Note: Descriptions are shown in the official language in which they were submitted.
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USE OF OEXTROMETHORPHAN OR DEXTRORPHAN FOR THE TREATMENT OF URINARY
INCONTINENCE
v
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for
treating urinary incontinence.
2. Description of Related Art
Urinary incontinence is a fairly common medical
problem in which urine is involuntarily lost. Urinary
incontinence may be transient or persistent. Common causes
of transient urinary incontinence include infection,
atrophic urethritis, administration of diuretics and
delirium. Persistent urinary incontinence is classified
into four types: (1) stress incontinence which involves
involuntary loss of urine during coughing, sneezing,
laughing, or other physical activity; (2) urge incontinence
which involves involuntary loss of urine associated with an
abrupt or strong desire to void; (3) overflow incontinence
which involves involuntary loss of urine associated with
over-distension of the bladder; and (4) mixed incontinence
which involves a combination of at least two of the above
types.
Persistent urinary incontinence can result from
spastic or hyperactive bladder smooth muscle such as
detrusor originating incontinence. In certain instances
such incontinence is caused by loss of control resulting
from spinal injury, parkinsonism, multiple sclerosis or
recurrent bladder infection to name a few. Treatment of
incontinence may involve surgery or administration of any
of various pharmacological agents, e.g., a anticholinergic
such as oxybutynin, atropine, propantheline, terodiline,
dicyclomine and others, a sympathomimetic such as
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ephedrine, pseudoephedrine, phenylpropanolamine and others,
a tricyclic antidepressant such as amitriptyline,
imipramine, doxepin and others, an estrogen or a direct
acting antispasmodic such as flavoxate. In addition to '
treating incontinence, such pharmacological agents may
cause other powerful physiologic responses such as
excitability (sympathomimetics), and dry mouth, drowsiness,
dizziness or hallucinations (anticholinergics or tricyclic
antidepressants).
Other compounds described as useful for treating
urinary incontinence are described, e.g., in U.S. Patent
Nos. 4,645,758, 4,865,843, 5,080,905, 5,236,956, 5,233,053,
5,252,589, 5,258,390, 5,272,163, 5,340,805, 5,340,819,
5,340,826, and 5,266,596. U.S. Patent No. 5,192,751
describes the use of certain competitive N-methyl-D-
aspartate (NMDA) receptor antagonists in the treatment of
urinary incontinence. It is noted therein that a non-
competitive NMDA receptor antagonist, MK-801, has been
reported to produce an increase in frequency in micturition
(Vera et al., Neurosci. Lett., 134, 135-138 (1991)).
Dextromethorphan and its main metabolite,
dextrorphan, are non-competitive NMDA receptor antagonists
having few, if any, side effects at indicated dosage
levels. Dextromethorphan and dextrorphan have been used as
antitussives, for treatment of chronic pain (U. S. Patent
No. 5,352,683) and for inhibiting the development of
tolerance to and/or dependence on a narcotic analgesic
(U. S. Patent No. 5,321,012). Surprisingly, it has now been
found that the non-competitive NMDA receptor antagonists
dextromethorphan and dextrorphan are useful in the
treatment of urinary incontinence.
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SUN~IARY OF THE INVENTION
In accordance with the present invention, there
is provided a method for the treatment of urinary
incontinence which comprises administering to a mammal
exhibiting urinary incontinence a urinary incontinence
alleviating amount of at least one morphinan selected from
the group consisting of dextromethorphan, dextrorphan and
pharmaceutically acceptable salts thereof. The method can
optionally include administration of one or more
pharmacologically active agents selected from the group
consisting of anticholinergics, sympathomimetics, tricyclic
antidepressants, antispasmodics, direct acting bladder
smooth muscle relaxants, estrogens, compounds having
estrogen-like activity, and any combination of the
foregoing. -
In another embodiment of the present invention,
there is provided a method of decreasing micturition
frequency in a mammal which comprises administering to a
mammal a micturition decreasing amount of at least one
morphinan selected from the group consisting of
dextromethorphan, dextrorphan and pharmaceutically
acceptable salts thereof. The method can optionally
include administration of any of the pharmacologically
active agents mentioned above.
BRIEF DESCRIPTION OF THE DRAWINGS
In the accompanying drawings:
Fig. 1 is a graphical representation of test
results showing therapeutic effects of intravenous
administration of dextromethorphan on absolute micturition
pressures in rats; and,
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Fig. 2 is a graphical representation of test
results showing therapeutic effects of intravenous
administration of dextromethorphan on micturition frequency
in rats. '
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Dextromethorphan ((+)-3-methoxy-N-
methylmorphinan) and dextrorphan ((+)-3-hydroxy-N-
methylmorphinan), their mixtures and pharmaceutically
acceptable salts are utilized in accordance with the method
of the present invention. Accordingly, dextromethorphan,
dextrorphan, their mixtures and/or pharmaceutically
acceptable salts are administered by any known route of
administration for the relief of symptoms of bladder
instability associated with voiding in patients with
uninhibited neurogenic or reflex neurogenic bladder such as
urgency, frequency, urine leakage, urge incontinence,
stress incontinence, overflow incontinence, mixed
incontinence or dysuria. Dextromethorphan, dextrorphan,
their mixtures and/or pharmaceutically acceptable salts are
also useful in the treatment-of interstitial cystitis, a
chronic inflammatory condition of unknown etiology
resulting in reduced bladder capacity and severe bladder
imitative symptoms. Administration of dextromethorphan,
dextrorphan, their mixtures and/or pharmaceutically
acceptable salts acts to quiet the bladder and reduce the
frequency of micturition.
Administration of dextromethorphan, dextrorphan
their mixtures and/or pharmaceutically acceptable salts can
be orally or transdermally or by intravenous,
intramuscular, subcutaneous, intrathecal, epidural or
intracerebro-ventricular injection. Effective dosage
levels can vary widely, e.g., from about 0.25 to about 250
mg/day, but actual amounts will, of course, depend on the
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state and circumstances of the patient being treated. As
those skilled in the art recognize, many factors that -
modify the action of the active substance herein will be
' taken into account by the treating physician such as the
age, body weight, sex, diet and condition of the patient,
the time of administration, the rate and route of
administration, and so forth. Optimal dosages for a given
set of conditions can be ascertained by those skilled in '
the art using conventional dosage determination tests in
view of the experimental data provided herein.
Therapeutic compositions containing
dextromethorphan, dextrorphan, their mixtures and/or
pharmaceutically acceptable salts will ordinarily be
formulated with one or more pharmaceutically acceptable
ingredients in accordance with known and established
practice. Thus, dextromethorphan, dextrorphan, their
mixtures and/or pharmaceutically acceptable salts can be
formulated as a liquid, powder, elixir, injectable
solution, etc. Formulations for oral use can be provided
as hard gelatin capsules wherein dextromethorphan,
dextrorphan, their mixtures and/or pharmaceutically
acceptable salts are mixed with an inert solid diluent such
as calcium carbonate, calcium phosphate or kaolin, or as
soft gelatin capsules wherein dextromethorphan,
dextrorphan, their mixtures and/or pharmaceutically
acceptable salts are mixed with an oleaginous medium, e.g.,
liquid paraffin or olive oil.
Aqueous suspensions can contain the
dextromethorphan, dextrorphan, their mixtures and/or
pharmaceutically acceptable salts in admixture with
pharmaceutically acceptable excipients such as suspending
agents, e.g., sodium carboxymethyl cellulose,
methylcellulose, hydroxypropylmethylcellulose, sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum
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acacia; dispersing or wetting agents such as naturally
occurring phosphatide, e.g., lecithin, or condensation
products of an alkaline oxide with fatty acids, e.g.,
polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, e.g,
heptadecaethylene-oxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids
and a hexitol, e.g., polyoxyethylene sorbitol monoleate or
condensation products of ethylene oxide with partial esters
derived from fatty acids and hexitol anhydrides, e.g.,
polyoxyethylene sorbitan monoleate. Such aqueous
suspensions can also contain one or more preservatives,
e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more
coloring agents, one or more flavoring agents and one or
more sweetening agents, such as sucrose, saccharin or
sodium or calcium cyclamate.
Dispersible powders and granules suitable for
preparation of an aqueous suspension by the addition of
water provide dextromethorphan, dextrorphan, their mixtures
and/or pharmaceutically acceptable salts in admixture with
a dispersing or wetting agent, suspending agent and one or
more preservatives. Suitable dispersing or wetting agents
and suspending agents are exemplified by those already
mentioned above. Additional excipients, e.g., sweetening,
flavoring and coloring agents, can also be present. Syrups
and elixirs can be formulated with sweetening agents, for
example glycerol, sorbitol or sucrose. Such formulations
can also contain a demulcent, a preservative and flavoring
and coloring agents.
Dextromethorphan, dextrorphan, their mixtures
and/or pharmaceutically acceptable salts are advantageously
provided in sustained release dosage form of which many
kinds are known, e.g., as described in U.S. Patent Nos.
4,788,055; 4,816,264; 4,828,836; 4,834,965; 4,834,985;
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4,996,047; 5,0?1,646; and, 5,133,974.
Tt is also within the scope of this invention to
administer dextromethnrphan, dextrorphan, their mixtures
and/or pharmaceutically acceptable salts prior to,
concurrently with, or after administration of any other
known pharmacologically active agent useful for treating
urinary incontinence. Such agents include, but are not
limited to, anticholinergics such as oxybutynin, atropine,
propantheline, terodiline, dicyclornine, etc.,
sympathomimetics such as ephedrine, pseudoephedrine,
epinephrine, phenylpropanolamine, etc., tricyclic
antinepressants such as imipramine, doxepin, amitriptylins,
etc., estrogens or estrogen-related compounds having
estrogen-like activity such as estradiol, estrone, etc.,
. and antispasmodics or direct acting bladder smooth muscle
relaxants such as flavoxate. For a detailed discussion of
these pharmacologically active agents, reference may be
made to "Goodman and Gillman's Pharmacological Basis of
Therapeutics", Goodman et al., eds. 7th ed., 1985,
Macmillan and Company, New York.
The examples that follow are illustrative of the
present invention and should not be construed as lim_ting.
FXA~PLE 1
Ten female Sprague-Dawley rats having a mean
weight of 263 ~ 29 g wexe anesthetized with urethane (1.2
g/k, sc.). A midline incision was performed to expase the
bladder and a 23G~catheter was inserted into the bladder
dome for the measurement of intravesical pressure. A non-
stop transvesical cystometrogram, as described in J.
Pharnacological. Methods, 15, pp. 157-167 (1986), was
used, at a filling rate of 0.216 ml/min. of saline, to
access the filling and voiding characteristics of the
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bladder. Through the continuous cystometry method thus
afforded, consecutive micturition could be recorded.
Dextromethorphan was given at intravenous does of: 1.0,
3.0, 10,'30, 50 mg/kg after the initial baseline '
micturition sequence was reliably measured for
approximately 12 min. From these recordings the absolute '
values in maximum pressure obtained and the frequency of
micturition was measured. A dose response curve
illustrating the effect of dextromethorphan on the absolute
micturition pressures in the range of 1-50 mg/kg is given
in Fig. 1. Data given are mean and SE.
The volume evoked micturition reflex was
suppressed in a dose sensitive manner as seen from the
effect of increasing doses of dextromethorphan on the
cystometrogram. In particular it was found that at doses
in the range of 10-30 mg/kg, the volume evoked micturition
contractions are almost totally suppressed. A significant
sustained reduction in detrusor pressure is produced at a
dose level of 3 mg/kg and a 50% reduction is evident at 10
mg/kg. As shown in Fig. 1, at higher doses of
dextromethorphan, the rate of decrease in detrusor pressure
is diminished. Furthermore at does higher than 10 mg/kg
the effect of the drug appears to be bimodal, producing an
initial increase in detrusor pressure before suppression.
The corresponding dose response effect of
dextromethorphan on the frequency of micturition is given
in Fig. 2. As shown, the frequency of micturition
decrements gradually with respect to dose when compared to
the pressure.
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EXAMPLE 2
A capsule containing dextromethorphan
hydrobromide contains the following ingredients:
Ingredient ma/Capsule
Dextromethorphan Hydrobromide USP 20
Pregelatinized Starch NF 50
Colloidal Silicon Dioxide i_5
EXAMPLE 3
A tablet containing dextromethorphan hydrobromide
contains the following ingredients:
Ingredient ma/Tablet
Dextromethorphan Hydrobromide USP 20
Microcrystalline Cellulose NF 1~
Lactose NF anhydrous 6g
Croscarmellose NF 1
Colloidal Silicon Dioxide 1.5
Magnesium Stearate NF 1.5
EXAMPLE 4
A controlled release tablet containing
dextromethorphan hydrobromide contains the following
ingredients:
Ingredient ma/Tablet
Dextromethorphan Hydrobromide USP 40
Lactose NF ~0
Methocel E 15LV 100
Ethylcellulose NF 35
Magnesium Stearate NF 15
Colloidal Silicon Dioxide NF 2
The embodiments and examples given above are
illustrative of the present invention. Consequently it
should be understood that modifications can be made by
those with ordinary skill in the art that are intended to
be covered by the following claims.
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