KR20220010721A - Non-hormonal treatment of hot flashes - Google Patents

Abstract

The present invention provides an affinity for dopamine D2, D3, or D4 receptors (D2 family) for the treatment of hot flashes, whether caused by natural aging in women or medical/surgical intervention of the HPG axis in either sex. The use of dopamine agonists with The D2 family of dopamine receptors responds mostly to D2 agonist molecules, but also responds to a number of other molecules that directly or indirectly utilize this pathway. Alpha-2-adrenergic agonists act synergistically, further reducing the frequency and severity of hot flashes and prolonging the duration of the effect of administration. Combination of D2 class dopamine agonists with alpha-2-adrenergic agonists, in addition to additional molecules capable of exploiting the D2 receptor class pathway through the formation of heterodimers, reveals the diverse efficacy of multiple molecules in the treatment of hot flashes in either women or men. makes it possible The present invention expands the available non-hormonal options for the treatment of hot flashes, which are otherwise most disruptive to the normal activities of daily living.

Description

Non-hormonal treatment of hot flashes

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed in U.S. Patent Application Serial No. 13/411,660, filed March 5, 2012, U.S. Patent Application Serial No. 14/245,509, filed April 4, 2014, March 2, 2017 U.S. Application Serial Nos. 15/447675, filed in ; and U.S. Application Serial No. 16/390,276, filed on April 22, 2019, claiming priority thereto. The aforementioned prior applications are incorporated herein by reference.

technical field

The present invention relates to the treatment and method of treatment of hot flushes. Hot flashes can result from menopause, which can be caused by a variety of treatment modalities for diseases and conditions that share a common biochemical pathway, the hypothalamic-pituitary-gonad (HPG) axis. The present invention utilizes the HPG neurochemical pathway for use in the non-hormonal treatment of hot flashes. The HPG axis pathway exists in both women and men, and the treatment modulates hot flashes in both men and women by simulating naturally occurring neurotransmitters.

Under normal circumstances, a signal from the brain mediated through the hypothalamus releases gonadotropin-releasing hormone (GnRH). This leads to the subsequent release of hormones that act directly on the gonads of either sex. These are LH, luteinizing hormone and FSH, follicle stimulating hormone. LH produces estrogen in the ovaries in women and testosterone in the testes in men. There are differences in the release cycle of these molecules that are characteristic of either sex. In women, the release of LH is pulsating and fluctuates through the menstrual cycle, whereas in men the release is tonic. FSH, follicle-stimulating hormone, also affects each sex. It induces maturation of ovarian follicles and also contributes to progesterone production in women affected by pregnancy. In males, FSH supports the development of sperm. Hormones produced in the ovaries or testes act on the hypothalamus to complete the HPG axis circuit and act in a feedback loop to regulate hormone levels within predictable limits during reproductive life. In women, with the onset of menopause, estrogen production decreases, and this effect carries over to the rest of the HPG axis. During this phase, GnRH, LH and FSH increase (see Figures 1 and 2). This is accompanied by the onset of hot flushes.

Hot flashes, regardless of the cause, are characterized by bursts of vasomotor symptoms that vary in frequency and intensity. In women going through menopause, hot flashes reflect the decline in estrogen normally associated with aging. This leads to the cessation of the normally synchronized menstrual cycle. This change is associated with an uncontrolled pulse of activity within the HPG axis. Hot flashes are often associated with sleep disturbances and other conditions. Hormone replacement therapy (HRT) has been previously proposed and utilized and is therapeutically effective. Unfortunately, HRT has been proven to increase the risk of vascular disease and malignancy. Effective non-hormonal methods to relieve hot flashes have long been sought to solve this dilemma.

There are hormonal and non-hormonal methods that affect the integrity of the HPG axis and affect hot flashes. Although the exact mechanisms of hot flashes have not been established with certainty, it has been empirically confirmed that they occur after a decrease in regulatory signals on the HPG axis, most commonly affecting GnRH, LH and FSH release.

Hot flashes are an important cause of discomfort and distress for the individual affected. In women, hot flashes represent a decrease in available estrogen most commonly associated with normal aging (menopause). This condition affects millions of women each year.

Hot flashes can occur in both men and women in different situations. This may include surgical removal of the ovary, which rapidly removes the main source of estrogen. In other circumstances, adjuvant hormone manipulation, such as used in the treatment of sex-hormone sensitive malignancies, also abolishes endogenous sex hormone activity. The latter group may include breast cancer in women and prostate cancer in men, each affecting a significant number of individuals each year. Hot flashes as a result of this form of adjuvant therapy may interfere with compliance with treatment, placing these individuals at increased risk from their primary disease.

For example, in women, hot flashes are frequently associated with therapeutic delivery of selective estrogen receptor modulators (SERMs) such as tamoxifen. This treatment is used in premenopausal women with hormone dependent breast, ovarian or uterine cancer. This limits the efficacy of circulating estrogen, which effectively creates a state of estrogen deficiency leading to hot flashes. Hot flashes can also occur after the use of medications to block an enzyme essential for estrogen synthesis (aromatase). There are several aromatase inhibitors (among others anastrozole, essemestane and lotrozole) used in postmenopausal women with hormone dependent breast, ovarian or uterine cancer. These molecules are also contemplated for the treatment of infertility, precocious puberty, endometriosis, gynecomastia, fibroids, precocious puberty and other conditions. In this case, hot flashes are a direct result of decreased estrogen production, which can be measured in circulation.

In men, hot flashes occur when they are treated with hormonal changes that interfere with the production of androgens (testosterone), such as in the treatment of prostate cancer. This may include radical therapy such as castration (orchiectomy), or may decrease hormone production by desensitizing the GnRH receptor. There is a large group of drugs used to stop the production or action of testosterone in the treatment of prostate cancer. These include GnRH agonists or analogs such as leuprolide, goserelin and tryptorelin; GnRH blockers that interfere with testosterone release (degarelix); anti-androgens that block the action of testosterone on prostate cancer cells (bicalutamide, flutamide, nilutamide); abiraterone to block the synthesis of androgens; and enzalutamide for blocking androgen receptor signaling. The result of treatment with these molecules is a decrease in testosterone, which leads to an increase in hot flashes.

Although various methods have been used to treat hot flashes in the past, these methods of treatment have proven inappropriate due to the lack of efficacy or the risks associated with side effects to the treatment. Hormone replacement therapy (HRT) is a form of treatment that supports hormones that are naturally present in the body. HRT treatment aims to complement the levels of estrogen and progestins to lower the levels of LH and FSH, thus reducing menopausal symptoms. However, HRT carries the risk of many other health risk factors including cancer, heart attack and stroke.

Hot flashes have also been treated with serotonin reuptake inhibitors (SSRIs). SSRIs increase the level of serotonin by inhibiting reuptake into presynaptic cells. Theoretically, by increasing the level of serotonin in the brain, the claimed benefits achieved as antidepressants, namely mood improvement and sleep promotion, also serve to alleviate hot flashes. However, the efficacy of SSRIs is controversial.

Selective estrogen receptor modulators (SERMs) are another category of drugs used to treat hot flashes. These drugs act as agonists or antagonists of estrogen receptors throughout the body. However, most SERMs are reported to actually increase hot flashes.

Other drugs, such as anticonvulsant medications (eg gabapentin) and blood pressure medications (eg clonidine), have also been used to treat hot flashes. The mechanism of action of these drugs is poorly understood, and the efficacy of these treatments is controversial. Therefore, there is still a need for effective and safe treatments to reduce the incidence of hot flashes.

The present invention provides a non-hormonal method for a safe and effective treatment strategy in the control of hot flashes. Since the component steps within the HPG axis regulating GnRH are the same in both sexes, this method applies equally to both females and males. The present invention utilizes non-hormonal molecules that mimic the activity of hormones and selectively interact with the HPG axis to modulate hot flashes in the various situations mentioned. Accordingly, the present invention provides a safe and effective method that overcomes the limitations of the prior art with the benefit of promoting compliance to adjuvant chemotherapy.

The present invention is based on a conventional mechanism of using non-hormonal therapy acting through the HPG axis to control hot flashes. This therapy utilizes _{the D 2} family of dopamine receptors as the target therapeutic target. The D ₂ receptor family includes the D ₂ , D ₃ and D ₄ receptors. The D ₂ receptor exists in two isoforms: D _{2 short} (D _2s ) and D _{2 long} (D _{2L ).} D _2s appears especially in the hypothalamus. Members of the D ₂ receptor family may be effective in this capacity through interaction with related molecules that act exclusively on either of these receptors, using certain dopamine agonists. The effect of this interaction can be enhanced through the synergistic effect of selective alpha-2-agonist addition.

The present invention utilizes the ability of molecules to interact with the D2 receptor family in a promiscuous manner to form a new entity, heterodimer. Through the formation of heterodimers, ligands that bind to receptors other than members _{of the D 2 family of receptors, such as D 1} , 5HT1 _B , alpha-2A-adrenergic receptors, can and do interact in novel ways. Specifically, a heterodimer receptor, partially composed of a D ₁ receptor and partially a D ₂ receptor, a D ₁ -D ₂ heterodimer functions as an example.

The heterodimer that is formed allows, depending on its properties, _{the binding of ligands that would otherwise not interact or would otherwise affect D 2} receptor family members to produce a therapeutic response. This has far-reaching implications for understanding the range of effects of molecules known to reduce hot flashes and for designing novel efficacious ligands.

Nevertheless, these molecules of varying composition are widely used in both men and women in the relief of hot flashes, whether caused by the natural events of aging (menopause), surgical removal of the ovaries, or as a result of adjuvant hormone therapy. has a use. This latter situation extends beyond the range of vasomotor symptoms of menopause, but nevertheless contributes to the symptoms of hot flashes, which are effectively treated by targeting the _{HPG axis in particular through the D 2 receptor family.} The present invention meets the long-term need to solve a very common problem and will also help individuals to tolerate adjuvant therapy for the treatment of hormone-induced malignancies, such as breast cancer in women or prostate cancer in men.

1 shows a flow diagram of the female hypothalamic-pituitary-gonad axis hormone feedback pathway.
Figure 2 shows a flow diagram of the male hypothalamic-pituitary-gonad axis hormone feedback pathway.
3 shows the interaction of various neurotransmitters from different presynaptic neurons on various receptors of the target neuron.

The present invention is based on a general mechanism of action using non-hormonal therapies that act via the HPG axis to control hot flashes. _{This therapy utilizes the D 2} family of dopamine receptors as the desired therapeutic target. The D ₂ receptor family includes the D ₂ , D ₃ and D ₄ receptors. The D ₂ receptor exists in two isoforms: D _{2 short} (D _2s ) and D _{2 long} (D _{2L ).} D _2s appears especially in the hypothalamus. Members of the D ₂ receptor family may be effective in this capacity through interaction with related molecules that act exclusively on either of these receptors, using certain dopamine agonists. The effect of this interaction may be enhanced through the synergistic effect of the addition of a selective alpha-2-agonist.

The present invention _{exploits the ability of molecules to interact indiscriminately with the D 2} receptor family to form a new entity, a heterodimer. As expected, this method produces a graded response. Through the formation of heterodimers, ligands that bind to receptors other than members _{of the D 2 family of receptors, such as D 1} , 5HT1 _B , alpha-2A-adrenergic receptors, can and do interact in novel ways. Specifically, the heterodimer receptor, D ₁ -D _{2 heterodimer, constituted in part by D 1} receptors and in part by D ₂ receptors serves as an example. 3 shows how a molecule interacts with one or more receptors and functions as a heterodimer. Presynaptic neurons release neurotransmitters or hormones that act as signals to activate or inhibit receptors on the target neuron. Hormonal signals can bind to specific receptors on target neurons and produce a neuronal response. However, hormonal signals can interact with a variety of receptor types and can interact with different classes of receptors, such as the D ₁ and D ₂ receptors, forming a heterodimer between the two receptors. In this way, typically at D ₂ receptors and cross neurotransmitter molecules that do not interact may influence neuronal responses through interaction with the D ₂ receptors as a dimer heterobifunctional. The _{neurotransmitter molecules with the greatest effect on the D 2} receptor family have the greatest effect on the HPG axis to reduce hot flashes.

The prior art does not address the molecular stimulatory effects of the _{D 2} receptor family, either alone or in combination with other receptors as heterodimers, to reduce hot flashes. This analysis demonstrates that a positive response of reduced hot flush frequency and intensity is graded and dependent on the evaluated ligand. This distinction is based on awareness of the breadth of effective molecules utilized and the neuro-regulatory circuits affected. The present invention, without being limited to a particular compound, provides a novel non-hormonal method for the control of hot flashes in a multi-clinical setting based on the site of action, the HPG axis.

The heterodimer formed allows, depending on its properties, the binding of a ligand that does not interact with or is expected to affect _{D 2 receptor family members.} In this way, _{molecules not expected to affect the D 2} receptor family can bind and provide a therapeutic response. This has broad implications for understanding the range of efficacy of molecules known to reduce hot flashes and for designing novel efficacious ligands.

As mentioned above, hot flashes can occur naturally in women. This is through the aging process in which estrogen levels decrease, leading to hot flashes. However, hot flashes can also be induced in men and women by treatment of other diseases or conditions that are hormone dependent, for example, in the treatment of hormone-dependent cancers. The present invention aims, in particular, to reduce the effect of hot flashes by targeting the HPG axis via the _{D 2 receptor family.} Therefore, _{molecules with relevant specific activity in the D 2} receptor family are active and effective in the reduction of hot flashes. Additionally, the molecule is effective in a graded response, based on heterodimer formation with receptors of the _{D 2 family.} Due to the promiscuous nature of the D ₂ receptor family trait, there are many possible combinations. The affinity of a particular ligand molecule and the unique heterodimer formed determine the extent of the response produced in the regulation of hot flashes.

Pramipexole (Mirapex) is listed as an example of _{a D 2} class receptor agonist (binding D ₂ , D ₃ or D ₄ receptor) that blocks hot flashes, including the vasomotor symptoms of menopause. Pramipexole (Mirapex) in combination with an alpha-2-agonist (eg, tizanidine or clonidine) has enhanced activity in blocking hot flashes, including the vasomotor symptoms of menopause, and a D ₂ receptor family agonist and alpha It has been clinically shown that the beneficial effects of -2-agonists are potentiated together, and thus they act synergistically together to reduce the frequency and intensity of hot flashes. The combined agents provide a longer duration of effect.

_{All D 2} ( _{binds to D 2} , D ₃ or D ₄ receptors) family members tested to date in controlling hot flashes, including vasomotor symptoms of menopause, i.e. ropinirole, pramipexole, loti Based on the unique observed activity of gotin and pyrivedil, current or future D ₂ class ( _{binding D 2} , D ₃ or D ₄ receptors) agonists, either individually or in combination with synergistic alpha-2-agonists However, there is evidence in the document that it is effective in the control of hot flashes, including the vasomotor symptoms of menopause.

Finally, based on observations, _{ligand molecules that are not related to a specific D 2} receptor family (eg paroxetine, venlafaxine, etc.) are not related to the D ₂ family of receptors (D ₂ , D ₃ or D ₄ ) through heterodimer formation. effective in a graded manner for use in alleviating hot flashes, including vasomotor symptoms of menopause consistent with indirect activity in

Nevertheless, these ligand molecules of varying composition are useful in alleviating hot flashes in men and women, whether caused by the natural events of aging (menopause), surgical removal of the ovaries or as a result of adjuvant hormone therapy. It is widely used by all. This latter situation extends beyond the range of vasomotor symptoms of menopause, but nevertheless contributes to the symptoms of hot flashes _{, which are nevertheless effectively treated, particularly by targeting the HPG axis through the D 2 receptor family.} The present invention meets the long-term need for a very common problem, and will also assist individuals who tolerate adjuvant therapy for the treatment of hormone-induced malignancies, such as breast cancer in women or prostate cancer in men.

clinical research

_{Clinical studies have shown that various molecules with D 2} receptor family activity (D ₂ , D ₃ , or D ₄ dopamine agonists) include hot flashes when treating menopausal symptoms in women, particularly when combined with alpha-2-adrenergic agonists. It clearly shows that it provides excellent control of menopausal symptoms. A case study of 4 different women was _{conducted by treating them with ropinirole (a D 2} receptor class dopamine agonist) and tizanidine (an alpha-2-adrenergic agonist). _{The efficacy of a D 2} agonist alone for treating hot flashes has been demonstrated in a study. Relief from hot flashes was further enhanced with further treatment with an alpha-2-adrenergic agonist. This combination provided an extended period of clinical benefit.

Patients were treated by escalating the dose of ropinirole to 4 mg and tested the hypothesis of a dopaminergic regulated pathway in the central nervous system affecting hot flashes. Ropinirole, a dopaminergic agonist, was increased from an initial dose of 0.25 mg to a final dose of 4 mg at bedtime, without side effects, and the previously intolerable menopausal hot flashes were dramatically stopped.

The first woman, JK (58 years old), started experiencing symptoms of insomnia and initially received low-dose hormone replacement therapy (HRT), which did not help her sleep cycle. Despite two changes in the dosage and formulation of HRT, no significant benefit was realized in the sleep cycle. No effort was made to treat her sleep problems with standard sedative hypnotics such as zolpidem, zaleplon, temazepam or clonazepam. Then hot flushes began, becoming more frequent and more intense. They were characterized by severe flushing of the face and upper chest with drenched sweat. Each hot flush typically lasts 30-90 seconds and is accompanied by intense heat. The hot flashes will then subside quickly with a cooling sensation that reflects the normal physiological function of sweat evaporation. A period of 10 minutes to 90 minutes will elapse before subsequent hot flashes occur both during the day and at night. Although not all of the same intensity, it was common to have as many as 20 to 30 hot flushes, and as many as 40 hot flushes throughout the day when the frequency peaked.

Treatment was initially initiated with tizanidine, a non-selective alpha-2-adrenergic agonist, with the aim of providing sleep aids. Tizanidine is available as a graded 4 mg tablet that can be easily divided into 4 1 mg portions. Therefore, the initial dose was 1 mg at bedtime and the dose was increased as needed, as needed, up to a maximum of 8 mg, usually at bedtime. However, if a maximum of 8 mg was not taken at bedtime, the patient could use a maximum residual dose of tizanidine, but not to exceed a total of 8 mg at night when waking up at night and found unable to go back to sleep. This was not necessary, and when sleeping, she was able to sleep at night, waking up intermittently but quickly returning to sleep.

Safety monitoring included ensuring that, as this was achieved, there were no problems with liver function, hypotension or abnormal dreams. Tizanidine, if necessary, can be re-administered at night without causing a morning "hangover" effect, with a sleep window of 4 hours available.

HRT was not an option for controlling her hot flashes because the woman was diagnosed with hormone receptor-positive breast cancer. She had additional challenges in the potential treatment of hot flashes because of a history of breast cancer. This is partly because she has undergone chemotherapy that causes peripheral neuropathy. As a result, the hot flashes she experienced were perceived more strongly, as the overwhelming sensation of increased body temperature was diametrically opposed to the constant freezing cold of neuropathy felt in both feet. Also, she was on an aromatase inhibitor (anastrozole, 1 mg daily), a drug that blocks the production of estrogen and progesterone, in fact an anti-HRT. This further exacerbated hot flashes as "super" hot flashes, a known side effect of these types of medications. For her, "super" hot flashes exceeded the intensity of menopausal hot flashes previously experienced. This hot flush was a blow. They interfered with her normal functioning, required changing underwear and clothes to work, interfered with sleep, and interfered with her ability to perform the normal activities of daily living. They also affected her safety and the safety of others, with respect to her ability to drive effectively and perform duties accurately.

Other medicinal alternatives reported in the medical literature with partial success in reducing hot flashes frequency and severity by 50% were evaluated by titration at the reported dose and maintained at that dose for at least a 2-week trial. These include clonidine at doses up to 0.4 mg, gabapentin at doses up to 1800 mg, and benflaxamine at doses up to 300 mg. However, this was not satisfactory in reducing hot flashes by more than 25% in this individual. Thus, after failed trials with these drugs, the focus shifted to trials with a novel drug, ropinirole, which is a dopamine agonist.

With ropinirole, the goal is to modulate GnRH and control the uninhibited LH pulses characteristic of menopause, through action on _{D 2} and D _{3 receptors in the hypothalamus.} Previous ineffective dopaminergic agonists used for this purpose have the opposite action on these molecules, as they act on the _{D 1} and D _{5 receptors.} The response of D ₁ and D ₅ receptors versus D ₂ , D ₃ and D ₄ receptors is opposite.

Ropinirole titrations were initiated at bedtime of 0.25 mg and, if tolerated, doses increased up to 1 mg (i.e. 0.25 mg, 0.50 mg, 0.25 mg, 0.50 mg; 0.75 mg, 1 mg). If higher doses were required, 1 mg or 2 mg thereafter, and 1 mg and 2 mg ropinirole tablets were used with titrations continued in 0.25 mg steps every 4 days, until a maximum of 4 mg was reached. A higher ropinirole dose was not required for clinical suppression of hot flashes in this woman and was not tested because of the higher likelihood of side effects such as nausea, hallucinations or agitation.

Using this protocol, we could help these patients fall asleep within 15 to 20 minutes instead of tossing and turning for up to two hours before sleep. In addition, this patient was able to sleep at night for 7 to 8 hours with this treatment and, without treatment, woke up 2-3 times per hour.

The combination of ropinirole and tizanidine, until the next evening's follow-up dosing, completely eliminates the frequency and severity of hot flashes experienced by this patient prior to treatment, thereby helping to provide sleep, sleep maintenance and significant additional relief. represents a novel combination. This was a very significant and dramatically noteworthy improvement compared to any of the previous options available. Ropinirole has been shown to reduce hot flashes as a dopaminergic agonist at _{D 2} , D ₃ and D _{4 receptors.} The novel combination of ropinirole and tizanidine was further effective in completely eliminating the most severe form of hot flashes, with the strongest vasomotor symptoms. This completely stopped the frequency and intensity of these symptoms. When the dose of ropinirole was removed, the symptoms reappeared. When ropinirole was re-administered at 4 mg, the hot flashes disappeared again. The remission period of the combination of ropinirole and tizanidine made it possible to administer once a day.

The second woman, JM, is a 52-year-old woman with multiple sclerosis (MS) for 26 years. She suffered from visual disturbances, inability to walk due to spinal symptoms, severe neurogenic bladder with incontinence, fatigue, and multiple hot flushes throughout the day causing intense sweating and burning sensations in her body. Ironically, along with a sense of heat, there was an overwhelming feeling of weakness and fatigue. This was probably reflecting what is known in MS as a "pseudoexacerbation" phenomenon. Central nervous system (CNS) nerve fibers that have already been physically damaged but have been physiologically compensated to some extent may lose their ability to compensate as body temperature rises. The function of these nerve fibers can once again improve as body temperature cools.

Patient JM is extremely sensitive to temperature and wears a cooling vest to remain on the cooling side for this very purpose. Prior to treatment with ropinirole for control of hot flashes, JM was experiencing hot flashes 15-20 times per day, accompanied by severe facial and chest redness and associated weakness. She tried to cool her body with a hand-held, battery-powered fan and drink ice-cooling liquid. The effort ameliorated her symptoms to some extent by shortening the duration of her hot flashes-related weakness, but did not prevent a recurrence. Hormone replacement therapy (HRT) was not an acceptable option for her due to her high risk profile and smoking history for deep vein thrombosis (DVT) due to stroke-induced immobility in MS.

She was using tizanidine for the treatment of convulsions, and the dose was adjusted to give 8 mg at bedtime to facilitate sleep. She also titrated up to 4 mg of ropinirole daily at bedtime, completely eliminating vasomotor symptoms (hot flushes) without side effects. The combination of ropinirole and tizanidine provided long-term benefits, enabling once-daily dosing. In addition, there was also a solution to the MS disabling phenomenon. The combination of these two drugs helps her to sleep, maintain sleep, and completely eliminate hot flashes of menopause, in situations where HRT is contraindicated due to immobility and high risk of vascular complications from smoking (DVT). provided a novel product that gave

A third woman, DH, is a 53 year old female with multiple peripheral nerve injury and diabetes. She entered menopause two years ago and developed menopause symptoms of hot flashes lasting 15-30 seconds each with a frequency of 15-20 hot flashes per day. During these hot flashes there was flushing and redness of the face and chest, along with sweat dripping, which interfered with the ability to get a normal night's sleep. Even before hot flashes started, she was able to sleep using the sedative hypnotic drug temazepam.

After hot flashes began, she had trouble sleeping all night because she felt very cold from the hot sweats associated with the hot nights. HRT was not an acceptable form of treatment due to metabolic problems associated with the control of diabetes. She was then given a combination of tizanidine titrated to a maximum of 8 mg at bedtime, and ropinirole titrated to 4 mg at bedtime, as with other patients. Her sleep improved, and her hot flashes were completely resolved with once-daily administration of ropinirole (4 mg) and tizanidine (8 mg) at bedtime without adverse side effects.

Stopping hot flashes in combination with uninterrupted sleep not only leads to more productive work, but also leads to a safer day, with respect to activities where attention is essential, such as driving a car. Her diabetes was kept under good control.

A fourth woman, PW, is a 48-year-old woman with chronic neuropathic pain disorder, who entered menopause at a younger age than most, but, like most women, developed hot sweats and hot sweats. Hot flushes were associated with flushing of the face and flushing of the chest. Each of these episodes lasted 15 to 30 seconds and occurred 10 to 15 times per day. She was already being treated with clonidine, gabapentin and benflaxamine for neuropathic pain and related depression, and developed these hot flashes despite these medications. Hormone replacement therapy (HRT) was contraindicated because of its potential to exacerbate depression. Tizanidine 4 mg was titrated for sleep to 8 mg at bedtime, and treatment with ropinirole was started and titrated to 4 mg at bedtime. She slept and took ropinirole 4 mg at bedtime, which completely resolved the frequency and severity of hot flashes without undesirable side effects. She previously exhibited irritability and poor concentration that seemed to improve as hot flashes faded and sleep improved.

The combination of these two agents (ropinirole and tizanidine) aids in sleep and sleep maintenance by completely eliminating the frequency and severity of hot flashes that are resistant to other medications described as potentially useful in the medical literature and significantly improves sleep. It represents a novel combination that provides relief. The duration of benefit of using this combination allows for once-daily dosing. HRT would not have been an acceptable alternative for this patient because of the potential for negative effects on the already altered mood states associated with pain disorders. This new product was effective in completely eliminating her strong vasomotor symptoms (hot flashes) and improving her sleep ability.

The two most incapacitating symptoms of menopause are hot flashes and disruption of normal sleep patterns. Although there have been numerous attempts to address each of these symptoms individually, treatment methods to date have not adequately addressed the symptoms, many of which have created additional health risks. Additionally, there is no single product that addresses all of these symptoms. The present invention describes novel and novel uses of _{D 2} receptor class dopamine agonists for alleviating and controlling menopausal symptoms, and in particular hot flashes, in women. As a dopamine agonist, ropinirole is believed to bind to D ₂ , D ₃ or D _{4 receptors, particularly at the D 3 site.} This affinity inhibits the production of GnRH, which reduces the production of LH and FSH in the pituitary gland. LH and FSH are vasodilators, and lower beat levels of LH and FSH reduce the incidence of hot flashes.

In another clinical study, a total of 6 women with dramatic vasomotor hot flashes and sleep disturbances were evaluated, including ropinirole (4 mg) (a D ₂ , D ₃ or D ₄ dopamine agonist), tizanidine (4 mg) ( Alpha-2-adrenergic agonist), clonidine (0.1 mg) (alpha-2-adrenergic agonist), rotigotine (1 mg) (D ₂ , D ₃ or D ₄ dopamine agonist), pramipexole (1.5 mg) (D ₂ , D ₃ or D ₄ dopamine agonists), or the D ₂ antagonists chlorpromazine (25 mg) or haloperidol (1 mg) as sedatives. Patients received each regimen at the stated dose for up to 4 weeks.

Symptoms were rated on a scale of 0 to 4, with 0 being unaffected, 1 being mild, 2 being moderate, 3 being severe, and 4 being very severe, and for each patient overnight vasomotor symptom frequency, severity, and sweating. , sleep and wakefulness were assessed at the end of the treatment period. The reported findings are based on the average of the reported symptoms of the six women studied.

Specifically, with regard to hot flush frequency, the evaluation was based on the number of hot flushes per day. The frequency of hot flashes was rated on a scale of 0-4, where 0 is not detected, 1 is 1-4 times/day (mild), 2 is 5-8 times/day (moderate), and 3 is 9-12. times/day (severe), 4 is more than 12 times/day (very severe).

The severity of hot flashes, which reflects hot flash duration, was also graded on a scale of 0-4, where 0 is not detected, 1 is mild (less than 1 min), 2 is moderate (1-2 min), and 3 is Severe (2-3 minutes), 4 is very severe (more than 4 minutes). This evaluation reflects the duration and intensity of the individual's evaluation.

The sweating response was also rated on a scale of 0-4, with 0 being not detected, 1 being mild (minimum wetting of the skin), 2 being moderate (wetting of the skin), and 3 being severe (significant sweating, hair loss). , ears, neck, chest) and 4 are very severe (sweating).

Falling asleep was also graded on a scale of 0-4, with 0 being no problem (less than 15 minutes), 1 being mild (15-20 minutes), 2 being moderate (20-40 minutes), and 3 being severe. (40-60 minutes), 4 is very severe (more than 60 minutes).

Waking was also rated on a scale of 0-4, with 0 being not detected, 1 being mild (1-5 waking/night), 2 being moderate (5-10 waking up/night), and 3 being Severe (10-15 wakings/night) and 4 are very severe (more than 15 wakings/night).

The D ₂ receptor family (D ₂ , D ₃ or D ₄ ) agonists ropinirole, rotigotine and pramipexole were investigated _{and compared to the D 2} receptor family antagonists chlorpromazine or haloperidol. Ropinirole and pramipexole were evaluated alone and in combination with the alpha-2-adrenergic agonist tizanidine or clonidine.

Additionally, venlafaxine, paroxetine, gabapentin and pregabilin interact with and affect the _{D 2 receptor, and act as D 2} agonists. Venlafaxine and paroxetine form a heterodimer with the _{D 2} receptor and exhibit a response similar to that of a _{D 2 agonist.} Additionally, there are a number of interactions between gabapentin and pregabalin and _{the D 2} family of receptors that cause the release of dopamine and also include effects on N-type calcium channel receptors. Venlafaxine, paroxetine, gabapentin and pregabilin were also evaluated compared to tizanidine.

The table below summarizes the treatment results.

cure hot flushes
frequency hot flushes
severity Sweat Reactivity sleep waking up unprocessed 3 3 3 2 4 D ₂ agonist group ropinirole 0 0 0 One One rotigitin 0 0 0 0 One pramipexole 0 0 0 0 One venlafaxine 2 2 3 2 3 paroxetine 2 2 3 2 2 gabapentin 2 2 3 2 2 pregabilin 2 2 3 2 One Alpha-2-adrenergic agonists tizanidine 2 2 3 0 One clonidine 2 2 3 One 2 Ropinirole and Tizanidine 0 0 0 0 One Ropinirole and Clonidine 0 0 0 0 One pramipexole and tizanidine 0 0 0 0 One pramipexole and clonidine 0 0 0 0 One venlafaxine and tizanidine 2 One 2 0 One Paroxetine and Tizanidine 2 One 3 0 One Gabapentin and Tizanidine One One 2 0 One Pregabilin and Tizanidine One 2 3 0 One D ₂ antagonist group chlorpromazine 4 4 4 0 4 haloperidol 4 4 4 0 4

All six patients experienced very significant symptoms without treatment. With ropinirole, rotigotine or pramipexole alone, the frequency and severity of vasomotor symptoms were significantly reduced, and sweating was also reduced. The effect on sleep was limited. With tizanidine or clonidine alone, there was a very slight decrease in vasomotor symptoms, but an impressive effect on sleep. The combination of ropinirole or pramipexole with tizanidine or clonidine was synergistic and provided a stronger response. In addition, the duration of the effect was _{greater in the combination of the D 2} receptor family agonist and the alpha-2 agonist _{than when the D 2} agonist alone was used, so that once-daily administration was possible using this combination. Venlafaxine (75 mg), paroxetine (20 mg), gabapentin (300 mg), and pregabilin (50 mg) also reduced hot flashes compared to untreated patients. When tizanidine (4 mg) was administered in combination with venlafaxine, paroxetine, gabapentin and pregabilin, this combination was synergistic and produced a stronger response in the reduction of hot flashes and other vasomotor symptoms.

In contrast, D ₂ receptor family antagonists, chlorpromazine or haloperidol, exacerbate menopausal symptoms, confirming a central role of the _{D 2 receptor family in the development of these symptoms.}

In another clinical study, _{the results of treatment with a combination of a D 2} , D ₃ or D ₄ dopamine agonist and an alpha-2-adrenergic agonist were found to be more beneficial than the cumulative effect of treatment with these compounds individually, thus D ₂ , D ₃ or D ₄ demonstrate that dopamine agonists and alpha-2-adrenergic agonists act synergistically together. In this study, a total of 8 women with menopausal vasomotor symptoms and sleep disturbances were evaluated, including ropinirole (4 mg) (a D ₂ , D ₃ or D ₄ dopamine agonist), tizanidine (4 mg) (alpha-2 -adrenergic agonist), ramelteon (8 mg) (substances that are not classified as sedatives, but have sedative effects), ropinirole (4 mg)/tizanidine (4 mg) or ropinirole (4 mg)/ramelteon (8 mg) treated at bedtime. Patients received each regimen at the stated dose for at least 4 weeks.

Symptoms were rated on a scale of 1 to 4, with 1 being mild, 2 being moderate, 3 being severe, and 4 being very severe, and the expression of any one of vasomotor symptom frequency, severity, sweating, sleep and nocturnal waking was each Evaluate the patient and at the end of the treatment period. The findings were based on the average of symptoms reported for the eight women investigated.

In particular, with regard to hot flash frequency, the evaluation was based on the number of hot flashes per day. The frequency of hot flashes was rated on a scale of 1-4, with 1 being 1-4 times/day (mild), 2 being 5-8 times/day (moderate), and 3 being 9-12 times/day (severe). , and 4 are 12 or more/day (very severe).

The severity of hot flashes was rated on a scale of 1-4, with 1 being mild (less than 1 minute), 2 being moderate (1-2 minutes), 3 being severe (2-3 minutes), and 4 being very severe (4). minutes or more). This assessment reflects the duration and intensity of the assessment by the individual.

Perspiration reactivity was rated on a scale of 1 to 4, with 1 being mild (minimal wetting of the skin), 2 being moderate (wetting the skin), 3 being severe (significant sweating, hair, ears, neck, chest), and 4 being Very severe (sweating).

Sleep was rated on a scale of 1-4, with 1 being mild (15-20 minutes), 2 being moderate (20-40 minutes), 3 being severe (40-60 minutes), and 4 being very severe (60 minutes). above).

Awakening was rated on a scale of 1-4, with 1 being mild (1-5 waking/night), 2 being moderate (5-10 waking/night), and 3 being severe (10-15 waking/night). ) and 4 are very severe (more than 15 wakings/night).

The table below summarizes the treatment results:

cure hot flushes
frequency hot flushes
severity Sweat Reactivity sleep waking up unprocessed 4 4 3 4 3 Ropinirole (4 mg) One One One 3 3 Tizanidine (4 mg) 3 3 3 2 2 Ramelteon (8mg) 4 4 3 3 3 Ropinirole/tizanidine 0 0 0 0 One ropinirole/ramelteon One 2 2 3 3

All eight patients experienced very severe symptoms without treatment. Ropinirole alone significantly but incompletely reduced the frequency and severity of vasomotor symptoms and also reduced sweating. The effect on sleep was limited. Tizanidine alone reduced vasomotor symptoms very slightly, but had a more impressive effect on sleep. The sleeping pill ramelteon had no effect on vasomotor symptoms and had a limited effect on sleep in this postmenopausal population. The combination of ropinirole and tizanidine was synergistic, and when used alone, it showed a more remarkable effect on vasomotor symptoms and sleep than any other drug. Vasomotor symptoms were completely eliminated, sleep duration was significantly improved, and waking was significantly reduced. Since the duration of effect was longer in _{the combination of the D 2} receptor class agonist and the alpha- ₂ agonist than the D 2 agonist alone, once-daily administration was possible using this combination. In contrast, the combination of ropinirole and ramelteon did not outperform either agent when used alone.

The present invention has been disclosed in terms of a preferred embodiment which fulfills all the objectives of the invention and overcomes the limitations of the prior art. Various changes, modifications and variations from the teachings of the present invention may be considered by those skilled in the art without departing from the intended spirit and scope of the present invention. It is intended that the invention be limited only by the terms of the appended claims.

Claims (12)

A method of treating hot flash, comprising:
administering to a person experiencing hot flashes an effective amount of a chemical composition, the composition being a dopamine agonist capable of binding to a _{D 2} , D ₃ , or D _{4 dopamine agent;} and evaluating the effect of administering the composition. The method of claim 1, wherein the method of administering the chemical composition comprises administration of the composition in a pill, oral administration of the composition in liquid form, intravenous administration of the composition in liquid form, and administration of the composition using a transdermal patch. , and administration of the composition by inhalation. A method of treating hot flushes comprising:
administering to a person experiencing hot flashes an effective amount of a chemical composition, wherein the composition is _{a dopaminergic agonist capable of binding D 2} , D ₃ , or D ₄ dopamine receptors, binding to an alpha-2-adrenergic receptor A method comprising administering to a human an effective amount of a chemical composition that is an alpha-2-adrenergic agonist capable of acting, and evaluating the effect of administering the composition. 4. The method of claim 3, wherein the method of administering the chemical composition which is a dopamine agonist is by administration of the composition in pills, oral administration of the composition in liquid form, intravenous administration of the composition in liquid form, administration of the composition using a transdermal patch, and inhalation. The method of administration of the chemical composition selected from the group consisting of administration of the composition, wherein the chemical composition is an alpha-2-adrenergic agonist is administration of the composition in pills, oral administration of the composition in liquid form, intravenous administration of the composition in liquid form, and a transdermal patch. wherein said method is selected from the group consisting of administration of the composition, and administration of the composition by inhalation. A composition for the treatment of hot flushes, comprising a substance that is a dopamine agonist capable of binding to a D ₂ , D ₃ or D _{4 dopamine receptor, and a substance that is an alpha-2-adrenergic agonist.} The composition according to claim 5, comprising a form that can be administered to an individual as a pill. 7. The composition of claim 6, comprising a form that can be administered to an individual as a pill, wherein the dopamine agonist and the alpha-2-adrenergic agonist are separately disposed in the pill. 7. The composition of claim 6, comprising a form that can be administered to an individual as a pill, wherein the dopamine agonist and the alpha-2-adrenergic agonist are combined in the pill. 6. The composition of claim 5, comprising a form that can be administered orally to an individual as a liquid. 6. The composition of claim 5, comprising a form for intravenous administration to an individual as a liquid. 6. The composition of claim 5, comprising a form that can be administered to an individual by inhalation. The method according to claim 5, wherein the _{substance which is a dopamine agonist capable of binding to D 2} , D ₃ or D ₄ dopamine receptors is ropinirole, rotizitin, pramipexole, pyrivedil, venlafaxine, paroxetine, gabapentin and pregabilin. wherein the substance is selected from the group consisting of tizanidine and clonidine, wherein the substance is an alpha-2-adrenergic agonist.

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