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EP1846105A2 - Utilisation d'antagonistes alpha-2b pour le traitement de symptomes vasomoteurs - Google Patents

Utilisation d'antagonistes alpha-2b pour le traitement de symptomes vasomoteurs

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Publication number
EP1846105A2
EP1846105A2 EP04794977A EP04794977A EP1846105A2 EP 1846105 A2 EP1846105 A2 EP 1846105A2 EP 04794977 A EP04794977 A EP 04794977A EP 04794977 A EP04794977 A EP 04794977A EP 1846105 A2 EP1846105 A2 EP 1846105A2
Authority
EP
European Patent Office
Prior art keywords
reuptake inhibitor
pharmaceutically acceptable
methyl
ethyl
receptor antagonist
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04794977A
Other languages
German (de)
English (en)
Inventor
Darlene Coleman Deecher
Chad Edward Beyer
Liza Leventhal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34468478&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1846105(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US10/685,812 external-priority patent/US20040152710A1/en
Priority claimed from US10/962,897 external-priority patent/US20050130987A1/en
Application filed by Wyeth LLC filed Critical Wyeth LLC
Publication of EP1846105A2 publication Critical patent/EP1846105A2/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/41—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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • 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
    • 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
    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention is directed to pharmaceutical compositions, comprising: at least one selective adrenergic 02 B receptor antagonist or a pharmaceutically acceptable salt thereof; at least one norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.
  • at least one selective adrenergic 02 B receptor antagonist or a pharmaceutically acceptable salt thereof at least one norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.
  • NRI/SRI norepinephrine reuptake inhibitor/serotonin reuptake inhibitor
  • Figure 3 shows the results of the microdialysis studies measuring the effects of imiloxan, an adrenergic 2B receptor antagonist, on extracellular levels of NE and 5-HT in the rat preoptic area of the hypothalamus; imiloxan 10 mg/kg, ip. * indicates p ⁇ 0.05 compared to vehicle control (referred to in EXAMPLE 3).
  • a selective adrenergic ⁇ 2 B receptor antagonist when administered alone or when co-administered with a NRl compound, resulted in a dose-dependent abatement of a naloxone-induce flush.
  • the efficacy of an NRl may be potentiated when administered in combination with an adrenergic ⁇ 2 ⁇ receptor antagonist. It is believed that the present invention described presents a substantial breakthrough in the field of treatment, alleviation, inhibition, and/or prevention of vasomotor instability and/or symptoms.
  • the invention also includes pharmaceutical compositions comprising, as the active ingredient(s), selective adrenergic ⁇ 2 B antagonists alone, selective adrenergic ⁇ 2 B antagonists in combination with norepinephrine reuptake inhibitors (NRI) (as a single compound or as a combination of two or more compounds), or selective adrenergic ⁇ 2 ⁇ antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRI/SRI) (as a single compound or as a combination of two or more compounds).
  • NRI norepinephrine reuptake inhibitors
  • SRI selective adrenergic ⁇ 2 ⁇ antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors
  • TST TST skin temperature
  • Norepinephrine transporter is abbreviated NET.
  • Human norepinephrine transporter is abbreviated hNET.
  • SERT Human norepinephrine transporter
  • hSERT Human serotonin transporter
  • Norepinephrine reuptake inhibitor is abbreviated NRl.
  • Selective norepinephrine reuptake inhibitor is abbreviated SNRI.
  • SRI Serotonin reuptake inhibitor
  • SSRI Selective serotonin reuptake inhibitor
  • Norepinephrine is abbreviated NE. - -
  • vasomotor symptoms include, but are not limited to, hot flushes (flashes), insomnia, sleep disturbances, mood disorders, irritability, excessive perspiration, night sweats, fatigue, and the like, caused by, inter alia, thermoregulatory dysfunction.
  • hot flush is an art-recognized term that refers to an episodic disturbance in body temperature typically consisting of a sudden skin flushing, usually accompanied by perspiration in a subject.
  • the term “hot flush” may be used interchangeably with the terms vasomotor symptoms, vasomotor instability, vasomotor dysfunction, night sweats, vasomotor disturbances, and hot flash.
  • premature menopause or “artificial menopause” refer to ovarian failure of unknown cause that may occur before age 40. It may be associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may result from oophorectomy, chemotherapy, radiation of the pelvis, or any process that impairs ovarian blood supply.
  • ovariectomy means removal of an ovary or ovaries and can be effected according to Merchenthaler et al., Maturitas, 1998; 30(3): 307-316.
  • selective adrenergic ⁇ 2 B receptor antagonist refers to an adrenergic ⁇ 2 receptor antagonist compound that preferentially binds to the adrenergic Q 2B receptor relative to the adrenergic ⁇ 2 A receptor or adrenergic ⁇ 2c receptor, and may be measured by the ratio of the in vitro or in vivo IC 50 value for antagonist activity at the adrenergic ⁇ -.B receptor, divided by the IC50 value for antagonist activity at the adrenergic ⁇ 2A or c-
  • a selective adrenergic ⁇ 2 B receptor antagonist is any adrenergic ⁇ 2 receptor antagonist for which this ratio is greater than about 1
  • substantially no serotonin reuptake inhibitor (SRI) activity refers to a norepinephrine reuptake inhibitor that has a selectivity ratio of SERT:NET activity, as measured by the EC5 0 value or by % specific bound NE uptake for the human transporter, of greater than about 2:1 , preferably, greater than about 5:1 , and more preferably, greater than about 10:1.
  • the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability of the components (alone or in combination with one or more combination drugs) to elicit a desired response in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.
  • component used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacologic and/or physiologic effect by local and/or systemic action.
  • the component herein may contain norepinephrine reuptake inhibiting activity or combined serotonin reuptake inhibiting activity and the norepinephrine reuptake inhibiting activity.
  • the component herein may contain combined norepinephrine reuptake inhibiting activity and the adrenergic ⁇ 2B receptor antagonist activity.
  • modulation refers to the capacity to either enhance or inhibit a functional property of a biological activity or process, for example, receptor binding or signaling activity. Such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway and/or may be manifest only in particular cell types.
  • the modulator is intended to comprise any compound, e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule, or peptide.
  • patient comprises female animals including humans and, among humans, not only women of advanced age who have passed through menopause but also women who have undergone hysterectomy or for some other reason have suppressed estrogen production, such as those who have undergone long-term administration of corticosteroids, suffer from Cushing's syndrome or have gonadal dysgenesis.
  • patient is not intended to be limited to a woman.
  • side effect refers to a consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other then the one sought to be benefited by its administration.
  • side effect may refer to such conditions as, for example, vomiting, nausea, sweating, and flushes (Janowsky, et al., Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
  • inhibitor is intended to comprise any _ compound, e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule or peptide, that exhibits a partial, complete, competitive and/or inhibitory effect on mammalian, preferably the human norepinephrine reuptake or both serotonin reuptake and the norepinephrine reuptake, thus diminishing or blocking, preferably diminishing, some or all of the biological effects of endogenous norepinephrine reuptake or of both serotonin reuptake and the norepinephrine reuptake.
  • Suitable non-organic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothe ⁇ ic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most preferably is the hydrochloride salt.
  • the compounds of the present invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purpose of the present invention.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to adrenergic ⁇ 2 B receptor antagonists, NRIs, and NRI/SRIs.
  • adrenergic ⁇ 2 B receptor antagonists e.g. by hydrolysis
  • NRIs adrenergic ⁇ 2 B receptor antagonists
  • NRI/SRIs adrenergic ⁇ 2 B receptor antagonists
  • Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, ef al., (ed).
  • the invention is directed to methods for treating a vasomotor symptom in a subject in need thereof, comprising the step of: administering to said subject a composition comprising: an effective amount of an active ingredient consisting essentially of at least one selective adrenergic ⁇ 2 B receptor antagonist or a pharmaceutically acceptable salt thereof.
  • the invention is directed to methods for treating a vasomotor symptom in a subject in need thereof, comprising the step of: administering to said subject a composition comprising: an effective amount of at least one selective adrenergic ⁇ 2 B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one norepinephrine reuptake inhibitor (NRl) or a pharmaceutically acceptable salt thereof.
  • a composition comprising: an effective amount of at least one selective adrenergic ⁇ 2 B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one norepinephrine reuptake inhibitor (NRl) or a pharmaceutically acceptable salt thereof.
  • the norepinephrine reuptake inhibitor (NRl) is administered simultaneously with the selective adrenergic ⁇ 2B receptor antagonist. In certain other embodiments, the norepinephrine reuptake inhibitor (NRl) is administered sequentially with the selective adrenergic ⁇ 2 B receptor antagonist.
  • the selective adrenergic ⁇ 2 B receptor antagonist and the norepinephrine reuptake inhibitor (NRl) are a single compound. In certain embodiments, the selective adrenergic ⁇ 2B receptor antagonist and the norepinephrine reuptake inhibitor (NRl) are separate compounds.
  • the norepinephrine reuptake inhibitor has substantially no serotonin reuptake inhibitor (SRI) activity. - -
  • the invention is directed to methods for treating a vasomotor symptom in a subject in need thereof, comprising the step of: administering to said subject a composition comprising: an effective amount of at least one selective adrenergic Q 2B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one dual norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof.
  • a composition comprising: an effective amount of at least one selective adrenergic Q 2B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one dual norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof.
  • the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor is administered simultaneously with the selective adrenergic ⁇ 2 B receptor antagonist. In certain other embodiments, the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) is administered sequentially with the selective adrenergic ⁇ 2 B receptor antagonist.
  • the selective adrenergic ⁇ 2B receptor antagonist and the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor are a single compound.
  • the selective adrenergic D2B receptor antagonist and the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor are separate compounds.
  • the invention is directed to pharmaceutical compositions, comprising: an active ingredient consisting essentially of at least one selective adrenergic ⁇ 2B receptor antagonist or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.
  • the invention is directed to pharmaceutical compositions, comprising: at least one selective adrenergic ⁇ 2 B receptor antagonist or a pharmaceutically acceptable salt thereof; _ _ at least one norepinephrine reuptake inhibitor (NRl) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.
  • the invention is directed to pharmaceutical compositions, comprising: at least one selective adrenergic ⁇ 2 ⁇ receptor antagonist or a pharmaceutically acceptable salt thereof; at least one norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.
  • at least one selective adrenergic ⁇ 2 ⁇ receptor antagonist or a pharmaceutically acceptable salt thereof at least one norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof
  • NRI/SRI norepinephrine reuptake inhibitor/serotonin reuptake inhibitor
  • Suitable selective adrenergic ⁇ 2B receptor antagonist include, but are not limited, to 2-(1-ethyl-2-imidazoyl)methyl-1,4-benzodioxan (imiloxan), 2-[(2,3-dihydro- 1 ,4-benzodioxin-2-yl)methyl]-1 -ethyl-1 H-imidazole, 2-[2-[4-(2-methoxy ⁇ henyl)-1 - piperazinyl]ethyl]-4,4-dimethyl-1 ,3(2H,4H)-isoquinolinedione (ARC 239), or a combination or a pharmaceutically salt thereof.
  • Imiloxan is a preferred selective adrenergiC ⁇ B receptor antagonist.
  • Suitable norepinephrine reuptake inhibitors include, but are not limited to, maprotiline; reboxetine; norpramine, desipramine; nisoxetine; atomoxetine; amoxapine; doxepin; lofepramin; amitryptyline; 1-[1-(3-fluorophenyl)-2- (4-methyl-1 -piperazinyl)ethyl]cyclohexanol; 1 -[1 -(3-chlorophenyl)-2-(4-methyl-1 - piperazinyl) ethyljcyclohexanol; 1 -[2-(4-methyl-1 -piperazinyl)-1 -[3-(trifluoromethyl)- phenyl]ethyl] cyclohexanol; 1 -[1 -(4-methoxy phenyl)-2-[4-methyl
  • Preferred NRIs include is desipramine and 1 -[1 -(3-chlorophenyl)-2-(4- methyl-1-piperazinyl)ethyIjcyc)ohexano), particularly pure R and S enantiomers of 1- [1 -(3-chlorophenyl)-2-(4-methyl-1 -piperazinyl)ethyl]cyclohexanol.
  • the dimethyl amine derivatives may be synthesized as described, for example, in US-A- 4,535,186, the disclosure of which is incorporated herein by reference in its entirety.
  • the piperazine derivatives may be synthesized as described, for example, in US-A- 4,826,844, the disclosure of which is incorporated herein by reference in its entirety.
  • Suitable dual norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) compounds are venlafaxine, O-desmethyl-venlafaxine (DVS-233 or ODV), milnacipran, duloxetine, and combinations and pharmaceutically acceptable salts thereof.
  • the compound may exhibit more SRI, approximately equivalent NRl and SRI activity, or preferably more NRl activity.
  • the adrenergic ⁇ 2 B receptor antagonists, NRIs, and NRI/SRIs may be prepared in the form of pharmaceutically acceptable salts, solvates, and prodrugs.
  • Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereofsomers (i.e. enantiomers).
  • the present invention includes all such stereoisomers and any mixtures thereof including racemic mixtures. Racemic mixtures of the stereoisomers as well as the - i - substantially pure stereoisomers are within the scope of the invention.
  • the term "substantially pure,” as used herein, refers to at least about 90 mole %, more preferably at least about 95 mole %, and most preferably at least about 98 mole % of the desired stereoisomer is present relative to other possible stereoisomers.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron, 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).
  • HPLC high performance liquid chromatography
  • compositions of the present invention contain, as active ingredient(s), selective adrenergic ⁇ 2B antagonists alone, selective adrenergic ⁇ 2B antagonists in combination with norepinephrine reuptake inhibitors (NRl) (as a single compound or as a combination of two or more compounds), or selective adrenergic ⁇ 2 B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRI/SRI) (as a single compound or as a combination of two or more compounds).
  • NRl norepinephrine reuptake inhibitors
  • NRI/SRI selective adrenergic ⁇ 2 B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors
  • compositions of the present invention may also comprise at least one pharmaceutically acceptable carrier, adjuvants, and/or excipients, and the like (collectively referred to herein as "pharmaceutically acceptable carrier") that are well known in the art, for example as described in the Hand Book of Pharmaceutical Excipients, second edition, American Pharmaceutical Association, 1994 (incorporated herein by reference).
  • pharmaceutically acceptable carrier for example as described in the Hand Book of Pharmaceutical Excipients, second edition, American Pharmaceutical Association, 1994 (incorporated herein by reference).
  • the selective adrenergicoc 2B antagonist compound may be administered either alone or in combination therapy with the norepinephrine reuptake inhibitors (NRl) or the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor compounds (NRI/SRI) to patients in the daily dosage range of from about 0.1 to about 500 mg per day for a time sufficient to reduce and/or substantially eliminate the number and/or severity of hot flushes.
  • a more preferred range is about 1 to about 300 mg per day, the most preferred daily dosage being about 10 to about 200 mg per day.
  • the norepinephrine reuptake inhibitors may be administered in combination therapy with the selective antagonist compound to patients in the daily dosage range of from about 0.1 mg/day to about 500 mg/day for a time sufficient to reduce and/or substantially eliminate the number and/or severity of hot flushes.
  • a more preferred range is about 1 mg/day to about 300 mg/day, the most preferred daily dosage being about 1 mg/day to about 200 mg/day.
  • the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor compounds (NRI/SRI) in combination therapy with the selective adrenergicoc 2 B antagonist compound may be administered to patients in the daily dosage range of from about 0.10 mg/day to about 200 mg/day for a time sufficient to reduce and/or substantially eliminate the number and/or severity of hot flushes.
  • a more preferred range is about 1 mg/day to about 100 mg/day, the most preferred daily dosage being about 10 mg/day to about 50 mg day.
  • the selective adrenergic 2B antagonist compound alone or combination therapies of this invention may be in any dosage form, such as those described herein, and can also be administered in various ways, as described herein.
  • the combination products of the invention are formulated together, in a single dosage form (that is, combined together in one capsule, tablet, powder, or liquid, etc.).
  • the selective adrenergic 2 B antagonists in combination with norepinephrine reuptake inhibitors (NRl), or selective adrenergic ⁇ B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRI/SRI) may be administered at the same time or simultaneously (that is, together), or in any order.
  • the administration of selective adrenergic 2 ⁇ antagonists in combination with norepinephrine reuptake inhibitors (NRl), or selective adrenergica 2 B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRI/SRI) occurs less than about one hour apart, more preferably less than about 30 minutes apart, even more preferably less than about 15 minutes apart, and still more preferably less than about 5 minutes apart.
  • compositions of the invention are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985).
  • Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
  • the compounds and composition of the invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the active ingredient(s), (selective adrenergicoc2B antagonist, NRl, or NRI/SRI or a pharmaceutically acceptable salt thereof) will be present at a level of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, and pharmaceutically acceptable carrier, if present, will be present at a level of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition.
  • the active ingredient(s), (selective adrenergic 2 B antagonist, NRl, or NRI/SRI or a pharmaceutically acceptable salt thereof) will be present at a level of from about 1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, and pharmaceutically acceptable carrier, if present, will be present at a level of from about 1 %, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition.
  • the active ingredient(s), (selective adrenergic ⁇ ,2B antagonist, NRl, or NRI/SRI or a pharmaceutically acceptable salt thereof) will be present at a level of from about 5%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, and pharmaceutically acceptable carrier, if present, will be present at a level of from about 5%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition.
  • the active ingredient(s), (selective adrenergic ⁇ 2 B antagonist, NRl, or NRI/SRI or a pharmaceutically acceptable salt thereof) will be present at a level of from about 10%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, and pharmaceutically acceptable carrier, if present, will be present at a level of from about 10%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition.
  • the active ingredient(s), (selective adrenergic ⁇ 2B antagonist, NRl, or NRI/SRI or a pharmaceutically acceptable salt thereof) will be present at a level of from about 25%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, and pharmaceutically acceptable carrier, if present, will be present at a level of from about 25%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition.
  • the route of administration may be any route, which effectively transports the active ingredient(s) to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (i.e. enantiomers).
  • the present invention includes all such stereoisomers and any mixtures thereof including racemic mixtures. Racemic mixtures of the stereoisomers as well as the substantially pure stereoisomers are within the scope of the invention.
  • the term "substantially pure,” as used herein, refers to at least about 90 mole %, more preferably at least about 95 mole %, and most preferably at least about 98 mole % of the desired stereoisomer is present relative to other possible stereoisomers.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron, 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).
  • HPLC high performance liquid chromatography
  • the route of administration may be any route, which effectively transports the active norepinephrine reuptake inhibitor(s) or serotonin reuptake inhibitor(s) and norepinephrine reuptake inhibitor(s) to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment. Furthermore, the administration of norepinephrine reuptake inhibitor(s) and serotonin reuptake inhibitor(s) may be concurrent or simultaneous.
  • Imiloxan can be purchased commercially (TocrisCookson Inc, Ellisville, MO) Desipramine can be prepared as described in U.S. Pat. No. 3,454,554. The following reagents were purchased commercially: morphine alkaloid pellets (Murty Pharmaceuticals, Lexington, KY),ketamine (Phoenix Pharmaceuticals, Belmont, CA), and naloxone (Research Biochemicals International, St. Louis, MO).
  • Dosing All doses were prepared based on mg/kg. Compounds were dissolved in either sterile water, or 2.0% Tween/methylcellulose and injected subcutaneously (sc) or intraperitoneally (ip) and used at the following dosages: imiloxan (1, 10, 15 and 30 mg/kg), desipramine (0.01, 1.0, 10, and 30 mg/kg), Ketamine (Ketaject, Phoenix Pharmaceuticals, Belmont, CA) was injected intramuscularly in the hindlimb at a dosage (40mg/kg) that was determined to be mildly sedative but did not cause a change in tail skin temperature.
  • sc subcutaneously
  • ip intraperitoneally
  • Animals Ovariectomized Sprague-Dawley rats (180-220 g) were obtained from a commercial vendor (Taconic, Germantown, NY) and individually housed under 12 hours light/dark cycle in a room maintained at 25°C.
  • male Sprague-Dawley rats (275-350 g) were obtained from Charles River (Wilmington, MA) and group housed until time of surgery. Animals were provided with standard rat chow and water ad libitum.
  • Morphine-dependent model Ovariectomized rats were injected once daily for 8-9 days with vehicle to minimize stress responses and then administered compound(s) on test day. On day 4 of dosing, morphine dependence was induced by sc implantation of two slow-release morphine pellets (75 mg/pellet) in the dorsal scapular region. This model is based upon an established morphine-dependent naloxone-induced flush paradigm that is reversible by estrogen treatment (Katovich et al., Proceedings of the Society for Experimental Biology & Medicine, 1990. 193(2): p. 129-35).
  • morphine withdrawal was induced with an opioid antagonist (naloxone) that causes a transient increase in TST.
  • naloxone an opioid antagonist
  • rats were administered their final dose of test compound 40-60 minutes prior to naloxone injection.
  • Rats were mildly sedated with ketamine and a thermistor connected to a MacLab data acquisition system was taped to the base of the tail.
  • Tail skin temperature was then monitored continuously for 35 minutes to establish a baseline temperature.
  • Naloxone was subsequently administered and TST was measured for an additional 35-60 minutes (total recording time 70-95 minutes).
  • Telemetry model This model has been modified from a previously reported protocol describing estrogen regulation of diurnal TST patterns (Berendsen et. al., 2001). Over a 24 hour period, intact cycling rats decrease TST during the active (dark) phase and TST remains elevated during the inactive (light) phase. In OVX rats, TST is elevated over the entire 24 hour period, thus the usual decrease in TST during the active (dark) phase is lost, thus, a compound's ability to restore this lowering of TST during the active phase was examined.
  • a temperature and physical activity transmitter (PhysioTel TA10TA-F40, Data Sciences International) was implanted subcutaneously in the dorsal scapular region and the tip of the temperature probe was tunneled subcutaneously 2.5 cm beyond the base of the tail. After a 7-day recovery period, TST readings were continuously recorded for the remainder of the study. Tail skin temperature readings were collected from each animal every 5 minutes with values obtained over a 10 second sampling period. The day before test day, an average baseline TST value was calculated for each animal by averaging temperature readings recorded during the 12 hours active (dark) phase. In these studies, animals were dosed approximately 1 hour prior to the onset of dark cycle.
  • a microdialysis guide cannula (CMA/12; CMA Microdialysis, Sweden) was directed toward the preoptic area of the hypothalamus using the following coordinates: -0.4 mm anterior to bregma, -1.0 mm lateral from the midline and -6.9 mm ventral to dura with a flat skull (Paxinos and Watson, 1986).
  • Guide cannulae were fixed to the skull with two stainless-steel screws (Small Parts, Roanoke, VA) and dental acrylic (Plastics One, Roanoke, VA). Following surgery, animals were individually housed in acrylic cages (45 cm sq.) for approximately 24 hours and had access to food and water ad libitum.
  • Microdialysis probes (CMA/12; 20 kD cut-off) were purchased from CMA/Microdialysis and consisted of a 2-mm active membrane (OD 0.5 mm) and 14- mm stainless steel shaft (OD 0.64mm). Probes were perfused with artificial CSF (aCSF; 125 mM NaCI, 3 mM KCI, 0.75 mM MgS0 4 and 1.2 mM CaCI 2 , pH 7.4) according to manufacturer's specifications. On the day of experiments, microdialysis probes were inserted, via the guide cannula, into the hypothalamus and perfused with aCSF at a flow rate of 1 ⁇ l/min.
  • CSF artificial CSF
  • a 3-hour stabilization period was allowed following probe insertion after which time dialysate was collected every 20 minutes into plastic tubes (CMA) located in a CMA/142 microfraction collector.
  • CMA plastic tubes
  • Dialysate (10 ⁇ l) containing NE and 5-HT were separated by HPLC (C18 ODS3 column, 150 x 3.0 mm, Metachem, Torrance, CA) and detected using an ANTEC electrochemical detector (ANTEC, Netherlands) set at a potential of 0.65V vs. a Ag/AgCI reference electrode.
  • Neurochemical data were compared to an external standard curve and all data was acquired using the Atlas software package (Thermo Labsystems, Beverley, MA) for the PC.
  • Efficacy of hot flush abatement was determined by evaluating statistical differences at the peak response time of 15 minutes post-naloxone, when the maximal change in TST is observed.
  • a customized SAS-excel (SAS Institute, Cary, NC) application was used applying a four parameter logistic model to determine ED 50 values.
  • a logistic dose transformation was performed on ⁇ TST.
  • Maximum flush ( ⁇ TST at 15 minutes post-naloxone) was used in the analysis and the minimum was locked at zero.
  • the ED 50 value is reported as the dose of test compound that abates 50% of the naloxone- induced flush.
  • Statisticians in the Biometrics Department (Wyeth Research, Collegeville, PA) developed a customized JMP application.
  • EXAMPLE 1 Effect of a select adrenergic ⁇ 2 B receptor antagonist in alleviating vasomotor instability using a naioxone-induced flush model in rats
  • EXAMPLE 2 Effect of a select adrenergic ⁇ 2 ⁇ receptor antagonist in alleviating vasomotor instability using a naioxone-induced flush model in rats [0097] Method used as described in the general method section under telemetry rat model with the following exceptions: Rats were injected subcutaneously with vehicle (2%Tween/0.5% methylcellulose) or 30 or 60 mg/kg, sc imiloxan (Tocris) dissolved in 2%Tween/0.5% methylcellulose. The effect of imiloxan was measured by evaluating the following parameters in this model: onset of action, duration of effect on TST, maximal change in TST and mean change in TST over the duration of the imiloxan's effect. The results are shown in Figure 2.
  • Imiloxan (adrenergic 2 ⁇ receptor antagonist) restored normal TST in an OVX-induced thermoregulatory dysfunction telemetry model (telemetry model) 30 mg/kg, sc * indicates p ⁇ 0.05 compared to vehicle control .
  • EXAMPLE 3 Effect of compounds with adrenergic ⁇ 2 B receptor antagonist activity and NRl activity
  • Rats were injected subcutaneously with vehicle (2%Tween/0.5% methylcellulose) or imiloxan, 15 mg/kg, sc, or desipramine, 1 mg/kg, sc, dissolved in 2%Tween/0.5% methylcellulose 40 minutes prior to a naioxone-induced flush (maximal flush (15 minutes post-naloxone; ⁇ °C, Mean + SEM) the combination of imiloxan and desipramine effectively abated the induced flush.
  • naioxone-induced flush maximum flush (15 minutes post-naloxone; ⁇ °C, Mean + SEM
  • EXAMPLE 4 Neurochemicaf effect of a select adrenergic ⁇ 2 B receptor antagonist on levels of NE and 5-HT in the preoptic area of the rat hypothalamus

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Abstract

L'invention concerne des antagonistes adrénergiquesα2B sélectifs, isolément, et ces mêmes antagonistes combinés avec des inhibiteurs de réabsorption de norépinéphrine (NRI) (en composé unique ou en combinaison avec deux ou plus de deux composés), ou bien ces mêmes antagonistes combinés avec des inhibiteurs doubles de réabsorption de norépinéphrine /sérotonine (NRI/SRI) (en composé unique ou en combinaison avec deux ou plus de deux composés), ainsi que des procédés d'utilisation correspondants pour le traitement des symptômes vasomoteurs.
EP04794977A 2003-10-14 2004-10-13 Utilisation d'antagonistes alpha-2b pour le traitement de symptomes vasomoteurs Withdrawn EP1846105A2 (fr)

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US51089703P 2003-10-14 2003-10-14
US10/685,812 US20040152710A1 (en) 2002-10-15 2003-10-14 Use of norepinephrine reuptake modulators for preventing and treating vasomotor symptoms
PCT/US2003/032759 WO2004035058A1 (fr) 2002-10-15 2003-10-15 Utilisation de modulateurs du recaptage de la noradrenaline en prevention et traitement de symptomes vasomoteurs
US10/962,897 US20050130987A1 (en) 2003-10-14 2004-10-12 Methods of treating vasomotor symptoms
PCT/US2004/033754 WO2005037260A2 (fr) 2003-10-14 2004-10-13 Procede de traitement de symptomes vasomoteurs

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US20040152710A1 (en) * 2002-10-15 2004-08-05 Deecher Darlene Coleman Use of norepinephrine reuptake modulators for preventing and treating vasomotor symptoms
US7345096B2 (en) * 2002-10-15 2008-03-18 Wyeth Use of norepinephrine reuptake modulators for preventing and treating vasomotor symptoms
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