U.S. patent application number 12/356406 was filed with the patent office on 2009-10-01 for gnrh analogues for treatment of urinary incontinence.
This patent application is currently assigned to University of Zuerich. Invention is credited to Susi ARNOLD, Madeleine HUBLER, Iris REICHLER.
Application Number | 20090246209 12/356406 |
Document ID | / |
Family ID | 8174999 |
Filed Date | 2009-10-01 |
United States Patent
Application |
20090246209 |
Kind Code |
A1 |
ARNOLD; Susi ; et
al. |
October 1, 2009 |
GNRH ANALOGUES FOR TREATMENT OF URINARY INCONTINENCE
Abstract
The use of at least one GnRH analogue for the preparation of a
medicament for the prevention and/or treatment of side effects of
ovarectomy or symptoms associated with reproductive senescence in
female mammals, in particular urinary incontinence, hot flushes,
and skin/hair changes are disclosed.
Inventors: |
ARNOLD; Susi; (Moeriken,
CH) ; REICHLER; Iris; (Zurich, CH) ; HUBLER;
Madeleine; (Wernetshausen, CH) |
Correspondence
Address: |
JOYCE VON NATZMER;PEQUIGNOT + MYERS LLC
200 Madison Avenue, Suite 1901
New York
NY
10016
US
|
Assignee: |
University of Zuerich
Zuerich
CH
|
Family ID: |
8174999 |
Appl. No.: |
12/356406 |
Filed: |
January 20, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10415519 |
Apr 30, 2003 |
7498303 |
|
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PCT/CH01/00636 |
Oct 26, 2001 |
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12356406 |
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Current U.S.
Class: |
424/158.1 ;
514/44A |
Current CPC
Class: |
A61P 13/00 20180101;
A61P 13/02 20180101; A61K 45/06 20130101; A61K 38/09 20130101; A61P
15/00 20180101; A61P 15/12 20180101 |
Class at
Publication: |
424/158.1 ;
514/44.A |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 31/7052 20060101 A61K031/7052; A61P 13/02
20060101 A61P013/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 30, 2000 |
EP |
EP 00811011.6 |
Claims
1.-20. (canceled)
21. A method for the treatment of urinary incontinence in a female
mammal in need of such treatment comprising administering at least
one GnRH analogue to said female mammal in an urinary incontinence
in female mammals treating effective amount.
22. A method of claim 21, wherein the GnRH analogue is at least one
GnRH agonist or a GnRH antagonist.
23. A method according to claim 22 wherein said GnRH agonist
results in a temporary overproduction of gonadotropins leading to a
downregulation of follicle stimulating hormone (FSH) and/or
luteinizing hormone (LH).
24. A method according to claim 22, wherein said GnRH antagonist
suppresses the activity of GnRH by binding GnRH receptors on target
cells and thereby blocks its biological activity or decreases
production/release of endogenous GnRH.
25. The method of claim 24, wherein said GnRH antagonist is an
antibody.
26. The method of claim 24, wherein said GnRH antagonist is an
antisense gene construct.
27. A method according to claim 21 or 22, wherein a further active
substance is administered to said individual, and wherein said
substance is selected from the group consisting of an estrogenic
agent, a partial estrogenic agent, a progestational agent and
mixtures thereof.
28. A method according to claim 27, wherein said estrogenic agent
is estradiol valerate, a conjugated equine estrogen,
17.beta.-estradiol, estrone or estriol; the partial estrogenic
agent is raloxifene, centchroman, toremifen or tamoxifen; and the
progestational agent is progesterone, hydroxygesterone,
medroxyprogesterone, norethisterone, levonogestrel, norgestrel,
gestodene or drospirenone.
29. A method according to claim 21 or 22, wherein a further active
substance is administered to said individual, and wherein said
active substance is alpha-adrenergic agonist, beta adrenergic
receptor blocking agent, cholinergic receptor blocking compound,
cholinergic receptor stimulating drug, smooth muscle relaxant,
nitric oxide synthase substrate, a nitric oxide donor, or a mixture
thereof.
30. A method according to claim 21, wherein at least said GnRH
analogue is administered in a slow release formulation.
31. A method according to claim 21, wherein said treatment consists
essentially of administering at least one said GnRH analogue.
32. A method according to claim 22, wherein at least said GnRH
agonist or antagonist is administered in a slow release
formulation.
33. A method according to claim 22, wherein said treatment consists
essentially of administering at least one GnRH agonist or
antagonist.
34. A method according to claim 21 or 22, wherein said female
mammal is a human female pre-or postmenopausal, or a female
dog.
35. A method according to claim 21, wherein said at least one GnRH
analogue is administered as part of a formulation for subcutaneous
administration.
36. A method according to claim 21, wherein said at least one GnRH
analogue is administered as part of a formulation for parenteral,
oral or rectal administration.
37. A method according to claim 21, wherein said at least one GnRH
analogue is administered as part of a formulation for intranasal,
transdermal or intravaginal administration.
38. A method according to claim 22, wherein said at least one GnRH
agonist or antagonist is administered as part of a formulation for
subcutaneous administration.
39. A method according to claim 22, wherein said at least one GnRH
agonist or antagonist is administered as part of a formulation for
parenteral, oral or rectal administration.
40. A method according to claim 22, wherein said at least one GnRH
agonist or antagonist is administered as part of a formulation for
intranasal, transdermal or intravaginal administration.
Description
TECHNICAL FIELD
[0001] The present invention provides pharmaceutical compositions
for the prevention and treatment of side effects of ovarectomy or
symptoms associated with reproductive senescence, especially
urinary incontinence, as well as mood changes, skin changes, hair
changes, vasomotor symptoms, especially hot flushes, in mammalian
females, particularly in post menopausal women and in spayed
bitches. Connected with such treatments is the prevention of
urinary tract infections.
BACKGROUND OF THE INVENTION
[0002] If the endocrine activity of the gonads decreases or if the
gonads are removed, women and dogs show similar changes. With the
reproductive senescence in women, as well as after ovarectomy in
the bitch, symptoms such as urinary incontinence,vasomotor
symptoms, in particular hot flushes, changes of the mood, skin and
hair increasingly occur. After ovarectomy, as well as at the
beginning of the reproductive senescence, corresponding hormonal
changes occur with a great increase in serum concentrations of FSH
(Follicle stimulating hormone) and LH (Luteinising hormone).
[0003] 1. Urinary Incontinence in General
[0004] Urinary incontinence is defined by the International
Continence Society [1] as the objective demonstration of
involuntary loss of urine consequent to bladder and/or urethral
sphincter dysfunction.
[0005] If the anatomical conditions are normal, two different
pathophysiological mechanisms can lead to urinary incontinence: an
increased tone of the bladder with a normal closure function of the
urethra, or an insufficient closure function of the urethra with a
normal bladder pressure during the filling phase.
[0006] An insufficient closure function of the urethra plays a
crucial role in both the urinary incontinence in bitches due to
spaying and the stress incontinence in women [2] [3] [4].
[0007] 2. Removal of the Ovaries (Spaying) in the Bitch
[0008] Side Effects
[0009] Gonadectomy can lead to side effects. The most common is
urinary incontinence, which occurs in one in five spayed bitches.
The continuous hair loss, which is due to the shortened life span
of the hairs after spaying, can be disturbing to the owner. Less
common, and mainly in particular breeds, is the excessive growth of
the undercoat which leads to a "baby-coat". If food is offered ad
libitum the increased appetite can lead to adipositas and
vulvapyodermia. In case of dominant bitches gonadectomy may
increase aggressivity.
[0010] Endocrine Principles
[0011] Twice per year the bitch is on heat for about 3 weeks. Her
seasonal mono-oestrous cycle is divided into 4 periods, anestrus,
pro-oestrus, oestrus and metoestrus. During anoestrus the plasma
concentrations of sexual steroids are very low. The level of
progesterone is below 1 ng/ml, and that of estrogen is below 10
pg/ml. Towards the end of anoestrus, about four weeks before the
onset of the next heat, slight increases in estradiol
concentrations can be measured. At the onset of the heat, starting
with pro-oestrus, the internal secretion of estradiol is slightly
increased by the growing follicles. At the end of pro-oestrus a
sudden increase of the internal estradiol secretion occurs over two
to three days, resulting in a peak serum estradiol of 40 to 90
pg/ml. During the pro-oestrous period the follicular growth is
stimulated by pulsatile FSH and LH release and 24 to 72 hours after
the last LH-peak ovulation is triggered. The actual oestrus, which
is characterized by the bitch's acceptance of the male dog, is
dominated by an increasing serum progesterone concentration,
whereas the estrogen level returns to basal concentrations of less
than 10 pg/ml. The corpora lutea produce progesterone for about
three months. The progesterone production is independent of whether
the bitch is pregnant or not pregnant. The luteal phase is called
metoestrus. After the luteolysis, serum progesterone levels are
below 1 ng/ml, the bitch is in the period of ovarian quiescence,
the anoestrus. During this period the average concentrations of the
gonadotropins FSH and LH are about 114 ng/ml and 1.1 ng/ml
respectively [5].
[0012] With gonadectomy the source of the sexual steroids estrogen
and progesterone is removed and afterwards, they are only
measurable in very low serum concentrations that are not different
from those measured during anoestrus. As there is no longer a feed
back mechanism, FSH and LH are secreted unhindered, resulting in
average concentrations of 1086 ng/ml and 7.4 ng/ml respectively
[5]
[0013] Relationship Between Endocrine Changes and Side Effects of
Gonadectomy
[0014] Until now, the side effects of spaying have been explained
as resulting from the missing estrogen secretion. But various
observations do not agree with this hypothesis. In sexual intact
bitches the endogenous estrogen concentration is elevated only for
a short period only once or twice per year. In many bitches which
are treated with depot gestagens for suppressing of the estrous
cycle for years, the endogenous estrogen concentration is
permanently reduced to basal levels. In these bitches with a
permanently suppressed ovarian activity most of the side effects
seen after spaying, in particular urinary incontinence, do not
occur. If low estrogen concentrations would be responsible for the
occurrence of urinary incontinence, it could be assumed that the
replacement therapy with estrogens would be successful, but in
fact, it is effective only in 65% of the cases [6]. Conversely, it
would be expected that in sexually intact bitches urinary
incontinence does not occur, especially not during the heat. Apart
from the many incontinent bitches, due to spaying, seen as patients
at the Department of Reproduction, University of Zurich, there are
several intact bitches which are incontinent exclusively during
estrus. Urodynamic data supports these observations, showing a
significantly reduced urethral closure pressure under the influence
of estrogens, during the estrus.
[0015] Urinary Incontinence of the Bitch
[0016] Urinary incontinence is the most common and embarrassing
side effect of spaying for both the owner and the dog [3]. In all
bitches gonadectomy leads to a significant reduction in the
urethral closure pressure within one year. In 20% of the bitches
the urethral closure pressure drops below the critical threshold
value of 7.5 cm H.sub.2O, leading to urinary incontinence [3].
Urinary incontinence also has medical consequences: Due to the
lowered urethral closure function the ascension of bacteria,
leading to an urinary tract infection, is enhanced. Additionally,
the continuous contamination of the perineal region with urine can
result in skin ulceration.
[0017] Therapy is aimed at improving the urethral closure pressure
which can be achieved by conservative or surgical methods. First
choice are alpha-adrenergic substances such as
ephedrinhydrochloride or phenylpropanolamine, at 1.5 mg/kg BW p.o.
two to three times per day. If these medications are given every 8
hours, continence was achieved in 74%, and at least 24% showed some
improvement. But, for the owner it is not always possible to
administer tablets this frequently. Side effects such as diarrhea,
vomiting, anxiety and nervousness are observed only infrequently.
Alpha-adrenergic substances are contraindicated in case of
glaucoma, cardiac arrhythmia and progressive nephropathy. As an
alternative therapy estrogens can be used, which improve the
responsiveness of catecholamine receptors of the urethra. But given
alone, their effectiveness is inferior to that of the
alpha-adrenergic substances, for they were found ineffective in 24%
of the cases [3]. The substitution with estrogens in dogs can lead
to a bone marrow depression, which can be fatal. Quite a common
side effect of the estrogen therapy is recurrence of heat-like
symptoms and with it sexual attractiveness to male dogs. These side
effects can even be observed after therapy with phytoestrogens.
[0018] If therapy with medication is unsuccessful, too much trouble
to the owner, accompanied with side effects, or even
contraindicated, a surgical or endoscopic procedure can be
considered. The injection of collagen into the submucosa of the
proximal urethra, under endoscopic control, is successful in 75% of
the cases and can be repeated if necessary. But this therapy
requires a full anesthesia, it is expensive and its success is
dependent on the experience of the surgeon. Even more invasive, and
therefore expensive, is a surgical method, the classical retropubic
urethropexy for incontinent women [7] which has been adapted for
dogs [8]. This colposuspension, which is performed in full
anesthesia after laparotomy, is only effective in 53% of the dogs
with continence [9].
[0019] 3. Reproductive Senescence in Women
[0020] Occurrence
[0021] Declining reproductive function is an inevitable part of the
aging process [10]. The dramatic endocrine changes brought about by
reproductive senescence have biological, social and cultural
implications that profoundly influence the latter half of a woman's
life.
[0022] Symptoms
[0023] Women may experience a number of symptoms such as hot
flushes, mood changes and altered sleep pattern during the
transition from the reproductive to the non-reproductive stage of
life. Menopause is associated with an accelerated bone loss which
may lead to the development of osteoporosis in women. Vaginal
dryness with its sequelae, such as urogenital infections and
impaired sex life, are well known problems of menopause. The
incidence of urinary tract infections increases in women with
increasing age.
[0024] Correlation Between Endocrine Changes and Symptoms of the
Reproductive Senescence
[0025] As one of the first signs of the impending transition to
menopause, in middle aged regularly menstruating women, the
frequency of LH pulses decreases and the width of the peak
increases before any change in the amount of plasma estradiol [11].
These changes are accompanied by elevated FSH concentrations during
the early follicular phase [12] [13] [14].
[0026] Following, on the one hand there is a continuous increase of
serum FSH and LH, while on the other hand a concomitant decrease in
estradiol and estrone can be observed, as yearly examinations of
women have shown during the transition from the reproductive to the
non-reproductive stage of life [15]. Initial symptoms of the
reproductive senescence, such as hot flushes and sweating, already
occur in normocycling women and were significantly associated with
high levels of FSH and LH and with low levels of estradiol [16 ].
Exacerbation of the symptoms was consistent with changes in
gonadotropin levels [17] [18].
[0027] Urinary Incontinence in Women
[0028] Urinary incontinence also affects many women of all age
groups. The prevalence of incontinence has been estimated to be
between 9 and 74% [19] [20] [21] [22] [23] [24][25].
[0029] Until now, the etiology of urinary incontinence is not
elucidated, but most likely is caused by several factors. Different
studies have shown a correlation between the risk of urinary
incontinence and age [26], number of births [20], age of giving
birth [25], body mass index [23] [25], race [23] level of education
[25], frequency of bed-wetting during childhood[25], physical
exercise or menopausal estrogen deficiency [12]. With the
development of menopause the frequency of lower urinary tract
symptoms, such as urgency, hesitancy and frequency, seem to
increase. [27]
[0030] The difference of the mean maximum urethral closure pressure
is 20 cm H.sub.2O between continent and incontinent women of
corresponding age. The closure function of the urethra deteriorates
in an age dependent relationship in a similar way in continent as
well as incontinent women, but is based on different initial values
[28] [29] [2] [30].
[0031] Urinary incontinence predisposes to urinary tract
infections, pressure ulcers, perineal rashes, and urosepsis.
[0032] 4. Comparison of the Reproductive Senescence in Women and
the Side Effects of Spaying in the Bitch
[0033] The symptoms associated with reproductive senescence in
women have amazing similarities with the side effects of spaying in
the bitch. In both species there is an increased incidence of
vaginal dryness, mood and behavioral changes, and urinary
incontinence. A characteristic feature of urinary incontinence in
women, as well as in dogs, is a reduced urethral closure function.
In the bitch, spaying is proven to be the trigger for urinary
incontinence.
[0034] Until now, neither the pathophysiological correlation
between spaying and urinary incontinence in the bitch nor the cause
of urinary incontinence in women is elucidated. But it can be
assumed that similar mechanisms are involved, because for
conservative treatment the same substances are recommended in both
species.
[0035] In reproductive senescence in women as well as after spaying
of bitches the levels of FSH and LH increase many times. Because LH
receptors are not limited to the genital tract [31] [32] but are
also found, among others, in the urinary bladder [33] and the skin
[34], a correlation between the increased FSH- and LH levels and
the clinical changes after menopause or spaying is most likely. In
post menopausal women the number of LH receptors in the bladder
decreases, most likely because of a down-regulation of the LH
receptors by increased gonadotropin levels [33]. A down-regulation
of receptors is also known to occur on a higher level, for example
the pituitary gland. Prolonged exposure of GnRH receptors to GnRH
results in loss of responsiveness to the hormone, through receptor
alteration [35]. The outcome of such a down-regulation of
sensitivity to GnRH results in a suppression of circulating levels
of gonadotropins [36] [37] [38] [39] [40] [41].
[0036] Despite recent progress in understanding the pathophysiology
of urinary incontinence, successful management continues to be a
challenge. Medical treatment for urinary incontinence in women, or
urinary incontinence in the bitch, include estrogen and/or
progesterone replacement, supplementation with alpha-adrenergic
agonists, beta-adrenergic receptor blocking agents, cholinergic
receptor blocking compounds, cholinergic receptor stimulating
drugs, nitric oxide synthase substrates, nitric oxide donors or
both. Other treatment procedures include behavioral therapy, nerve
stimulation, injection therapy, mechanical devices [42] [43] and
surgery.
[0037] The hitherto existing medical treatments for incontinence
have either unsatisfactory success or show severe side effects and
can therefore not be administered to patients with e.g. glaucoma,
hypertonia and cardiac arrhythmias. Therefore there exists a great
need in effective pharmaceutical compositions and medicaments for
the successful treatment or prevention of incontinence in female
mammals with minimal adverse effects on the treated individual.
[0038] It has now surprisingly been found that a compound, or a
pharmaceutical composition comprising a compound that modulates the
level of biologically active gonadotropins is an effective
medicament for the treatment or prevention of urinary incontinence
in female mammals.
DISCLOSURE OF THE INVENTION
[0039] Hence it is an object of the present invention to use at
least one GnRH analogue for the preparation of a medicament for the
treatment and/or prevention of side effects of ovarectomy or
symptoms associated with reproductive senescence in female
mammals.
[0040] The term GnRH analogue as used herein encompasses GnRH
agonists and GnRH antagonists. A GnRH antagonist is a compound
which suppresses the activity of GnRH by e.g. binding the GnRH
receptors on target cells and thereby blocking its biological
activity or which decreases the production/release of endogenous
GnRH. A GnRH agonist is a compound leading to a temporary
overproduction of gonadotropins which leads to a downregulation of
at least one gondadotropin i.e. FSH and/or LH.
[0041] The term GnRH analogue comprises compounds such as e.g.
antibodies against GnRH and compounds leading to a cessation of
GnRH production due to the use of a specific antisense gene
construct.
[0042] Said GnRH analogue is preferably selected from the group
consisting of peptides, polypeptides and proteins.
[0043] Side effects and symptoms in the scope of the present
invention comprise vasomotor symptoms, especially hot flushes, mood
changes, such as e.g. depression and aggressivity, skin changes,
hair changes, and in particular urinary incontinence.
[0044] For specific treatments, a medicament of the present
invention may comprise at least one further active compound
selected from the group consisting of: an estrogenic agent, a
partial estrogenic agent, a progestational agent, alpha adrenergic
agonist, beta-adrenergic receptor blocking agent,
cholinergic-receptor blocking compound,
cholinergic-receptor-stimulating drug, smooth muscle relaxant,
nitric oxide substrate, nitric oxide donor, and mixtures
thereof.
[0045] A medicament comprising a second and/or further active
compound may be, and preferably is, a combination of specific
dosage units, comprising a first dosage form for the GnRH analogue,
e.g. a slow release dosage form, and at least one further dosage
form comprising one or more further active compounds, whereby said
first and said second dosage form may be administered at the same,
or at different times, and with the same or different
frequencies.
[0046] In another aspect, the present invention relates to a method
for the treatment and/or prevention of side effects of ovarectomy
or symptoms associated with reproductive senescence in female
mammals, in particular incontinence, said method comprising the
administration of a composition or a medicament of the present
invention to an individual in need thereof.
[0047] Upon further studies of the specification and appended
claims, further aspects, objects and advantages of this invention
will become apparent to those skilled in the art.
MODES FOR CARRYING OUT THE INVENTION
[0048] Thus, this invention relates to the use of a GnRH analogue
for the preparation of a medicament for treating and/or preventing
side effects of ovarectomy or symptoms associated with reproductive
senescence, in particular urinary incontinence and vasomotor
symptoms, in female mammals, in particular women and bitches.
[0049] Preferably, the amount of said at least one GnRH analogue is
effective to improve the side effects of ovarectomy or symptoms
associated with reproductive senescence, in particular urinary
incontinence or vasomotor symptoms, by changing the pulsatile and
tonic pattern of FSH and/or LH release and/or lowering the
blood-level of circulating FSH and/or LH in a female mammal to whom
the composition is administered.
[0050] By the methods of the present invention side effects of
ovarectomy or symptoms associated with reproductive senescence, in
particular urinary incontinence and vasomotor symptoms, in female
mammals, in particular women and bitches, which are manifesting the
symptoms thereof, can be treated and prevented.
[0051] Because the conditions of reproductive senescence and the
side effects of ovarectomy are produced or aggravated by changes in
the pulsatile patterns of FSH and LH and/or elevated FSH and/or
LH-levels, one or more compounds leading to a decreased synthesis
or a decreased release of said hormones such as e.g. deslorelin,
goserelin, buserelin, triptorelin, leuprolid or their acetates or a
combination of them are useful for ameliorating the side effects of
ovarectomy or symptoms associated with reproductive senescence.
[0052] In certain cases an additive effect can be achieved and the
severity of the symptoms can be decreased when a estrogenic agent
is administered concurrently with said GnRH analogue. In the case
of a female mammal, an estrogen or a progestin can be administered,
or an estrogen can be administered concurrently with a
progestin.
[0053] In other cases an additional effect can be achieved and the
severity of the symptoms can be decreased when said at least one
GnRH analogue is administered either with estrogen or progestin and
supplemented with at least one compound selected from the group
consisting of: alpha-adrenergic agonists, beta-adrenergic receptor
blocking agents, cholinergic receptor blocking compounds,
cholinergic receptor stimulating drugs, smooth muscle relaxants,
nitric oxide substrates and/or nitric oxide donor receptors.
[0054] Thus, the method aspects of this invention and the
medicament aspects of this invention employ one or more GnRH
analogue and optionally one or more of, e.g, an estrogen (e.g.
Progynova, Schering) or a progestin (e.g. progesterone, norgestrel,
proligeston, medroxyprogesteronacetate, chlormadinaonacetate), with
or without at least one compound selected from the group consisting
of: alpha-adrenergic agonists, beta-adrenergic receptor blocking
agents, cholinergic receptor blocking compounds, cholinergic
receptor stimulating drugs, smooth muscle relaxants, nitric oxide
substrates and/or nitric oxide donor receptors.
[0055] Examples of typical substances leading to a decreased blood
concentration of FSH and LH are:
[0056] Deslorelin acetate, Goserelin acetate, Nafarelin acetate,
Buserelin acetate, Triptorelin acetate, Gonadorelin acetate,
Leuprolid acetate, Danazolum, and Cetrorelix.
[0057] The amounts may be in the range known for down-regulation of
LH/FSH, whereby the amount depends e.g on the formula, the
intervalls, the root of administration and the responsiveness of
the individual. For example Deslorelin acetate usually is
administered to bitches in amounts of 1 to 100 mg, preferably 3 to
20 mg at intervalls from 1 month to 2 years. The amount depends on
the dog's size, whereby the amount usually is at least about 0.1
mg/kg, preferably at least 5 mg/kg.
[0058] Substances leading to a decreased concentration of Follicle
stimulating hormone (FSH) and/or Luteinizing hormone (LH) and/or to
a decreased or increased concentration or activity of Gonadotropin
releasing hormone (GnRH) can be administered preferentially by a
subcutaneous or intramuscular implant.
[0059] Examples of second or further active agents, or combinations
thereof which can be administered concurrently with a GnRH analogue
are estrogens, partial estrogen agonists (partial estrogens), and
progestins.
[0060] Estrogens and/or partial estrogens and/or progestins--if
any--are usually administered to supplement endogenous production,
the amount of estrogen being bioequivalent to approximately 0.005
mg-2 mg per day of estradiol (e.g.Progynova, Schering), the amount
of a partial estrogen being bioequivalent to approximately 0.002
mg-200 mg per day of e.g. raloxifene, and the amount of the
progestational agent administered being bioequivalent to 50-300 mg
of injected progesterone.
[0061] Estrogens may e.g. be administered as estradiol, estradiol
valerate, estradiol hemihydrate, vaginal estradiol tablets, vaginal
estradiol creams and/or vaginal estradiol rings.
[0062] Partial Estrogen Agonists (partial estrogens) are e.g.
raloxifene, tamoxifen, nafoxidin, centchroman, and toremifen.
[0063] Further optionally present agents include:
[0064] Alpha-adrenergic-receptor-agonists, e.g. Phenylpropanolamine
and Phenylephrine;
[0065] Beta-receptor-blocking agents, e.g. Propranolol, Befaxolol,
Acebutolol, Atenolol, and Bisoprolol;
[0066] Cholinergic-receptor blocking compounds, e.g. Benztropine,
Biperiden, and Propantheline;
[0067] Cholinergic-stimulating drugs, e.g. Bethanecol and
Nitroglycerine.
[0068] Combinations of smooth muscle relaxants and anticholinergics
may also be present and comprise e.g. oxybutynin, dicyclomine, and
flavoxate. Such smooth muscle relaxants, may be combined with e.g.
anticholinergics and .alpha.-adrenergics such as imipramine and/or
desipramine.
[0069] Many other examples of compounds in each of the foregoing
categories are well known and can be employed in this invention in
the above described combination.
[0070] A GnRH analogue can be administered either alone, or in
combination with other active substances, in admixture with
conventional excipients, i.e., pharmaceutically acceptable liquid,
semi-liquid or solid organic or inorganic carriers, in particular
carriers suitable, e.g., for parenteral or enteral application. It
goes without saying that such carriers are much preferred that do
not deleteriously react with the active compound in admixture
therewith. Suitable pharmaceutically acceptable carriers include
but are not limited to water, salt solutions, alcohols, vegetable
oils, polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
[0071] The pharmaceutical preparations can be and preferably are
sterilized. The pharmaceutical preparations can--if desired--be
mixed with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, coloring, flavoring and/or aromatic
substances and the like which do not deleteriously react with the
active compounds.
[0072] For parenteral application particularly suitable are
solutions, preferably oily or aqueous solutions, as well as
suspensions, emulsions, or implants, including transdermal patches,
and vaginal gels, creams and foams. Ampoules are convenient unit
dosages. Another suitable dosage form, especially for long lasting
effects, are microencapsulated drugs.
[0073] For enteral application, particularly suitable are unit
dosage forms, e.g. for rectal application suppositories, for oral
application tablets, dragees, capsules or, having talc and/or
carbohydrate carrier or binder or the like, the carrier preferably
being lactose and/or corn starch and/or potato starch; particulate
solids, e.g., granules; and liquids and semi-liquids, e.g., syrups
and elixirs or the like, wherein preferably a sweetened vehicle is
employed. Sustained release compositions can be formulated
including those wherein the active compound is protected with
differentially degradable coatings, e.g., by microencapsulation,
multiple coatings, etc.
[0074] Suitable for oral administration are, inter alia, tablets,
dragees, capsules, pills, granules, suspensions and solutions.
[0075] As already mentioned above, a GnRH analogue can be
administered as an admixture with an estrogen and/or partial
estrogen and/or progestational agent and/or any other optional
active agent, or it can be administered as a separate unit dosage
form, either simultaneously with a unit form of a second and/or
further active compound at the same time or at different times
during a day, or at different days, and with the same or different
intervals.
[0076] For administration by injection or implant the active agents
are preferably formulated as slow release formulations which
deliver the active agents continuously. Such formulations may be
designed for different frequencies of administration such as once a
day, once a week, once a month, once all six months, once a year,
or even for administration at larger intervals, whereby
administration once all six months to once a year is presently
preferred.
[0077] If administration by injection or implant at intervalls of
e.g. six months to one year is chosen for the GnRH analogue, a
second or further active substance may be administered at shorter
intervalls, e.g. in the form of tablets thereby allowing easy
adaptation of the dosage of one such substance or the sequential
administration of different substances in the same or different
dosages, e.g. to better react on naturally occurring hormonal
changes. The frequency of such administration of a second and/or
further active substance may e.g. be once a day, once a week, once
a month etc.
[0078] In mammals, suitable ratios at which an at least one GnRH
analogue should preferably produce in humans FSH and LH blood
plasma levels <3 IU/l or <6 IU/l respectively.
BRIEF DESCRIPTION OF THE EXPERIMENTS
[0079] Fifteen bitches suffering from urinary incontinence after
spaying, which did not respond to or tolerate an other incontinence
treatment before, such as a treatment with ephedrine, estrogen,
flavoxate, phenylpropanolamine or collagen deposits, were first
clinically examined and thereafter a GnRH analogue in a dosage of
3.75-12 mg, in slow release form, was subcutaneously implanted
between the shoulder blades. Additionally, for a limited period the
dogs were treated with phenylpropanolamine in a dosage of 1.5 mg/kg
BW tid orally. Combined treatment completely resolved the
incontinence in 12 bitches and in one bitch the incontinence was
significantly less severe. Only two dogs out of fifteen did not
respond with an improvement in continence, whereby one of said dogs
was treated with an amount below the proposed minimal dosage.
[0080] After discontinuation of the shortacting phenylpropanolamine
8 bitches remained continent. Their continence was therefore
achieved solely by the treatment with the composition as described
in the present invention. Seven out of fifteen dogs seemed to be
much happier and in none of the dogs did the general condition
deteriorate. Three dogs, which were aggressive against other dogs
before the treatment, were less aggressive against other dogs after
the treatment. The respective results are shown in more detail in
table 1.
[0081] In a second ongoing study, 16 client owned dogs suffering
from urinary incontinence were enrolled in a double-blind,
placebo-control study. In the initial phase of the study, dogs were
randomly assigned to treatment with a long-acting GnRH analogue
(leuprolide acetate) or placebo (dog owners and the investigators
were blinded to treatment) along with a short course of therapy
with phenylpropanolamine. 5 weeks after treatment with drug or
placebo, dogs were evaluated and, if not fully continent, treated
with a long-acting GnRH analogue (leuprolide acetate) in an open
label phase of the study. To date only 1 of 10 dogs treated with
placebo became continent vs. 3 to 8 dogs treated with drug during
the blinded portion of the study. Overall, the results generated
thus far indicate 6 of 15 dogs treated with the long-acting GnRH
analogue became continent and 9 of the remaining dogs improved
after discontinuation of the short acting phenylpropanolamine. Only
1 dog of 15 treated with the GnRH analogue was considered not to
have improved following treatment with the drug.
[0082] Two cocker spaniel bitches belonging to the same owner were
showing excessive growth of the undercoat due to spaying. One of
theses dogs did not tolerate estrogen treatment before. Both dogs
were first clinically examined and thereafter a GnRH analogue
(Deslorelin) in a dosage of 5 mg, in slow release form, was
subcutaneously implanted between the shoulder blades. 5 weeks after
the injection an obvious amelioration of the coat quality was seen
in both dogs, 21 weeks after injection no signes of "baby coat"
were apparent anymore.
[0083] As use in humans is concerned, a perimenopausal woman with
urge incontinence and hotflushes reported both symptoms improved
considerably for a period of about 4 weeks after treatment with
3.75 mg triptorelinacetate. A second menopausal woman, suffering
from stress incontinence for at least 6 years, was treated with a
single dose of 3.75 mg of leuprolide acetate. 24 hour pad tests
conducted prior to treatment with the drug indicated she lost
between 10 and 130 ml of urine on a daily basis due to her
incontinence. A pad test conducted 2 weeks after treatment with
leuprolide acetate indicated daily urine loss had decreased to only
1 ml of urine and the patient claimed to be very satisfied with the
effects of the therapy.
[0084] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0085] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
TABLE-US-00001 TABLE 1 Duration of Duration dog incontinence Effect
on of effect weight prior to inconti- after (kg) treatment Other
problems Treatment Side effects nence treatment Comments 44 2 years
No 6 mg Deslore- -- 100% >344 d linacetate 28 10 months Atopy 6
mg Deslore- More playfull 100% >340 d linacetate 6 2 years Too
short ure- 6 mg Deslore- with PPA >336 d thra linacetate 100% 28
4 years Timid 12 mg Deslore- More self- with PPA 135 d Collagen
linacetate assured 80% 60 2.3 years Cardiomyopathy, 12 mg Deslore-
-- 100% 64 d Euthana- Vaginitis linacetate tized os- teo- sarcoma
28 2 years proteinuria 12 mg Deslore- -- 100% >64 d linacetate
32 5 years -- 12 mg Deslore- with PPA >318 d linacetate 100% 20
2 years Isosthenuria, 12 mg Deslore- More tolerant with PPA >225
d polydipsia linacetate against males 100% 40 1 months Aggressive
12 mg Deslore- less aggres- 100% >209 d linacetate siv, more
activ 36 4 months polydipsia, 3.75 mg Tripto- -- Not effec- 0 *
dose timid relinacetate * tive too low 60 2 years 6.3 mg Busere- --
100% 44 d linacetate 28 2 years sebaceous ade- 6.3 mg Busere-
agile, more 100% 83 d nitis epilep- linacetate playfull sia 6 mg
Deslore- agile, more 100% >47 d linacetate playfull 30 1.5 years
11.25 mg Leu- Better mood Not effec- 0 prorelinace- tive tate 25? 4
months proteinuria 11.25 mg Leu- Less aggressiv with PPA >64 d
prorelinace- 100% tate 18? 21 months 11.25 mg Leu- -- 100% >14 d
prorelin ace- tate
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