U.S. patent application number 14/637200 was filed with the patent office on 2015-09-03 for methods for treating or preventing symptoms of hormonal variations.
The applicant listed for this patent is Yung Shin Pharm. Ind. Co., Ltd.. Invention is credited to Hung-Ming Wu.
Application Number | 20150246056 14/637200 |
Document ID | / |
Family ID | 39528142 |
Filed Date | 2015-09-03 |
United States Patent
Application |
20150246056 |
Kind Code |
A1 |
Wu; Hung-Ming |
September 3, 2015 |
METHODS FOR TREATING OR PREVENTING SYMPTOMS OF HORMONAL
VARIATIONS
Abstract
A method for treating or preventing symptoms of hormonal
variation includes administering an effective amount of a receptor
antagonist to a subject having one or more symptoms of hormonal
variations, wherein the receptor antagonist binds to at least one
selected from the group consisting of a serotonin type 2A
(5-HT.sub.2A) and a dopamine type 2 (D.sub.2) receptors.
Inventors: |
Wu; Hung-Ming; (Taichung
City, TW) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Yung Shin Pharm. Ind. Co., Ltd. |
Tachia |
|
TW |
|
|
Family ID: |
39528142 |
Appl. No.: |
14/637200 |
Filed: |
March 3, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12636552 |
Dec 11, 2009 |
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14637200 |
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11638282 |
Dec 13, 2006 |
7645750 |
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12636552 |
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Current U.S.
Class: |
514/211.13 ;
514/220; 514/253.07; 514/254.04; 514/259.41; 514/431 |
Current CPC
Class: |
A61P 5/24 20180101; A61P
25/06 20180101; A61K 31/519 20130101; A61P 25/20 20180101; A61K
31/519 20130101; A61P 1/08 20180101; A61K 31/554 20130101; A61P
25/02 20180101; A61K 31/496 20130101; A61P 43/00 20180101; A61K
31/5513 20130101; A61P 5/00 20180101; A61K 31/551 20130101; A61K
2300/00 20130101; A61P 15/12 20180101; A61P 25/22 20180101; A61K
31/38 20130101; A61P 3/00 20180101; A61P 9/00 20180101 |
International
Class: |
A61K 31/554 20060101
A61K031/554; A61K 31/38 20060101 A61K031/38; A61K 31/551 20060101
A61K031/551; A61K 31/496 20060101 A61K031/496; A61K 31/519 20060101
A61K031/519; A61K 31/5513 20060101 A61K031/5513 |
Claims
1. A method for treating or preventing symptoms of hormonal
variation, comprising: administering an effective amount of a
receptor antagonist to a subject having one or more symptoms of
hormonal variations, wherein the receptor antagonist binds to at
least one selected from the group consisting of a serotonin type 2A
(5-HT.sub.2A) receptor and a dopamine type 2 (D.sub.2) receptor,
and wherein the symotoms of hormonal variation are associated with
perimenonause or postmenopause.
2. The method of claim 1, wherein the symptoms of hormonal
variation comprises at least one selected from hot flashes,
dizziness, nausea, headaches, palpitations, profuse sweating, and
night sweats.
3. The method of claim 1, wherein the receptor antagonist is at
least one selected from risperidone, 9-hydroxyrisperidone,
quetiapine, clozapine, olanzapine, aripiprazole, ziprasidone, and
zotepine.
4. The method of claim 3, wherein the effective amount of the
receptor antagonist is from 0.1 to 50 mg per day for an adult
patient.
5. The method of claim 3, wherein the effective amount of the
receptor antagonist is from 0.1 to 20 mg per day for an adult
patient.
7. The method of claim 3, wherein the effective amount of the
receptor antagonist is from 0.1 to 6 mg per day for an adult
patient.
8. The method of claim 3, wherein the effective amount of the
receptor antagonist is from 0.1 to 2 mg per day for an adult
patient.
9. The method of claim 1, wherein the effective amount of the
receptor antagonist is administered by using a pharmaceutically
acceptable formulation.
10. The method of claim 9, wherein the pharmaceutically acceptable
formulation is an oral formulation, injection, inhalation, or
transdermal patch.
Description
[0001] This application is a continuation U.S. patent application
Ser. No. 12/636,552, filed Dec. 11, 2009; which is a continuation
U.S. patent application Ser. No. 11/638,282, filed Dec. 13, 2006,
now U.S. Pat. No. 7,645,750. The contents of the above-identified
applications are incorporated herein by reference in their
entireties.
BACKGROUND OF INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to treatment or
prevention of symptoms of hormonal variation, such as hot flashes,
night sweats, and insomnia.
[0004] 2. Background Art
[0005] Hot flashes (also called vasomotor flashes) are the most
common symptoms experienced by women who are perimenopausal or
postmenopausal. A hot flash is a sudden sensation of warmth, which
is usually accompanied by skin reddening, perspiration,
palpitation, anxiety, irritability, and even panic, and night
sweats. A chill may follow a hot flash because of a subsequent drop
in core temperature. Hot flashes vary: they can be several times a
week or once per hour, they can be characterized by mild warmth to
profuse sweating, and they can last from several seconds to 60
minutes. Such symptoms can disrupt sleep and work and interfere
with quality of life.
[0006] Almost 60-70% of postmenopausal women have hot flashes, and
approximately 10-20% of all postmenopausal women will report
intolerable symptoms, including hot flashes. Some women may suffer
from these symptoms for up to 15 years (Kronenberg F. "Hot flashes:
epidemiology and physiology," Ann. N.Y. Acad. Sci.,
592:52-86(1990)). Thus, the identification and proper management of
menopausal symptoms are crucial to maintaining a woman's quality of
life.
[0007] Typical hot flashes occur with sudden onsets of sensation of
warmth in the chest, which then spreads upward to involve the neck
and face. Hot flashes can last from a few seconds to several
minutes. However, the severity of the sensations vary greatly both
from time to time in the same woman and from woman to woman. Hot
flashes may be accompanied by dizziness, nausea, headaches,
palpitations, profuse sweating and night sweats. How often a woman
experiences hot flashes also varies, ranging from many times a day
to once a week or less. Such symptoms can disrupt sleep and work
and interfere with quality of life. In some women, hot flashes are
provoked by several factors such as hot weather, stress, eating, or
drinking alcohol.
[0008] Although the pathophysiology of hot flashes is not
completely understood, it has been postulated that hot flashes
result from a transient lowering of the hypothalamic temperature
regulatory set point (Steams et al., "Hot flushes," Lancet,
360:1851-1861 (2002)). Because of the temporal relation between
changes in sexual hormone concentrations and the onset of hot
flashes, it is believed that such symptoms result from declining
estrogen levels or increased gonadotropin concentrations. Thus, hot
flashes occur commonly in menopausal women, but also in women
taking anti-estrogen drugs, such as tamoxifen. Men on androgen
deprivation treatment may also experience such symptoms.
[0009] Although estrogen replacement therapy can effectively
minimize or prevent hot flashes in women, many women are concerned
about potential risks of hormone replacement therapy. This is
especially true for women who suffer from breast cancer or have a
family history of breast cancer, and/or a history of clotting
disorder (Col et al., "Patient-specific decisions about hormone
replacement therapy in postmenopausal women," JAMA,
277;1140-1147(1997); Gail et al., "The menopause," Lancet,
353:571-580 (1999)).
[0010] Various non-hormonal agents have been tested as well, such
as clonidine. Clonidine is a centrally-acting .alpha..sub.2
adrenergic receptor agonist. It selectively stimulates receptors in
the brain that monitor catecholamine levels in the blood. These
receptors close a negative feedback loop that begins with
descending sympathetic nerves from the brain that control the
production of catecholamines (e.g., epinephrine, also known as
adrenaline, and norepinephrine) in the adrenal medulla. By tricking
the brain into believing that catecholamine levels are higher than
they really are, clonidine causes the brain to reduce its signals
to the adrenal medulla, leading to lower catecholamine production.
The result is a lowered heart rate and blood pressure. In
randomized clinical trials, clonidine was shown to be moderately
more efficacious than placebo (Goldberg et al., "Transdermal
clonidine for ameliorating tamoxifen-induced hot flashes," J. Clin.
Oncol., 12:155-158 (1994); Pandya et al., "Oral clonidine in
postmenopausal patients with breast cancer experiencing
tamoxifen-induced hot flashes: a University of Rochester Cancer
Center Community Clinical Oncology Program study," Ann Intern Med.
132:788-793 (2000)), but adverse effects are common, including dry
mouth, dizziness, and blurred vision.
[0011] Recent randomized clinical trials also confirmed that some
selective serotonin-reuptake inhibitors (SSRI), such as venlafaxine
and paroxetine, are more effective than placebo in minimizing the
occurrence and severity of hot flashes (Loprinzi et al.,
"Venlafaxine in management of hot flashes in survivors of breast
cancer: a randomized controlled trial," Lancet 356:2059-2063
(2000); Stearns et al., "Paroxetine controlled release in the
treatment of menopausal hot flashes: A randomized controlled
trial," JAMA 289:2827-2834 (2003)). However, adverse effects with
SSRIs are moderate, including headache, agitation, tremor,
sedation, and sexual dysfunction.
[0012] Given the risks of estrogen replacement therapy and marginal
benefits of current non-hormonal treatments, there is a continued
need for alternative methods or drugs for treating or preventing
symptoms associated with menopause, including hot flashes.
SUMMARY OF INVENTION
[0013] In one aspect, embodiments of the invention relate to
methods for treating or preventing symptoms of hormonal variation.
A method in accordance with one embodiment of the invention
includes administering an effective amount of a receptor antagonist
to a subject having one or more symptoms of hormonal variations,
wherein the receptor antagonist binds to at least one selected from
the group consisting of a serotonin type 2A (5-HT.sub.2A) receptor
and a dopamine type 2 (D.sub.2) receptor. The receptor antagonist
is one selected from risperidone, quetiapine, clozapine,
olanzapine, aripiprazole, ziprasidone, zotepine, and
9-hydroxyrisperidone.
[0014] Other aspects and advantages of the invention will become
apparent from the following description and attached claims.
DETAILED DESCRIPTION
[0015] Embodiments of the invention relate to methods for treating
or preventing symptoms associated with hormonal variations,
particularly those associated with hormonal changes accompanying
menopause. In the following description, numerous details are set
forth to provide an understanding of the present invention.
However, it would be understood by those skilled in the art that
the present invention may be practiced without these details and
that numerous variations or modifications from the described
embodiments are possible without departing from the scope of the
invention. The methods of the invention may involve administering
an effective amount of a therapeutic agents by oral administration,
injection, inhalation, transdermal patch, or any other routes
commonly used in the art.
[0016] Furthermore, the following describes several examples to
illustrate embodiments of the invention. These examples are for
illustrative purpose only. One of ordinary skill in the art would
appreciate that these examples are not exhaustive and they are not
intended to limit the scope of the invention. In addition, it
should be understood that throughout this specification, when a
concentration or amount range is described as being useful, or
suitable, or the like, it is intended that any and every
concentration or amount within the range, including the end points,
is to be considered as having been stated. Furthermore, each
numerical value should be read once as modified by the term "about"
(unless already expressly so modified) and then read again as not
to be so modified unless otherwise stated in context. For example,
"a range of from 1 to 10" is to be read as indicating each and
every possible number along the continuum between about 1 and about
10. In other words, when a certain range is expressed, even if only
a few specific data points are explicitly identified or referred to
within the range, or even when no data points are referred to
within the range, it is to be understood that the inventors
appreciate and understand that any and all data points within the
range are to be considered to have been specified, and that the
inventor have possession of the entire range and all points within
the range.
[0017] Although menopause is a natural process that occurs in
women's lives as part of normal aging. Some women go through these
courses with few symptoms, while others have significant or even
disabling symptoms such as hot flashes. Hot flashes are generally
systemic and likely result from an alteration in the
thermoregulatory set-point centre, which is located in the
pre-optic anterior hypothalamus, with involvement of dopamine,
serotonin, nor-epinephrine, and alpha-adrenergic receptors. (Steams
et al., "Hot flushes," Lancet 360:1851-1861 (2002)).
[0018] Among various receptors, inventor of the present invention
had found that specific subtypes of dopamine, serotonin, and a
adrenergic receptors are effective targets for the treatment of hot
flashes and other symptoms associated with hormonal variations.
Specifically, 5-HT.sub.2A antagonist and/or D.sub.2 dopamine
antagonist are found to be effective in reducing or eliminating
symptoms associated with hormonal variations.
[0019] Thus, in accordance with some embodiments of the invention,
a method for treating or preventing symptoms of hormonal variations
may comprise the use of an effective amount of an antagonist of
5-HT.sub.2A serotonin receptor and/or D.sub.2 dopamine receptor. An
effective amount of an antagonist that binds 5-HT.sub.2A and/or
D.sub.2 receptors will depend on the mode of administration,
frequency of administration, and the type of pharmaceutical
composition used to deliver the compound into a patient, as well as
weight, gender, age, and physical conditions of the patient.
Generally, effective amounts of such compounds will be about 0.002
mg to about 0.5 mg/kg body weight per day, preferably about 0.005
mg to 0.1 mg/kg body weight per day, and more preferably about
0.005 to about 0.034 mg/kg body weight per day. For example, daily
doses may range from about 0.1 to about 25 mg per day for an adult
patient weighing about 50 Kg (110 lb), or from about 0.2 to about
50 mg per day for an adult patient weighing about 100 Kg (220 lb).
While individual needs vary, determination of optimal range of
effective amounts of each compound is within the skills of one
skilled in the art. By treating the symptoms of hormonal
variations, including hot flashes, embodiments of the invention
either reduce the number (occurrence or frequency), duration,
and/or severity of symptomatic events. Administering a compound of
the invention to a patient may be via any suitable route used for
administering similar pharmaceuticals to a patient, including oral
administration, injection, and transdermal patch, to name a few.
The compound may be administered with any pharmaceutically
acceptable carrier or excipient.
[0020] Serotonin (5-HT) receptors comprise about 15 different
receptors. Type 2 (5-HT.sub.2) serotonin receptors are
G.sub.q/G.sub.11 coupled receptors that mediate cellular effects by
increasing cellular levels of inositol triphosphate (IP.sub.3) and
diacylglycerol (DAG). In accordance with some embodiments of the
invention, serotonin type 2A receptor is the target for treating or
preventing symptoms associated with hormonal variation. Rreduction
in 5-HT levels increases the sensitivity of 5-HT.sub.2A receptor in
the hypothalamus, which is involved in thermoregulation. Therefore,
modulators of 5-HT.sub.2A receptors may be useful in the management
of symptoms associated with hormone variations.
[0021] In accordance with one embodiment of the invention,
risperidone may be used to treat symptoms of hormonal variations.
Risperidone (Belivon.RTM., Rispen.RTM., Risperdal.RTM. in the
United States) is an antipsychotic medication that functions by
interfering with the communication among nerves in the brain.
Risperidone acts as a 5-HT.sub.2A antagonist and can be used to
quickly and effectively block the effects of 5-HT.sub.2A agonists
at a low dose. Risperidone is also a potent dopamine type 2
(D.sub.2), and .alpha..sub.2 adrenergic receptor antagonist. Thus,
risperidone has been used in the treatment of psychotic disorders,
for example, schizophrenia. However, as described in the following
sections, risperidone has been unexpectedly found to be effective
in reducing or eliminating symptoms associated with hormonal
variations.
[0022] In accordance with another embodiment of the invention,
9-hydroxyrisperidone may be used as a treatment for the symptoms of
hormonal variations. 9-Hydroxyrisperidone is the principal active
metabolite of risperidone, and they had similar binding profiles
and affinity for 5-HT.sub.2A receptors and D.sub.2
receptors.(Leysen et al., "Risperidone: a novel antipsychotic with
balanced serotonin-dopamine antagonism, receptor occupancy profile,
and pharmacologic activity," J Clin Psychiatry: 55 Suppl: 5-12
(1994)). Like risperidone, 9-hydroxyrisperidone can effectively
treat or prevent the symptoms associated with hormonal variations
its antagonist activity for 5-HT.sub.2A and/or dopamine
receptors.
[0023] In addition to risperidone and 9-hydroxyrisperidone, other
receptor antagonists that can bind to 5-HT.sub.2A and/or D.sub.2
dopamine receptors may also be used to control symptoms associated
with hormonal variations. These other antagonists, for example, may
include quetiapine, clozapine, olanzapine, aripiprazole,
ziprasidone, and zotepine.
[0024] In accordance with another embodiment of the invention,
quetiapine may be used as a treatment for the symptoms of hormonal
variations. The antipsychotic effect of quetiapine is thought to be
mediated by its antagonist activity against dopamine and 5-HT
receptors. Specifically, dopamine receptors D.sub.1, D.sub.2, and
5-HT receptors, 5-HT.sub.1A and 5-HT.sub.2 subtypes, are
antagonized.
[0025] Serial PET scans evaluating the D.sub.2 dopamine receptor
occupancy of quetiapine have revealed that quetiapine rapidly
disassociates from the D.sub.2 receptor. Theoretically, this allows
for normal physiological surges of dopamine to elicit their normal
effects in areas such as the nigrostriatal and tuberoinfundibular
pathways, thus minimizing the risk of side effects such as
pseudo-Parkinsonism and elevations in prolactin. Quetiapine also
has an antagonistic effect on the H.sub.1 histamine receptor. This
may be responsible for the sedative effect of the drug.
[0026] In accordance with some embodiments of the invention,
clozapine may be used as a treatment for the symptoms of hormonal
variations. Clozapine is classified as an `atypical` antipsychotic
drug because its profile of binding to dopamine receptors and its
effects on various dopamine-mediated behaviors differ from those
exhibited by more typical anti-psychotics. In particular, clozapine
has a high affinity for the D4 receptor and it also interferes to a
lower extent with the binding of dopamine with D.sub.1, D.sub.2,
D.sub.3 and D.sub.5 dopamine receptors. However, clozapine does not
induce catalepsy, nor does it inhibit apomorphine-induced phenotype
in animal models seen with `conventional` neuroleptics. This
evidence suggests that clozapine is preferentially more active at
limbic than at striatal dopamine receptors and may explain its
relatively mild extra-pyramidal side effects and its strong
anti-cholinergic activity. Clozapine is also a strong antagonist of
different subtypes of adrenergic, cholinergic, histaminergic and
serotonergic receptors.
[0027] In accordance with some embodiments of the invention,
olanzapine may be used as a treatment for symptoms of hormonal
variations. Olanzapine is structurally similar to clozapine, and
has a high affinity for dopamine and serotonin receptors.
Olanzapine has a low affinity for histamine, cholinergic muscarinic
and .alpha.-adrenergic receptors. The mechanism of action of
olanzapine is unknown. However, it is thought that olanzapine's
antipsychotic activity is mediated primarily by antagonism of
dopamine receptors, specifically D.sub.2 dopamine receptor. 5-HT
antagonism may also play a role in the effectiveness of olanzapine.
However, the significance of 5-HT.sub.2A antagonism is debated
among researchers. In accordance with some embodiments of the
invention, aripiprazole may be used as a treatment of symptoms of
hormonal variations. Aripiprazole (Abilify.RTM. from Bristol-Myers
Squibb) is a new atypical antipsychotic medication awaiting
approval by the FDA for the treatment of schizophrenia.
Aripiprazole has been approved by the FDA for the treatment of
acute manic and mixed episodes associated with bipolar disorder.
Aripiprazole appears to mediate its antipsychotic effects primarily
by acting as a partial agonist of the D.sub.2 receptor. Partial
agonism at D.sub.2 receptors has been shown to modulate
dopaminergic activity in areas where dopamine activity may be high
or low, such as the mesolimbic and mesocortical areas of the
schizophrenic brain, respectively. In addition to partial agonist
activity of the D.sub.2 receptor, aripiprazole is also a partial
agonist of the 5-HT.sub.1A receptor Like other atypical
anti-psychotics, aripiprazole exhibits antagonist activities
against the 5-HT.sub.2A receptor. Aripiprazole has moderate
affinities for histamine and .alpha.-adrenergic receptors, but no
appreciable affinity for cholinergic muscarinic receptors.
[0028] In accordance with some embodiments of the invention,
ziprasidone may be used as a treatment of symptoms of hormonal
variations. Ziprasidone has a high affinity for dopamine,
serotonin, and alpha-adrenergic receptors and a moderate affinity
for histaminic receptors. Ziprasidone is somewhat unique among the
"atypicals" in that it can also inhibit synaptic reuptake of
serotonin and norepinephrine, although the clinical significance of
this is unknown. The mechanism of action of ziprasidone is unknown.
However, it is thought that its antipsychotic activity is mediated
primarily by its antagonism against dopamine receptors,
specifically D.sub.2 dopamine receptor. Serotonin antagonism may
also play a role in the effectiveness of ziprasidone, but the
significance of 5-HT.sub.2A antagonism of ziprasidone is debated
among researchers. Antagonism at histaminic and alpha adrenergic
receptors likely explains some of the side effects of ziprasidone,
such as sedation and orthostasis.
[0029] In accordance with some embodiments of the invention,
zotepine may be used as a treatment of symptoms of hormonal
variations. Zotepine has a high affinity for the D.sub.1 and
D.sub.2 dopamine receptors. It also affects the 5HT2.sub.A,
5HT2.sub.C, 5HT.sub.6, and 5HT.sub.7 receptors. In addition, it can
also inhibit the reuptake of noradrenaline.
Clinical Examples
[0030] The following examples are provided to illustrate that
embodiments of the present invention can reduce the symptoms of
hormone variations, including hot flashes, night sweats, and blood
pressure fluctuations. Embodiments of the invention are effective
for patients under various conditions. However, one of ordinary
skill in the art would appreciate that these examples are for
illustration only and by no means are intended to limit the scope
of the invention.
[0031] Embodiments of the invention involve administering a
therapeutically effective amount of an antagonist (such as
risperidone or 9-hydroxyrisperidone) of 5-HT.sub.2A and/or D.sub.2
dopamine receptor to alleviate symptoms associated with hormone
variations. For example, risperidone has been used on several
patients to successfully alleviate the occurrence of hot flashes or
other symptoms of hormonal variations. The following describe four
specific examples from four different patients to illustrate the
effectiveness of risperidone in alleviating symptoms associated
with hormone variations. One of ordinary skill in the art would
appreciate that these specific examples are not intended to limited
the scope of the invention. For example, embodiments of the
invention may use other regimens, including other antagonists of
5-HT.sub.2A and/or D.sub.2 dopamine receptors.
[0032] Patient 1: Risperidone Resolved Hot Flashes in a Case with
Hysterectomy
[0033] A 68-year-old woman was admitted to the hospital in December
of 2004 due to hot flashes, hypertension, and restlessness. She had
been told that she was suffering from essential hypertension for 16
years and had taken anti-hypertension medications for several
years. However, her blood pressure still fluctuated and frequently
dropped below critical level after taking sublingual adalate (10
mg) for sudden onsets of high blood pressure. She had no history of
psychiatric or systemic diseases, except for a total abdominal
hysterectomy at age 45. On admission, it was observed that her hot
flash attacks occurred many times a day, lasting a few minutes and
was usually followed by high blood pressure up to 180-200/84-96
mmHg, general shivers, and anxiety for 20-60 minutes. Such clinical
symptoms started around age 50 and grew progressively worse.
[0034] Her biochemical and hematological results, such as sodium
and potassium levels, 140 mmol/L and 4.0 mmol/L, respectively, were
all within normal ranges. Plasma cortisol levels were within the
normal range and showed diurnal rhythm. The plasma adrenaline,
nor-adrenaline, VMA, epinephrine, and dopamine levels as well as
thyroid hormones, including T3, T4, and TSH, were also normal. SSR
and RRIV tests to assess sympathetic and parasympathetic functions,
respectively, demonstrated her autonomic nervous system was normal.
EEG showed no focal epileptiform discharges nor abnormal background
activities. Brain MRI showed aging brain changes, but no lesion in
hypothalamus or brain stem. 24-hour Holter's scan showed normal
sinus rhythm. Echocardiography demonstrated normal cardiac chamber
size, normal LV systolic performance, and wall motion.
[0035] After one month of observation, the patient received
treatments of Premarin.RTM. 0.625 mg/day, Prozac.RTM. 20 mg/day and
Tofranil.RTM. 20 mg/day, each for 1-2 months with limited success.
Because estrogen withdrawal may alter the thermoregulatory
set-point located in the hypothalamus, by increasing the
sensitivity of hypothalamic 5-HT2A receptor, a regimen of a
5-HT.sub.2A antagonist may provide an effective therapy for
symptoms of hormonal variations, such as hot flashes. Thus, the
patient was treated with risperidone (2 mg/day). After three days
of treatment, her hot flashes reduced markedly to a frequency of
once per 1-2 weeks. Associated symptoms, such as palpitation and
anxiety, also improved significantly. Thereafter, the dosage of
anti-hypertension drugs was reduced. With the patient's permission,
risperidone therapy was discontinued and hot flashes reoccurred
within 2-3 days after discontinuing the treatment. The symptoms
were again alleviated 3-4 days after resuming risperidone
treatment.
[0036] Patient 2: Risperidone Resolved Hot Flashes of Natural
Menopause
[0037] Patient 2 was a 57-year-old woman who began developing
intolerable hot flashes and night sweats after natural menopause
that occurred seven years ago. Although she responded well to
hormone replacement therapy (Premarin.RTM. 0.625 mg per day), she
discontinued the therapy one year prior to this study because she
was concerned about the potential risk of breast cancer. One month
after discontinuing hormone replacement therapy, she developed hot
flashes up to ten times per day, night sweats up to three times per
night that disrupted her sleep, and headaches. The patient then
sought neurological consultation. The patient also suffered from
headaches twice per day and fluctuating blood pressure. Risperidone
was started at a dose of 2 mg per day and the patient reported that
the occurrence of hot flashes reduced markedly two days after
starting risperidone treatment and was completely eliminated by day
7. In addition, she slept well and her blood pressure stabilized.
To assess the relationship between risperidone therapy and the
resolution of hot flashes, risperidone was tapered off over 2 days.
The patient experienced hot flashes and night sweats again two days
after risperidone treatment was completely discontinued.
Risperidone 2 mg daily was resumed and the patient has not suffered
another hot flash since.
[0038] Patient 3: Risperidone Resolved Hot Flashes in a
Perimenopausal Case
[0039] Patient 3 was a 46-year-old woman who was diagnosed with
perimenopause, based on increased levels of follicle-stimulating
hormone, increased variability in menstrual cycle length,
development of hot flashes, and insomnia. The patient had had these
symptoms for two years. She responded well to estrogen therapy.
Because of health risks, the patient discontinued estrogen
treatment and sought supplementary therapy, such as soy
isoflavones, but without success. Risperidone treatment (1 mg per
night) was started. At that time, the patient was experiencing
seven hot flashes per day. The patient reported that the frequency
and intensity of her hot flashes were markedly reduced three days
after starting risperidone therapy. With her permission,
risperidone was tapered off over two days, and the hot flashes
developed again three days later. After risperidone treatment (1 mg
daily) was resumed, the patient no longer experienced hot flashes,
and the quality of her sleep and her life improved. Three months
later, the dosage of risperidone was decreased to 0.25 mg or less
per day, and the patient's hot flashes were still markedly
eliminated
[0040] Patient 4: Risperidone Resolved Residual Hot Flashes in a
Case with Hormone Replacement Therapy
[0041] Patient 4 was a 56-year-old woman who had developed hot
flashes, with a frequency of once per hour, palpitation, insomnia,
headache, restlessness, and unstable blood pressure for over seven
years. Initially, the patient visited a psychiatrist for her sleep
disorder and a cardiovascular specialist for her high blood
pressure. A year later, because of intolerable hot flashes and
other menopausal symptoms, she received hormone replacement therapy
(Divina.RTM.)). Although her hot flashes were reduced to twice per
day, headaches persisted and her blood pressure fluctuated from 180
to 210/110 to 90 mm Hg despite treatment with anti-hypertension
drugs. The patient was started on risperidone treatment, 1 mg at
bedtime for the first two days, followed by 2 mg per night, for
residual hot flashes. The patient's hot flashes were completely
eliminated three days after starting the risperidone therapy.
Additionally, the patient was able to take hormone four times a day
and discontinue the use of all anti-hypertension drugs because her
blood pressure stabilized within the normal range.
[0042] The above data clearly show that risperidone or similar
receptor antagonists are effective in alleviating the symptoms
associated with hormonal variations, such as hot flashes and blood
pressure fluctuations. It is also contemplated that administration
of a compound of the invention for alleviating symptoms associated
with hormonal variations may be carried out in combination with
other suitable therapeutic treatments which are useful for treating
symptoms of hormonal variations, including hot flashes.
[0043] While not intended to be bound by the mechanisms of how
these receptor antagonists function to alleviate symptoms
associated with hormonal variations, the inventor believes these
drugs probably function by inhibiting 5-HT.sub.2A serotonin
receptor, D.sub.2 dopamine receptor, and/or
.alpha..sub.1-adrenergic receptor.
[0044] Menopause is a natural process that occurs in women's lives
as part of normal aging. Approximately one-third of women
experience few or no symptoms, while the remaining may have
significant or even disabling symptoms such as severe hot flashes.
Hot flashes are generally systemic and likely result from an
alteration in the thermoregulatory set-point centre, which is
located in the pre-optic anterior hypothalamus, with involvement of
dopamine, serotonin, nor-epinephrine, and alpha-adrenergic
receptors (Steams et al., "Hot flashes," Lancet 360;1851-1861
(2002)).
[0045] Risperidone, a benzisoxazole derivative, is an atypical
antipsychotic drug, which binds with high affinity to the serotonin
type 2A 5-HT.sub.2A, dopamine type 2 (D.sub.2), and
.alpha..sub.1-adrenergic receptors. Risperidone binds with lower
affinities to the .alpha..sub.2-adrenergic and H.sub.1 histamine
receptors. Risperidone does not bind to D.sub.1 dopamine receptors
and has no affinity (when tested at concentrations >10.sup.-5 M)
for muscarinic cholinergic receptors. (Grant and Fitton,
"Risperidone. A review of its pharmacology and therapeutic
potential in the treatment of schizophrenia," Drug, 48:253-273
(1994); Ota et al., "Peripheral injection of risperidone, an
atypical antipsychotic, alters the body weight gain of rats," Clin
Exp pharmacol. physiol., 29:980-989 (2002)).
[0046] Experimental data suggest that stimulation of 5-HT2 and
dopamine receptors can increase body temperatures. For example,
direct stimulation of 5-HT.sub.2A receptors can also induce
hyperthermia in animal models, while administration of 5-HT.sub.2A
antagonists can prevent hyperthermia in the animal model for
serotonin syndrome. However, administration of 5-HT.sub.1A agonists
to rodent or human leads to a reduction in core body temperature.
These results suggest that the two 5-HT receptor subtypes,
5-HT.sub.1A and 5-HT.sub.2A, are closely associated with body
temperature control (Oether et al., "Involvement of 5-HT.sub.1A and
5-HT.sub.1B receptors for citalopram-induced hypothermia in the
rat," Psychopharmacology, 154:429-434 (2001); Salmi and Ahlenius,
"Evidence for functional interactions between 5-HT.sub.1A and
5-HT.sub.2A receptors in rat thermoregulatory mechanisms,"
Pharmacol. Toxicol., 82:122-127 (1998)).
[0047] During menopause, a marked decline in sexual hormones,
especially estrogen levels, may lead to a significant reduction in
blood serotonin (5-HT) levels. The reduction in serotonin levels
increases the sensitivity of the 5-HT.sub.2A receptors in the
hypothalamus (Berendsen H H, "The role of serotonin in hot
flashes," Maturiatas, 36:155-164 (2000)). Thus, when an internal
and an external stimulus, such as anxiety, induces the release of
serotonin to stimulate the enhanced sensitivity 5-HT.sub.2A
receptors, the set-point for body temperature is changed and hot
flashes occur.
[0048] Pulsatile luteinizing hormone (LH) secretion theory is
another common explanation for the development of hot flashes
because administration of LH-RH agonist can result in hot flashes.
The dopaminergic system seems to be involved in both pulsatile LH
secretion and hot flashes in post-menopausal women.
Anti-dopaminergic drugs could act on the thermoregulatory nucleus
to reduce hot flashes by directly decreasing adrenergic effects on
the thermoregulatory nucleus, or indirectly through mechanisms such
as the short-loop feedback exerted by hyperprolactinaemia on the
tuberoinfundibular dopamine neurons with a secondary dopamine-like
activity, or by stimulating the opioid system (Melis G B et al.,
"Effects of the dopamine antagonist veralipride on hot flashes and
luteinizing hormone secretion in postmenopausal somen," Obstet.
Gynecol. 72:688-692 (1988); Wesel et al., Veralipride versus
conjugated oestrogens: a double-blind study in the management of
menopausal hot flashes," Curr. Med. Res. Opin., 8:696-700
(1984)).
[0049] Risperidone has high affinities for 5-HT.sub.2A and D.sub.2
receptors. Risperidone can counteract enhancement of 5-HT activity
as well as decrease nor-epinephrine activity in the anterior
hypothalamus in the serotonin syndrome (Nisijima et al.,
"Risperidone counteracts lethality in an animal model of the
serotonin syndrome," Psychopharmacology 150:9-14 (2000)). In
addition, risperidone may elevate circulating prolactin levels in
healthy subjects and schizophrenic patients (Markianos et al.,
"Neuroendocrine serotonergic and dopaminergic responsivity in male
schizophrenic patients during treatment with neuroleptics and after
switch to risperidone," Psychopharmacology, 157:55-59 (2001)).
Risperidone can also reduce or prevent hot flashes through
anti-dopaminergic effects on the loop of tuberoinfundibular
dopamine neurons and on nor-epinephrine activity in the anterior
hypothalamus.
[0050] Advantages of embodiments of the invention may include one
or more of the following. Embodiments of the invention can provide
compositions and methods for the treatment of the symptoms of
hormonal variations including hot flashes and night sweats.
Additionally, these methods and compositions can also achieve
normalization of blood pressure and elimination/reduction of
palpitations. Compositions of the invention may comprise a
serotonin type 2A (5-HT.sub.2A) receptor, dopamine type 2 (D.sub.2)
receptor, and/or .alpha..sub.1-adrenergic receptor antagonist and
can provide a plethora of treatment options for improving the
quality of life of women experiencing the symptoms of hormonal
variations.
[0051] While the invention has been described with respect to a
limited number of embodiments, those skilled in the art will
appreciate that other embodiments can be devised which do not
depart from the scope of the invention as disclosed herein.
Accordingly, the scope of the invention should be limited only by
the attached claims.
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