Cav2.2 subunit calcium channel modulators" which are
capable of binding to the Cav2.2 subunit of a calcium channel to
produce a physiological effect, such as opening, closing, blocking,
up-regulating expression, or down-regulating expression of the
channel. Unless otherwise indicated, the term "Cav2.2 subunit
calcium channel modulator" is intended to include amino acid
compounds, peptide, nonpeptide, peptidomimetic, small molecular
weight organic compounds, and other compounds that modulate or
interact with the Cav2.2 subunit of a calcium channel (e.g., a
binding event) or proteins associated with the Cav2.2 subunit of a
calcium channel (e.g., a binding event) such as anchor proteins, as
well as salts, esters, amides, prodrugs, active metabolites, and
other derivatives thereof. Further, it is understood that any
salts, esters, amides, prodrugs, active metabolites or other
derivatives are pharmaceutically acceptable as well as
pharmacologically active.
[0207] Cav2.2 subunit calcium channel modulator useful as an
additional therapeutic agent in the practice of the invention
include, but are not limited to:
[0208] a. .omega.-conotoxin GVIA or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0209] b. .omega.-conotoxin MVIIA or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0210] c. .omega.-conotoxin CNVIIA or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0211] d. .omega.-conotoxin CVIID or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0212] e. .omega.-conotoxin AM336 or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0213] f. Cilnidipine or a salt, enantiomer, analog, ester, amide,
prodrug, active metabolite, or derivative thereof;
[0214] g. Amlodipine or a salt, enantiomer, analog, ester, amide,
prodrug, active metabolite, or derivative thereof;
[0215] h. L-cysteine derivative 2A or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0216] i. .omega.-agatoxin IVA or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0217] j. N,N-dialkyl-dipeptidylamines or a salt, enantiomer,
analog, ester, amide, prodrug, active metabolite, or derivative
thereof;
[0218] k. Levetiracetam or a salt, enantiomer, analog, ester,
amide, prodrug, active metabolite, or derivative thereof; and
[0219] l. Ziconotide (SNX-111) or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative
thereof;
[0220] m. (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (illustrated
below) and disclosed in U.S. Pat. Nos. 4,943,639, 4,837,223, and
4,696,943, or a salt, enantiomer, analog, ester, amide, prodrug,
active metabolite, or derivative, thereof;
[0221] n. Substituted peptidylamines as disclosed in PCT
Publication No. WO 98/54123, or a salt, enantiomer, analog, ester,
amide, prodrug, active metabolite, or derivative, thereof;
[0222] o. PD-173212 or a salt, enantiomer, analog, ester, amide,
prodrug, active metabolite, or derivative, thereof;
[0223] p. Reduced dipeptide analogues as disclosed in U.S. Pat. No.
6,316,440 and PCT Publication No. WO 00/06559, or a salt,
enantiomer, analog, ester, amide, prodrug, active metabolite, or
derivative, thereof;
[0224] q. Amino acid derivatives as disclosed in PCT Publication
No. WO 99/02146, or a salt, enantiomer, analog, ester, amide,
prodrug, active metabolite, or derivative, thereof;
[0225] r. Benzazepine derivatives as disclosed in Japanese
Publication No. JP 2002363163, or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative,
thereof;
[0226] s. Compounds disclosed in PCT Publication No. WO 02/36567,
or a salt, enantiomer, analog, ester, amide, prodrug, active
metabolite, or derivative, thereof;
[0227] t. Compounds disclosed in PCT Publication No. WO 03/018561,
or a salt, enantiomer, analog, ester, amide, prodrug, active
metabolite, or derivative, thereof;
[0228] u. Compounds disclosed in U.S. Patent Publication No.
2004009991 and PCT Publication No. WO 02/22588, or a salt,
enantiomer, analog, ester, amide, prodrug, active metabolite, or
derivative, thereof;
[0229] v. Dihydropyridine derivatives as disclosed in U.S. Pat. No.
6,610,717, U.S. Patent Publication No. 2002193605, and PCT
Publication No. WO 00/78720, or a salt, enantiomer, analog, ester,
amide, prodrug, active metabolite, or derivative, thereof;
[0230] w. Diarylalkene and diarylalkane derivatives as disclosed in
PCT Publication No. WO 03/018538, or a salt, enantiomer, analog,
ester, amide, prodrug, active metabolite, or derivative, thereof;
and
[0231] Additional Cav2.2 subunit calcium channel modulator useful
as an additional therapeutic agent in the practice of the invention
include, but are not limited to non-peptide, and peptidomimetic
drug-like molecules that bind to Cav2.2-containing calcium channels
as disclosed in Lewis et al. (2000) J. Biol. Chem. 10: 35335-44;
Smith et al. (2002) Pain 96: 119-27; Takahara et al. (2002) Eur. J.
Pharmacol. 434: 43-7; Favreau et al. (2001) Biochemistry, 40:
14567-575; Seko et al. (2001) Bioorg. Med. Chem. Lett. 11: 2067-70;
Hu et al. (2000) Bioorg. Med. Chem. Lett. 8: 1203-12; Lew et al.
(1997) J. Biol. Chem. 272: 12014-23. It is understood that the
present invention also encompasses any pharmaceutically acceptable,
pharmacologically active salts, enantiomers, analogs, esters,
amides, prodrugs, active metabolites, and derivatives of the
aforementioned compounds.
[0232] The identification of other agents that have affinity for
the Cav2.2 subunit of a calcium channel and would be useful in the
present invention can be determined by performing Cav2.2 subunit
binding affinity, electrophysiolgic, and/or other screening methods
as described in Feng et al. (J. Biol. Chem., 278: 20171-20178,
2003), Feng et al. (J. Biol. Chem., 276: 15728-15735, 2001),
Favreau et al. (Biochemistry, 40: 14567-575, 2001), and/or U.S.
Pat. No. 6,387,897 assigned to NeuroMed Technologies Inc
[0233] The term "spasmolytic" (also known as "antispasmodic") is
used in its conventional sense to refer to a compound that relieves
or prevents muscle spasms, especially of smooth muscle. Unless
otherwise indicated, the term "spasmolytic" is intended to include
spasmolytic agents as disclosed further herein, as well as acids,
salts, esters, amides, prodrugs, active metabolites, and other
derivatives thereof. Further, it is understood that any salts,
esters, amides, prodrugs, active metabolites or other derivatives
are pharmaceutically acceptable as well as pharmacologically
active. In general, spasmolytics have been implicated as having
efficacy in the treatment of bladder disorders (See. e.g., Takeda
et al. (2000) J. Pharmacol. Exp. Ther. 293: 939-45).
[0234] Compounds that have been identified as spasmolytic agents
and are useful in the present invention include, but are not
limited to:
[0235] a. .alpha.-.alpha.-diphenylacetic
acid-4-(N-methyl-piperidyl) esters as disclosed in U.S. Pat. No.
5,897,875 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0236] b. Human and porcine spasmolytic polypeptides in
glycosylated form and variants thereof as disclosed in U.S. Pat.
No. 5,783,416 or acids, salts, enantiomers, analogs, esters,
amides, prodrugs, active metabolites, and derivatives thereof;
[0237] c. Dioxazocine derivatives as disclosed in U.S. Pat. No.
4,965,259 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0238] d. Quaternary
6,11-dihydro-dibenzo-[b,e]-thiepine-11-N-alkylnorscop- ine ethers
as disclosed in U.S. Pat. No. 4,608,377 or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0239] e. Quaternary salts of dibenzo[1,4]diazepinones,
pyrido-[1,4]benzodiazepinones, pyrido[1,5]benzodiazepinones as
disclosed in U.S. Pat. No. 4,594,190 or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0240] f. Endo-8,8-dialkyl-8-azoniabicyclo (3.2.1)
octane-6,7-exo-epoxy-3-- alkyl-carboxylate salts as disclosed in
U.S. Pat. No. 4,558,054 or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0241] g. Pancreatic spasmolytic polypeptides as disclosed in U.S.
Pat. No. 4,370,317 or acids, salts, enantiomers, analogs, esters,
amides, prodrugs, active metabolites, and derivatives thereof;
[0242] h. Triazinones as disclosed in U.S. Pat. No. 4,203,983 or
acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof;
[0243] i. 2-(4-Biphenylyl)-N-(2-diethylamino alkyl)propionamide as
disclosed in U.S. Pat. No. 4,185,124 or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0244] j. Piperazino-pyrimidines as disclosed in U.S. Pat. No.
4,166,852 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0245] k. Aralkylamino carboxylic acids as disclosed in U.S. Pat.
No. 4,163,060 or acids, salts, enantiomers, analogs, esters,
amides, prodrugs, active metabolites, and derivatives thereof;
[0246] l. Aralkylamino sulfones as disclosed in U.S. Pat. No.
4,034,103 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0247] m. Smooth muscle spasmolytic agents as disclosed in U.S.
Pat. No. 6,207,852 or acids, salts, enantiomers, analogs, esters,
amides, prodrugs, active metabolites, and derivatives thereof;
and
[0248] n. Papaverine or acids, salts, enantiomers, analogs, esters,
amides, prodrugs, active metabolites, and derivatives thereof.
[0249] The identification of further compounds that have
spasmolytic activity and would therefore be useful in the present
invention can be determined by performing bladder strip
contractility studies as described in U.S. Pat. No. 6,207,852;
Noronha-Blob et al. (1991) J. Pharmacol. Exp. Ther.256: 562-567;
and/or Kachur et al. (1988) J. Pharmacol. Exp. Ther. 247:
867-872.
[0250] The term "neurokinin receptor antagonist" is used in its
conventional sense to refer to a compound that binds to and
antagonizes neurokinin receptors. Unless otherwise indicated, the
term "neurokinin receptor antagonist" is intended to include
neurokinin receptor antagonist agents as disclosed further herein,
as well as acids, salts, esters, amides, prodrugs, active
metabolites, and other derivatives thereof. Further, it is
understood that any salts, esters, amides, prodrugs, active
metabolites or other derivatives are pharmaceutically acceptable as
well as pharmacologically active.
[0251] Suitable neurokinin receptor antagonists for use in the
present invention that act on the NK1 receptor include, but are not
limited to:
1-imino-2-(2-methoxy-phenyl)-ethyl)-7,7-diphenyl-4-perhydroisoindolone(3a-
R,7aR) ("RP 67580");
2S,3S-cis-3-(2-methoxybenzylamino)-2-benzhydrylquinuc- lidine ("CP
96,345"); and (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,1- 0,
11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-
naphthyridine-6,13-dione)("TAK-637"). Suitable neurokinin receptor
antagonists for use in the present invention that act on the NK2
receptor include but are not limited to:
((S)-N-methyl-N-4-(4-acetylamino-4-phenyl-
piperidino)-2-(3,4-dichloropheny l)butylbenzamide ("SR 48968");
Met-Asp-Trp-Phe-Dap-Leu ("MEN 10,627"); and
cyc(Gln-Trp-Phe-Gly-Leu-Met) ("L 659,877"). Suitable neurokinin
receptor antagonists for use in the present invention also include
acids, salts, esters, amides, prodrugs, active metabolites, and
other derivatives of any of the agents mentioned above. The
identification of further compounds that have neurokinin receptor
antagonist activity and would therefore be useful in the present
invention can be determined by performing binding assay studies as
described in Hopkins et al. (1991) Biochem. Biophys. Res. Comm.
180: 1110-1117; and Aharony et al. (1994) Mol. Pharmacol. 45:
9-19.
[0252] The term "bradykinin receptor antagonist" is used in its
conventional sense to refer to a compound that binds to and
antagonizes bradykinin receptors. Unless otherwise indicated, the
term "bradykinin receptor antagonist" is intended to include
bradykinin receptor antagonist agents as disclosed further herein,
as well as acids, salts, esters, amides, prodrugs, active
metabolites, and other derivatives thereof. Further, it is
understood that any salts, esters, amides, prodrugs, active
metabolites or other derivatives are pharmaceutically acceptable as
well as pharmacologically active.
[0253] Suitable bradykinin receptor antagonists for use in the
present invention that act on the B1 receptor include but are not
limited to: des-arg10HOE 140 (available from Hoechst
Pharmaceuticals) and des-Arg9bradykinin (DABK). Suitable bradykinin
receptor antagonists for use in the present invention that act on
the B2 receptor include but are not limited to: D-Phe7-BK;
D-Arg-(Hyp3-Thi5,8-D-Phe7)-BK ("NPC 349"); D-Arg-(Hyp3-D-Phe7)-BK
("NPC 567"); D-Arg-(Hyp3-Thi5-D-Tic7-Oic8)-BK ("HOE 140");
H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7gamma-10alp-
ha)("MEN11270");
H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH("Icatibant- ");
(E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinol-
inyl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide
("FRI73567"); and WIN 64338. These compounds are more fully
described in Perkins, M. N., et. al., Pain, supra; Dray, A., et.
al., Trends Neurosci., supra; and Meini et al. (2000) Eur. J.
Pharmacol. 388: 177-82. Suitable neurokinin receptor antagonists
for use in the present invention also include acids, salts, esters,
amides, prodrugs, active metabolites, and other derivatives of any
of the agents mentioned above. The identification of further
compounds that have bradykinin receptor antagonist activity and
would therefore be useful in the present invention can be
determined by performing binding assay studies as described in
Manning et al. (1986) J. Pharmacol. Exp. Ther. 237: 504 and U.S.
Pat. No. 5,686,565.
[0254] The term "nitric oxide donor" is used in its conventional
sense to refer to a compound that releases free nitric oxide when
administered to a patient. Unless otherwise indicated, the term
"nitric oxide donor" is intended to include nitric oxide donor
agents as disclosed further herein, as well as acids, salts,
esters, amides, prodrugs, active metabolites, and other derivatives
thereof. Further, it is understood that any salts, esters, amides,
prodrugs, active metabolites or other derivatives are
pharmaceutically acceptable as well as pharmacologically
active.
[0255] Suitable nitric oxide donors for the practice of the present
invention include but are not limited to:
[0256] a. Nitroglycerin or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0257] b. Sodium nitroprusside or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0258] c. FK 409 (NOR-3) or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0259] d. FR 144420 (NOR-4) or acids, salts, enantiomers, analogs,
esters, amides, prodrugs, active metabolites, and derivatives
thereof;
[0260] e. 3-morpholinosydnonimine or acids, salts, enantiomers,
analogs, esters, amides, prodrugs, active metabolites, and
derivatives thereof;
[0261] f. Linsidomine chlorohydrate ("SIN-1") or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0262] g. S-nitroso-N-acetylpenicillamine ("SNAP") or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0263] h. AZD3582 (CINOD lead compound, available from NicOx S.A.)
or acids, salts, enantiomers, analogs, esters, amides, prodrugs,
active metabolites, and derivatives thereof;
[0264] i. NCX 4016 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0265] j. NCX 701 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0266] k. NCX 1022 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0267] l. HCT 1026 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0268] m. NCX 1015 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0269] n. NCX 950 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0270] o. NCX 1000 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0271] p. NCX 1020 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0272] q. AZD 4717 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0273] r. NCX 1510/NCX 1512 (available from NicOx S.A.) or acids,
salts, enantiomers, analogs, esters, amides, prodrugs, active
metabolites, and derivatives thereof;
[0274] s. NCX 2216 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0275] t. NCX 4040 (available from NicOx S.A.) or acids, salts,
enantiomers, analogs, esters, amides, prodrugs, active metabolites,
and derivatives thereof;
[0276] u. Nitric oxide donors as disclosed in U.S. Pat. No.
5,155,137 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0277] v. Nitric oxide donors as disclosed in U.S. Pat. No.
5,366,997 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0278] w. Nitric oxide donors as disclosed in U.S. Pat. No.
5,405,919 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0279] x. Nitric oxide donors as disclosed in U.S. Pat. No.
5,650,442 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0280] y. Nitric oxide donors as disclosed in U.S. Pat. No.
5,700,830 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0281] z. Nitric oxide donors as disclosed in U.S. Pat. No.
5,632,981 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0282] aa. Nitric oxide donors as disclosed in U.S. Pat. No.
6,290,981 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0283] bb. Nitric oxide donors as disclosed in U.S. Pat. No.
5,691,423 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0284] cc. Nitric oxide donors as disclosed in U.S. Pat. No.
5,721,365 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0285] dd. Nitric oxide donors as disclosed in U.S. Pat. No.
5,714,511 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof;
[0286] ee. Nitric oxide donors as disclosed in U.S. Pat. No.
6,511,911 or acids, salts, enantiomers, analogs, esters, amides,
prodrugs, active metabolites, and derivatives thereof; and
[0287] ff. Nitric oxide donors as disclosed in U.S. Pat. No.
5,814,666.
[0288] The identification of further compounds that have nitric
oxide donor activity and would therefore be useful in the present
invention can be determined by release profile and/or induced
vasospasm studies as described in U.S. Pat. Nos. 6,451,337 and
6,358,536, as well as Moon (2002) IBJU Int. 89: 942-9 and
Fathian-Sabet et al. (2001) J. Urol. 165: 1724-9.
[0289] Subject, as used herein, refers to animals such as mammals,
including, but not limited to, primates (e.g., humans), cows,
sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats,
mice or other bovine, ovine, equine, canine, feline, rodent or
murine species.
[0290] As used herein, treating and treatment refer to a reduction
in at least one symptom selected from urinary frequency, urinary
urgency, urinary urge incontinence, nocturia and enuresis, which is
associated with lower urinary tract disorder.
[0291] As used herein, therapeutically effective amount refers to
an amount sufficient to elicit the desired biological response. In
the present invention the desired biological response is a
reduction (complete or partial) of at least one symptom associated
with the lower urinary tract disorder being treated wherein the
symptom is selected from urinary frequency, urinary urgency,
urinary urge incontinence, nocturia and enuresis. As with any
treatment, particularly treatment of a multi-symptom disorder, for
example, overactive bladder, it is advantageous to treat as many
disorder-related symptoms which the subject experiences.
[0292] Pharmaceutically acceptable carrier, includes pharmaceutical
diluents, excipients or carriers suitably selected with respect to
the intended form of administration, and consistent with
conventional pharmaceutical practices. For example, solid
carriers/diluents include, but are not limited to, a gum, a starch
(e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose,
mannitol, sucrose, dextrose), a cellulosic material (e.g.,
microcrystalline cellulose), an acrylate (e.g.,
polymethylacrylate), calcium carbonate, magnesium oxide, talc, or
mixtures thereof.
[0293] Pharmaceutically acceptable carriers can be aqueous or
non-aqueous solvents. Examples of non-aqueous solvents are
propylene glycol, polyethylene glycol, and injectable organic
esters such as ethyl oleate. Aqueous carriers include water,
alcoholic/aqueous solutions, emulsions or suspensions, including
saline and buffered media.
Modes of Administration
[0294] The compounds for use in the method or kits of the invention
can be formulated for administration by any suitable route, such as
for oral or parenteral, for example, transdermal, transmucosal
(e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal
(e.g., trans- and perivaginally), (intra)nasal and (trans)rectal),
intravesical, intraduodenal, intrathecal, subcutaneous,
intramuscular, intradermal, intra-arterial, intravenous,
inhalation, and topical administration.
[0295] Suitable compositions and dosage forms include tablets,
capsules, caplets, pills,
[0296] gel caps, troches, dispersions, suspensions, solutions,
syrups, granules, beads, transdermal patches, gels, powders,
pellets, magmas, lozenges, creams, pastes, plasters, lotions,
discs, suppositories, liquid sprays for nasal or oral
administration, dry powder or aerosolized formulations for
inhalation, compositions and formulations for intravesical
administration and the like. Further, those of ordinary skill in
the art can readily deduce that suitable formulations involving
these compositions and dosage forms, including those formulations
as described elsewhere herein.
[0297] The term intravesical administration is used herein in its
conventional sense to mean delivery of a drug directly into the
bladder.
[0298] For oral administration the compounds can be of the form of
tablets or capsules prepared by conventional means with
pharmaceutically acceptable excipients such as binding agents
(e.g., polyvinylpyrrolidone, hydroxypropylcellulose or
hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose,
microcrystalline cellulose or calcium phosphate); lubricants (e.g.,
magnesium stearate, talc, or silica); disintegrates (e.g., sodium
starch glycollate); or wetting agents (e.g., sodium lauryl
sulphate). If desired, the tablets can be coated using suitable
methods and coating materials such as OPADRY.RTM. film coating
systems available from Colorcon, West Point, Pa. (e.g., OPADRY.RTM.
OY Type, OY-C Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A
Type, OY-PM Type and OPADRY.RTM. White, 32K18400). Liquid
preparation for oral administration can be in the form of
solutions, syrups or suspensions. The liquid preparations can be
prepared by conventional means with pharmaceutically acceptable
additives such as suspending agents (e.g., sorbitol syrup, methyl
cellulose or hydrogenated edible fats); emulsifying agent (e.g.,
lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily
esters or ethyl alcohol); and preservatives (e.g., methyl or propyl
p-hydroxy benzoates or sorbic acid).
[0299] Tablets may be manufactured using standard tablet processing
procedures and equipment. One method for forming tablets is by
direct compression of a powdered, crystalline or granular
composition containing the active agent(s), alone or in combination
with one or more carriers, additives, or the like. As an
alternative to direct compression, tablets can be prepared using
wet-granulation or dry-granulation processes. Tablets may also be
molded rather than compressed, starting with a moist or otherwise
tractable material; however, compression and granulation techniques
are preferred.
[0300] The dosage form may also be a capsule, in which case the
active agent-containing composition may be encapsulated in the form
of a liquid or solid (including particulates such as granules,
beads, powders or pellets). Suitable capsules can be hard or soft,
and are generally made of gelatin, starch, or a cellulosic
material, with gelatin capsules preferred. Two-piece hard gelatin
capsules are preferably sealed, such as with gelatin bands or the
like. (See, for e.g., Remington: The Science and Practice of
Pharmacy, supra), which describes materials and methods for
preparing encapsulated pharmaceuticals. If the active
agent-containing composition is present within the capsule in
liquid form, a liquid carrier can be used to dissolve the active
agent(s). The carrier should be compatible with the capsule
material and all components of the pharmaceutical composition, and
should be suitable for ingestion.
[0301] Transmucosal administration is carried out using any type of
formulation or dosage unit suitable for application to mucosal
tissue. For example, the selected active agent can be administered
to the buccal mucosa in an adhesive tablet or patch, sublingually
administered by placing a solid dosage form under the tongue,
lingually administered by placing a solid dosage form on the
tongue, administered nasally as droplets or a nasal spray,
administered by inhalation of an aerosol formulation, a non-aerosol
liquid formulation, or a dry powder, placed within or near the
rectum ("transrectal" formulations), or administered to the urethra
as a suppository, ointment, or the like.
[0302] Preferred buccal dosage forms will typically comprise a
therapeutically effective amount of an active agent and a
bioerodible (hydrolyzable) polymeric carrier that may also serve to
adhere the dosage form to the buccal mucosa. The buccal dosage unit
can be fabricated so as to erode over a predetermined time period,
wherein drug delivery is provided essentially throughout. The time
period is typically in the range of from about 1 hour to about 72
hours. Preferred buccal delivery preferably occurs over a time
period of from about 2 hours to about 24 hours. Buccal drug
delivery for short term use should preferably occur over a time
period of from about 2 hours to about 8 hours, more preferably over
a time period of from about 3 hours to about 4 hours. As needed
buccal drug delivery preferably will occur over a time period of
from about 1 hour to about 12 hours, more preferably from about 2
hours to about 8 hours, most preferably from about 3 hours to about
6 hours. Sustained buccal drug delivery will preferably occur over
a time period of from about 6 hours to about 72 hours, more
preferably from about 12 hours to about 48 hours, most preferably
from about 24 hours to about 48 hours. Buccal drug delivery, as
will be appreciated by those skilled in the art, avoids the
disadvantages encountered with oral drug administration, e.g., slow
absorption, degradation of the active agent by fluids present in
the gastrointestinal tract and/or first-pass inactivation in the
liver.
[0303] The amount of the active agent in the buccal dosage unit
will of course depend on the potency of the agent and the intended
dosage, which, in turn, is dependent on the particular individual
undergoing treatment, the specific indication, and the like. The
buccal dosage unit will generally contain from about 1.0 wt. % to
about 60 wt. % active agent, preferably on the order of from about
1 wt. % to about 30 wt. % active agent. With regard to the
bioerodible (hydrolyzable) polymeric carrier, it will be
appreciated that virtually any such carrier can be used, so long as
the desired drug release profile is not compromised, and the
carrier is compatible with the active agents to be administered and
any other components of the buccal dosage unit. Generally, the
polymeric carrier comprises a hydrophilic (water-soluble and
water-swellable) polymer that adheres to the wet surface of the
buccal mucosa. Examples of polymeric carriers useful herein include
acrylic acid polymers and co, e.g., those known as "carbomers"
(Carbopol.RTM., which may be obtained from B. F. Goodrich, is one
such polymer). Other suitable polymers include, but are not limited
to: hydrolyzed polyvinylalcohol; polyethylene oxides (e.g., Sentry
Polyox.RTM. water soluble resins, available from Union Carbide);
polyacrylates (e.g., Gantrez.RTM., which may be obtained from GAF);
vinyl polymers and copolymers; polyvinylpyrrolidone; dextran; guar
gum; pectins; starches; and cellulosic polymers such as
hydroxypropyl methylcellulose, (e.g., Methocel.RTM., which may be
obtained from the Dow Chemical Company), hydroxypropyl cellulose
(e.g., Klucel.RTM., which may also be obtained from Dow),
hydroxypropyl cellulose ethers (see, e.g., U.S. Pat. No. 4,704,285
to Alderman), hydroxyethyl cellulose, carboxymethyl cellulose,
sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose,
cellulose acetate phthalate, cellulose acetate butyrate, and the
like.
[0304] Other components can also be incorporated into the buccal
dosage forms described herein. The additional components include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like.
Examples of disintegrants that may be used include, but are not
limited to, cross-linked polyvinylpyrrolidones, such as
crospovidone (e.g., Polyplasdone.RTM. XL, which may be obtained
from GAF), cross-linked carboxylic methylcelluloses, such as
croscarmelose (e.g., Ac-di-sol.RTM., which may be obtained from
FMC), alginic acid, and sodium carboxymethyl starches (e.g.,
Explotab.RTM., which can be obtained from Edward Medell Co., Inc.),
methylcellulose, agar bentonite and alginic acid. Suitable diluents
include those which are generally useful in pharmaceutical
formulations prepared using compression techniques, e.g., dicalcium
phosphate dihydrate (e.g., Di-Tab.RTM., which may be obtained from
Stauffer), sugars that have been processed by cocrystallization
with dextrin (e.g., co-crystallized sucrose and dextrin such as
Di-Pak.RTM., which may be obtained from Amstar), calcium phosphate,
cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered
sugar and the like. Binders, if used, include those that enhance
adhesion. Examples of such binders include, but are not limited to,
starch, gelatin and sugars such as sucrose, dextrose, molasses, and
lactose. Particularly preferred lubricants are stearates and
stearic acid, and an optimal lubricant is magnesium stearate.
[0305] Sublingual and lingual dosage forms include tablets, creams,
ointments, lozenges, pastes, and any other suitable dosage form
where the active ingredient is admixed into a disintegrable matrix.
The tablet, cream, ointment or paste for sublingual or lingual
delivery comprises a therapeutically effective amount of the
selected active agent and one or more conventional nontoxic
carriers suitable for sublingual or lingual drug administration.
The sublingual and lingual dosage forms of the present invention
can be manufactured using conventional processes. The sublingual
and lingual dosage units can be fabricated to disintegrate rapidly.
The time period for complete disintegration of the dosage unit is
typically in the range of from about 10 seconds to about 30
minutes, and optimally is less than 5 minutes.
[0306] Other components can also be incorporated into the
sublingual and lingual dosage forms described herein. The
additional components include, but are not limited to binders,
disintegrants, wetting agents, lubricants, and the like. Examples
of binders that can be used include water, ethanol,
polyvinylpyrrolidone; starch solution gelatin solution, and the
like. Suitable disintegrants include dry starch, calcium carbonate,
polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,
stearic monoglyceride, lactose, and the like. Wetting agents, if
used, include glycerin, starches, and the like. Particularly
preferred lubricants are stearates and polyethylene glycol.
Additional components that may be incorporated into sublingual and
lingual dosage forms are known, or will be apparent, to those
skilled in this art (See, e.g., Remington: The Science and Practice
of Pharmacy, supra).
[0307] With regard to transurethal administration, the formulation
can comprise a urethral dosage form containing the active agent and
one or more selected carriers or excipients, such as water,
silicone, waxes, petroleum jelly, polyethylene glycol ("PEG"),
propylene glycol ("PG"), liposomes, sugars such as mannitol and
lactose, and/or a variety of other materials, with polyethylene
glycol and derivatives thereof particularly preferred. A
transurethral permeation enhancer can be included in the dosage
from. Examples of suitable permeation enhancers include
dimethylsulfoxide ("DMSO"), dimethyl formamide ("DMF"),
N,N-dimethylacetamide ("DMA"), decylmethylsulfoxide ("C10 MSO"),
polyethylene glycol monolaurate ("PEGML"), glycerol monolaurate,
lecithin, the 1-substituted azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.), SEPA.RTM. (available from Macrochem Co., Lexington,
Mass.), surfactants as discussed above, including, for example,
Tergitol.RTM., Nonoxynol-9.RTM. and TWEEN-80.RTM., and lower
alkanols such as ethanol.
[0308] Transurethral drug administration, as explained in U.S. Pat.
Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020, can be carried
out in a number of different ways using a variety of urethral
dosage forms. For example, the drug can be introduced into the
urethra from a flexible tube, squeeze bottle, pump or aerosol
spray. The drug can also be contained in coatings, pellets or
suppositories that are absorbed, melted or bioeroded in the
urethra. In certain embodiments, the drug is included in a coating
on the exterior surface of a penile insert. It is preferred,
although not essential, that the drug be delivered from at least
about 3 cm into the urethra, and preferably from at least about 7
cm into the urethra. Generally, delivery from at least about 3 cm
to about 8 cm into the urethra will provide effective results in
conjunction with the present method.
[0309] Urethral suppository formulations containing PEG or a PEG
derivative can be conveniently formulated using conventional
techniques, e.g., compression molding, heat molding or the like, as
will be appreciated by those skilled in the art and as described in
the pertinent literature and pharmaceutical texts. (See, e.g.,
Remington: The Science and Practice of Pharmacy, supra), which
discloses typical methods of preparing pharmaceutical compositions
in the form of urethral suppositories. The PEG or PEG derivative
preferably has a molecular weight in the range of from about 200 to
about 2,500 g/mol, more preferably in the range of from about 1,000
to about 2,000 g/mol. Suitable polyethylene glycol derivatives
include polyethylene glycol fatty acid esters, for example,
polyethylene glycol monostearate, polyethylene glycol sorbitan
esters, e.g., polysorbates, and the like. Depending on the
particular active agent, urethral suppositories may contain one or
more solubilizing agents effective to increase the solubility of
the active agent in the PEG or other transurethral vehicle.
[0310] It may be desirable to deliver the active agent in a
urethral dosage form that provides for controlled or sustained
release of the agent. In such a case, the dosage form can comprise
a biocompatible, biodegradable material, typically a biodegradable
polymer. Examples of such polymers include polyesters,
polyalkylcyanoacrylates, polyorthoesters, polyanhydrides, albumin,
gelatin and starch. As explained, for example, in PCT Publication
No. WO 96/40054, these and other polymers can be used to provide
biodegradable microparticles that enable controlled and sustained
drug release, in turn minimizing the required dosing frequency.
[0311] The urethral dosage form will preferably comprise a
suppository that is from about 2 to about 20 mm in length,
preferably from about 5 to about 10 mm in length, and less than
about 5 mm in width, preferably less than about 2 mm in width. The
weight of the suppository will typically be in the range of from
about 1 mg to about 100 mg, preferably in the range of from about 1
mg to about 50 mg. However, it will be appreciated by those skilled
in the art that the size of the suppository can and will vary,
depending on the potency of the drug, the nature of the
formulation, and other factors.
[0312] Transurethral drug delivery may involve an "active" delivery
mechanism such as iontophoresis, electroporation or phonophoresis.
Devices and methods for delivering drugs in this way are well known
in the art. Iontophoretically assisted drug delivery is, for
example, described in PCT Publication No. WO 96/40054, cited above.
Briefly, the active agent is driven through the urethral wall by
means of an electric current passed from an external electrode to a
second electrode contained within or affixed to a urethral
probe.
[0313] Preferred transrectal dosage forms can include rectal
suppositories, creams, ointments, and liquid formulations (enemas).
The suppository, cream, ointment or liquid formulation for
transrectal delivery comprises a therapeutically effective amount
of the selected phosphodiesterase inhibitor and one or more
conventional nontoxic carriers suitable for transrectal drug
administration. The transrectal dosage forms of the present
invention can be manufactured using conventional processes. The
transrectal dosage unit can be fabricated to disintegrate rapidly
or over a period of several hours. The time period for complete
disintegration is preferably in the range of from about 10 minutes
to about 6 hours, and optimally is less than about 3 hours.
[0314] Other components can also be incorporated into the
transrectal dosage forms described herein. The additional
components include, but are not limited to, stiffening agents,
antioxidants, preservatives, and the like. Examples of stiffening
agents that may be used include, for example, paraffin, white wax
and yellow wax. Preferred antioxidants, if used, include sodium
bisulfite and sodium metabisulfite.
[0315] Preferred vaginal or perivaginal dosage forms include
vaginal suppositories, creams, ointments, liquid formulations,
pessaries, tampons, gels, pastes, foams or sprays. The suppository,
cream, ointment, liquid formulation, pessary, tampon, gel, paste,
foam or spray for vaginal or perivaginal delivery comprises a
therapeutically effective amount of the selected active agent and
one or more conventional nontoxic carriers suitable for vaginal or
perivaginal drug administration. The vaginal or perivaginal forms
of the present invention can be manufactured using conventional
processes as disclosed in Remington: The Science and Practice of
Pharmacy, supra (see also drug formulations as adapted in U.S. Pat.
Nos. 6,515,198; 6,500,822; 6,417,186; 6,416,779; 6,376,500;
6,355,641; 6,258,819; 6,172,062; and 6,086,909). The vaginal or
perivaginal dosage unit can be fabricated to disintegrate rapidly
or over a period of several hours. The time period for complete
disintegration is preferably in the range of from about 10 minutes
to about 6 hours, and optimally is less than about 3 hours.
[0316] Other components can also be incorporated into the vaginal
or perivaginal dosage forms described herein. The additional
components include, but are not limited to, stiffening agents,
antioxidants, preservatives, and the like. Examples of stiffening
agents that may be used include, for example, paraffin, white wax
and yellow wax. Preferred antioxidants, if used, include sodium
bisulfite and sodium metabisulfite.
[0317] The active agents can also be administered intranasally or
by inhalation. Compositions for intranasal administration are
generally liquid formulations for administration as a spray or in
the form of drops, although powder formulations for intranasal
administration, e.g., insufflations, nasal gels, creams, pastes or
ointments or other suitable formulators can be used. For liquid
formulations, the active agent can be formulated into a solution,
e.g., water or isotonic saline, buffered or unbuffered, or as a
suspension. Preferably, such solutions or suspensions are isotonic
relative to nasal secretions and of about the same pH, ranging
e.g., from about pH 4.0 to about pH 7.4 or, from about pH 6.0 to
about pH 7.0. Buffers should be physiologically compatible and
include, for example, phosphate buffers. Furthermore, various
devices are available in the art for the generation of drops,
droplets and sprays, including droppers, squeeze bottles, and
manually and electrically powered intranasal pump dispensers.
Active agent containing intranasal carriers can also include nasal
gels, creams, pastes or ointments with a viscosity of, e.g., from
about 10 to about 6500 cps, or greater, depending on the desired
sustained contact with the nasal mucosal surfaces. Such carrier
viscous formulations can be based upon, for example,
alkylcelluloses and/or other biocompatible carriers of high
viscosity well known to the art (see e.g., Remington: The Science
and Practice of Pharmacy, supra). Other ingredients, such as
preservatives, colorants, lubricating or viscous mineral or
vegetable oils, perfumes, natural or synthetic plant extracts such
as aromatic oils, and humectants and viscosity enhancers such as,
e.g., glycerol, can also be included to provide additional
viscosity, moisture retention and a pleasant texture and odor for
the formulation. Formulations for inhalation may be prepared as an
aerosol, either a solution aerosol in which the active agent is
solubilized in a carrier (e.g., propellant) or a dispersion aerosol
in which the active agent is suspended or dispersed throughout a
carrier and an optional solvent. Non-aerosol formulations for
inhalation can take the form of a liquid, typically an aqueous
suspension, although aqueous solutions may be used as well. In such
a case, the carrier is typically a sodium chloride solution having
a concentration such that the formulation is isotonic relative to
normal body fluid. In addition to the carrier, the liquid
formulations can contain water and/or excipients including an
antimicrobial preservative (e.g., benzalkonium chloride,
benzethonium chloride, chlorobutanol, phenylethyl alcohol,
thimerosal and combinations thereof), a buffering agent (e.g.,
citric acid, potassium metaphosphate, potassium phosphate, sodium
acetate, sodium citrate, and combinations thereof), a surfactant
(e.g., polysorbate 80, sodium lauryl sulfate, sorbitan
monopalmitate and combinations thereof), and/or a suspending agent
(e.g., agar, bentonite, microcrystalline cellulose, sodium
carboxymethylcellulose, hydroxypropyl methylcellulose, tragacanth,
veegum and combinations thereof). Non-aerosol formulations for
inhalation can also comprise dry powder formulations, particularly
insufflations in which the powder has an average particle size of
from about 0.1 .mu.m to about 50 .mu.m, preferably from about 1
.mu.m to about 25 .mu.m.
[0318] One common system utilized for intrathecal administration is
the APT Intrathecal treatment system available from Medtronic, Inc.
APT Intrathecal uses a small pump that is surgically placed under
the skin of the abdomen to deliver medication directly into the
intrathecal space. The medication is delivered through a small tube
called a catheter that is also surgically placed. The medication
can then be administered directly to cells in the spinal cord
involved in conveying sensory and motor signals associated with
lower urinary tract disorders.
[0319] Another system available from Medtronic that is commonly
utilized for intrathecal administration is the fully implantable,
programmable SynchroMed.RTM. Infusion System. The SynchroMed.RTM.
Infusion System has two parts that are both placed in the body
during a surgical procedure: the catheter and the pump. The
catheter is a small, soft tube. One end is connected to the
catheter port of the pump, and the other end is placed in the
intrathecal space. The pump is a round metal device about one inch
(2.5 cm) thick, three inches (8.5 cm) in diameter, and weighs about
six ounces (205 g) that stores and releases prescribed amounts of
medication directly into the intrathecal space. It can be made of
titanium, a lightweight, medical-grade metal. The reservoir is the
space inside the pump that holds the medication. The fill port is a
raised center portion of the pump through which the pump is
refilled. The doctor or a nurse inserts a needle through the
patient's skin and through the fill port to fill the pump. Some
pumps have a side catheter access port that allows the doctor to
inject other medications or sterile solutions directly into the
catheter, bypassing the pump.
[0320] The SynchroMed.RTM. pump automatically delivers a controlled
amount of medication through the catheter to the intrathecal space
around the spinal cord, where it is most effective. The exact
dosage, rate and timing prescribed by the doctor are entered in the
pump using a programmer, an external computer-like device that
controls the pump's memory. Information about the patient's
prescription can be stored in the pump's memory. The doctor can
easily review this information by using the programmer. The
programmer communicates with the pump by radio signals that allow
the doctor to tell how the pump is operating at any given time. The
doctor also can use the programmer to change your medication
dosage.
[0321] Methods of intrathecal administration can include those
described above available from Medtronic, as well as other methods
that are known to one of skill in the art.
[0322] Suitable methods for intravesical administration can be
found in U.S. Pat. Nos. 6,207,180 and 6,039,967, for example.
[0323] For other parenteral administration, the compounds for use
in the method of the invention can be formulated for injection or
infusion, for example, intravenous, intra-arterial, intramuscular
or subcutaneous injection or infusion, or for administration in a
bolus dose and/or continuous infusion. Suspensions, solutions or
emulsions in an oily or aqueous vehicle, optionally containing
other formulatory agents such as suspending, stabilizing and/or
dispersing agents can be used.
Additional Dosage Formulations and Drug Delivery Systems
[0324] As compared with traditional drug delivery approaches, some
controlled release technologies rely upon the modification of both
macromolecules and synthetic small molecules to allow them to be
actively instead of passively absorbed into the body. For example,
XenoPort Inc. utilizes technology that takes existing molecules and
re-engineers them to create new chemical entities (unique
molecules) that have improved pharmacologic properties to either:
1) lengthen the short half-life of a drug; 2) overcome poor
absorption; and/or 3) deal with poor drug distribution to target
tissues. Techniques to lengthen the short half-life of a drug
include the use of prodrugs with slow cleavage rates to release
drugs over time or that engage transporters in small and large
intestines to allow the use of oral sustained delivery systems, as
well as drugs that engage active transport systems. Examples of
such controlled release formulations, tablets, dosage forms, and
drug delivery systems, and that are suitable for use with the
present invention, are described in the following published US and
PCT patent applications assigned to Xenoport Inc.: US20030158254;
US20030158089; US20030017964; US2003130246; WO02100172; WO02100392;
WO02100347; WO02100344; WO0242414; WO0228881; WO0228882; WO0244324;
WO0232376; WO0228883; and WO0228411. In particular, Xenoport's
XP13512 is a transported Prodrug of gabapentin that has been
engineered to utilize high capacity transport mechanisms located in
both the small and large intestine and to rapidly convert to
gabapentin once in the body. In contrast to gabapentin itself,
XP13512 was shown in preclinical and clinical studies to produce
dose proportional blood levels of gabapentin across a broad range
of oral doses, and to be absorbed efficiently from the large
intestine.
[0325] Some other controlled release technologies rely upon methods
that promote or enhance gastric retention, such as those developed
by Depomed Inc. Because many drugs are best absorbed in the stomach
and upper portions of the small intestine, Depomed has developed
tablets that swell in the stomach during the postprandial or fed
mode so that they are treated like undigested food. These tablets
therefore sit safely and neutrally in the stomach for 6, 8, or more
hours and deliver drug at a desired rate and time to upper
gastrointestinal sites. Specific technologies in this area include:
1) tablets that slowly erode in gastric fluids to deliver drugs at
almost a constant rate (particularly useful for highly insoluble
drugs); 2) bi-layer tablets that combine drugs with different
characteristics into a single table (such as a highly insoluble
drug in an erosion layer and a soluble drug in a diffusion layer
for sustained release of both); and 3) combination tablets that can
either deliver drugs simultaneously or in sequence over a desired
period of time (including an initial burst of a fast acting drug
followed by slow and sustained delivery of another drug). Examples
of such controlled release formulations that are suitable for use
with the present invention and that rely upon gastric retention
during the postprandial or fed mode, include tablets, dosage forms,
and drug delivery systems in the following U.S. patents assigned to
Depomed Inc.: U.S. Pat. No. 6,488,962; U.S. Pat. No. 6,451,808;
U.S. Pat. No. 6,340,475; U.S. Pat. No. 5,972,389; U.S. Pat. No.
5,582,837; and U.S. Pat. No. 5,007,790. Examples of such controlled
release formulations that are suitable for use with the present
invention and that rely upon gastric retention during the
postprandial or fed mode, include tablets, dosage forms, and drug
delivery systems in the following published U.S. and PCT patent
applications assigned to Depomed Inc.: US20030147952;
US20030104062; US20030104053; US20030104052; US20030091630;
US20030044466; US20030039688; US20020051820; WO0335040; WO0335039;
WO0156544; WO0132217; WO9855107; WO9747285; and WO9318755.
[0326] Other controlled release systems include those developed by
ALZA Corporation based upon: 1) osmotic technology for oral
delivery; 2) transdermal delivery via patches; 3) liposomal
delivery via intravenous injection; 4) osmotic technology for
long-term delivery via implants; and 5) depot technology designed
to deliver agents for periods of days to a month. ALZA oral
delivery systems include those that employ osmosis to provide
precise, controlled drug delivery for up to 24 hours for both
poorly soluble and highly soluble drugs, as well as those that
deliver high drug doses meeting high drug loading requirements.
ALZA controlled transdermal delivery systems provide drug delivery
through intact skin for as long as one week with a single
application to improve drug absorption and deliver constant amounts
of drug into the bloodstream over time. ALZA liposomal delivery
systems involve lipid nanoparticles that evade recognition by the
immune system because of their unique polyethylene glycol (PEG)
coating, allowing the precise delivery of drugs to disease-specific
areas of the body. ALZA also has developed osmotically driven
systems to enable the continuous delivery of small drugs, peptides,
proteins, DNA and other bioactive macromolecules for up to one year
for systemic or tissue-specific therapy. Finally, ALZA depot
injection therapy is designed to deliver biopharmaceutical agents
and small molecules for periods of days to a month using a
nonaqueous polymer solution for the stabilization of macromolecules
and a unique delivery profile.
[0327] Examples of controlled release formulations, tablets, dosage
forms, and drug delivery systems that are suitable for use with the
present invention are described in the following U.S. patents
assigned to ALZA Corporation: U.S. Pat. No. 4,367,741; U.S. Pat.
No. 4,402,695; U.S. Pat. No. 4,418,038; U.S. Pat. No. 4,434,153;
U.S. Pat. No. 4,439,199; U.S. Pat. No. 4,450,198; U.S. Pat. No.
4,455,142; U.S. Pat. No. 4,455,144; U.S. Pat. No. 4,484,923; U.S.
Pat. No. 4,486,193; U.S. Pat. No. 4,489,197; U.S. Pat. No.
4,511,353; U.S. Pat. No. 4,519,801; U.S. Pat. No. 4,526,578; U.S.
Pat. No. 4,526,933; U.S. Pat. No. 4,534,757; U.S. Pat. No.
4,553,973; U.S. Pat. No. 4,559,222; U.S. Pat. No. 4,564,364; U.S.
Pat. No. 4,578,075; U.S. Pat. No. 4,588,580; U.S. Pat. No.
4,610,686; U.S. Pat. No. 4,612,008; U.S. Pat. No. 4,618,487; U.S.
Pat. No. 4,627,851; U.S. Pat. No. 4,629,449; U.S. Pat. No.
4,642,233; U.S. Pat. No. 4,649,043; U.S. Pat. No. 4,650,484; U.S.
Pat. No. 4,659,558; U.S. Pat. No. 4,661,105; U.S. Pat. No.
4,662,880; U.S. Pat. No. 4,675,174; U.S. Pat. No. 4,681,583; U.S.
Pat. No. 4,684,524; U.S. Pat. No. 4,692,336; U.S. Pat. No.
4,693,895; U.S. Pat. No. 4,704,119; U.S. Pat. No. 4,705,515; U.S.
Pat. No. 4,717,566; U.S. Pat. No. 4,721,613; U.S. Pat. No.
4,723,957; U.S. Pat. No. 4,725,272; U.S. Pat. No. 4,728,498; U.S.
Pat. No. 4,743,248; U.S. Pat. No. 4,747,847; U.S. Pat. No.
4,751,071; U.S. Pat. No. 4,753,802; U.S. Pat. No. 4,755,180; U.S.
Pat. No. 4,756,314; U.S. Pat. No. 4,764,380; U.S. Pat. No.
4,773,907; U.S. Pat. No. 4,777,049; U.S. Pat. No. 4,781,924; U.S.
Pat. No. 4,783,337; U.S. Pat. No. 4,786,503; U.S. Pat. No.
4,788,062; U.S. Pat. No. 4,810,502; U.S. Pat. No. 4,812,313; U.S.
Pat. No. 4,816,258; U.S. Pat. No. 4,824,675; U.S. Pat. No.
4,834,979; U.S. Pat. No. 4,837,027; U.S. Pat. No. 4,842,867; U.S.
Pat. No. 4,846,826; U.S. Pat. No. 4,847,093; U.S. Pat. No.
4,849,226; U.S. Pat. No. 4,851,229; U.S. Pat. No. 4,851,231; U.S.
Pat. No. 4,851,232; U.S. Pat. No. 4,853,229; U.S. Pat. No.
4,857,330; U.S. Pat. No. 4,859,470; U.S. Pat. No. 4,863,456; U.S.
Pat. No. 4,863,744; U.S. Pat. No. 4,865,598; U.S. Pat. No.
4,867,969; U.S. Pat. No. 4,871,548; U.S. Pat. No. 4,872,873; U.S.
Pat. No. 4,874,388; U.S. Pat. No. 4,876,093; U.S. Pat. No.
4,892,778; U.S. Pat. No. 4,902,514; U.S. Pat. No. 4,904,474; U.S.
Pat. No. 4,913,903; U.S. Pat. No. 4,915,949; U.S. Pat. No.
4,915,952; U.S. Pat. No. 4,917,895; U.S. Pat. No. 4,931,285; U.S.
Pat. No. 4,946,685; U.S. Pat. No. 4,948,592; U.S. Pat. No.
4,954,344; U.S. Pat. No. 4,957,494; U.S. Pat. No. 4,960,416; U.S.
Pat. No. 4,961,931; U.S. Pat. No. 4,961,932; U.S. Pat. No.
4,963,141; U.S. Pat. No. 4,966,769; U.S. Pat. No. 4,971,790; U.S.
Pat. No. 4,976,966; U.S. Pat. No. 4,986,987; U.S. Pat. No.
5,006,346; U.S. Pat. No. 5,017,381; U.S. Pat. No. 5,019,397; U.S.
Pat. No. 5,023,076; U.S. Pat. No. 5,023,088; U.S. Pat. No.
5,024,842; U.S. Pat. No. 5,028,434; U.S. Pat. No. 5,030,454; U.S.
Pat. No. 5,071,656; U.S. Pat. No. 5,077,054; U.S. Pat. No.
5,082,668; U.S. Pat. No. 5,104,390; U.S. Pat. No. 5,110,597; U.S.
Pat. No. 5,122,128; U.S. Pat. No. 5,125,894; U.S. Pat. No.
5,141,750; U.S. Pat. No. 5,141,752; U.S. Pat. No. 5,156,850; U.S.
Pat. No. 5,160,743; U.S. Pat. No. 5,160,744; U.S. Pat. No.
5,169,382; U.S. Pat. No. 5,171,576; U.S. Pat. No. 5,176,665; U.S.
Pat. No. 5,185,158; U.S. Pat. No. 5,190,765; U.S. Pat. No.
5,198,223; U.S. Pat. No. 5,198,229; U.S. Pat. No. 5,200,195; U.S.
Pat. No. 5,200,196; U.S. Pat. No. 5,204,116; U.S. Pat. No.
5,208,037; U.S. Pat. No. 5,209,746; U.S. Pat. No. 5,221,254; U.S.
Pat. No. 5,221,278; U.S. Pat. No. 5,229,133; U.S. Pat. No.
5,232,438; U.S. Pat. No. 5,232,705; U.S. Pat. No. 5,236,689; U.S.
Pat. No. 5,236,714; U.S. Pat. No. 5,240,713; U.S. Pat. No.
5,246,710; U.S. Pat. No. 5,246,711; U.S. Pat. No. 5,252,338; U.S.
Pat. No. 5,254,349; U.S. Pat. No. 5,266,332; U.S. Pat. No.
5,273,752; U.S. Pat. No. 5,284,660; U.S. Pat. No. 5,286,491; U.S.
Pat. No. 5,308,348; U.S. Pat. No. 5,318,558; U.S. Pat. No.
5,320,850; U.S. Pat. No. 5,322,502; U.S. Pat. No. 5,326,571; U.S.
Pat. No. 5,330,762; U.S. Pat. No. 5,338,550; U.S. Pat. No.
5,340,590; U.S. Pat. No. 5,342,623; U.S. Pat. No. 5,344,656; U.S.
Pat. No. 5,348,746; U.S. Pat. No. 5,358,721; U.S. Pat. No.
5,364,630; U.S. Pat. No. 5,376,377; U.S. Pat. No. 5,391,381; U.S.
Pat. No. 5,402,777; U.S. Pat. No. 5,403,275; U.S. Pat. No.
5,411,740; U.S. Pat. No. 5,417,675; U.S. Pat. No. 5,417,676; U.S.
Pat. No. 5,417,682; U.S. Pat. No. 5,423,739; U.S. Pat. No.
5,424,289; U.S. Pat. No. 5,431,919; U.S. Pat. No. 5,443,442; U.S.
Pat. No. 5,443,459; U.S. Pat. No. 5,443,461; U.S. Pat. No.
5,456,679; U.S. Pat. No. 5,460,826; U.S. Pat. No. 5,462,741; U.S.
Pat. No. 5,462,745; U.S. Pat. No. 5,489,281; U.S. Pat. No.
5,499,979; U.S. Pat. No. 5,500,222; U.S. Pat. No. 5,512,293; U.S.
Pat. No. 5,512,299; U.S. Pat. No. 5,529,787; U.S. Pat. No.
5,531,736; U.S. Pat. No. 5,532,003; U.S. Pat. No. 5,533,971; U.S.
Pat. No. 5,534,263; U.S. Pat. No. 5,540,912; U.S. Pat. No.
5,543,156; U.S. Pat. No. 5,571,525; U.S. Pat. No. 5,573,503; U.S.
Pat. No. 5,591,124; U.S. Pat. No. 5,593,695; U.S. Pat. No.
5,595,759; U.S. Pat. No. 5,603,954; U.S. Pat. No. 5,607,696; U.S.
Pat. No. 5,609,885; U.S. Pat. No. 5,614,211; U.S. Pat. No.
5,614,578; U.S. Pat. No. 5,620,705; U.S. Pat. No. 5,620,708; U.S.
Pat. No. 5,622,530; U.S. Pat. No. 5,622,944; U.S. Pat. No.
5,633,011; U.S. Pat. No. 5,639,477; U.S. Pat. No. 5,660,861; U.S.
Pat. No. 5,667,804; U.S. Pat. No. 5,667,805; U.S. Pat. No.
5,674,895; U.S. Pat. No. 5,688,518; U.S. Pat. No. 5,698,224; U.S.
Pat. No. 5,702,725; U.S. Pat. No. 5,702,727; U.S. Pat. No.
5,707,663; U.S. Pat. No. 5,713,852; U.S. Pat. No. 5,718,700; U.S.
Pat. No. 5,736,580; U.S. Pat. No. 5,770,227; U.S. Pat. No.
5,780,058; U.S. Pat. No. 5,783,213; U.S. Pat. No. 5,785,994; U.S.
Pat. No. 5,795,591; U.S. Pat. No. 5,811,465; U.S. Pat. No.
5,817,624; U.S. Pat. No. 5,824,340; U.S. Pat. No. 5,830,501; U.S.
Pat. No. 5,830,502; U.S. Pat. No. 5,840,754; U.S. Pat. No.
5,858,407; U.S. Pat. No. 5,861,439; U.S. Pat. No. 5,863,558; U.S.
Pat. No. 5,876,750; U.S. Pat. No. 5,883,135; U.S. Pat. No.
5,840,754; U.S. Pat. No. 5,897,878; U.S. Pat. No. 5,904,934; U.S.
Pat. No. 5,904,935; U.S. Pat. No. 5,906,832; U.S. Pat. No.
5,912,268; U.S. Pat. No. 5,914,131; U.S. Pat. No. 5,916,582; U.S.
Pat. No. 5,932,547; U.S. Pat. No. 5,938,654; U.S. Pat. No.
5,941,844; U.S. Pat. No. 5,955,103; U.S. Pat. No. 5,972,369; U.S.
Pat. No. 5,972,370; U.S. Pat. No. 5,972,379; U.S. Pat. No.
5,980,943; U.S. Pat. No. 5,981,489; U.S. Pat. No. 5,983,130; U.S.
Pat. No. 5,989,590; U.S. Pat. No. 5,995,869; U.S. Pat. No.
5,997,902; U.S. Pat. No. 6,001,390; U.S. Pat. No. 6,004,309; U.S.
Pat. No. 6,004,578; U.S. Pat. No. 6,008,187; U.S. Pat. No.
6,020,000; U.S. Pat. No. 6,034,101; U.S. Pat. No. 6,036,973; U.S.
Pat. No. 6,039,977; U.S. Pat. No. 6,057,374; U.S. Pat. No.
6,066,619; U.S. Pat. No. 6,068,850; U.S. Pat. No. 6,077,538; U.S.
Pat. No. 6,083,190; U.S. Pat. No. 6,096,339; U.S. Pat. No.
6,106,845; U.S. Pat. No. 6,110,499; U.S. Pat. No. 6,120,798; U.S.
Pat. No. 6,120,803; U.S. Pat. No. 6,124,261; U.S. Pat. No.
6,124,355; U.S. Pat. No. 6,130,200; U.S. Pat. No. 6,146,662; U.S.
Pat. No. 6,153,678; U.S. Pat. No. 6,174,547; U.S. Pat. No.
6,183,466; U.S. Pat. No. 6,203,817; U.S. Pat. No. 6,210,712; U.S.
Pat. No. 6,210,713; U.S. Pat. No. 6,224,907; U.S. Pat. No.
6,235,712; U.S. Pat. No. 6,245,357; U.S. Pat. No. 6,262,115; U.S.
Pat. No. 6,264,990; U.S. Pat. No. 6,267,984; U.S. Pat. No.
6,287,598; U.S. Pat. No. 6,289,241; U.S. Pat. No. 6,331,311; U.S.
Pat. No. 6,333,050; U.S. Pat. No. 6,342,249; U.S. Pat. No.
6,346,270; U.S. Pat. No. 6365183; U.S. Pat. No. 6,368,626; U.S.
Pat. No. 6,387,403; U.S. Pat. No. 6,419,952; U.S. Pat. No.
6,440,457; U.S. Pat. No. 6,468,961; U.S. Pat. No. 6,491,683; U.S.
Pat. No. 6,512,010; U.S. Pat. No. 6,514,530; U.S. Pat. No. 6534089;
U.S. Pat. No. 6,544,252; U.S. Pat. No. 6,548,083; U.S. Pat. No.
6,551,613; U.S. Pat. No. 6,572,879; and U.S. Pat. No.
6,596,314.
[0328] Other examples of controlled release formulations, tablets,
dosage forms, and drug delivery systems that are suitable for use
with the present invention are described in the following published
U.S. patent application and PCT applications assigned to ALZA
Corporation: US20010051183; WO0004886; WO0013663; WO0013674;
WO0025753; WO0025790; WO0035419; WO0038650; WO0040218; WO0045790;
WO0066126; WO0074650; WO0119337; WO0119352; WO0121211; WO0137815;
WO0141742; WO0143721; WO0156543; WO3041684; WO03041685; WO03041757;
WO03045352; WO03051341; WO03053400; WO03053401; WO9000416;
WO9004965; WO9113613; WO9116884; WO9204011; WO9211843; WO9212692;
WO9213521; WO9217239; WO9218102; WO9300071; WO9305843; WO9306819;
WO9314813; WO9319739; WO9320127; WO9320134; WO9407562; WO9408572;
WO9416699; WO9421262; WO9427587; WO9427589; WO9503823; WO9519174;
WO9529665; WO9600065; WO9613248; WO9625922; WO9637202; WO9640049;
WO9640050; WO9640139; WO9640364; WO9640365; WO9703634; WO9800158;
WO9802169; WO9814168; WO9816250; WO9817315; WO9827962; WO9827963;
WO9843611; WO9907342; WO9912526; WO9912527; WO9918159; WO9929297;
WO9929348; WO9932096; WO9932153; WO9948494; WO9956730; WO9958115;
and WO9962496.
[0329] Another drug delivery technology suitable for use in the
present invention is that disclosed by DepoMed, Inc. in U.S. Pat.
No. 6,682,759, which discloses a method for manufacturing a
pharmaceutical tablet for oral administration combining both
immediate-release and prolonged-release modes of drug delivery. The
tablet according to the method comprises a prolonged-release drug
core and an immediate-release drug coating or layer, which can be
insoluble or sparingly soluble in water. The method limits the drug
particle diameter in the immediate-release coating or layer to 10
microns or less. The coating or layer is either the particles
themselves, applied as an aqueous suspension, or a solid
composition that contains the drug particles incorporated in a
solid material that disintegrates rapidly in gastric fluid.
[0330] Andrx Corporation has also developed drug delivery
technology suitable for use in the present invention that includes:
1) a pelletized pulsatile delivery system ("PPDS"); 2) a single
composition osmotic tablet system ("SCOT"); 3) a solubility
modulating hydrogel system ("SMHS"); 4) a delayed pulsatile
hydrogel system ("DPHS"); 5) a stabilized pellet delivery system
("SPDS"); 6) a granulated modulating hydrogel system ("GMHS"); 7) a
pelletized tablet system ("PELTAB"); 8) a porous tablet system
("PORTAB"); and 9) a stabilized tablet delivery system ("STDS").
PPDS uses pellets that are coated with specific polymers and agents
to control the release rate of the microencapsulated drug and is
designed for use with drugs that require a pulsed release. SCOT
utilizes various osmotic modulating agents as well as polymer
coatings to provide a zero-order drug release. SMHS utilizes a
hydrogel-based dosage system that avoids the "initial burst effect"
commonly observed with other sustained-release hydrogel
formulations and that provides for sustained release without the
need to use special coatings or structures that add to the cost of
manufacturing. DPHS is designed for use with hydrogel matrix
products characterized by an initial zero-order drug release
followed by a rapid release that is achieved by the blending of
selected hydrogel polymers to achieve a delayed pulse. SPDS
incorporates a pellet core of drug and protective polymer outer
layer, and is designed specifically for unstable drugs, while GMHS
incorporates hydrogel and binding polymers with the drug and forms
granules that are pressed into tablet form. PELTAB provides
controlled release by using a water insoluble polymer to coat
discrete drug crystals or pellets to enable them to resist the
action of fluids in the gastrointestinal tract, and these coated
pellets are then compressed into tablets. PORTAB provides
controlled release by incorporating an osmotic core with a
continuous polymer coating and a water soluble component that
expands the core and creates microporous channels through which
drug is released. Finally, STDS includes a dual layer coating
technique that avoids the need to use a coating layer to separate
the enteric coating layer from the omeprazole core.
[0331] Examples of controlled release formulations, tablets, dosage
forms, and drug delivery systems that are suitable for use with the
present invention are described in the following U.S. patents
assigned to Andrx Corporation: U.S. Pat. No. 5,397,574; U.S. Pat.
No. 5,419,917; U.S. Pat. No. 5,458,887; U.S. Pat. No. 5,458,888;
U.S. Pat. No. 5,472,708; U.S. Pat. No. 5,508,040; U.S. Pat. No.
5,558,879; U.S. Pat. No. 5,567,441; U.S. Pat. No. 5,654,005; U.S.
Pat. No. 5,728,402; U.S. Pat. No. 5,736,159; U.S. Pat. No.
5,830,503; U.S. Pat. No. 5,834,023; U.S. Pat. No. 5,837,379; U.S.
Pat. No. 5,916,595; U.S. Pat. No. 5,922,352; U.S. Pat. No.
6,099,859; U.S. Pat. No. 6,099,862; U.S. Pat. No. 6,103,263; U.S.
Pat. No. 6,106,862; U.S. Pat. No. 6,156,342; U.S. Pat. No.
6,177,102; U.S. Pat. No. 6,197,347; U.S. Pat. No. 6,210,716; U.S.
Pat. No. 6,238,703; U.S. Pat. No. 6,270,805; U.S. Pat. No.
6,284,275; U.S. Pat. No. 6,485,748; U.S. Pat. No. 6,495,162; U.S.
Pat. No. 6,524,620; U.S. Pat. No. 6,544,556; U.S. Pat. No.
6,589,553; U.S. Pat. No. 6,602,522; and U.S. Pat. No.
6,610,326.
[0332] Examples of controlled release formulations, tablets, dosage
forms, and drug delivery systems that are suitable for use with the
present invention are described in the following published US and
PCT patent applications assigned to Andrx Corporation:
US20010024659; US20020115718; US20020156066; WO0004883; WO0009091;
WO0012097; WO0027370; WO0050010; WO0132161; WO0134123; WO0236077;
WO0236100; WO02062299; WO02062824; WO02065991; WO02069888;
WO02074285; WO03000177; WO9521607; WO9629992; WO9633700; WO9640080;
WO9748386; WO9833488; WO9833489; WO9930692; WO9947125; and
WO9961005.
[0333] Some other examples of drug delivery approaches focus on
non-oral drug delivery, providing parenteral, transmucosal, and
topical delivery of proteins, peptides, and small molecules. For
example, the Atrigel.RTM. drug delivery system marketed by Atrix
Laboratories Inc. comprises biodegradable polymers, similar to
those used in biodegradable sutures, dissolved in biocompatible
carriers. These pharmaceuticals may be blended into a liquid
delivery system at the time of manufacturing or, depending upon the
product, may be added later by a physician at the time of use.
Injection of the liquid product subcutaneously or intramuscularly
through a small gauge needle, or placement into accessible tissue
sites through a cannula, causes displacement of the carrier with
water in the tissue fluids, and a subsequent precipitate to form
from the polymer into a solid film or implant. The drug
encapsulated within the implant is then released in a controlled
manner as the polymer matrix biodegrades over a period ranging from
days to months. Examples of such drug delivery systems include
Atrix's Eligard.RTM., Atridox.RTM./Doxirobe.RTM., Atrisorb.RTM.
FreeFlow.TM./Atrisorb.RTM.-D FreeFlow, bone growth products, and
others as described in the following published U.S. and PCT patent
applications assigned to Atrix Laboratories Inc.: U.S. Pat. No.
RE37950; U.S. Pat. No. 6,630,155; U.S. Pat. No. 6,566,144; U.S.
Pat. No. 6,610,252; U.S. Pat. No. 6,565,874; U.S. Pat. No.
6,528,080; U.S. Pat. No. 6,461,631; U.S. Pat. No. 6,395,293; U.S.
Pat. No. 6,261,583; U.S. Pat. No. 6,143,314; U.S. Pat. No.
6,120,789; U.S. Pat. No. 6,071,530; U.S. Pat. No. 5,990,194; U.S.
Pat. No. 5,945,115; U.S. Pat. No. 5,888,533; U.S. Pat. No.
5,792,469; U.S. Pat. No. 5,780,044; U.S. Pat. No. 5,759,563; U.S.
Pat. No. 5,744,153; U.S. Pat. No. 5,739,176; U.S. Pat. No.
5,736,152; U.S. Pat. No. 5,733,950; U.S. Pat. No. 5,702,716; U.S.
Pat. No. 5,681,873; U.S. Pat. No. 5,660,849; U.S. Pat. No.
5,599,552; U.S. Pat. No. 5,487,897; U.S. Pat. No. 5,368,859; U.S.
Pat. No. 5,340,849; U.S. Pat. No. 5,324,519; U.S. Pat. No.
5,278,202; U.S. Pat. No. 5,278,201; US20020114737, US20030195489;
US20030133964; US 20010042317; US20020090398; US20020001608; and
US2001042317.
[0334] Atrix Laboratories Inc. also markets technology for the
non-oral transmucosal delivery of drugs over a time period from
minutes to hours. For example, Atrix's BEMA.TM. (Bioerodible
Muco-Adhesive Disc) drug delivery system comprises pre-formed
bioerodible discs for local or systemic delivery. Examples of such
drug delivery systems include those as described in U.S. Pat. No.
6,245,345. Other drug delivery systems marketed by Atrix
Laboratories Inc. focus on topical drug delivery. For example,
SMP.TM. (Solvent Particle System) allows the topical delivery of
highly water-insoluble drugs. This product allows for a controlled
amount of a dissolved drug to permeate the epidermal layer of the
skin by combining the dissolved drug with a microparticle
suspension of the drug. The SMP.TM. system works in stages whereby:
1) the product is applied to the skin surface; 2) the product near
follicles concentrates at the skin pore; 3) the drug readily
partitions into skin oils; and 4) the drug diffuses throughout the
area. By contrast, MCA.RTM. (Mucocutaneous Absorption System) is a
water-resistant topical gel providing sustained drug delivery.
MCA.RTM. forms a tenacious film for either wet or dry surfaces
where: 1) the product is applied to the skin or mucosal surface; 2)
the product forms a tenacious moisture-resistant film; and 3) the
adhered film provides sustained release of drug for a period from
hours to days. Yet another product, BCP.TM. (Biocompatible Polymer
System) provides a non-cytotoxic gel or liquid that is applied as a
protective film for wound healing. Examples of these systems
include Orajel.RTM.-Ultra Mouth Sore Medicine as well as those as
described in the following published U.S. patents and applications
assigned to Atrix Laboratories Inc.: U.S. Pat. No. 6,537,565; U.S.
Pat. No. 6,432,415; U.S. Pat. No. 6,355,657; U.S. Pat. No.
5,962,006; U.S. Pat. No. 5,725,491; U.S. Pat. No. 5,722,950; U.S.
Pat. No. 5,717,030; U.S. Pat. No. 5,707,647; U.S. Pat. No.
5,632,727; and US20010033853.
[0335] Additional formulations and compositions available from Teva
Pharmaceutical Industries Ltd., Warner Lambert & Co., and
Godecke Aktiengesellshaft that include gabapentin and are useful in
the present invention include those as described in the following
U.S. patents and published US and PCT patent applications: U.S.
Pat. No. 6,531,509; U.S. Pat. No. 6,255,526; U.S. Pat. No.
6,054,482; US2003055109; US2002045662; US2002009115; WO 01/97782;
WO 01/97612; EP 2001946364; WO 99/59573; and WO 99/59572.
[0336] Additional formulations and compositions that include
oxybutynin and are useful in the present invention include those as
described in the following U.S. patents and published US and PCT
patent applications: U.S. Pat. No. 5,834,010; U.S. Pat. No.
5,601,839; and U.S. Pat. No. 5,164,190.
Topical Formulations
[0337] Topical formulations can be in any form suitable for
application to the body surface, and may comprise, for example, an
ointment, cream, gel, lotion, solution, paste or the like, and/or
may be prepared so as to contain liposomes, micelles, and/or
microspheres. Preferred topical formulations herein are ointments,
creams and gels.
[0338] Ointments, as is well known in the art of pharmaceutical
formulation, are semisolid preparations that are typically based on
petrolatum or other petroleum derivatives. The specific ointment
base to be used, preferably provides for optimum drug delivery,
and, preferably, will provides for other desired characteristics as
well, e.g., emolliency or the like. The ointment base is preferably
inert, stable, nonirritating and nonsensitizing. As explained in
Remington: The Science and Practice of Pharmacy, supra, ointment
bases can be grouped in four classes: oleaginous bases;
emulsifiable bases; emulsion bases; and water-soluble bases.
Oleaginous ointment bases include, for example, vegetable oils,
fats obtained from animals, and semisolid hydrocarbons obtained
from petroleum. Emulsifiable ointment bases, also known as
absorbent ointment bases, contain little or no water and include,
for example, hydroxystearin sulfate, anhydrous lanolin and
hydrophilic petrolatum. Emulsion ointment bases are either
water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and
include, for example, cetyl alcohol, glyceryl monostearate, lanolin
and stearic acid. Preferred water-soluble ointment bases are
prepared from polyethylene glycols of varying molecular weight
(See, e.g., Remington: The Science and Practice of Pharmacy,
supra).
[0339] Creams, as also well known in the art, are viscous liquids
or semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also called the "internal"
phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or stearyl alcohol. The aqueous phase usually,
although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant.
[0340] As will be appreciated by those working in the field of
pharmaceutical formulation, gels-are semisolid, suspension-type
systems. Single-phase gels contain organic macromolecules
distributed substantially uniformly throughout the carrier liquid,
which is typically aqueous, but also, preferably, contain an
alcohol and, optionally, an oil. Preferred "organic
macromolecules," i.e., gelling agents, are crosslinked acrylic acid
polymers such as the "carbomer" family of polymers, e.g.,
carboxypolyalkylenes that may be obtained commercially under the
Carbopol.RTM. trademark. Also preferred are hydrophilic polymers
such as polyethylene oxides, polyoxyethylene-polyoxypropylene
copolymers and polyvinylalcohol; cellulosic polymers such as
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl methylcellulose phthalate, and
methylcellulose; gums such as tragacanth and xanthan gum; sodium
alginate; and gelatin. In order to prepare a uniform gel,
dispersing agents such as alcohol or glycerin can be added, or the
gelling agent can be dispersed by trituration, mechanical mixing,
and/or stirring.
[0341] Various additives, known to those skilled in the art, may be
included in the topical formulations. For example, solubilizers may
be used to solubilize certain active agents. For those drugs having
an unusually low rate of permeation through the skin or mucosal
tissue, it may be desirable to include a permeation enhancer in the
formulation; suitable enhancers are as described elsewhere
herein.
Transdermal Administration
[0342] The compounds of the invention may also be administered
through the skin or mucosal tissue using conventional transdermal
drug delivery systems, wherein the agent is contained within a
laminated structure (typically referred to as a transdermal
"patch") that serves as a drug delivery device to be affixed to the
skin. Transdermal drug delivery may involve passive diffusion or it
may be facilitated using electrotransport, e.g., iontophoresis. In
a typical transdermal "patch," the drug composition is contained in
a layer, or "reservoir," underlying an upper backing layer. The
laminated structure may contain a single reservoir, or it may
contain multiple reservoirs. In one type of patch, referred to as a
"monolithic" system, the reservoir is comprised of a polymeric
matrix of a pharmaceutically acceptable contact adhesive material
that serves to affix the system to the skin during drug delivery.
Examples of suitable skin contact adhesive materials include, but
are not limited to, polyethylenes, polysiloxanes, polyisobutylenes,
polyacrylates, polyurethanes, and the like. Alternatively, the
drug-containing reservoir and skin contact adhesive are separate
and distinct layers, with the adhesive underlying the reservoir
which, in this case, may be either a polymeric matrix as described
above, or it may be a liquid or hydrogel reservoir, or may take
some other form.
[0343] The backing layer in these laminates, which serves as the
upper surface of the device, functions as the primary structural
element of the laminated structure and provides the device with
much of its flexibility. The material selected for the backing
material should be selected so that it is substantially impermeable
to the active agent and any other materials that are present, the
backing is preferably made of a sheet or film of a flexible
elastomeric material. Examples of polymers that are suitable for
the backing layer include polyethylene, polypropylene, polyesters,
and the like.
[0344] During storage and prior to use, the laminated structure
includes a release liner. Immediately prior to use, this layer is
removed from the device to expose the basal surface thereof, either
the drug reservoir or a separate contact adhesive layer, so that
the system may be affixed to the skin. The release liner should be
made from a drug/vehicle impermeable material.
[0345] Transdermal drug delivery systems may in addition contain a
skin permeation enhancer. That is, because the inherent
permeability of the skin to some drugs may be too low to allow
therapeutic levels of the drug to pass through a reasonably sized
area of unbroken skin, it is necessary to coadminister a skin
permeation enhancer with such drugs. Suitable enhancers are well
known in the art and include, for example, those enhancers listed
above in transmucosal compositions.
[0346] The formulations of the present invention can be, but are
not limited to, short-term, rapid-offset, controlled, for example,
sustained release, delayed release and pulsatile release
formulations.
[0347] The term sustained release is used in its conventional sense
to refer to a drug formulation that provides for gradual release of
a drug over an extended period of time, and that preferably,
although not necessarily, results in substantially constant blood
levels of a drug over an extended time period. The period of time
can be as long as a month or more and should be a release which is
longer that the same amount of agent administered in bolus
form.
[0348] For sustained release, the compounds can be formulated with
a suitable polymer or hydrophobic material which provides sustained
release properties to the compounds. As such, the compounds for use
the method of the invention can be administered in the form of
microparticles for example, by injection or in the form of wafers
or discs by implantation.
[0349] The term delayed release is used herein in its conventional
sense to refer to a drug formulation that provides for an initial
release of the drug after some delay following drug administration
and that preferably, although not necessarily, includes a delay of
from about 10 minutes up to about 12 hours.
[0350] The term pulsatile release is used herein in its
conventional sense to refer to a drug formulation that provides
release of the drug in such a way as to produce pulsed plasma
profiles of the drug after drug administration.
[0351] The term immediate release is used in its conventional sense
to refer to a drug formulation that provides for release of the
drug immediately after drug administration.
[0352] As used herein, short-term refers to any period of time up
to and including about 8 hours, about 7 hours, about 6 hours, about
5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour,
about 40 minutes, about 20 minutes, or about 10 minutes after drug
administration.
[0353] As used herein, rapid-offset refers to any period of time up
to and including about 8 hours, about 7 hours, about 6 hours, about
5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour,
about 40 minutes, about 20 minutes, or about 10 minutes after drug
administration.
Coadministration
[0354] In practicing the methods of the invention, coadministration
refers to administration of a first amount of a 5-HT.sub.3 receptor
antagonist compound and a second amount of a NARI compound to treat
a lower urinary tract disorder. Coadministration encompasses
administration of the first and second amounts of the compounds of
the coadministration in an essentially simultaneous manner, such as
in a single pharmaceutical composition, for example, capsule or
tablet having a fixed ratio of first and second amounts, or in
multiple, separate capsules or tablets for each. In addition, such
coadministration also encompasses use of each compound in a
sequential manner in either order. When coadministration involves
the separate administration of the NARI and 5-HT.sub.3 receptor
antagonist, the compounds are administered sufficiently close in
time to have the desired therapeutic effect.
Dosing
[0355] The therapeutically effective amount or dose of (a) a
compound having dual therapeutic modes of action (i.e., 5-HT.sub.3
receptor antagonist activity and NARI activity) or (b) a 5-HT.sub.3
receptor antagonist and NARI in combination will depend on the age,
sex and weight of the patient, the current medical condition of the
patient and the nature of the lower urinary tract disorder being
treated. The skilled artisan will be able to determine appropriate
dosages depending on these and other factors.
[0356] As used herein, continuous dosing refers to the chronic
administration of a selected active agent.
[0357] As used herein, as-needed dosing, also known as "pro re
nata" "prn" dosing, and "on demand" dosing or administration is
meant the administration of a therapeutically effective dose of the
compound(s) at some time prior to commencement of an activity
wherein suppression of a lower urinary tract disorder would be
desirable. Administration can be immediately prior to such an
activity, including about 0 minutes, about 10 minutes, about 20
minutes, about 30 minutes, about 1 hour, about 2 hours, about 3
hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours,
about 8 hours, about 9 hours, or about 10 hours prior to such an
activity, depending on the formulation.
[0358] In a particular embodiment, drug administration or dosing is
on an as-needed basis, and does not involve chronic drug
administration. With an immediate release dosage form, as-needed
administration can involve drug administration immediately prior to
commencement of an activity wherein suppression of the symptoms of
overactive bladder would be desirable, but will generally be in the
range of from about 0 minutes to about 10 hours prior to such an
activity, preferably in the range of from about 0 minutes to about
5 hours prior to such an activity, most preferably in the range of
from about 0 minutes to about 3 hours prior to such an
activity.
[0359] A suitable dose of the 5-HT.sub.3 receptor antagonist can be
in the range of from about 0.001 mg to about 500 mg per day, such
as from about 0.01 mg to about 100 mg, for example, from about 0.05
mg to about 50 mg, such as about 0.5 mg to about 25 mg per day. The
dose can be administered in a single dosage or in multiple dosages,
for example from 1 to 4 or more times per day. When multiple
dosages are used, the amount of each dosage can be the same or
different.
[0360] A suitable dose of the NARI compound can be in the range of
from about 0.001 mg to about 1000 mg per day, such as from about
0.05 mg to about 500 mg, for example, from about 0.03 mg to about
300 mg, such as about 0.02 mg to about 200 mg per day. The dose can
be administered in a single dosage or in multiple dosages, for
example from 1 to 4 or more times per day. When multiple dosages
are used, the amount of each dosage can be the same or
different.
[0361] A suitable dose of the compound having both 5-HT.sub.3
receptor antagonist and NARI activity can be in the range of from
about 0.001 mg to about 1000 mg per day, such as from about 0.05 mg
to about 500 mg, for example, from about 0.03 mg to about 300 mg,
such as from about 0.02 mg to about 200 mg per day. In a particular
embodiment, a suitable dose of the compound having both 5-HT.sub.3
receptor antagonist and NARI activity can be in the range of from
about 0.1 mg to about 50 mg per day, such as from about 0.5 mg to
about 10 mg per, day such as about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 mg per day. The dose per day can be administered in a single
dosage or in multiple dosages, for example from 1 to 4 or more
times per day. When multiple dosages are used, the amount of each
dosage can be the same or different. For example a dose of 1 mg per
day can be administered as two 0.5 mg doses, with about a 12 hour
interval between doses.
[0362] It is understood that the amount of compound dosed per day
can be administered every day, every other day, every 2 days, every
3 days, every 4 days, every 5 days, etc. For example, with every
other day administration, a 5 mg per day dose can be initiated on
Monday with a first subsequent 5 mg per day dose administered on
Wednesday, a second subsequent 5 mg per day dose administered on
Friday, etc.
[0363] The compounds for use in the method of the invention can be
formulated in unit dosage form. The term "unit dosage form" refers
to physically discrete units suitable as unitary dosage for
subjects undergoing treatment, with each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, optionally in association with a
suitable pharmaceutical carrier. The unit dosage form can be for a
single daily dose or one of multiple daily doses (e.g., about 1 to
4 or more times per day). When multiple daily doses are used, the
unit dosage form can be the same or different for each dose.
[0364] For the compounds having both NARI and 5-HT.sub.3 receptor
antagonist activity, each dosage can typically contain from about
0.001 mg to about 1000 mg, such as from about 0.05 mg to about 500
mg, for example, from about 0.03 mg to about 300 mg, such as about
0.02 mg to about 200 mg of the active ingredient.
[0365] When the method of treatment comprises coadministration of a
NARI and a 5-HT.sub.3 receptor antagonist each dose can typically
contain from about 0.001 mg to about 1000 mg, such as from about
0.05 mg to about 500 mg, for example, from about 0.03 mg to about
300 mg, such as about 0.02 mg to about to about 200 mg of the NARI
and typically can contain from about 0.001 mg to about 500 mg, such
as from about 0.01 mg to about 100 mg, for example, from about 0.05
mg to about 50 mg, such as about 0.5 mg to about 25 mg of the
5-HT.sub.3 receptor antagonist.
[0366] The invention further includes a kit for treating at least
one symptom of a lower urinary tract disorder in a subject in need
of treatment, wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urge
incontinence, nocturia and enuresis. The kit comprises a compound
having 5-HT.sub.3 receptor antagonist activity and instructions for
use with a compound having NARI activity, according to the method
of the invention.
[0367] The invention further includes a kit for treating at least
one symptom of a lower urinary tract disorder in a subject in need
of treatment, wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urge
incontinence, nocturia and enuresis. The kit comprises a compound
having NARI activity and instructions for use with a compound
having 5-HT.sub.3 receptor antagonist activity, according to the
method of the invention.
[0368] The invention further includes a kit for treating at least
one symptom of a lower urinary tract disorder in a subject in need
of treatment, wherein the symptom is selected from the group
consisting of urinary frequency, urinary urgency, urge
incontinence, nocturia and enuresis. The kit comprises at least one
compound having both 5-HT.sub.3 receptor antagonist activity and
NARI activity (i.e., a single compound) and an instructional insert
for administering the compound, according to the method of the
invention. In another embodiment, the kit can comprise a first
compound which has 5-HT.sub.3 receptor antagonist activity and a
second compound having NARI activity and an instructional insert
for administering the first and second compounds, according to the
method of the invention.
[0369] Compounds can be in separate dosage forms or combined in a
single dosage form. In other embodiments of the kits, the
instructional insert further includes instructions for
administration with an additional therapeutic agent as described
herein.
[0370] It is understood that in practicing the method or using a
kit of the present invention that administration encompasses
administration by different individuals (e.g., the subject,
physicians or other medical professionals) administering the same
or different compounds.
[0371] As used herein, the term pharmaceutically acceptable salt
refers to a salt of the administered compounds prepared from
pharmaceutically acceptable non-toxic acids including inorganic
acids, organic acids, solvates, hydrates, or clathrates thereof.
Examples of such inorganic acids are hydrochloric, hydrobromic,
hydroiodic, nitric, sulfuric, and phosphoric. Appropriate organic
acids may be selected, for example, from aliphatic, aromatic,
carboxylic and sulfonic classes of organic acids, examples of which
are formic, acetic, propionic, succinic, camphorsulfonic, citric,
fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric,
para-toluenesulfonic, glycolic, glucuronic, maleic, furoic,
glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic,
embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic,
benzenesulfonic (besylate), stearic, sulfanilic, alginic,
galacturonic, and the like.
[0372] It is understood that 5-HT.sub.3 receptor antagonists, NARIs
and single compounds having both NARI and 5-HT.sub.3 antagonist
activities can be identified, for example, by screening libraries
or collections of molecules using suitable methods. Another source
for the compounds of interest are combinatorial libraries which can
comprise many structurally distinct molecular species.
Combinatorial libraries can be used to identify lead compounds or
to optimize a previously identified lead. Such libraries can be
manufactured by well-known methods of combinatorial chemistry and
screened by suitable methods.
[0373] The invention also relates to a method of processing a claim
under a health insurance policy submitted by a claimant seeking
reimbursement for costs associated with the treatment of a
functional bowel disorder as described herein.
[0374] In one embodiment, the method for processing a claim under a
health insurance policy submitted by a claimant seeking
reimbursement for costs associated with treatment of at least one
symptom of a lower urinary tract disorder wherein, said treatment
comprises coadministering to a subject a first amount of a
5-HT.sub.3 receptor antagonist and a second amount of a
noradrenaline reuptake inhibitor, wherein the first and second
amounts together comprise a therapeutically effective amount
comprising: reviewing said claim; determining whether said
treatment is reimbursable under said insurance policy; and
processing said claim to provide partial or complete reimbursement
of said costs.
[0375] In one embodiment, the lower urinary tract disorder being
treated is selected from the group consisting of overactive
bladder, interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0376] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0377] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0378] The invention also relates to a method for processing a
claim under a health insurance policy submitted by a claimant
seeking reimbursement for costs associated with treatment of at
least one symptom of a lower urinary tract disorder wherein, said
treatment comprises coadministering to a subject a therapeutically
effective amount of a 5-HT.sub.3 receptor antagonist and a
therapeutically effective amount of a noradrenaline reuptake
inhibitor comprising: reviewing said claim; determining whether
said treatment is reimbursable under said insurance policy; and
processing said claim to provide partial or complete reimbursement
of said costs.
[0379] In one embodiment, the lower urinary tract disorder being
treated is selected from the group consisting of overactive
bladder, interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0380] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0381] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
[0382] The invention further relates to a method for processing a
claim under a health insurance policy submitted by a claimant
seeking reimbursement for costs associated with treatment of at
least one symptom of a lower urinary tract disorder wherein, said
treatment comprises administering to a subject a therapeutically
effective amount of a compound having 5-HT.sub.3 receptor
antagonist activity and noradrenaline reuptake inhibitor acitivity
comprising: reviewing said claim; determining whether said
treatment is reimbursable under said insurance policy; and
processing said claim to provide partial or complete reimbursement
of said costs.
[0383] In a particular embodiment the compound having 5-HT.sub.3
receptor antagonist activity and noradrenaline reuptake inhibitor
acitivity is MCI-225.
[0384] In one embodiment, the lower urinary tract disorder being
treated is selected from the group consisting of overactive
bladder, interstitial cystitis, prostatitis, prostadynia and benign
prostatic hyperplasia.
[0385] In another embodiment, the lower urinary tract disorder is
overactive bladder.
[0386] In yet another embodiment, the lower urinary tract disorder
is interstitial cystitis.
Pharmacological Methods
[0387] Acute Models: Dilute Acetic Acid Model and Protamine
Sulfate/Physiological Urinary Potassium Model
[0388] The acute models described below provide methods for
evaluating active agents in the treatment of overactive bladder.
Briefly, the models provide a method for reducing the bladder
capacity of test animals by infusing either protamine sulfate and
potassium chloride (See, Chuang, Y. C. et al., Urology 61(3):
664-670 (2003)) or dilute acetic acid (See, Sasaki, K. et al., J.
Urol. 168(3): 1259-1264 (2002)) into the bladder. The infusates
cause irritation of the bladder and a reduction in bladder capacity
by selectively activating bladder afferent fibers, such as C-fiber
afferents. Following irritation of the bladder, an active agent
(drug) can be administered and the ability of the active agent to
reverse (partially or totally) the reduction in bladder capacity
resulting from the irritation, can be determined. Substances which
reverse the reduction in bladder capacity can be used in the
treatment of overactive bladder.
[0389] Animal Preparation for Acute Models
[0390] Female rats (250-275 g BW) are anesthetized with urethane
(1.2 g/kg) and a saline-filled jugular catheter (PE-50) is inserted
for intravenous drug administration and a heparinized (100
units/ml) saline-filled carotid catheter (PE-50) is inserted for
blood pressure monitoring. Via a midline abdominal incision from
xyphoid to navel, a PE-50 catheter is inserted into the bladder
dome for bladder filling and pressure recording. The abdominal
cavity is moistened with saline and closed by covering with a thin
plastic sheet in order to maintain access to the bladder for
filling cystometry emptying purposes. Fine silver or stainless
steel wire electrodes are inserted into the external urethral
sphincter (EUS) percutaneously for electromyography (EMG).
[0391] Dilute Acetic Acid Model
[0392] Saline and all subsequent infusates are continuously infused
at a rate of about 0.055 ml/min via the bladder filling catheter
for 30-60 minutes to obtain a baseline of lower urinary tract
activity (continuous cystometry; CMG). Bladder pressure traces act
as direct measures of bladder and urethral outlet activity, and
EUS-EMG phasic firing and voiding act as indirect measures of lower
urinary tract activity during continuous transvesical cystometry.
Following the control period, a 0.25% acetic acid solution in
saline (AA) is infused into the bladder to induce bladder
irritation. Following 30 minutes of AA infusion, 3 vehicle
injections are made at 20 minute intervals to determine vehicle
effects, if any. Subsequently, increasing doses of a selected
active agent are administered intravenously at 30 minute intervals
in order to construct a cumulative dose-response relationship. At
the end of the control saline cystometry period, the third vehicle
injection, and 20 minutes following each subsequent treatment, the
infusion pump is stopped, the bladder is emptied by fluid
withdrawal via the infusion catheter and a single filling
cystometrogram is performed at the same flow rate in order to
determine changes in bladder capacity caused by the irritation
protocol and subsequent drug administration. In this acute model,
C-fiber afferent pathways within the bladder are selectively
activated.
[0393] Protamine Sulfate/Physiological Urinary Potassium Model
[0394] Saline and all subsequent infusates are continuously infused
at a rate of about 0.055 ml/min via the bladder filling catheter
for about 30-60 minutes to obtain a baseline of lower urinary tract
activity (continuous cystometry; CMG). Bladder pressure traces act
as direct measures of bladder and urethral outlet activity, and
EUS-EMG phasic firing and voiding act as indirect measures of lower
urinary tract activity during continuous transvesical cystometry.
Following the control period, a 10 mg/mL protamine sulfate (PS) in
saline solution is infused for about 30 minutes in order to
permeabilize the urothelial diffusion barrier. After PS treatment,
the infusate is switched to 300 mM KCl in saline to induce bladder
irritation. Once a stable level of lower urinary tract
hyperactivity is established (20-30 minutes), 3 vehicle injections
are made at about 30 minute intervals to assess the effects of the
vehicle. Subsequently, increasing doses of a selected active agent
are administered intravenously at about 30 minute intervals in
order to construct a cumulative dose-response relationship. At the
end of the control saline cystometry period, the third vehicle
injection, and 20 minutes following each subsequent treatment, the
infusion pump is stopped, the bladder is emptied by fluid
withdrawal via the infusion catheter and a single filling
cystometrogram is performed at the same flow rate in order to
determine changes in bladder capacity caused by the irritation
protocol and subsequent drug administration. This model acutely
activates bladder afferent fibers, including, C-fiber
afferents.
[0395] Chronic Model: Chronic Spinal Cord Injury Model
[0396] The following is a model of neurogenic bladder, in which
C-fiber afferents are chronically activated as a result of spinal
cord injury (See, Yoshiyama, M. et al., Urology 54(5): 929-933
(1999)). Following spinal cord injury an active agent (drug) can be
administered and the ability of the active agent to reverse
(partially or totally) the reduction in bladder capacity resulting
from spinal cord injury can be determined. Substances which reverse
the reduction in bladder capacity can be used in the treatment of
overactive bladder, for example, neurogenic bladder.
[0397] Animal Preparation for Chronic Model
[0398] Female Sprague-Dawley rats (Charles River, 250-300 g) are
anesthetized with isofluorane (4%) and a laminectomy is performed
at the T9-10 spinal level. The spinal cord is transected and the
intervening space filled with Gelfoam. The overlying muscle layers
and skin are sequentially closed with suture, and the animals are
treated with antibiotic (100 mg/kg ampicillin s.c.). Residual urine
is expressed prior to returning the animals to their home cages,
and thereafter 3 times daily until terminal experimentation four
weeks later. On the day of the experiment, the animals are
anesthetized with isofluorane (4%) and a jugular catheter (PE10) is
inserted for access to the systemic circulation and tunneled
subcutaneously to exit through the midscapular region. Via a
midline abdominal incision, a PE50 catheter with a fire-flared tip
is inserted into the dome of the bladder through a small cystotomy
and secured by ligation for bladder filling and pressure recording.
Small diameter (75 .mu.m) stainless steel wires are inserted
percutaneously into the external urethral sphincter (EUS) for
electromyography (EMG). The abdominal wall and the overlying skin
of the neck and abdomen are closed with suture and the animal is
mounted in a Ballman-type restraint cage. A water bottle is
positioned within easy reach of the animal's mouth for ad libitum
access to water. The bladder catheter is hooked up to the perfusion
pump and pressure transducer, and the EUS-EMG electrodes to their
amplifier. Following a 30 minute recovery from anesthesia and
acclimatization, normal saline is infused at a constant rate
(0.100-0.150 ml/min) for control cystometric recording.
[0399] Chronic Spinal Cord Injury Model
[0400] Following a 60-90 minute control period of normal saline
infusion (0.100-0.150 m/min) to collect baseline continuous open
cystometric data, the pump is turned off, the bladder is emptied,
the pump turned back on, and bladder capacity is estimated by a
filling cystometrogram. At 3.times.20-30 minute intervals, vehicle
is administered intravenously in order to ascertain vehicle effects
on bladder activity. Following the third vehicle control, bladder
capacity is again estimated as described above. Subsequently, a
cumulative dose-response is performed with the agent of choice.
Bladder capacity is measured 20 minutes following each dose. This
is a model of neurogenic bladder, in which C-fiber afferents are
chronically activated.
Exemplification
[0401] The present invention will now be illustrated by the
following Example, which is not intended to be limiting in any
way.
Treatment of Overactive Bladder Using MCI-225
[0402]
[0403] The effect of the administration of MCI-225 was assessed
using the Dilute Acetic Acid Model. Specifically, the ability of
MCI-225 to reverse the irritation-induced reduction in bladder
capacity caused by continuous intravesical infusion of dilute
acetic acid was assessed.
[0404] Dilute Acetic Acid Model--Rats
[0405] Female rats (250-275 g BW, n=8) were anesthetized with
urethane (1.2 g/kg) and a saline-filled catheter (PE-50) was
inserted into the proximal duodenum for intraduodenal drug
administration. A flared-tipped PE-50 catheter was inserted into
the bladder dome, via a midline lower abdominal incision, for
bladder filling and pressure recording and secured by ligation. The
abdominal cavity was moistened with saline and closed by covering
with a thin plastic sheet in order to maintain access to the
bladder for emptying purposes. Fine silver or stainless steel wire
electrodes were inserted into the external urethral sphincter (EUS)
percutaneously for electromyography (EMG). Animals were positioned
on a heating pad which maintained body temperature at 37.degree.
C.
[0406] Saline and all subsequent infusates were continuously
infused at a rate of about 0.055 ml/min via the bladder filling
catheter for about 60 minutes to obtain a baseline of lower urinary
tract activity (continuous cystometry; CMG). At the end of the
control saline cystometry period, the infusion pump was stopped,
the bladder was emptied by fluid withdrawal via the infusion
catheter and a single filling cystometrogram was performed using
saline at the same flow rate as the continuous infusion, in order
to measure bladder capacity. Bladder capacity (ml) was calculated
as the flow rate of the bladder filling solution (ml/min)
multiplied by the elapsed time between commencement of bladder
filling and occurrence of bladder contraction (min).
[0407] Following the control period, a 0.25% acetic acid solution
in saline (AA) was infused into the bladder to induce bladder
irritation. Following 30 minutes of AA infusion, 3 vehicle
injections (10% TWEEN.RTM. 80 in saline, 1 ml/kg dose) were
administered intraduodenally at 20 minute intervals to determine
vehicle effects on the intercontraction interval and to achieve a
stable level of irritation with the dilute acetic acid solution.
Following injection of the third vehicle control, bladder capacity
was again measured, as described above but using AA to fill the
bladder. Increasing doses of MCI-225 (3, 10 or 30 mg/kg, as a 1
ml/kg dose) were then administered intraduodenally at 60 minute
intervals in order to construct a cumulative dose-response
relationship. Bladder capacity was measured as described above
using AA to fill the bladder, at 20 and 50 minutes following each
subsequent drug treatment.
[0408] Data Analysis
[0409] Bladder capacity was determined for each treatment regimen
as described above (flow rate of the bladder filling solution
(ml/min) multiplied by the elapsed time between commencement of
bladder filling and occurrence of bladder contraction (min)) and
converted to % Bladder Capacity normalized to the last vehicle
measurement of the AA/Veh 3 treatment group. Data were then
analyzed by non-parametric ANOVA for repeated measures (Friedman
Test) with Dunn's Multiple Comparison test. All comparisons were
made from the last vehicle measurement (AA/Veh 3). The 30 and 60
minute post-drug measures were very similar, so the average of
these two measures was used as the effect for each dose. P<0.050
was considered significant.
[0410] Results
[0411] Intraduodenal MCI-225 resulted in a dose-dependent increase
in bladder capacity in the dilute acetic acid model, as measured by
filling cystometry in rats (n=8) during continuous irritation. This
effect was statistically significant at the dose range of 3-30
mg/kg (p=0.0005 by Friedman test), the 10 mg/kg and 30 mg/kg
responses were significantly higher than AA/Veh 3 (p<0.05 and
p<0.001 by Dunn's multiple comparison test, respectively). The
results are set forth graphically in the FIG. 1 (Sal=saline).
[0412] Conclusion
[0413] The ability of MCI-225 to reverse the irritation-induced
reduction in bladder capacity suggests both a direct effect of this
compound on bladder C-fiber activity via 5-HT.sub.3 receptor
antagonism and an enhancement of sympathetic inhibition of bladder
activity via noradrenaline reuptake inhibition. The effectiveness
of MCI-225 in this model is predictive of efficacy in the treatment
of lower urinary tract disorders in humans.
[0414] Dilute Acetic Acid Model--Cats
[0415] The ability of MCI-225 to reverse the reduction in bladder
capacity seen following continuous infusion of dilute acetic acid
in a cat model, a commonly used model of overactive bladder (Thor
and Katofiasc, 1995, J. Pharmacol. Exptl. Ther. 274: 1014-24).
[0416] Materials and Methods
[0417] Six alpha-chloralose anesthetized (50-100 mg/kg) normal
female cats (2.5-3.5 kg; Harlan) were utilized in this study.
[0418] Drugs and Preparation
[0419] MCI-225 was dissolved in 5% methylcellulose in water at 3.0,
10.0 or 30 mg/ml Animals were dosed by volume of injection=body
weight in kg.
[0420] Acute Anesthetized In Vivo Model
[0421] Female cats (2.5-3.5 kg; Harlan) had their food removed the
night before the study. The following morning, the cats were
anesthetized with isoflurane and prepped for surgery using aseptic
technique. Polyethylene catheters were surgically placed to permit
the measurement of bladder pressure, urethral pressure, arterial
pressure, respiratory rate as well as for the delivery of drugs.
Fine wire electrodes were implanted alongside the external urethral
anal sphincter. Following surgery, the cats were slowly switched
from the gas anesthetic isoflurane (2-3.5%) to alpha-chloralose
(50-100 mg/kg). During control cystometry, saline was slowly
infused into the bladder (0.5-1.0 ml/min) for 1 hour. The control
cystometry was followed by 0.5% acetic acid in saline for the
duration of the experiment. After assessing the cystometric
variables under these baseline conditions, the effects of MCI-225
on bladder capacity were determined via a 3 point dose response
protocol.
[0422] Data Analysis
[0423] Data was analyzed using a non-parametric One-Way ANOVA
(Friedman Test) with the post-hoc Dunn's multiple comparison t
test. P<0.05 was considered significant.
[0424] Results and Conclusions
[0425] MCI-225 caused a significant dose-dependent increase in
bladder capacity following acetic acid irritation (P<0.0103),
with individual dose significance attained at the 30 mg/kg dose
(P<0.05) (FIG. 2). These data support the initial positive
findings in the rat, demonstrating that MCI-225 is effective in
increasing bladder capacity in commonly utilized models of OAB in
two species. These results are also predictive of the efficacy of
MCI-225 in the treatment of BPH, for example, the irritative
symptoms of BPH.
[0426] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *