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WO2008060397A2 - Procédé de traitement d'un dysfonctionnement de la thermorégulation - Google Patents

Procédé de traitement d'un dysfonctionnement de la thermorégulation Download PDF

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WO2008060397A2
WO2008060397A2 PCT/US2007/022813 US2007022813W WO2008060397A2 WO 2008060397 A2 WO2008060397 A2 WO 2008060397A2 US 2007022813 W US2007022813 W US 2007022813W WO 2008060397 A2 WO2008060397 A2 WO 2008060397A2
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day
compound
administered
amount
antidepressant
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WO2008060397A3 (fr
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Patricia Allison Tewes Richards
Michael S. Satow
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Noven Therapeutics LLC
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Noven Therapeutics LLC
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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

Definitions

  • the present invention relates to a method for treating a patient suffering from a thermoregulatory dysfunction, especially hot flashes and flushes associated with hormonal changes due to naturally occurring menopause (whether male or female) or due to chemically or surgically induced menopause.
  • the method is also applicable to treating the vasomotor symptoms, hot flashes, hot flushes, or night sweats associated with disease states that disrupt normal hormonal regulation of body temperature.
  • the invention further relates to use of selective serotonin reuptake inihibitors (SSRIs) and/or selective norepinepherine uptake inhibitors (SNRIs) or their combination or selective serotonin/norepinephrine uptake inhibitors (SS/NRIs) or monoamine oxidase inhibitors (MAOIs) or buspirone or other antidepressants .
  • SSRIs selective serotonin reuptake inihibitors
  • SNRIs selective norepinepherine uptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • buspirone or other antidepressants BACKGROUND OF THE INVENTION
  • Hot flashes or flushes are most typically seen in women who are in the process of going through menopause, but are also seen in women who have undergone surgical or chemically induced menopause. They are also seen (less frequently) in men who are undergoing the so-called "male menopause” or who have undergone hormonal ablative therapy.
  • the hot flashes and flushes are connected with a disruption of the hormonal control of thermoregulatory function.
  • disease states which disrupt the normal hormonal control over thermoregulatory function also result in such hot flashes and flushes.
  • US 2006-0100263 relates to combinations of bicifadine and another drug for hot flashes.
  • Paroxetine is one of the "other" drugs mentioned as suitable for the combination therapy.
  • US 2006-0020015 claims the use of combinations of norepinepherine reuptake inhibitors in combination with serotonin reuptake inhibitors.
  • the '015 application also mentions that selective serotonin reuptake inhibitors are being clinically evaluated in hot flashes and particularly mentions that fluoxetine is mentioned in this context in WO 9944601. US 2006-0020014 and US 2004-0130987 have similar disclosures.
  • norepinepherine reuptake inhibitors optionally in combination with serotonergic reuptake inhibitors for the treatment of vasomotor symptoms (the class to which hot flashes and flushes as well as night sweats belong) with the specific mention of the norepinephrine reuptake inhibitors maprotiline; reboxetine; norpramine/desipramine; nisoxetine; atomoxetine; amoxapine; doxepin; lofepramin; amitryptyline; l-[l-(3-fluorophenyl)-2-(4-methyl-l-p- iperazinyl)ethyl]cyclohexanol; 1- [ 1 -(3 -chlorophenyl)-2-(4-methyl- 1 -piperaz- inyl)ethyl]cyclohexanol; 1 - [2-(4-methyl-methyl-
  • sertraline was found to be effective to some degree in hot flashes as a standalone therapy in Trott, et al An Open Trial of Sertraline for Menopausal Hot Flushes: Potential Involvement of Serotonin in Vasomotor Instability; Del. Med. JrI, September 1997, vol. 69, No. 9, 481-482 and in Roth et al; SERTRALINE RELIEVES HOT FLASHES SECONDARY TO MEDICAL CASTRATION AS TREATMENT OF ADVANCED PROSTATE CANCER; Psycho-Oncology 7: 129-132 (1998).
  • US 6,498,184 discusses the role of selective 5-HT 2 c (a serotonin receptor subtype) agonists for the treatment of hot flushes.
  • US 2004-0092519 relates to use of reboxetine (a selective noradrenaline reuptake inhibitor, i.e. NARI)) for treating hot flaushes.
  • reboxetine a selective noradrenaline reuptake inhibitor, i.e. NARI
  • NARI noradrenaline reuptake inhibitor
  • Nelson et al; Nonhormonal Therapies for Menopausal Hot flashes; JAMA, May 3, 2006, Vol. 295, No 17, 2057-2071 discusses the use of paroxetine, venlafaxine, fluoxetine, and citalopram in this indication.
  • thermoregulatory dysfunction or vasomotor symptoms a dosage form of an antidepressant compound suitable for administration of from 0.1 mg/day to less than an antidepressant effective dosage thereof per day.
  • Another object of the invention is to provide to a patient suffering from a thermoregulatory dysfunction or vasomotor symptoms a dosage form of an antidepressant compound suitable for administration of from 0.1 mg/day to less than 10 mg/day.
  • Still another object of the invention is to provide to a patient suffering from a thermoregulatory dysfunction a treatment thereof with an antidepressant that substantially avoids most and/or substantially reduces the side effects typically obtained from an antidepressant effective amount of thereof.
  • thermoregulatory dysfunction or vasomotor symptom using a compound selected from a selective serotonin reuptake inhibitor (SSRI), a selective norepinepherine reuptake inhibitor (SNRI), a dual action serotonin reuptake inhibitor/norepinepherine reuptake inhibitor (SRI-NRI) as free base or free acid (as appropriate) or a pharmaceutically acceptable salt thereof, in an anhydrate, a hydrate, or solvate form, in any non-crystalline or any crystalline polymorphic form of any of the foregoing in a dosage of from about 1 % up to not more than about 90% of the minimum recommended antidepressant dosage for such compound based on oral dosage forms, and dosage amounts of such compounds in non-oral dosage forms corresponding to the blood levels obtained from such oral dosage forms.
  • SSRI selective serotonin reuptake inhibitor
  • SNRI selective norepinepherine reuptake inhibitor
  • SRI-NRI dual action serotonin reuptake
  • the compounds may be used in amounts up to and including antidepressantly effective amounts thereof, but preferably are used in amounts that are subtherapeutic for antidepressant effects.
  • minimum therapeutic effectiveness for antidepressant effect will be considered a dose which achieves comparable results to the minimum label recommended doses for antidepressant use for one or more of the SSRIs marketed in the US as of the filing date of this application..
  • the patient receives the benefits of the treating the vasomotor symptoms while avoiding the use of hormonal therapy and simultaneously avoids (or has a much reduced level) of the side effects of the compounds being administered, most notably, reductions in weight gain, lesser amounts of sexual dysfunction, and lesser amounts of nausea which are associated with the compounds being used herein when used in the larger antidepressant dosages.
  • the present invention is a method of treating a thermoregulatory dysfunction treatment or treatment of vasomotor symptoms including hot flashes or flushes and night sweats using an antidepressant compound selected from SSRI, SNRIs and dual action SRI-NRIs as free base or free acid (as appropriate) or a pharmaceutically acceptable salt thereof, in an anhydrate, a hydrate, or solvate form, in any non-crystalline or any crystalline polymorphic form of any of the foregoing in a dosage of from about 1% to about 90% of the recommended minimum antidepressant effective amount, preferably not more than about 85%, more preferably not more than about 80% of the minimum recommended effective antidepressant amount.
  • an antidepressant compound selected from SSRI, SNRIs and dual action SRI-NRIs as free base or free acid (as appropriate) or a pharmaceutically acceptable salt thereof, in an anhydrate, a hydrate, or solvate form, in any non-crystalline or any crystalline polymorphic form of any of the fore
  • the amounts used are at least about 2%, more preferably at least about 2.5%, still more preferably about 5%, yet more preferably at least about 10%, even more preferably at least about 20%, yet more preferably at least about 25%, even more preferably at least about 33%, even more preferably at least about 40% of the minimum recommended antidepressant effective amount.
  • the minimum effective antidepressant amount can be found in the published labeling and is specifically the following amounts for the oral dosage forms of the following drugs: citalopram 20 mg/day; escitalopram 10 mg/day, fluoxetine 10 mg/day; paroxetine 20 mg/day, sertraline 50 mg/day; and venlafaxine 75 mg/dayday. These amounts are based on the free base of each and not the particular salt thereof. Furthermore, for purposes of this invention, the minimum effective antidepressant dosage being referred to is without consideration of initial dosages that might be used as initial dosings for about 1 week or less in order to ramp up to the minimum effective dose.
  • any specific salt will be the amount comparable to deliver the above dosages of the free base in question.
  • the minimum effective amount will be considered the amount that delivers a blood level of the active moiety comparable to the oral dosage form.
  • a minimum antidepressant effective amount (of an SSRI, an SNRI, or an SS/NRI) shall be considered that amount which delivers an antidepressant effect comparable to one or more of citalopram, escitalopram, fluoxetine, sertraline, or venlafaxine.
  • the minimum effective antidepressant amount of such compound shall be considered to be 30 mg (1/2 of 60 mg) since the minimum effective amount for citalopram is 20 mg (1/2 of 40 mg).
  • the compounds may be used in the present invention context at larger doses as well, into the antidepressant effective range, but preferably are used in the antidepressant sub-therapeutic range.
  • the invention is also a dosage form of the antidepressant compound in a dose which is less than that effective for its use as an antidepressant.
  • the antidepressant compound may be in the form of the free base or free acid or any pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts include, but are not limited to, hydrohalides (such as hydrochloride, hydrobromide, hydroiodide), sufates (such as sulfate, bisulfate), phosphates (such as mono, di, or tri basic phosphate), oxalate, mesylate, tosylate, pamoate, citrate, carbonate, bicarbonate, maleate, malate, fumarate, as well as many others set forth in the patent references indicated in paragraph 0010 above.
  • the salts may further include the alkali metal salts, the alkaline earth metal salts, and the ammonium salt of such acidic functionality.
  • the antidepressant is preferably present as the free base, the hydrochloride salt, or the mesylate salt, the oxalate salt, or mixtures thereof.
  • paroxetine is the antidepressant compound, it is most preferably present as the hydrochloride salt or the mesylate salt.
  • Paroxetine for use in the present invention may be in the anhydrate, hemihydrate, monohydrate, or higher hydrate forms.
  • Paroxetine for use in the present invention may also be either amorphous or crystalline, the choice being made by the formulator depending upon the formulation and dissolution characteristics desired. Crystalline forms have better stability, but amorphous forms have faster dissolution profiles.
  • citalopram is the antidepressant compound, it is preferably present as the free base, or the hydrobromide or the oxalate salt. Most of the other antidepressant compounds are preferably present as the free base or the hydrochloride salt.
  • Duloxetine N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine- , is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which shows its high potency. The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule;
  • Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compound A in that patent;
  • Paroxetine trans-(-)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4-fluo- rophenyl)piperidine, may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196.
  • Paroxetine is a well characterized molecule in the pharmaceutical and patent literature. Chemical processes for its manufacture are detailed in US 4,861,893; US 6,172,233; US 6,326,496; US 6,433,179; US 6,541,637US 6,686,473; US 6,716,985; US 6,881,845; US 6,900,327; and US 6,956,121 to name a few.
  • Paroxetine has also been indicated for a wide range of treatments ranging from its use as an antidepressant (US 4,007,196) to neurologic and mental disorders, (US 5,470,846) to CNS disorders (US 5,985,322) to treatments for nicotine withdrawal, premenstrual symptoms, post-traumatic stress disorder, heroin addiction, etc.
  • US 4,007,196 to neurologic and mental disorders
  • US 5,470,846 to CNS disorders
  • US 5,985,322 to treatments for nicotine withdrawal, premenstrual symptoms, post-traumatic stress disorder, heroin addiction, etc.
  • Sertraline (1 S-cis)-4-(3,4-dichlorophenyl)-l ,2,3,4-tetrahydro-N-me- thyl-1- naphthylamine hydrochloride, is a serotonin reuptake inhibitor which is marketed as an antidepressant. It is disclosed by U.S. Pat. No. 4,536,518;
  • the SRI can be venlafaxine or a derivative thereof.
  • the SRI can be a compound represented in the following formula, or a pharmaceutically acceptable salts thereof:
  • Ri is hydrogen or alkyl of 1 to 6 carbon atoms
  • R 2 is alkyl of 1 to 6 carbon atoms
  • R 3 is hydrogen or alkyl of 1 to 6 carbon atoms
  • R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms;
  • R 5 and R 6 are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo, trifluoromethyl, or, when taken together, methylene dioxy; and
  • n is one of the integers 0, 1, 2, 3 or 4.
  • the nontricyclic compound venlafaxine chemically named ( ⁇ )-l-[2- (dimethylamino)-l-(4-methoxyphenyl)ethyl]-cyclohexanol, is an antidepressant which has been studied extensively and which is described in, for example, U.S. Pat. No. 4,761,501
  • Venlafaxine includes active derivatives of venlafaxine.
  • the term "derivative" includes metabolites. Venlafaxine derivatives include: O-desmethylvenlafaxine and the single enantiomers of the two compounds.
  • the venlafaxine compound is provided in optically pure form, such as optically pure (-)-N-desmethylvenlafaxine, chemically named (-)-l-[2-(methylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol; optically pure (- )-N,N-didesmethylvenlafaxine, chemically named (-)-l-[2-(amino)-l-(4- methoxyphenyl)ethyl]cyclohexanol; optically pure (-)-O-desmethylvenlafaxine, chemically named (-)-l-[2-(dimethylamino)-l-(4-phenol)ethyl
  • the SRI compound is an optically pure derivative of (+)- venlafaxine, such as (+)-O-desmethylvenlafaxine.
  • US Patent 6197828 provides additional examples of derivatives of (+)- venlafaxine.
  • the SRI is a selective serotonin reuptake inhibitor (SSRI).
  • SSRIs include fluoxetinoids, sertraline (ZOLOFT), citalopram (CELEXA), paroxetine (PAXIL), and fluvoxamine (LUVOX), cericlamine, femoxetine, ifoxetine, cyanodothiepin, and litoxetine.
  • the terms such as "sertraline,” “citalopram,” “paroxetine,” and “fluvoxamine” include active derivatives and metabolites, such as the desmethyl metabolites of norfluoxetine, desmethylsertraline, and desmethylcitalopram.
  • Preferred SSRIs are fluoxetinoids, paroxetine, and citalopram (and their derivatives). More preferred SSRIs are fluoxetinoids and paroxetine.
  • Fluoxetinoids useful in the present methods and compositions include compounds that inhibit serotonin reuptake and have structures of the following formula:
  • Ri independently for each occurrence, represents H or lower alkyl, preferably H or Me;
  • R 2 , R 3 , and R 4 each independently represent H, methyl, substituted or unsubstituted phenyl, or substituted or unsubstituted phenylmethyl, such that exactly one Of R 2 , R 3 , and R» is a substituted or unsubstituted phenyl, or substituted or unsubstituted phenylmethyl;
  • Y represents O, S, or -S(O) 2 -, preferably O;
  • Q represents a substituted or unsubstituted aryl or heteroaryl ring, including polycyclic ring systems.
  • At least one occurrence of Ri represents hydrogen.
  • R 2 and R 3 are selected from H and Me, preferably H, and R 4 represents a substituted or unsubstituted phenyl ring.
  • Q is a substituted or unsubstituted phenyl ring.
  • a fluoxetinoid has a structure of the following formula:
  • R 5 independently for each occurrence, represent H or Me
  • R 6 represents a substituted or unsubstituted phenyl ring, preferably unsubstituted;
  • Y represents O, S, or -S(O) 2 -, preferably O;
  • R 7 represents from 1-5 substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, substituted or unsubstituted phenyl, and CF 3 .
  • at least one occurrence of R 5 bound to N is a hydrogen.
  • R 6 represents an unsubstituted phenyl group.
  • R 7 represents from 1 -2 substituents selected from halogen and CF 3 .
  • Fluoxetine is metabolized far more slowly, with the primary metabolic derivative being norfluoxetine, which is similar to fluoxetine in selectivity and potency. Any combination of these compounds, racemic or enriched for either enantiomer, and pharmaceutically acceptable salts thereof may be employed in the methods and compositions described herein, and any one of these compounds is included in the term 'fluoxetinoids' as the term is used herein.
  • the SSRI is sertraline or a derivative thereof.
  • the SSRI can be a compound represented in Formula, or a pharmaceutically acceptable salts thereof:
  • R 8 is selected from the group consisting of hydrogen and normal alkyl of from 1 to 3 carbon atoms;
  • R's is normal alkyl of from 1 to 3 carbon atoms
  • R 9 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and alkoxy of from 1 to 3 carbon atoms;
  • Rn and Ri 2 are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, alkoxy of from 1 to 3 carbon atoms and cyano, with at least one of Ri 1 and Ri 2 being other than hydrogen.
  • Sertraline derivatives include N-desmethylsertraline.
  • the compound is, as appropriate, the cis- isomeric base of the above formula.
  • cis-isomeric refers to the relative orientation of the N(R' 8 )Rg and Ri 0 moieties on the cyclohexene ring (i.e. they are both oriented on the same side of the ring). Because both the 1- and 4- carbons of the formula are asymmetrically substituted, each cis- compound has two optically active enantiomeric forms denoted (with reference to the 1-carbon) as the cis-(lR) and cis-(lS) enantiomers.
  • the preferred embodiment is the (IS) enantiomer, e.g., cis-(lS)-N-methyl-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine and its pharmaceutically acceptable acid addition salts.
  • the SSRI is paroxetine or a derivative thereof.
  • the SSRI can be a compound represented in Formula, or a pharmaceutically acceptable salts thereof:
  • Rn represents hydrogen or an alkyl group of 1-4 carbon atoms
  • Ri 4 represents hydrogen, alkyl having 1-4 carbon atoms, C 1-6 alkoxy, C 1-6 trifluoroalkyl (preferably, trifluoromethyl), hydroxy, halogen, methylthio, or C 1-6 aryl(Cl-6) alkyloxy (e.g., phenyl(Cl-6)alkyloxy and benzyl(Cl-6)alkyloxy), and Ri 5 represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C 1-4 alkyl, C 1-6 alkylthio, C 1-6 alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl.
  • the SSRI is a compound represented in Formula, or a pharmaceutically acceptable salts thereof:
  • Rn represents hydrogen or an alkyl group of 1-4 carbon atoms
  • R H is a halogen.
  • Ri 3 is a fluorine.
  • R 1 is hydrogen and the fluorine is in para position.
  • the SSRI is citalopram or a derivative thereof.
  • the SSRI can be a compound represented in Formula, or a pharmaceutically acceptable salts thereof:
  • Citalopram was first disclosed in DE 2,657,271 corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method which may be used for preparing citalopram Methods of preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No 4,943,590, such as (+)-l -(3 -Dimethylaminopropyl)-1 - ⁇ '-fluorophenyl)- 1,3- dihydroisobenzofuran-5-carbonitrile. Citalopram derivatives include desmethylcitalopram and didesmethylcitalopram, and the single enantiomers of all three compounds.
  • the SSRI is fluvoxamine or a derivative thereof.
  • the SSRI can be a compound represented in Formula, or a pharmaceutically acceptable salts thereof:
  • Ri 9 represents a cyano group, a cyanomethyl group, a methoxymethyl group or an ethoxymethyl group. Fluvoxamine and other oxime ethers are disclosed in US Patent No. 4,085,225.
  • Monoamine oxidase inhibitors that are also of use in the present invention include phenelzine (antidepressant usual oral dose 30-60 mg/day); tranylcypromine (antipressant usual oral dose 20-30 mg/day);isocarboxazid (antidepressant usual oral dose 40-60 mg/day) and selegiline (usual antidepressant oral dose 10 mg/day and transdermally 6 mg/day).
  • the compound buspirone is also useful in the present invention.
  • Any suitable route of administration may be employed for providing the patient with effective dosages of an SRI.
  • oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, inhalation and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches and the like.
  • salts may be prepared using pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzene-sulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like.
  • Particularly preferred are hydrobromic, hydrochloric, phosphoric and sulfuric acids.
  • compositions include compositions suitable for oral, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), transdermal, and inhalation routes, although the most suitable route in any given case will depend on the nature and severity of the condition being treated.
  • the most preferred route of the present invention is oral. They may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Dosage forms that are fractions of daily doses given multiple times per day as well as once daily dosage forms are each suitable for use in the present invention.
  • the dosage of most of the compounds for use in the present invention is about 0.1 mg/day up to less than an antidepressant effective amount of of the compound (based on the free base, anhydrate); preferably up to about 9.5 mg/day.
  • compounds can be administered to achieve the invention in amounts of at least 0.5 mg/day, more preferably at least 1 mg/day, still more preferably at least 2 mg/day, even more preferably at least 4 mg/day, up to preferably not more than about 9 mg/day, more preferably not more than about 8.5 mg/day, still more preferably not more than 8 mg/day.
  • Non-limiting dosages that are specifically suitable for the present invention include 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, 5 mg/day, 5.5 mg/day, 6 mg/day, 6.5 mg/day, 7 mg/day, 7.5 mg/day, 8 mg/day, and 8.5 mg/day. These are especially useful for paroxetine, escitalopram, fluoxetine, selegiline, and buspirone, and their derivatives. Compounds such as citalopram and tranylcypromine (and their derivatives can be used up to maximums that are twice as many mg as the stated upper amounts above ( and preferred maximum amounts further include twice the preferred mg amounts stated above for these compounds).
  • Penelzine and its derivatives can be used in amounts up to maximums that are three times the mg amounts stated above (and preferred maximums include three times those stated above).
  • maximums and preferred maximums (a) for fluovoxamine can be 2.5 to 10 times, (b) for sertraline and its derivatives can be up to 5 times, and (c) for venlafaxine and its derivatives the maximums and preferred maximums can be up to 7.5 times and (d) for mirtazepine and its derivatives the maximums and preferred maximums can be up to 3 times the mg amounts stated above.
  • thermoregulatory dysfunction is applicable to the treatment of thermoregulatory dysfunction and in particular to such conditions (without limitation) as vasomotor symptoms, hot flushes, hot flashes, night sweats, etc. whether or not related to menopause (female or male), perimenopause, hormone ablative therapy (including, but not limited to, anti-estrogenic therapy and antiandrogenic therapy), treatments with other chemical agent or therapeutic agents that are antiestrogenic or antiandrogenic or interfere with thermoregulatory function, surgical procedures (such as, without limitation castration, hysterectomy, ooectomy, etc), and disease states interfering with normal thermoregulatory functioning.
  • hormone ablative therapy including, but not limited to, anti-estrogenic therapy and antiandrogenic therapy
  • treatments with other chemical agent or therapeutic agents that are antiestrogenic or antiandrogenic or interfere with thermoregulatory function surgical procedures (such as, without limitation castration, hysterectomy, ooectomy, etc), and disease states interfering with normal thermoregulatory functioning
  • the present invention is directed to the treatment of perimenopausal and postmenopausal hot flashes, hot flushes and night sweats in women, whether due to aging, therapeutically induced menopause, or surgically induced menopause.
  • the invention is also preferably directed to hot flashes or hot flushes or night sweats in men whether such symptoms are due to aging, chemical castration, hormonal ablative therapy, or surgical castration.
  • Example 1 The following non-limiting Examples are presented only to exemplify various embodiments of the invention and do not limit it in any fashion.
  • Example 1
  • paroxetine based on free base non-solvate, anhydrate
  • paroxetine based on free base non-solvate, anhydrate
  • Females having hot flashes associated with menopause are administered selegiline or buspirone(based on free base non-solvate, anhydrate) as follows:

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Abstract

La présente invention concerne un procédé pour traiter un patient souffrant d'un dysfonctionnement de la thermorégulation, en particulier des bouffées congestives et bouffées de chaleur associées à des changements hormonaux en raison d'une ménopause se produisant naturellement (mâle ou femelle) ou en raison d'une ménopause induite chimiquement ou chirurgicalement. Le procédé est également applicable à un traitement de bouffées de chaleur, ou de sueurs nocturnes associées à des affections pathologiques qui interrompent une régulation hormonale normale de la température corporelle.
PCT/US2007/022813 2006-11-03 2007-10-29 Procédé de traitement d'un dysfonctionnement de la thermorégulation Ceased WO2008060397A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011064769A1 (fr) * 2009-11-24 2011-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions pharmaceutiques pour le traitement des bouffées de chaleur
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

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MXPA05001803A (es) * 2002-08-15 2005-08-16 Wyeth Corp Agonismo del receptor de 5ht2a para el tratamiento de disfuncion termorreguladora.
US20040180879A1 (en) * 2002-10-15 2004-09-16 Deecher Darlene Coleman Novel method of treating vasomotor symptoms

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011064769A1 (fr) * 2009-11-24 2011-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions pharmaceutiques pour le traitement des bouffées de chaleur
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

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