WO2020219270A1 - Traitement non hormonal de bouffées de chaleur - Google Patents

Traitement non hormonal de bouffées de chaleur Download PDF

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WO2020219270A1
WO2020219270A1 PCT/US2020/027238 US2020027238W WO2020219270A1 WO 2020219270 A1 WO2020219270 A1 WO 2020219270A1 US 2020027238 W US2020027238 W US 2020027238W WO 2020219270 A1 WO2020219270 A1 WO 2020219270A1
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Prior art keywords
hot flashes
composition
administration
agonist
treatment
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PCT/US2020/027238
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English (en)
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Robert L. KNOBLER
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Knobler Robert L
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Priority claimed from US16/390,276 external-priority patent/US11903926B1/en
Application filed by Knobler Robert L filed Critical Knobler Robert L
Priority to AU2020262851A priority Critical patent/AU2020262851A1/en
Priority to JP2021563312A priority patent/JP2022532851A/ja
Priority to KR1020217037881A priority patent/KR20220010721A/ko
Priority to EP20795747.3A priority patent/EP3958862A4/fr
Priority to BR112021021260A priority patent/BR112021021260A2/pt
Priority to CA3137710A priority patent/CA3137710A1/fr
Priority to SG11202112822VA priority patent/SG11202112822VA/en
Publication of WO2020219270A1 publication Critical patent/WO2020219270A1/fr
Priority to IL287457A priority patent/IL287457A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • Hot flashes may be caused by menopause and they may be caused by various methods of treatment of diseases and conditions which share a common biochemical pathway, the hypothalamic-pituitary-gonadal (HPG) axis.
  • HPG hypothalamic-pituitary-gonadal
  • the subject invention exploits the HPG neurochemical pathway for use in the non-hormonal treatment of hot flashes.
  • the HPG axis pathway is present in both women and men, and the treatment simulates naturally occurring neurotransmitters to control hot flashes in both men and women.
  • GnRH gonadotropin releasing hormone
  • Hot flashes are characterized by bursts of vasomotor symptoms that vary in frequency and intensity.
  • hot flashes reflect a reduction in estrogen associated with normal aging. This leads to disruption of the normally synchronized menstrual cycle. This change is associated with dysregulated pulses of activity within the HPG axis.
  • the hot flashes are often associated with sleep disturbances and other symptoms.
  • Hormone replacement therapy HRT has previously been suggested, utilized, and is therapeutically effective. U n nowadays, HRT has been demonstrated to increase the risk of vascular and malignant disease. An effective non-hormonal method of relieving hot flashes has long been sought to remedy this dilemma.
  • Hot flashes are an important cause of discomfort and distress to affected individuals.
  • Hot flashes may also occur in both men or women under other circumstances as well. This can include the surgical removal of the ovaries, which rapidly eliminates the primary source of estrogen. In other circumstances, adjunctive hormonal manipulation, such as that utilized in the treatment of sex hormone-sensitive malignant diseases, also eliminates endogenous sex hormone activity. The latter groups can include breast cancer in women and prostate cancer in men, which each also affect significant numbers of individuals annually. Hot flashes as a consequence of this form of adjuvant therapy can impede compliance with treatment, putting these individuals at increased risk from their primary disease.
  • SERMs selective estrogen receptor modulators
  • tamoxifen a selective estrogen receptor modulator
  • This treatment is utilized in pre-menopausal women with hormone-dependent breast, ovarian or uterine cancer.
  • Hot flashes may also follow the use of medication to block the enzyme (aromatase), essential for the synthesis of estrogen.
  • aromatase inhibitors anastrozole, exemestane and letrozole amongst others
  • GnRH agonists or analogues such as, leuprolide, goserelin and triptorelin; GnRH blocking agents (degarelix) to impede testosterone release; anti androgens (bicalutamide, flutamide, nilutamide), which block the action of testosterone on prostate cancer cells; abiraterone, to block the synthesis of androgen; and, enzalutamide, to block androgen receptor signaling.
  • GnRH agonists or analogues such as, leuprolide, goserelin and triptorelin
  • GnRH blocking agents degarelix
  • anti androgens biutamide, flutamide, nilutamide
  • abiraterone to block the synthesis of androgen
  • enzalutamide to block androgen receptor signaling.
  • H RT Hormonal Replacement Therapy
  • HRT treatment aims to supplement levels of estrogen and progestin to reduce levels of LH and FSH and thus reduce menopausal symptoms.
  • H RT brings with it the risk of a number of other health risks including cancer, heart attack, and strokes.
  • Hot flashes have also been treated with serotonin re-uptake inhibitors (SSRIs).
  • SSRIs increase levels of serotonin by inhibiting its re-uptake into presynaptic cells.
  • the claimed benefits achieved as an anti- depressant i.e. improving mood and promoting sleep, also serve to alleviate hot flashes.
  • SERMs Selective Estrogen Receptor Modulators
  • the subject invention provides a non-hormonal method for a safe and effective treatment strategy in the control of hot flashes. Because the component steps within the HPG axis that regulate GnRH are identical in the two sexes, this method is equally applicable to both women and to men.
  • the invention utilizes non-hormonal molecules, which mimic the activity of the hormones and selectively interact with the HPG axis to regulate hot flashes under the varied circumstances noted.
  • the invention therefore, provides a safe, effective method which overcomes the limitations of the prior art with the benefit of facilitating compliance to adjunctive chemotherapy.
  • the present invention is based upon a common mechanism of action utilizing non- hormonal treatments, acting through the HPG axis to control hot flashes.
  • This treatment exploits the D 2 family of dopamine receptors as the desired therapeutic target.
  • the D 2 family of receptors includes D 2 , D 3 and D 4 receptors.
  • the D 2 receptor exists in two isoforms, the D 2 sho r t (D 2s ) and the D 2
  • the D 2s is notably represented within the hypothalamus.
  • the D 2 receptor family members may be effective in this capacity through interaction with relevant molecules acting exclusively on any one of these receptors, utilizing specific dopamine agonists. The effectiveness 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 interacting with the D 2 receptor family in a promiscuous manner, to form a new entity, a heterodimer.
  • ligands which bind to receptors other than members of the D 2 family of receptors such as Di, 5HT1 B , alpha-2A-adrenergic receptors, can and do interact in a novel manner.
  • a heterodimer receptor composed in part by the Di receptor and in part by the D 2 receptor, a DI-D 2 heterodimer serves as an example.
  • the heterodimer that is formed allows binding of a ligand that would not otherwise interact or be anticipated to influence the D 2 receptor family member to yield a therapeutic response. This has broad implications in
  • Fig. 1 shows a flowchart of the female hypothalamic-pituitary-gonadal axis hormonal feedback pathway.
  • Fig. 2 shows a flowchart of the male hypothalamic-pituitary-gonadal axis hormonal feedback pathway.
  • Fig. 3 shows the interaction of various neurotransmitters from different presynaptic neurons on the various receptors of a target neuron.
  • the present invention is based upon a common mechanism of action utilizing non- hormonal treatments, acting through the H PG axis to control hot flashes.
  • This treatment exploits the D 2 family of dopamine receptors as the desired therapeutic target.
  • the D 2 family of receptors includes D 2 , D 3 and D 4 receptors.
  • the D 2 receptor exists in two isoforms, the D 2 short (D 2s ) and the D 2
  • the D 2s is notably represented within the hypothalamus.
  • the D 2 receptor family members may be effective in this capacity through interaction with relevant molecules acting exclusively on any one of these receptors, utilizing specific dopamine agonists. The effectiveness 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 interacting with the D 2 receptor family in a promiscuous manner, to form a new entity, a heterodimer. Predictably, this method yields a graded response.
  • ligands which bind to receptors other than members of the D 2 family of receptors such as Di, 5HIT1 B , alpha-2A-adrenergic receptors, can and do interact in a novel manner.
  • a heterodimer receptor composed in part by the Di receptor and in part by the D 2 receptor, a DI-D 2 heterodimer serves as an example.
  • Figure 3 illustrates how molecules may interact with more than one receptor and function as a heterodimer.
  • Presynaptic neurons release neurotransmitters or hormones which act as signals to activate or inhibit receptors on target neurons.
  • the hormonal signals may bind to a specific receptor on the target neuron to produce a neuronal response.
  • hormonal signals may interact with various receptor types and may interact with different families of receptors, for example, Di and D 2 receptors forming a heterodimer between the two receptors. In this manner,
  • neurotransmitter molecules which would not typically interact with the D 2 receptor, may influence the neuronal response through interaction with the D 2 receptor as a heterodimer.
  • the neurotransmitter molecules which have the greatest impact on the D 2 receptor family will have the greatest effect on the HPG axis to reduce hot flashes.
  • the prior art does not address the effect of molecular stimulation of the D 2 receptor family, alone or in combination with other receptors as a heterodimer, to reduce hot flashes.
  • This analysis demonstrates that a positive response, of reduced hot flash frequency and intensity, is graded and dependent on the ligand evaluated. This distinction is based upon recognition of the breadth of effective molecules utilized, and the neuro-regulatory circuit impacted.
  • the present invention provides a new, non-hormonal method for regulation of hot flashes in multiple clinical settings based upon the site of action, the HPG axis, and not confined to a specific compound.
  • the heterodimer that is formed allows binding of a ligand that would not otherwise interact or be anticipated to influence the D 2 receptor family member. In this way, molecules, not otherwise anticipated to impact the D 2 receptor family, can bind and yield a therapeutic response. This has broad implications in understanding the scope of effectiveness of molecules known to reduce hot flashes and in the design of new effective ligands.
  • hot flashes may naturally be caused in women. This is through the aging process during which estrogen levels become reduced, leading to hot flashes.
  • hot flashes may also be caused in men and women by treatment of other diseases or conditions which are hormone dependent, for example in treatment of hormone- dependent cancers.
  • the subject invention seeks to reduce the effect of hot flashes by targeting the HPG axis , specifically through the D 2 receptor family. Therefore, molecules with relevant specific activity at the D 2 receptor family are active and effective in reducing hot flashes. Additionally, molecules are also effective, in a graded response, based upon the formation of heterodimers with the D 2 family of receptors. There are many possible combinations, due to the promiscuous nature of the D 2 receptor family properties. The affinity of the specific ligand molecule and the unique heterodimer formed will determine the degree of response generated in the regulation of hot flashes.
  • Pramipexole (Mirapex) is listed as an example of a D 2 family receptor agonist (binding to D 2 , D 3 or D 4 receptors) in blocking hot flashes, including vasomotor symptoms of menopause.
  • Pramipexole (Mirapex) combined with an alpha-2-agonist (e.g. tizanidine or clonidine), has enhanced activity in blocking hot flashes, including vasomotor symptoms of menopause and it has been clinically shown that the beneficial effect of the D 2 receptor family agonist and the alpha-2-agonist together are enhanced such that they synergistically work together to reduce hot flash frequency and intensity.
  • the combined agents provide a longer duration of effect.
  • ligand molecules unrelated to the specific D 2 family of receptors e.g., paroxetine, venlafaxine, etc.
  • D 2 , D 3 or D 4 D 2 family of receptors
  • the patients were treated by escalating the dose of ropinirole to 4mg, testing the hypothesis of a dopaminergically regulated pathway within the central nervous system which impacts hot flashes.
  • the dopaminergic agonist ropinirole was escalated from an initial dose of 0.25mg to a final dose of 4mg at bedtime without side effects and with the dramatic shutdown of previously intolerable hot flashes of menopause.
  • HRT Hormone Replacement Therapy
  • the hot flash would then rapidly su bside with a sense of being chilled, reflecting the normal physiologic function of evaporation of perspiration. A period of 10 to 90 minutes would elapse before the next hot flash would occur, both during the daytime and throughout the night. It was common for there to be between 20 to 30, and as many as 40 hot flashes over the course of a day at their peak in frequency, although not all would be of the same intensity.
  • Treatment was initiated with tizanidine, a non-selective alpha-2-adrenergic agonist, initially for the purpose of providing a sleep aide. Tizanidine is available as a scored 4mg tablet that can easily be broken into four lmg portions.
  • the initial dose provided was lmg at bedtime, and the dose was raised as needed, every fourth day, to a maximum of 8mg, if needed, usually at bedtime.
  • the maximum of 8mg was not taken at bedtime, the patient was permitted to use up to the remaining amount of tizanidine, but not more than a total of 8mg for the night, if she awoke during the night and found that she could not fall back to sleep. This was not necessary, and once asleep, she was able to sleep through the night waking infrequently but rapidly falling back to sleep.
  • HRT was not an option for controlling her hot flashes since this woman had been diagnosed with hormone receptor positive breast cancer. She had additional challenges in the potential treatment of hot flashes because of the history of breast cancer. This was in part because she had received chemotherapy which caused a peripheral neuropathy.
  • Ropinirole titration was initiated with 0.25mg at bedtime, and if tolerated, by escalating the dose by 0.25mg every fourth day to a maximum of lmg (i.e., 0.25mg, 0.50mg, 0.75mg, lmg), until there was reduction in both the frequency and severity of hot flashes. If higher doses were needed, then both lmg, or later 2mg and both 1 and 2mg ropinirole tablets were used along with the continued titration by 0.25mg steps every fourth day until a maximum of 4mg was reached. Higher ropinirole doses were not needed to accomplish clinical suppression of the hot flashes in this woman, and were not tested due to a greater likelihood of side effects such as nausea, hallucinations or jitteriness.
  • the combination of ropinirole and tizanidine represented a new combination that provided aide in falling asleep, staying asleep and providing significant additional relief by completely eliminating the frequency and severity of hot flashes that this patient had experienced prior to treatment until the next dosing the following evening. This was a highly significant and dramatically notable improvement compared to any prior option available.
  • Ropinirole was shown to reduce hot flashes as a dopamine agonist on the D 2 , D 3 and D 4 receptors.
  • the new combination of ropinirole and tizanidine was additionally effective in totally eliminating the most severe form of hot flashes, with the most intense vasomotor symptoms. It completely stopped the frequency and intensity of these symptoms. When the dose of ropinirole was removed, the symptoms returned. When the ropinirole was re-administered at 4mg, the hot flashes once again disappeared.
  • the duration of relief of the combined ropinirole and tizanidine allowed once a day dosing.
  • the second woman, JM is a 52-year-old woman with multiple sclerosis (MS) for 26 years. She had been experiencing difficulty with vision, inability to walk due to spinal symptoms, severe neurogenic bladder with incontinence, fatigue and multiple hot flashes throughout the day causing severe sweats and a sensation of heat overcoming her body. Ironically, with the sensation of heat there was an overwhelming sense of weakness and fatigue. This possibly reflected what is known as the "pseudoexacerbation" phenomenon in MS. Central nervous system (CNS) nerve fibers that already are physically damaged, but somewhat physiologically compensated, can lose their ability to compensate as body temperature rises. The function of these nerve fibers can improve once again as body temperature cools.
  • CNS Central nervous system
  • HTR Hormone Replacement Therapy
  • DH The third woman, DH is a 53-year-old woman with multiple peripheral nerve injuries and diabetes. She entered menopause two years ago and developed the menopausal symptom of hot flashes with a frequency of 15-20 hot flashes per day, with each one lasting 15-30 seconds in duration. There was flushing and reddening of the face and the chest, with associated beading of sweat, during these hot flashes and they interfered with her ability to obtain a full night of normal sleep. She had been able to fall asleep with the use of sedative hypnotic medication, temazepam, even prior to the onset of the hot flashes.
  • the fourth woman, PW is a 48-year-old woman with a chronic neuropathic pain disorder who entered menopause at a younger age than most, but developed hot flashes with drenching night sweats as significant symptoms like most.
  • the hot flashes were associated with facial flushing and flushing of the chest. These episodes lasted 15-30 seconds each and would occur 10-15 times per day. She already was under treatment with clonidine, gabapentin and venflaxamine for her neuropathic pain and associated depression, and developed these hot flash symptoms despite those medications.
  • HRT Health Treatment Therapy
  • Tizanidine 4mg was titrated for sleep to 8mg at bedtime, and treatment with ropinirole was initiated and titrated to 4mg at bedtime. She slept and on the ropinirole 4mg at bedtime she had complete resolution of the frequency and severity of the hot flashes without untoward side effects. She previously had manifested irritability and difficult concentrating which seemed to improve as the hot flashes abated and sleep improved.
  • the combination of these two agents represents a new combination that provides aide in falling asleep, staying asleep and providing significant relief by completely eliminating the frequency and severity of hot flashes which were resistant to other medication described as potentially useful in the medical literature.
  • the duration of benefit utilizing this combination allows once daily dosing. HRT would not have been an acceptable alternative for this patient because of the probability of it having a negative impact on her already altered mood state associated with her pain disorder.
  • This new product was effective in totally eliminating her intense vasomotor symptoms (hot flashes), and improving her ability to sleep.
  • the subject invention describes a novel and new use of a D 2 receptor family dopamine agonist to alleviate and control menopausal symptoms in women, and in particular, hot flashes.
  • ropinirole is believed to bind to the D 2 , D 3 , or D 4 receptors, particularly at the D 3 site. This affinity inhibits production of GnRH which reduces production of LH and FSH in the pituitary.
  • LH and FSH are vasodilators, and lower pulsatile levels of LH and FSH result in reduced incidence of hot flashes.
  • chlorpromazine 25mg
  • haloperidol lmg
  • Symptoms were evaluated on a scale from 0 to 4, with 0 being not affected, 1 being mild, 2 being moderate, 3 being severe, and 4 being a very severe expression of either vasomotor symptom frequency, severity, sweating, falling asleep and waking during the night for each patient and evaluated at the end of the treatment period.
  • the findings reported are based on an average of the reported symptoms of the six women studied.
  • hot flash frequency evaluation was based upon the number of hot flashes per day.
  • the frequency of hot flashes was graded on a scale of 0-4, with 0 as none detected, 1 as 1-4/day (mild), 2 as 5-8/day (moderate), 3 as 9-12/day (severe), and 4 as more than 12/day (very severe).
  • the sweating response was graded on a scale of 0-4 as well, with 0 being not detected, 1 being mild (minimally moist skin), 2 moderate (moisture of the skin), 3 severe (noticeable perspiration, hair, ears, neck, chest), and 4 very severe (soaking sweat).
  • Falling asleep was also graded on a scale of 0-4, with 0 being no issue (less than 15 minutes), 1 being mild (15-20 minutes), 2 moderate (20-40 minutes), 3 severe (40-60 minutes), and 4 very severe (greater than 60 minutes).
  • Wakings were graded on a scale of 0-4 as well, with 0 being not detected, 1 being mild (1-5 wakings/night), 2 moderate (5-10 wakings/night), 3 severe (10-15 wakings/night), and 4 very severe (greater than 15 wakings/night).
  • D 2 receptor family (D 2 , D 3 or D 4 ) agonists ropinirole, rotigotine and pramipexole were examined, and contrasted with D 2 receptor family antagonists chlorpromazine or haloperidol. Ropinirole and pramipexole were evaluated alone and with either alpha-2- adrenergic agonist tizanidine or clonidine.
  • venlafaxine, paroxetine, gabapentin, and pregabilin interact with and effect D 2 receptors and produce affects as D 2 agonists.
  • Venlafaxine and paroxetine form heterodimers with the D 2 receptors and effectuate a response akin to D 2 agonists.
  • Venlafaxine (75mg), paroxetine (20mg), gabapentin (300mg), and pregabilin (50mg) also reduced hot flash symptoms over untreated patients.
  • tizanidine (4mg) was administered with venlafaxine, paroxetine, gabapentin, and pregabilin, the combination was synergistic and produced a more robust response in the reduction of hot flash symptoms and other vasomotor symptoms.
  • D 2 receptor family antagonists chlorpromazine or haloperidol aggravated menopausal symptoms, confirming the pivotal role of the D 2 receptor family in expression of these symptoms.
  • Symptoms were evaluated on a scale from 1 to 4, with 1 being mild, 2 being moderate, 3 being severe, and 4 being a very severe expression of either vasomotor symptom frequency, severity, sweating, falling asleep and wakings during the night were evaluated for each patient and evaluate at the end of the treatment period.
  • the findings were based on an average of the reported symptoms of the eight women studied.
  • hot flash frequency evaluation was based upon the number of hot flashes per day.
  • the frequency of the hot flashes was graded on a scale of 1- 4, with 1 as 1-4/day (mild), 2 as 5-8/day (moderate), 3 as 9-12/day (severe), and 4 as more than 12/day (very severe).
  • the severity of the hot flashes was graded on a scale of 1-4, with 1 being mild (less than 1 minute), 2 moderate (1-2 minutes), 3 severe (2-3 minutes), and 4 very severe (greater than 4 minutes). This evaluation reflects the duration and intensity as rated by the individual.
  • the sweating response was graded on a scale of 1-4, with 1 being mild (minimally moist skin), 2 moderate (moisture on skin), 3 severe (noticeable perspiration, hair, ears, neck, chest), and 4 very severe (soaking sweat).
  • Falling asleep was graded on a scale of 1-4, with 1 being mild (15-20 minutes), 2 moderate (20-40 minutes), 3 severe (40-60 minutes), and 4 very severe (greater than 60 minutes).
  • Wakings were graded on a scale of 1-4, with 1 being mild (1-5 wakings/night), 2 moderate (5-10 wakings/night), 3 severe (10-15 wakings/night), and 4 very severe (greater than 15 wakings/night).
  • the duration of effect was greater with the combination of a D 2 recptor family agonist and alpha-2-agonist than the D 2 agonist alone, so once daily dosing was possible utilizing the combination.
  • the combination of ropinirole and ramelteon was no better than either agent when used alone.

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Abstract

La présente invention concerne l'utilisation d'agonistes de la dopamine ayant une affinité pour les récepteurs de la dopamine D2, D3, ou D4 (la famille D2) pour le traitement de bouffées de chaleur, indépendamment du fait qu'elles soient causées par le vieillissement naturel chez la femme ou par une intervention médicale/chirurgicale de l'axe HPG chez l'un ou l'autre sexe. La famille D2 de récepteurs de la dopamine est la plus sensible à des molécules agonistes de D2, mais est également sensible à de multiples autres molécules qui utilisent directement ou indirectement cette voie. Les agonistes alpha-2-adrénergiques agissent de manière synergique pour réduire davantage la fréquence et la sévérité des bouffées de chaleur et prolonger la durée de l'efficacité de dosage. La combinaison d'un agoniste de la dopamine de la famille D2 et d'un agoniste alpha-2-adrénergique, ainsi que de molécules supplémentaires qui peuvent utiliser la voie de la famille des récepteurs D2 par la formation d'hétérodimères, permet une multitude de molécules d'efficacité variable pour le traitement de bouffées de chaleur chez les femmes ou chez les hommes. La présente invention étend les options non hormonales disponibles pour le traitement de bouffées de chaleur qui sont par ailleurs les plus perturbatrices des activités normales de la vie quotidienne.
PCT/US2020/027238 2019-04-22 2020-04-08 Traitement non hormonal de bouffées de chaleur WO2020219270A1 (fr)

Priority Applications (8)

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AU2020262851A AU2020262851A1 (en) 2019-04-22 2020-04-08 Non-hormonal treatment of hot flashes
JP2021563312A JP2022532851A (ja) 2019-04-22 2020-04-08 ホットフラッシュの非ホルモン治療
KR1020217037881A KR20220010721A (ko) 2019-04-22 2020-04-08 안면 홍조의 비-호르몬 치료
EP20795747.3A EP3958862A4 (fr) 2019-04-22 2020-04-08 Traitement non hormonal de bouffées de chaleur
BR112021021260A BR112021021260A2 (pt) 2019-04-22 2020-04-08 Tratamento não hormonal de ondas de calor
CA3137710A CA3137710A1 (fr) 2019-04-22 2020-04-08 Traitement non hormonal de bouffees de chaleur
SG11202112822VA SG11202112822VA (en) 2019-04-22 2020-04-08 Non-hormonal treatment of hot flashes
IL287457A IL287457A (en) 2019-04-22 2021-10-21 Non-hormonal treatment of hot flashes

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US16/390,276 2019-04-22
US16/390,276 US11903926B1 (en) 2012-03-05 2019-04-22 Non-hormonal treatment of hot flashes

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US20050267176A1 (en) * 2004-02-18 2005-12-01 Sepracor Inc. Dopamine-agonist combination therapy for improving sleep quality
US20110218213A1 (en) * 2010-03-02 2011-09-08 Royster Jr George E Methods and Compositions for Treating or Preventing Symptoms of Hormonal Variations
US8420624B2 (en) * 2007-12-04 2013-04-16 Yung Shin Pharm. Ind. Co., Ltd. Methods for treating or preventing symptoms of hormonal variations
US9468631B1 (en) * 2012-03-05 2016-10-18 Robert L. Knobler Method and compound for treatment of menopausal symptoms

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Publication number Priority date Publication date Assignee Title
WO2001007037A1 (fr) * 1999-07-22 2001-02-01 University Of Rochester Methode de traitement de symptomes de variations hormonales, y compris des bouffees de chaleur

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US20050267176A1 (en) * 2004-02-18 2005-12-01 Sepracor Inc. Dopamine-agonist combination therapy for improving sleep quality
US8420624B2 (en) * 2007-12-04 2013-04-16 Yung Shin Pharm. Ind. Co., Ltd. Methods for treating or preventing symptoms of hormonal variations
US20110218213A1 (en) * 2010-03-02 2011-09-08 Royster Jr George E Methods and Compositions for Treating or Preventing Symptoms of Hormonal Variations
US9468631B1 (en) * 2012-03-05 2016-10-18 Robert L. Knobler Method and compound for treatment of menopausal symptoms

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CA3137710A1 (fr) 2020-10-29
AU2020262851A1 (en) 2021-11-18
EP3958862A1 (fr) 2022-03-02
BR112021021260A2 (pt) 2022-02-08
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EP3958862A4 (fr) 2023-01-25

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