WO .2005/037260 1 PCT/US2004/033754 METHODS OF TREATING VASOMOTOR SYMPTOMS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to: (a) U.S. Application No. 10/ filed October 12, 2004, which claims the benefit of U.S. Application No. 60/510,897 filed October 14, 2003, (b) U.S. Application No. 10/685,812 filed October 14, 2003; and (c) International Application No. PCT/US03/32759 filed October 15, 2003, the entire disclosures of each are herein incorporated by reference. FIELD OF THE INVENTION : [0002] The present invention relates to the use of compounds and composition of compounds that modulate norepinephrine levels for the treatment of, inter alia, vasomotor symptoms (VMS). In particular, the present invention relates to the use of compounds and compositions of compounds having adrenergicoc2B antagonist activity for the modulation of the norepinephrine system. BACKGROUND OF THE INVENTION [0003] Vasomotor symptoms (VMS), referred to as hot flushes and night sweats, are the most common symptoms associated with menopause, occurring in 60% to 80% of all women following natural or surgically-induced menopause. VMS are likely \o be an adaptive response of the central nervous system (CNS) to declining sex steroids. To date, the most effective therapies for VMS are hormone-based treatments, including estrogens and/or some progestins. Hormonal treatments are very effective at alleviating VMS, but they are hot appropriate for all women. It is well recognized that VMS are caused by fluctuations of sex steroid levels arid can be disruptive and disabling in both males and females. A hot flush can fast up to thirty minutes and vary in its frequency from several times a week to multiple occurrences per day. The patient experiences a hot flush as a sudden feeling of heat that WO 2005/037260 PCT/US2004/033754 2 spreads quickly from the face to the chest and back and then over the rest of the body. It is usually accompanied by outbreaks of profuse sweating. It may sometimes occur several times an hour, and it often occurs at night. Hot flushes and outbreaks of sweats occurring during the night can cause sleep deprivation. Psychological and emotional symptoms observed, such as nervousness, fatigue, irritability, insomnia, depression, memory loss, headache, anxiety, nervousness or inability to concentrate are considered to be caused by the sleep deprivation following hot flush and night sweats (Kramer et ai, In: Murphy et ai, 3rd Int'l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)). [0004] Hot flushes may be even more severe in women treated for breast cancer for several reasons: (1) many survivors of breast cancer are given tamoxifen, the most prevalent side effect of which is hot flush; (2) many women treated for breast cancer undergo premature menopause from chemotherapy; (3) women with a history of breast cancer have generally been denied estrogen therapy because of concerns about potential recurrence of breast cancer (Loprinzi, et ai, Lancet, 2000, 356(9247): 2059-2063). [0005] Men also experience hot flushes following steroid hormone (androgen) withdrawal. This is true in cases of age-associated androgen decline (Katovich, et ai, Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormone deprivation associated with treatments for prostate cancer (Berendsen, et al., European Journal of Pharmacology, 2001, 419(1): 47-54. As many as one-third of these patients will experience persistent and frequent symptoms severe enough to cause significant discomfort and inconvenience. [0006] The precise mechanism of the VMS is unknown but generally is thought to represent disturbances to normal homeostatic mechanisms controlling thermoregulation and vasomotor activity (Kronenberg et al., "Thermoregulatory Physiology of Menopausal Hot Hashes: A Review," Can. J. Physioi Pharmacol., WO 2005/037260 3 PCT/US2004/033754 1987,65:1312-1324). [0007] The fact that estrogen treatment (e.g. estrogen replacement therapy) relieves the symptoms establishes the link between these symptoms and an estrogen deficiency. For example, the menopausal stage of life Is associated with a wide range of other acute symptoms, as described above, and these symptoms are generally estrogen responsive. [0008] It has been suggested that estrogens may stimulate the activity of both the norepinephrine (NE) and/or serotonin (5-HT) systems (J. Pharmacology & Experimental Therapeutics, 1988, 236(3) 646-652). It is hypothesized that estrogens modulate NE and 5-HT levels providing homeostasis in the thermoregulatory center of the hypothalamus. The descending pathways from the hypothalamus via brainstem/spinalcord and the adrenals to the skin are involved in maintaining normal skin temperature. The action of NE and 5-HT reuptake inhibitors is known to impinge on both the CNS and peripheral nervous system (PNS). The pathophysiology of VMS is mediated by both central and peripheral mechanisms and, therefore, the interplay between the CNS and PNS may account for the efficacy of dual acting SRl/NR!s in the treatment of thermoregulator/ dysfunction. In fact, the physiological aspects and the CNS/PNS involvement in VMS may account for the lower doses proposed to treat VMS (Loprinzi, et aL, Lancet, 2000, 356:2059-2063; Stearns et aL, JAMA, 2003, 289:2827-2834) compared to doses used to treat the behavioral aspects of depression. The interplay of the CNS/PNS in the pathophysiology of VMS and the presented data within this document were used to support the claims that the norepinephrine system could be targeted to treat VMS. [0009J Although patients with VMS are most commonly treated by hormone therapy (orally, transdermally, or via an implant), some patients cannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3): 155-164, Fink et aL, Nature, 1996, 383(6598): 306). In addition, hormone replacement therapy is usually not recommended for women or men with or at risk for hormonally sensitive cancers (e.g. breast or prostate cancer). Thus, non-hormona/ therapies (e.g. fluoxetine, WO 2005/037260 PCT/US2004/033754 -4- . paroxetine [SRIs] and clonidine) i are being evaluated clinically. WO9944601 discloses a method for decreasing hot flushes in a human female by administering fluoxetine. Other options have been studied for the treatment of hot flushes, including steroids, alpha-adrenergic agonists, and beta-blockers, with varying degree of success (Waldingeref a/.,/Wafor/fas, 2000,36(3): 165-168). [0010] It has been reported that a2-adrenergic receptors play a role in thermoregulatory dysfunctions (Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3). These receptors are located both pre- and post-synaptically and mediate an inhibitory role in the central and peripheral nervous system. There are four distinct subtypes of the adrenergica2 receptors, i.e., axe a2A, CC2B, OC2C and CC2D (Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Then, 1995, 68: 175). It has been reported that a non-select oc2-adrenoceptor antagonist, yohimbine, induces a flush and an a2-adrenergic receptor agonist, clonidine, alleviates the yohimbine effect (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3). Clonidine has been used to treat hot flush. However, using such treatment is associated with a number of undesired side effects caused by high doses necessary to abate hot fiush described herein and known in the reiated arts. [0011] Given the complex multifaceted nature of thermoregulation and the interplay between the CNS and PNS in maintaining thermoregulatory homeostasis, multiple therapies and approaches can be developed to target vasomotor symptoms. The present invention focuses on methods directed to these and other important uses. SUMMARY OF THE INVENTION [0012] The present invention provides methods for treating a subject afflicted with vasomotor symptoms. WO 2005/037260 -5- PCT/US2004/033754 [0013] In one aspect, 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 adrenergica2B receptor antagonist or a pharmaceutically acceptable salt thereof. [0014] In another aspect, 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 Jeast one selective adrenergica2B 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. [0015] In yet another aspect, 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' adrenergicQ2B 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. [0016] In yet a further aspect, the invention is directed to pharmaceutical compositions, comprising: an active ingredient consisting essentially of' at least one selective adrenergiCc2B receptor antagonist or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. WO 2005/037260 PCT/US2004/033754 -6- [0017] In another aspect, the invention is directed to pharmaceutical compositions, comprising: at least one selective adrenergica2B receptor antagonist or a pharmaceutically acceptable salt thereof; at least one norepinephrine reuptake inhibitor (NRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. [0018] In yet another aspect, the invention is directed to pharmaceutical compositions, comprising: . ' at least one selective adren£rgica2B 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. BRIEF DESCRIPTION OF THE DRAWINGS [0019] The invention can he more fully understood from the following detailed description and the accompanying drawings that form a part of this application. [0020] Figure 1 is the dose response for imiloxan, an adrenergicoc2B receptor antagonist, in morphine-dependent rat model of hot flush (MD model); imiloxan ED50 value=15 mg/kg, sc . * indicates p< 0.05 compared to vehicle control (referred to in EXAMPLE 1). [0021] Figure 2 shows the'result of the administration of imiloxan, an adrenergica2B receptor antagonist, at 2 doses (30 and 60 mg/kg, sc) in telemetry rat model of ovariectomy-induced thermoregulatory dysfunction (referred to in EXAMPLE 2). [0022] Figure 3 shows the results of the microdialysis studies measuring the WO 2005/037260 PCT/US2004/033754 -7- effects of imiloxan, an adrenergica2B 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). DETAILED DESCRIPTION OF THE INVENTION [0023] Adrenergica2 receptor antagonists are known to induce hot flush. Surprisingly, we have discovered that a selective adrenergica2B receptor antagonist, when administered alone or when co-administered with a NRf compound, resulted in a dose-dependent abatement of a naloxone-induce flush. Furthermore, we have discovered that the efficacy of ah NRI may be potentiated when administered in combination with an adrenergica2B 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. [0024] The present invention provides methods for treating a subject afflicted with vasomotor symptoms by of recovering the reduced activity of norepinephrine. Norepinephrine activity in the hypothalamus or in the brainstem can be elevated by (i) blocking the activity of the adrenergica2B receptor with an antagonist and/or (ii) blocking the activity of the NE transporter. [0025] More specifically, the present invention provides methods for treating a subject afflicted with vasomotor symptoms comprising administering selective adrenergicoc2B antagonists alone, selective adrenergiccc2B antagonists in combination with norepinephrine reuptake inhibitors (NRI) (as a single compound or as a combination of two or more compounds), or selective adrenergica2B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRl/SRl) (as a single compound or as a combination of two or more compounds). The invention also includes pharmaceutical compositions comprising, as the active ingredient(s), selective adrenergica2e antagonists alone, selective adrenergicoc2B antagonists in combination with norepinephrine reuptake inhibitors WO 2005/037260 PCT/US2004/033754 -8- (NRI) (as a single compound or as a combination of two or more compounds), or selective adrenergica2B 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). [0026] The following definitions 'are provided for the full understanding of terms and abbreviations used in this specification. [0027] As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to "an antagonist" includes a plurality of such antagonists, and a reference to "a compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth. [0028] The abbreviations in the specification correspond to units of measure, techniques, properties, or compounds as follows: "min" means minutes, "h" means hour(s), "(jL" means microliter(s), "mL" means milfiliter(s), "mM" means millimolar, "M" means molar, "mmole" means millimole(s), "cm" means centimeters, "SEM" means standard error of the mean and "!U" means international Units. "A°C" and A TST mean change in tail skin temperature normalized for 15 minutes baseline TST prior to naloxone-induced flush. "ED50 value" means dose which results in 50% alleviation of the observed condition or effect (50% mean maximum endpoint). "Tail skin temperature" is abbreviated TST. "Norepinephrine transporter" is abbreviated NET. "Human norepinephrine transporter" is abbreviated hNET. "Serotonin transporter? is abbreviated SERT. "Human serotonin transporter" is abbreviated hSERT. "Norepinephrine reuptake inhibitor" is abbreviated NRl. "Selective norepinephrine reuptake inhibitor" is abbreviated SNRI. "Serotonin reuptake inhibitor" is abbreviated SRI. "Selective serotonin reuptake inhibitor" is abbreviated SSRI. "Norepinephrine" is abbreviated NE. c' WO 2005/037260 -9- PCT/US2004/033754 . "Serotonin is abbreviated 5-HT. "Subcutaneous" is abbreviated sc. "Intraperitoneal" is abbreviated ip. i "Oral" is abbreviated po. "High Performance Liquid Chromatography" is abbreviated HPLC. [0029] The terms "vasomotor symptoms," "vasomotor instability symptoms," and "vasomotor disturbances" 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. [0030] The term "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. [0031] The term "premenopausal," as used herein, means before the menopause, the term "perimenopausal," as used herein, means during the menopause and the term postmenopausal," as used herein, means after the menopause. [0032] The terms "premature < menopause" or "artificial menopause" refer to ovarian failure of unknown cause that may occur before age 40. lfmay.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. [0033] The term "ovariectomy," as used herein, means removal of an ovary or ovaries and can be effected according to Merchenthaler et a/., Maturitas, 1998; 30(3): 307-316. : WO 2005/037260 -10- PCT/US2004/033754 [0034] The term "selective adrenergica2B receptor antagonist," as used herein, refers to an adrenergica2 receptor antagonist compound that preferentially binds to the adrenergica2B receptor relative to the adrenergica2A receptor or adrenergica2c receptor, and may be measured by the ratio of the in vitro or in vivo IC50 value for antagonist activity at the adrenergica2B receptor, divided by the lC50 value for antagonist activity at the adrenergicQ2A or c- A selective adrenergicQ2B receptor antagonist is any adrenergica2 receptor antagonist for which this ratio is greater than about 1, preferably greater than about 2, more preferably greater than about 5, yet more preferably greater than about; 10, still more preferably greater than about 50, and more preferably still greater than about 100. [0035] The term "norepinepnrine reuptake inhibitor," as used herein, refers to a compound that alters the level of norepinephrine (NE) by inhibiting the uptake of NE through neurons of the centra) and/or peripheral nervous system and/or the peripheral system and that has a selectivity ratio of SERT:NET activity, as measured by the EC50 value or by % specific bound NE uptake for the human transporter, of at least about 1:1. Preferably, the selectivity ratio of SERT:NET does not exceed about 1000:1. Preferably, the selectivity ratio of SERTrNET is greater than about 2:1. More preferably, the selectivity ratio of SERT:NET is greater than about 5:1. Even more preferably, the selectivity ratio of SERT.-NET is greater than about 10:1. [0036] The phrase "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 EC50 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. [0037] The terms "norepinephrine reuptake inhibitor/serotonin reuptake inhibitor" and "(NR1/SRI)" as used herein, refers to a single compound having dual activity as a serotonin reuptake inhibitor and as a norepinephrine reuptake inhibitor. As used herein, a compound having a dual activity is a dual acting compound. WO 2005/037260 PCT/US2004/033754 -11- [0038] As term "treatment," as used herein, includes preventative (e.g., prophylactic), curative or palliative treatment and "treating" as used herein also includes preventative, curative and palliative treatment. [0039] The term "administering," as used herein, means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body. [0040] The term " effective amount," as used herein, refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result. In particular, " effective amount" refers to the amount of compound or composition of compounds that would increase norepinephrine levels to compensate in part or total for the lack of steroid availability; in subjects subject afflicted with a vasomotor symptom. Varying hormone levels will influence the amount of compound required in the present invention. For example, the pre-menopausal state may require a lower level of compound due to higher hormone levels than the peri-menopausal state. [0041] It will be appreciated that 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 therapeuticaily effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeuticaily WO 2005/037260 12 PCT/US2004/033754 beneficial effects. [0042] Preferably, the compounds of the present invention are administered at a dosage and for a time such that the number of hot flushes is reduced as compared to the number of hot flushes prior to the start of treatment. Such treatment can also be beneficial to reduce the overall severity or intensity distribution of any hot flushes still experienced, as compared to the severity of hot flushes prior to the start of the treatment. [0043] The terms "component", "drug" or "pharmacologically active agent" or "active agent" or "medicamenf are 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 pharrnacologic 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. Furthermore, the component herein may contain combined norepinephrine reuptake inhibiting activity and the adrenergic Q2B receptor antagonist activity. [0044] The term "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. [0045] The term "combination therapy" refers to the administration of two or more therapeutic agents or compounds, to treat a therapeutic condition or disorder described in the present disclosure, for example hot flush, sweating, thermoregulatory-related condition or disorder, or other. Such administration includes co-administration of these therapeutic agents or compounds in a WO 2005/037260 PCT/US2004/033754 -13- simultaneous manner, such as in a single compound having NRl/adrenergica2B receptor antagonist activity or in multiple, separate compounds for each NRI, NRI/SRI or adrenergica2 receptor antagonist activities (including separate compounds administered in a single dosage unit). In addition, such administration also includes use of each type of therapeutic agent in a concurrent manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. [0046] The term "subject" or "patient" refers to an animal including the human species that is treatable with the compositions, and/or methods of the present invention. The term "subject" or "subjects" is intended to refer to both the male and female gender unless one gender is specifically indicated. Accordingly, the term "patient" comprises any mammal which may benefit from treatment or prevention of vasomotor disturbances, such as a human, especially if the mammal is female, either in the pre-menopausal, peri-menopausal, or post-menopausal period. Furthermore, the term 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. However, the term "patient" is not intended to be limited to a woman. [0047] The term "side effect," as used herein, 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. In the case, for example, of high doses of NRIs or NRI/SRI compounds alone, the term "side effect" may refer to such conditions as, for example, vomiting, nausea, sweating, and flushes (Janowsky, et ai, Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9). i [0048] The term "inhibitor," as used herein, is intended to comprise any WO 2005/037260 -14- PCT/US2004/033754 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. [0049] The term "pbarmaceutically acceptable salts," as used herein, refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts, and organic salts. 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, muc'ic, nitric, pamoic, pantothenic, 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. [00501 Further, 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. In general, the solvated forms are considered equivalent to the unsolvated forms for the purpose of the present invention. [0051] The term, "prodrug," as used herein, means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to adrenergica2B receptor antagonists, NRls, and NRl/SRls. 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, et al., (ed). "Design and Application of Prodrugs," Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1S92, 8:1-38, Bundgaard, J. of Pharmaceutical WO 2005/037260 ' -15- PCT/US2004/033754 Sciences, 1988, 77:285 et seq.; and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975). [0052] In one aspect, 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 (east one selective adrenergica2B receptor antagonist or a pharmaceutically acceptable salt thereof. [0053} In another aspect, 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 adrenergica2B receptor antagonist or a pharmaceutically acceptable salt thereof; and an effective amount of at least one norepinephrine reuptake inhibitor (NRI) or a pharmaceutically acceptable salt thereof. [0054] !n certain embodiments, the norepinephrine reuptake inhibitor (NR!) is administered simultaneously with the selective adrenergica2B receptor antagonist. In certain other embodiments, the norepinephrine reuptake inhibitor (NRI) is administered sequentially with the selective adrenergica2B receptor antagonist. [0055] In certain embodiments, the selective adrenergico2B receptor antagonist and the norepinephrine reuptake inhibitor (NRI) are a single compound, fn certain embodiments, the selective adrenergica2B receptor antagonist and the norepinephrine reuptake inhibitor (NRI) are separate compounds. [0056] In certain preferred embodiments, the norepinephrine reuptake inhibitor has substantially no serotonin reuptake inhibitor (SRI) activity. WO 2005/037260 -16- PCT/US2004/033754 [0057] In yet another aspect, 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 adrenergica2B 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 pharmaceuticaliy acceptable salt thereof. [0058] In certain embodiments, the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRl/SRl) is administered simultaneously with the selective adrenergicQ2B receptor antagonist. In certain other embodiments, the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRl/SRl) is administered sequentially with the selective adrenergica2B receptor antagonist. [0059] In certain embodiments, the selective adrenergiCb2B receptor antagonist and the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) are a single compound. In certain embodiments, the selective adrenergicO2B receptor antagonist and the norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) are separate compounds. [0060] In yet a further aspect, the invention is directed to pharmaceutical compositions, comprising: an active ingredient consisting essentially of at least one selective adrenergicD2B receptor antagonist or a pharmaceuticafly acceptable salt thereof; and at least one pharmaceutically acceptable carrier. [0061] In another aspect, the invention is directed to pharmaceutical compositions, comprising: at least one selective adrenergica2B receptor antagonist or a pharmaceutically acceptable salt thereof; WO 2005/037260 -17- PCT/US2004/033754 at least one norepinephrine reuptake inhibitor (NR!) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. [0062] In yet another aspect, the invention is directed to pharmaceutical compositions, comprising: at least one selective adrenergica2B receptor antagonist or a pharmaceuticaKy acceptable salt thereof; at least one norepinephrine reuptake inh/bitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier. [0063] . Suitable selective adrenergica2B receptor antagonist include, but are not limited, to 2-(1-ethyi-2-imidazoyl)methyl-1,4-benzodioxan (imiloxan), 2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-1 -ethyl-1 H-imidazo)e, 2-[2-[4-(2-methoxyphenyI)-1 -piperazinyl]ethyl]-4,4-dimethyl-1,3(2H,4H)-isoquinolinedione (ARC 239), or a combination or a pharmaceuticaliy salt thereof. Imiloxan is a preferred selective adrenergicQ2B receptor antagonist. [0064] Suitable norepinephrine reuptake inhibitors (NRI) include, but are not fimited to, maprotiline; reboxetine; norpramine, desipramine; nisoxetine; atomoxetine; amoxapine; doxepin; lofepramin; amitryptyline; 1-[1-(3-fluorophenyl)-2- (4-methyi-1 -piperazinyl)ethyi]cyclohexanol; 1 -[1 -(3-chlorophenyl)-2-(4-methyI-1 - piperazinyl) ethyljcyclohexanol; 1 -[2-(4-methyl-1 -piperazinyl)-1-[3-(trifluoromethyl)- phenyllethyl] cyclohexanol; : 1-[1-(4-methoxy . phenyl)-2-[4-methyl-1- piperazinyl)ethyl]cyclohexanol; 1-[1-(3-chloropheny))-2-[4-(3-chloropheny))-1- piperazinyl]ethyl]cyc!ohexanol; 1-[1 -(3-methoxypheny!)-2-[4-pheny! methyl)-1 - piperazinyl]ethyl]cyclohexanol; 1 -[2-(3-ch!oro phenyl)1-piperazinyl]-1-[3- methoxyphenyl)ethyl]cyclohexanol; 1 -[2-[4-(6-chloro-2-pyrazinyl)-1 -piperazinyl]-1 -[3- methoxyphenyl)ethy!]cyclohexanol; 1-[2-[4-(phenyl methyl)]-1-piperazinyJ]-1-[3- (trifluoromethyl)phenyl]ethyl]cyclohexanol; 1 -[1 -(3-methoxyphenyl)-2-[4-{3- (trifluoromethyl)-pheny)]-1 -piperazinyljethy}] cyclohexano); 1 -[ 1 -(4-fluorophenyl)-2-[4- WO 2005/037260 PCT/US2004/033754 -18- (phenylmethyl)-i-piperazinyl] ethyl] cyclohexanol; 1-[1~(3-methoxyphenyl)-2-[4-[3- (trifluoromethyl)-phenyl]-1 -piperazinyOethyljcyclopentanol; 1-[1 -(4-fluorophenyI)-2-[4- (phenylmethyl)-1-piperazinyl]ethy!]cyc!ohexanol; 1-[2-(dimethylamino)-1-(3- trif luoromethyl pheny!)ethyl]cyclbhexanol; 1 -[1 -(3-fluorophenyl)~2-(4-methyM -pjperazinyl) ethyl]cyc)ohexano); 1 -[1 -(3-ch}orophenyl)-2-(dimethylamino)ethyl] cyclohexanol; 1-[2-dimethylamino)-1-(3-trifIuoromethylphenyl) ethyl]cyclohexanol; 1-[1-(3-chlorophenyI)-2-piperazin-1-yl-ethyl]-cyclohexano!; or a combination or pharmaceutically acceptable salt thereof [0065] Preferred NRIs include is desipramine and 1-[1-(3-chlorophenyl)-2-(4-methyl-1-piperaziny))ethy)]cyc]ohexano!, particularly pure R and S enantiomers of 1-n-(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. [0066] Suitable dual norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) compounds are venlafaxine, O-desrnethy!-ven!afaxine (DVS-233 or ODV), milnacipran, duloxetine, and combinations and pharmaceutically acceptable salts thereof. In the case of dual acting NRI/SRI compounds, the compound may exhibit more SRI, approximately equivalent NRI and SRI activity, or preferably more NRi activity. [0067] Within the present invention, the adrenergica2B receptor antagonists, NRIs, . and NRI/SRIs may be prepared in the form of pharmaceuticalJy acceptable salts, solvates, and prodrugs. [0068] 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 ail such stereoisomers and any mixtures thereof including racemic mixtures. Racemic mixtures of the stereoisomers as well as the WO 2005/037260 PCT/US2004/033754 -19- 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 stereoisorner 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 at., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., eta/., 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). [0069] The compositions of the present invention contain, as active ingredients), selective adrenergicoc2B antagonists alone, selective adrenergicoc2B antagonists in combination with norepinephrine reuptake inhibitors (NRl) (as a single compound or as a combination of two or more compounds), or selective adrenergicoc2B antagonists in combination with dual norepinephrine reuptake inhibitors/serotonin reuptake inhibitors (NRl/SRl) (as a single compound or as a combination of two or more compounds). The compositions of the present invention may afso comprise at least one pharmaceutically acceptable carrier, adjuvants, and/or excipients, and the like (collectively referred to herein as "pharmaceutically acceptable carrier") that are we1\ known m the art, for example as described in the Hand Book of Pharmaceutical Excipients, second edition, American Pharmaceutical Association, 1994 (incorporated herein by reference). [0070] The selective adrenergica2B antagonist compound may be administered either alone or in combination therapy with the norepinephrine reuptake inhibitors (NRf) 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 WO 2005/037260 -20- PCT/US2004/033754 about 300 mg per day, the most preferred daily dosage being about 10 to about 200. mg per day. [0071] The norepinephrine reuptake inhibitors (NRl) may be administered in combination therapy with the selective adrenergicc(2B 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. [0072] The norepinephrine reuptake inhibitor/serotonin reuptake inhibitor compounds (NRI/SRI) in combination therapy with the selective adrenergicoc2B 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. [0073] The selective adrenergicpc2B antagonist compound alone or combination therapies of this invention, such as pharmaceutical compositions comprising selective adrenergicaaB antagonists in combination with norepinephrine reuptake inhibitors (NRl), or selective adrenergic A product according to any ono of claims 15 to 17, wherein said norepinophrine reuptake inhibitor is a pure enantiomer of 1 -[1 -(3-chlorophenyl)-2-(4-methyl-1 -piperazinyl)ethyl)cyclohexanol. 22. A product according to any one of claims 15 to 17, wherein said dual norepinephrine reuptake inhibitor/serotonin reuptako inhibitor (NRI/SRI) is venlafaxine, O-desmothyl-venlafaxine (DVS-233 or ODV), milnacipran, duloxetine, or a combination or a pharmaceuticany salt thereof. 23. A product according to any one of claims 15 to 22", wherein said vasomotor symptom is hot flush . AMENDED PAGE. WO 2005/037260 37 PCT/US2004/033754 24 A product according to claim 23, wherein said subject is human. 25 A product according to claim 24, wherein said human is a female. 26 A product according to claim 25,. wherein said female is pre-menopausal. 27 A product according to claim 25, wherein said female is peri-menopausal. 1 28 A product according to claim US,. wherein said female is post-menbpausaL 29 A product according to claim ®A, wherein said human is a male. 30 A product according to claim729, wherein said male is naturally, chemically or surgically andropausal. 3l Use of an active ingredient consisting essentially of at least one selective adrenergiCc2B receptor antagonist or a pharmaeeutically acceptable salt thereof, in the preparation of a medicament for use in the treatment, of a vasomotor symptom in a subject. 32 Use of: at least one selective adrenergiCo2B receptor antagonist or a pharmaeeutically acceptable ?alt thereof, and at least one norept'nephrine reuptake inhtbftor (NR/) or norepfnephrine reuptake inhibitor/serotonin reuptake inhibitor (NRI/SRI) or a pharmaceutfcally "acceptable salt thereof; AMENDED PAGE, WO 2005/037260 PCT/US2OO4/033754 in the preparation of a medicament for use in the treatment of a vasomotor symptom in a subject. 33 Use of: at least one selective adrenergico e receptor antagonist or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the troatment of a vasomotor symptom in a subject; said medicament also comprising at least one norepinophrine reuptake inhibitor (NRI) or at least one norepinephrine reuptake inhibitor/serotonin reuptake inhibitor (NR1/SRI) or a pharmaceutically acceptable sail thereof. 34 use °f: at least one norepinephrine reuptake inhibitor (NRI) or at least one norepinephrine reuptako inhibitor/serotonin reuptake inhibitor (NRl/SRI) or pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of a vasomotor symptom in a subject; said medicament also comprising at loast one selective adrenorgiCoa) receptor antagonist or a pharmaceutically acceptable salt thereof. AMENDED PAGE