Novel treatment method of hot flash

Abstract

To provide a method for treating hot flash in a subject.SOLUTION: A method has administering a therapeutically effective amount of a transient receptor potential channel (TRP channel) blocker or pharmaceutically acceptable salt thereof. Preferably, the TRP channel blocker is a TRP channel subfamily V member 1 (TRPV1) blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present disclosure is in the medical and biomedical fields. [Background technology]

[0002] Background to the disclosure All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description contains information that may be useful in understanding the present invention. This is not an admission that any information provided herein is prior art or relevant to the invention claimed in this application, or that any publication specifically or implicitly referenced is prior art.

[0003] Hot flashes are a major medical problem that currently has no solution. Current treatments target cutaneous vasodilation as part of postmenopausal syndrome. Estrogen therapy is currently used to treat women's postmenopausal syndrome as a whole. Estrogen therapy is not selective for hot flashes and has some dangerous side effects. Recently, neurokinin-3 receptor antagonists have been tested in clinical trials to treat postmenopausal hot flashes in a more specific manner, but their development has been halted due to liver toxicity. Therefore, there is a need in the art for a selective treatment that targets hot flashes and does not have the side effects of estrogen therapy. There is also a need for at least one treatment that does not necessarily target cutaneous vasodilation, but targets the thermal discomfort that is the main discomfort symptom in hot flashes and causes other symptoms. Summary of the Invention

[0004] Disclosure Overview Various embodiments include a method for treating hot flashes in a subject, the method comprising providing a composition comprising a transient receptor potential channel (TRP channel) blocker or its pharmaceutical equivalent, analog, derivative or salt, and administering a therapeutically effective amount of the composition to the subject.In another embodiment, the TRP channel blocker is a TRP channel subfamily V member 1 (TRPV1) blocker or its pharmaceutical equivalent, analog, derivative or salt.In another embodiment, the TRPV1 channel blocker has the following structure: TIFF2025159082000001.tif30128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRPV1 channel blocker has the following structure: TIFF2025159082000002.tif27128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRPV1 channel blocker has the following structure: TIFF2025159082000003.tif28128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the subject is a female. In another embodiment, the subject is menopausal. In another embodiment, the subject is estrogen deficient. In another embodiment, the composition is a pellet, tablet, capsule, liquid, suspension, spray, emulsion, elixir, gel, cream, patch, plaster, suppository, and / or parenteral formulation. In another embodiment, treating hot flashes comprises suppressing, inhibiting, and / or reducing the risk of thermal discomfort. In another embodiment, the TRP channel blocker is one listed in Figure 5 herein. In another embodiment, the TRP channel blocker is one listed in Figure 6 herein. In another embodiment, the TRP channel blocker comprises capsazepine, A1165442, and / or SB366791. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000004.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000005.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the composition is administered topically to a subject. In another embodiment, the composition is administered as a patch, plaster, and / or spray.

[0005] Another embodiment includes a method for improving, reducing, or preventing thermal discomfort associated with hot flashes in a subject, comprising selecting a subject in need of hot flash treatment and administering to the subject a therapeutically effective amount of a transient receptor potential channel (TRP channel) blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker is a TRP channel subfamily V member 1 (TRPV1) blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000006.tif30128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000007.tif27128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000008.tif28128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the subject is a female. In another embodiment, the subject is menopausal. In another embodiment, the subject is estrogen-deficient. In another embodiment, the composition is a pellet, tablet, capsule, liquid, suspension, spray, emulsion, elixir, gel, cream, patch, plaster, suppository, or parenteral formulation. In another embodiment, the TRP channel blocker comprises capsazepine, A1165442, and / or SB366791. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000009.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker has the following structure: TIFF2025159082000010.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker is administered topically to a subject. In another embodiment, the TRP channel blocker is administered as a patch, plaster, and / or spray.

[0006] Other embodiments include compositions comprising one or more transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonists and a pharmaceutically acceptable carrier. In another embodiment, the one or more TRPV1 antagonists are those depicted in Figure 5 herein. In another embodiment, the one or more TRPV1 antagonists are those depicted in Figure 6 herein. In another embodiment, the one or more TRPV1 antagonists include capsazepine, A1165442, and / or SB36679. In another embodiment, the one or more TRPV1 antagonists are TIFF2025159082000011.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the one or more TRPV1 antagonists are TIFF2025159082000012.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the composition is formulated for topical administration to a subject. In another embodiment, the composition is formulated for administration as a patch, plaster, and / or spray.

[0007] [The present invention 1001] A method for treating hot flashes in a subject, comprising: providing a composition comprising a transient receptor potential channel (TRP channel) blocker or a pharmaceutical equivalent, analog, derivative, or salt thereof; and administering a therapeutically effective amount of the composition to the subject. [The present invention 1002] 1001. The method of claim 1001, wherein the TRP channel blocker is a TRP channel subfamily V member 1 (TRPV1) blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1003] The TRPV1 channel blocker has the following structure: TIFF2025159082000013.tif30128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1004] The TRPV1 channel blocker has the following structure: TIFF2025159082000014.tif27128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1005] The TRPV1 channel blocker has the following structure: TIFF2025159082000015.tif28128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1006] The method of claim 1001, wherein the subject is a female. [The present invention 1007] 1001. The method of claim 1001, wherein the subject is in menopause. [The present invention 1008] 1001. The method of claim 1001, wherein the subject is estrogen deficient. [The present invention 1009] The method of claim 1001, wherein the composition is a pellet, tablet, capsule, liquid, suspension, spray, emulsion, elixir, gel, cream, patch, plaster, suppository, and / or parenteral formulation. [The present invention 1010] The method of claim 1001, wherein treating hot flashes comprises suppressing, inhibiting, and / or reducing the risk of thermal discomfort. [The present invention 1011] The method of the present invention 1001, wherein the TRP channel blocker is one listed in Figure 5 herein. [The present invention 1012] The method of claim 1001, wherein the TRP channel blocker is one listed in Figure 6 herein. [The present invention 1013] 1001. The method of claim 1001, wherein the TRP channel blocker comprises capsazepine, A1165442, and / or SB366791. [The present invention 1014] The TRP channel blocker has the following structure: TIFF2025159082000016.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1015] The TRP channel blocker has the following structure: TIFF2025159082000017.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1016] The method of claim 1001, wherein the composition is administered topically to the subject. [The present invention 1017] The method of claim 1001, wherein the composition is administered as a patch, plaster and / or spray. [The present invention 1018] 1. A method for ameliorating, reducing, or preventing thermal discomfort associated with hot flashes in a subject, comprising: selecting a subject in need of treatment for hot flashes; and administering to the subject a therapeutically effective amount of a transient receptor potential channel (TRP channel) blocker or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1019] The method of claim 1018, wherein the TRP channel blocker is a TRP channel subfamily V member 1 (TRPV1) blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1020] The TRP channel blocker has the following structure: TIFF2025159082000018.tif30128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1021] The TRP channel blocker has the following structure: TIFF2025159082000019.tif27128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1022] The TRP channel blocker has the following structure: TIFF2025159082000020.tif28128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1023] The method of claim 1018, wherein the subject is a female. [The present invention 1024] The method of claim 1018, wherein the subject is menopausal. [The present invention 1025] The method of claim 1018, wherein the subject is estrogen deficient. [The present invention 1026] The method of claim 1018, wherein the TRP channel blocker is part of a pellet, tablet, capsule, liquid, suspension, emulsion, elixir, gel, cream, suppository, or parenteral formulation. [The present invention 1027] The method of claim 1018, wherein the TRP channel blocker comprises capsazepine, A1165442, and / or SB366791. [The present invention 1028] The TRP channel blocker has the following structure: TIFF2025159082000021.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1029] The TRP channel blocker has the following structure: TIFF2025159082000022.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1030] The method of claim 1018, wherein a TRP channel blocker is administered locally to a subject. [The present invention 1031] The method of claim 1018, wherein the TRP channel blocker is administered as a patch, plaster, and / or spray. [The present invention 1032] one or more transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonists; and Pharmaceutically acceptable carrier A composition comprising: [The present invention 1033] The composition of the present invention 1032, wherein the one or more TRPV1 antagonists are those described in Figure 5 herein. [The present invention 1034] The composition of the present invention 1032, wherein the one or more TRPV1 antagonists are those described in Figure 6 herein. [This invention 1035] The composition of claim 1032, wherein the one or more TRPV1 antagonists comprise capsazepine, A1165442, and / or SB36679. [The present invention 1036] One or more TRPV1 antagonists TIFF2025159082000023.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [This invention 1037] One or more TRPV1 antagonists TIFF2025159082000024.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. [The present invention 1038] A composition of the present invention 1032 formulated for topical administration to a subject. [This invention 1039] The composition of the present invention 1032 formulated for administration as a patch, plaster and / or spray. Other features and advantages of the present invention will become apparent from the following detailed description, which illustrates, by way of example, various aspects of the invention. [Brief explanation of the drawings]

[0008] [Figure 1] According to an embodiment of the present disclosure, preferred ambient temperatures are shown for ovariectomized rats with estradiol replacement (OVX-Estradiol), ovariectomized rats without estradiol replacement (OVX-Vehicle), and sham-operated rats (Sham-Vehicle) before and after a 10-minute mild heat exposure (shaded area). Horizontal lines with asterisks (*) indicate periods corresponding to significant differences (P<0.05) in preferred ambient temperatures between the OVX-Vehicle and Sham-Operated Vehicle groups, and between the OVX-Vehicle and OVX-Estradiol groups. [Figure 2] According to an embodiment of the present disclosure, preferred ambient temperatures are shown for ovariectomized rats pretreated with capsazepine (OVX vehicle + capsazepine) and without capsazepine pretreatment (OVX vehicle + vehicle), as well as for ovariectomized rats with estradiol replacement (OVX estradiol + vehicle) before and after a 10-minute mild heat exposure (shaded area). Horizontal lines with asterisks (*) indicate periods corresponding to significant differences (P<0.05) in preferred ambient temperatures between the OVX vehicle + capsazepine group and the OVX vehicle + vehicle group, and between the OVX vehicle + vehicle group and the OVX estradiol + vehicle group. [Figure 3] According to an embodiment of the present disclosure, preferred ambient temperatures are shown for ovariectomized rats pretreated with A1165442 (OVX vehicle + A1165442) and not pretreated with A1165442 (OVX vehicle + vehicle), as well as for ovariectomized rats with estradiol replacement (OVX estradiol + vehicle) before and after a 10-minute mild heat exposure (shaded area). Horizontal lines with asterisks (*) indicate periods corresponding to significant differences (P<0.05) in preferred ambient temperatures between the OVX vehicle + A1165442 group and the OVX vehicle + vehicle group, and between the OVX vehicle + vehicle group and the OVX estradiol + vehicle group. [Figure 4]1 shows a table illustrating experimental results according to an embodiment of the present specification. A: Cumulative intake of cold (27°C) or warm (40°C) sucrose solution by ovariectomized rats without estradiol replacement (OVX vehicle + vehicle) immediately after mild heat exposure. Horizontal lines with asterisks (*) indicate periods corresponding to significant differences (P<0.05) in intake of sucrose solution at different temperatures. B: Cumulative intake of cold or warm sucrose solution by ovariectomized rats with estradiol replacement (OVX vehicle + estradiol) immediately after mild heat exposure. C: Cumulative intake of warm sucrose solution by ovariectomized rats with SB366791 pretreatment (OVX vehicle + SB366791) or without SB366791 pretreatment (OVX vehicle + vehicle), as well as by ovariectomized rats with estradiol replacement (OVX vehicle + estradiol). Horizontal lines with asterisks (*) indicate the time periods corresponding to significant differences (P<0.05) in the intake of warm sucrose solution between the OVX vehicle + SB366791 group and the OVX vehicle + vehicle group, and between the OVX vehicle + vehicle group and the OVX estradiol + vehicle group. In all panels, the numbers in parentheses indicate the number of animals in the corresponding group. [Figure 5] In accordance with embodiments herein, a table is provided listing various examples of TRPV1 antagonists. In various embodiments herein, one or more TRPV1 antagonists as set forth in FIG. 5 may be administered for treatment. [Figure 6] 6 shows a table listing various examples of TRPV1 antagonists that have no or only a mild hyperthermic effect when administered according to embodiments of the present specification. In various embodiments of the present specification, one or more TRPV1 antagonists as shown in FIG. 6 may be administered for treatment. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description All references, publications and patents cited in this specification are incorporated herein by reference in their entirety, as if fully set forth.Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Hornyak, et al., Introduction to Nanoscience and Nanotechnology, CRC Press (2008); Singleton et al., Dictionary of Microbiology and Molecular Biology 3rd ed., J. Wiley & Sons (New York, NY 2001); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 7th ed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russell, Molecular Cloning: A Laboratory Manual 4th ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012) provide those skilled in the art with a general guide to many of the terms used in this application. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described.

[0010] As used herein, the term "topical application" means applied to a surface such as the skin.

[0011] As used herein, the term "topically active" refers to a composition or agent for topical application that primarily treats the surface to which it is applied.

[0012] As used herein, "treatment" or "treating" should be understood to include any indication of success in treating, alleviating, or ameliorating an injury, disease state, or condition. This may include parameters such as amelioration, relief, or reduction of symptoms; slowing the rate of degeneration or decline, lessening the debilitating end point of degeneration; improving the physical or mental well-being of the patient; or, in some circumstances, preventing the onset of disease.

[0013] As used herein, the terms "estrogen deficiency" and "estrogen deficiency" refer to low, no, or reduced levels of estrogen in a subject relative to levels found in healthy individuals.

[0014] As used herein, the term "hot flash" or "hot flush" or "night sweats" refers to a sudden, uncomfortable feeling of heat (thermal discomfort), flushing of the skin, and / or sweating. Such hot flashes can be caused by a variety of reasons, including, but not limited to, menopause, certain foods, as a side effect of prescription medication, or due to a disease such as cancer.

[0015] As used herein, the term "transient receptor potential channel" or "TRP channel" refers to a group of ion channels that are primarily located on the cell membrane of many animal cell types. There are several types of TRP channels, such as TRPC (canonical "C"), TRPV (vanilloid "V"), TRPM (melastatin "M"), TRPN, TRPA, TRPP (polycystic "P") and TRPML (mucolipin "ML"), and the term "TRP channel" as used herein encompasses all such channels. As used herein, "TRP channel blocker" refers to a TRP channel antagonist.

[0016] As used herein, the term "transient receptor potential cation channel subfamily V member 1" or "TRPV1" refers to an ion channel that has been implicated in mediating multiple types of pain. TRPV1 is a protein of the TRP family encoded by the TRPV1 gene. TRPV1 is sometimes also referred to as capsaicin receptor or vanilloid receptor 1. As used herein, a "TRPV1 channel blocker" refers to a TRPV1 channel antagonist.

[0017] As described herein, according to various embodiments herein, the present disclosure is directed to compositions and methods for treating, improving, and preventing thermal discomfort that may be associated with hot flashes.In one embodiment, the present inventor has invented a new treatment method for the hot, uncomfortable sensation (thermal discomfort) in hot flashes, rather than treating cutaneous vasodilation.The present inventor has used a TRPV1 antagonist with specific pharmacological properties to treat the thermal discomfort associated with hot flashes.This new treatment method for hot flashes will benefit subjects suffering from hot flashes.Instead of treating cutaneous vasodilation, the present inventors treat thermal discomfort, which is the main, if not the only, cause of patient complaints about hot flashes.

[0018] TRPV1 antagonists have been proposed as pain treatment drugs, and several compounds have been tested in clinical trials. However, the administration of several TRPV1 antagonists resulted in elevated body temperature, a severe side effect that prevented further development in experimental animals and human patients. The administration of some TRPV1 antagonists did not result in elevated body temperature, suggesting that these TRPV1 antagonist compounds did not block the proton mode of channel activation. Although these compounds did not induce hypothermia, they also did not block the pain response to acid, thus limiting their effectiveness as analgesics. Therefore, these TRPV1 antagonists with limited pharmacological properties have not been further developed.

[0019] As further described herein, those TRPV1 antagonists (most antagonists) that potently block the proton mode of activation of the TRPV1 channel cause hyperthermia. Because hyperthermia itself is likely to cause hot flashes, these antagonists were not preferred compounds. However, according to various embodiments herein, they may still be used if their hyperthermia effect can be reduced or prevented (e.g., by desensitization), or, for example, by administering them in a manner that does not cause hyperthermia (e.g., by topical application to the skin), or, for example, if their desired anti-thermal discomfort effect compensates for the harmful hyperthermia effect. These antagonists can be referred to as "Group A." In one embodiment, the present invention provides a method for treating hot flashes, comprising providing a TRPV1 antagonist that potently blocks the proton mode of activation of the TRPV1 channel and treating a subject by administering it in a manner that reduces and / or prevents the hyperthermia effect.

[0020] Furthermore, antagonists that do not cause an increase in body temperature (do not affect the proton mode of activation) may still be effective in preventing thermal discomfort and may be used to treat and / or prevent thermal discomfort and / or hot flashes according to various embodiments herein. For example, as further disclosed herein and according to embodiments herein, the inventors tested three such antagonists (i.e., capsazepine, A1165442, and SB366791) and found that they successfully treated thermal discomfort. These antagonists can be referred to as "Group B." In one embodiment, the present invention provides a method for treating hot flashes by providing a composition comprising one or more TRPV1 channel antagonists that do not affect the proton mode of activation and administering a therapeutically effective dose of the composition to a subject. In another aspect, the present invention provides a method for treating hot flashes by providing a composition comprising capsazepine, A1165442, and / or SB366791 and administering a therapeutically effective dose of the composition to a subject.

[0021] Figure 6 herein shows antagonists from both the aforementioned groups, Group A and Group B. For those that do not affect the proton mode of activation, Figure 6 herein lists those that have been shown to cause only a very mild increase in body temperature, e.g., by desensitization. In another embodiment, the present invention provides compositions comprising one or more antagonists described in Figure 6 herein and a pharmaceutical carrier. In another embodiment, the composition is formulated for topical administration to a subject to treat hot flashes.

[0022] As further disclosed herein and according to various embodiments, some antagonists cause hypothermia (they enhance the activation of TRPV1 by protons instead of blocking it). Examples of such antagonists supported by animal studies are A-1165901 and AMG7905. Experience has shown that these antagonists can be very effective against hot flashes by both blocking thermal discomfort (by blocking the thermal mode of TRPV1 activation) and reducing body temperature (by enhancing proton activation).

[0023] In one embodiment, the present inventors have disclosed the novel use of a specific TRPV1 antagonist (for example, a TRPV1 antagonist that does not cause body temperature elevation) to treat thermal discomfort in subjects with hot flashes.In some aspects, these compounds do not cause body temperature elevation, which is the most serious side effect of TRPV1 antagonists.Because the thermal discomfort of subjects with hot flashes is thermal in nature, the reduction in the effectiveness of the compounds of interest against acid-induced pain is irrelevant and does not affect their ability to block any thermal signals, including those that trigger thermal discomfort.Both male and female subjects suffering from hot flashes will benefit from this novel treatment method.In one embodiment, hot flashes can be caused by menopause.In another embodiment, hot flashes can be caused by estrogen deficiency.

[0024] In one embodiment, the present disclosure provides a method for treating hot flashes, comprising administering to a subject a therapeutically effective amount of a composition comprising a transient receptor potential channel (TRP channel) blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the present disclosure provides a method for suppressing or inhibiting the thermal discomfort associated with hot flashes, comprising administering to a subject a therapeutically effective amount of a composition comprising a TRP channel blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the present disclosure provides a method for improving, alleviating, and / or preventing the unpleasant sensation of heat in hot flashes, comprising selecting a subject in need of treatment for hot flashes and administering to the subject a therapeutically effective amount of a composition comprising a TRP channel blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the present disclosure provides a method for treating, ameliorating, and / or preventing thermal discomfort, comprising administering to a subject a therapeutically effective amount of a composition comprising a TRP channel blocker, or a pharmaceutical equivalent, analog, derivative, or salt thereof. In some embodiments, thermal discomfort can result from a subject experiencing a hormonal imbalance, such as insufficient estrogen levels (ie, compared to estrogen levels in healthy subjects).

[0025] In one embodiment, hot flashes are the result of menopause. In another embodiment, hot flashes are the result of low estrogen. In another embodiment, hot flashes are the result of spicy food, caffeine, alcohol, or heat exposure. As those skilled in the art can easily understand, hot flashes may be associated with some prescription medications, such as but not limited to Lupron (used to treat uterine fibroids), antihypertensives, antidepressants, and antianxiety medications, and various embodiments herein may be used in conjunction with administering prescription medications to subjects. In some embodiments, pancreatic tumors or other tumors in hormone-secreting organs may cause the thermal discomfort of hot flashes. In some embodiments, hyperthyroidism or thyroid cancer may cause hot flashes. Other causes of hot flashes may be cancers such as lymphoma and leukemia, HIV infection, or tuberculosis.

[0026] In some embodiments, the TRP channel blocker is a TRP channel subfamily V member 1 (TRPV1) blocker or a pharmaceutically acceptable salt thereof. In one embodiment, the TRPV1 channel blocker has the structure shown in Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof. In another embodiment, the TRP channel blocker has the structure shown in Formula IV: TIFF2025159082000026.tif39128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In another embodiment, the TRP channel blocker has the structure shown in Formula V: TIFF2025159082000027.tif26128 or a pharmaceutical equivalent, analog, derivative, or salt thereof. In one embodiment, the subject is female.In another embodiment, the subject is male.In one embodiment, the subject is menopausal and / or estrogen deficient.In one embodiment, the pharmaceutical composition is pellet, tablet, capsule, spray, liquid, suspension, emulsion, elixir, gel, cream, suppository or parenteral formulation.

[0027] In another aspect, the present invention provides a method of treating hot flashes by administering a therapeutically effective dose of a composition comprising one or more TRPV1 antagonists described in Figures 5 and / or 6 herein.

[0028] In various embodiments, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more TRPV1 antagonists and a pharmaceutically acceptable excipient.For example, in one embodiment, the present invention provides a composition comprising one or more TRPV1 antagonists as shown in Figure 5 and / or 6 herein and a pharmaceutically acceptable carrier or excipient.A " pharmaceutically acceptable excipient " generally refers to an excipient that is safe, non-toxic, and useful for preparing a desired pharmaceutical composition, including excipients that are acceptable for veterinary use and human pharmaceutical use.Such excipients can be solid, liquid, semi-solid, or gaseous in the case of aerosol compositions.

[0029] In various embodiments, the pharmaceutical compositions of the present invention may be formulated for delivery by any administration route. "Administration route" may refer to any administration route known in the art, including, but not limited to, aerosol administration, nasal administration, oral administration, transmucosal administration, transdermal administration, or parenteral administration. "Parenteral" generally refers to an administration route related to injection, including intraorbital, infusion, intraarterial, intraarticular, intracardiac, intranasal, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the composition may be in the form of a solution or suspension for injection or infusion, or may be a lyophilized powder.

[0030] The pharmaceutical composition of the present invention can also contain any pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle involved in the transport or transfer of a compound of interest from one tissue, organ, or part of the body to another tissue, organ, or part of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be "pharmaceutically acceptable" in that it must be compatible with the other components of the formulation. Each component must also be suitable for use in contact with any tissue or organ it may come into contact with, i.e., it must not pose a risk of toxicity, irritation, allergic reaction, immunogenicity, or any other complications that excessively outweigh its therapeutic benefits.

[0031] The pharmaceutical compositions of the present invention can also be encapsulated, tableted, or prepared in emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition or to facilitate the preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar, or gelatin. The carrier can also include sustained-release materials such as glyceryl monostearate or glyceryl distearate, alone or with wax.

[0032] Pharmaceutical preparations are prepared according to conventional pharmaceutical technology, including crushing, mixing, granulating and optionally compressing for tablet form; or crushing, mixing and filling for gelatin hard capsule form.When using liquid carrier, preparation is in the form of syrup, elixir, emulsion or aqueous or non-aqueous suspension.This liquid preparation can be administered orally directly or can be filled into gelatin soft capsule.

[0033] The pharmaceutical composition of the present invention may be delivered in a therapeutically effective amount.The precise therapeutically effective amount is the amount of the composition that produces the most effective results in terms of the effectiveness of treatment in a given subject.This amount will vary depending on various factors, including but not limited to, the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological state of the subject (including age, sex, type and stage of disease, general health, response to a given dose, and type of drug), the nature of the pharmaceutically acceptable carrier in the formulation, and the route of administration.Those skilled in the art of clinical and pharmacological sciences can determine the therapeutically effective amount through routine experimentation, for example, by monitoring the response of the subject to administration of the compound and adjusting the dose accordingly.

[0034] The typical dosage of the effective composition comprising one or more TRPV1 antagonists can be within the range recommended by manufacturers when using known therapeutic compounds, and can be shown to those skilled in the art by in vitro response in animal models.Such dosage can typically be reduced in concentration or amount by up to about one order of magnitude without losing relevant biological activity.Therefore, the actual dosage will depend on the judgment of the physician, the condition of the patient, and the effectiveness of the treatment based on the in vitro response of relevant primary cultured cells or tissue cultured tissue samples, such as biopsy malignant tumors, or the response observed in the above-mentioned suitable animal models.

[0035] The present invention also provides a kit for administering or preparing a composition comprising one or more TRPV1 antagonists.The kit is useful for carrying out, for example, the method for treating hot flashes of the present invention.The kit is a collection of materials or components, including at least one of the compositions of the present invention.Therefore, in some embodiments, the kit contains a composition comprising one or more compounds as shown in Figure 1 and / or 2 above.

[0036] The exact nature of the components configured in the kit of the present invention depends on its intended purpose. For example, some embodiments are configured to treat hot flashes. In one embodiment, the kit is specifically configured to treat mammalian subjects. In another embodiment, the kit is specifically configured to treat human subjects. In a further embodiment, the kit is configured for veterinary applications, treating subjects such as, but not limited to, livestock, farm animals, and laboratory animals.

[0037] The kit can also include instructions for use. " Instructions for use " typically includes a tangible label that describes the techniques used when using the components of the kit to achieve desired results, such as administering the composition that comprises one or more TRPV1 antagonists.Optionally, the kit also includes other useful components, such as diluent, buffer, pharmaceutically acceptable carrier, syringe, catheter, applicator, pipetting or measuring tool, bandage or other useful tools that are easily recognized by those skilled in the art.

[0038] The materials or components incorporated into the kit can be stored and provided to a physician in any convenient and appropriate manner that maintains their operability and usefulness. For example, the components can be dissolved, dehydrated, or lyophilized; they can be provided at room temperature, refrigerated temperature, or frozen temperature. The components are typically contained in suitable packaging materials. As used herein, the term "packaging material" refers to one or more physical structures used to contain the contents of the kit, such as the composition of the present invention. The packaging material is constructed in a well-known manner, preferably providing a sterile, contaminant-free environment. As used herein, the term "packaging" refers to a suitable solid matrix or material, such as glass, plastic, paper, or foil, that can hold individual kit components. Thus, for example, the package can be a glass vial used to contain an appropriate amount of the composition of the present invention, including one or more TRPV1 antagonists. The packaging material generally has an external label that indicates the contents and / or purpose of the kit and / or its components.

[0039] According to various embodiments herein, the active agent in the topical formulation comprises one or more TRPV1 antagonists. In some embodiments, the active agent can be capsazepine, A1165442, or SB36679, or a combination thereof. The concentration of the active agent in the topical formulation can range from about 0.1 to 30% (w / w). For example, the active agent can comprise about 0.1 to 5%, 0.5 to 3%, 1 to 2%, 1 to 3%, 2 to 10%, 5 to 10%, 5 to 15%, 10 to 15%, 15 to 20%, 10 to 20%, 20 to 25%, 15 to 30%, 20 to 30%, 10 to 30%, or 25 to 30% (w / w) of the topical formulation. According to various embodiments herein, the concentration of the active agent in the topical formulation described herein refers to the percentage of the total weight of the active agent in dry form of the total weight of the entire topical formulation.

[0040] In some embodiments, the topical formulations of the present invention may further comprise one or more emollients, fragrances, or dyes. According to various embodiments herein, the formulations may also further comprise, for example, thickeners, humectants, fillers, preservatives, crosslinkers, surfactants, and / or stabilizers.

[0041] In some embodiments, the topical formulation may be or include an ointment base. Alternatively, for example, the ointment base may be a cream base. In one embodiment, for example, the topical formulation may include one or more TRPV1 antagonists and include a cream base, where the cream base may contain more than 20% water and volatile substances, and / or typically contains less than 50% hydrocarbons, waxes, or polyols as a vehicle for the drug substance. The cream base may be a multi-phase preparation containing a lipophilic phase and an aqueous phase. In some examples, the cream base is a lipophilic cream base with a lipophilic phase as the continuous phase. Such a cream base may include a water-in-oil emulsifier such as wool alcohol, sorbitan ester, and monoglyceride. In other examples, the cream base may be a hydrophilic cream base with an aqueous phase as the continuous phase. Such cream bases may optionally contain oil-in-water emulsifiers, such as sodium or trolamine soap, sulfated fatty alcohols, polysorbates and polyoxyl fatty acid and fatty alcohol esters, which may be combined with water-in-oil emulsifiers.

[0042] According to various embodiments of the present specification, the present invention provides the composition that can be used for topical plaster application.For example, in one embodiment, the composition that comprises capsazepine, A1165442 and / or SB36679 can be formulated as a plaster for topical application to a subject.

[0043] In another embodiment, topical application may include a patch formulation. For example, such a patch for topical application at the site of action may generally consist of an adhesive, so-called matrix layer containing the drug, often a fabric backing layer, and a protective layer that is removed before use of the matrix.

[0044] In accordance with various aspects of the present specification, skin compatibility can play an important role in topical systems, where only good skin-compatible components for the matrix can be made from such a patch, and non-adhesive behavior must be excluded, taking into account that on the one hand the patch adheres reliably during the intended period of application, and on the other hand no excessive mechanical irritation to the skin occurs when removing the patch.

[0045] In addition, the patch must be able to deliver sufficient drug to reach a sufficiently high tissue level at the site of action, and must also meet the requirements for the dosage form's stability, release, and adhesive properties relative to the active ingredient content.

[0046] In one embodiment, the present invention comprises topical medicinal spray compositions.For example, in one embodiment, the present invention provides a composition comprising one or more TRPV1 antagonists, which is formulated to be applied to a subject as topical medicinal spray.In another embodiment, the one or more TRPV1 antagonists comprise capsazepine, A1165442, and / or SB36679.In one embodiment, the composition comprises a drug or drug combination as a solution or suspension in a vehicle optionally comprising a polymer or a combination of polymers, which forms a thin film on the skin when sprayed onto the surface of the skin. The compositions of the present invention preferably comprise up to about 30% (e.g., 0.0001% to about 30%) of at least one pharmaceutical agent, more preferably up to about 10% (e.g., 0.0001% to about 10%), and most preferably up to about 5% (e.g., 0.0001% to about 5%) of at least one pharmaceutical agent, dissolved or suspended in one or more vehicles that constitute up to 90% (e.g., 0.0001% to about 90%) of the composition. The compositions may further comprise one or more film-forming agents, solubilizers, penetration enhancers, and plasticizers. The compositions may contain one or more of these additives in amounts of up to about 10% film-forming agent (e.g., 0.0001% to about 10%), up to about 10% solubilizing agent (e.g., 0.0001% to about 10%), up to about 8% penetration enhancer (e.g., 0.0001% to about 8%), and up to about 10% plasticizer (e.g., 0.0001% to about 10%). The compositions of the present invention may be sprayed onto a topical site to form a stable, breathable film at the site from which the drug is available for topical application or transdermal delivery. Preferably, the compositions further contain up to about 7% (w / w) of one or more water-soluble additives (e.g., 0.0001% to about 7%). The drug or drug combination so accumulated in the film-forming agent matrix may remain solubilized or suspended. The exact formulation of the composition may vary depending on the properties (e.g., dissolution characteristics) and desired release profile of the particular drug used. The composition can be dispensed from any dispenser, preferably one that provides the composition as a spray, and can be used for systemic or local effect.The drug from the composition may be released over a period of time or immediately.

[0047] The compositions of the present invention are preferably applied in metered amounts to a predetermined surface area. Thus, the present invention may provide for administering the composition by spraying the composition from a dispenser. The present invention further provides methods for applying the composition and the resulting thin film.

[0048] Preferably, the composition is dispensed from a pump dispenser or an aerosol dispenser. In the latter case, the composition further comprises about 10% to 90% of a propellant to provide the appropriate pressure within the aerosol dispenser. Generally, a propellant is not required for compositions dispensed from a pump dispenser. However, if desired, such compositions may contain about 10% to 90% of a propellant that is liquid at room temperature.

[0049] In another aspect, the present invention may provide a method of preparing a pump dispenser containing a spray composition of the present invention, the method comprising mixing the components of the composition with or without a liquid propellant, and placing the mixed components into the pump dispenser.

[0050] Additionally, in another aspect, the present invention provides a method for preparing an aerosol dispenser containing a spray composition of the present invention, comprising mixing the components of the composition without a propellant and loading the mixture into the aerosol dispenser with a propellant. The composition is preferably dispensed from the selected dispenser.

[0051] The agent can be any pharmaceutical compound or combination of compounds in salt or base form, which is stable when mixed with the other components of the composition and which is effective for topical administration.

[0052] Aspects of the present disclosure are further described in the following examples, which are merely illustrative and do not in any way limit the scope of the claimed invention. [Example]

[0053] The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. To the extent that specific materials are mentioned, this is for illustrative purposes only and is not intended to limit the invention. Those skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity without departing from the scope of the invention.

[0054] Example 1 General Hot flushes (or hot flashes) have become the most common complaint of postmenopausal women. There is no treatment for hot flushes other than estrogen treatment, which treats the entire postmenopausal syndrome. Contrary to current belief, the present inventors have disclosed that abnormal thermal discomfort is involved in this disorder.

[0055] Many TRPV1 antagonists have been synthesized and tested by pharmaceutical companies as potential analgesics, but they have not been further developed due to a dangerous side effect, namely, hyperthermia. TRPV1 antagonist compounds that do not cause hyperthermia have reduced analgesic effects because they do not block the proton mode of TRPV1 activation. Therefore, these compounds will not work against inflammatory pain. However, in one embodiment, the inventors have disclosed that these compounds block the thermal mode. Therefore, TRPV1 antagonists are potential drugs for treating the abnormal thermal discomfort that occurs with hot flashes. Many such compounds have been designed, synthesized, and thoroughly tested, and are currently in stock at pharmaceutical companies around the world, but they have no application. The present disclosure provides a novel use of these compounds for treating the thermal discomfort associated with hot flashes.

[0056] TRPV1 antagonists have been proposed as a pain treatment, and several compounds have been tested in clinical trials. However, administration of several TRPV1 antagonists resulted in elevated body temperature, a severe side effect that prevented further development in experimental animals and human patients. Administration of some TRPV1 antagonists did not result in elevated body temperature, suggesting that these TRPV1 antagonist compounds did not block the proton mode of channel activation. Although these compounds did not induce hypothermia, they also did not block the pain response to acid, limiting their effectiveness as analgesics. Therefore, these TRPV1 antagonists with limited pharmacological properties have not been further developed.

[0057] Example 2 The TRPV1 antagonist "paradox" - further explanation As mentioned above and known to those skilled in the art, those TRPV1 antagonists (most antagonists) that strongly block the proton mode of activation of TRPV1 channel cause hyperthermia. Because hyperthermia itself is likely to cause hot flashes, these antagonists were not preferred compounds. However, according to various embodiments of the present specification, they may still be used if their hyperthermia effect can be reduced or prevented (e.g., by desensitization), or, for example, by administering them in a way that does not cause hyperthermia (e.g., by applying them topically to the skin), or, for example, if their desired anti-thermal discomfort effect compensates for the harmful hyperthermia effect. These antagonists may be referred to as "Group A" in this specification.

[0058] Furthermore, antagonists that do not cause an increase in body temperature (do not affect the proton mode of activation) may still be effective in preventing thermal discomfort and may be used to treat and / or prevent thermal discomfort and / or hot flashes according to various embodiments herein.For example, as further disclosed herein and according to embodiments herein, the inventors have tested three such antagonists (i.e., capsazepine, A1165442, and SB366791) and found that they successfully treat thermal discomfort.These antagonists may be referred to herein as "Group B."

[0059] Figure 6 herein shows antagonists from both of the aforementioned groups, Group A and Group B. For those that do not affect the proton mode of activation, Figure 6 herein lists those that have been shown to cause only a very mild increase in body temperature, e.g., by desensitization.

[0060] As further disclosed herein and according to various embodiments, some antagonists cause hypothermia (they enhance the activation of TRPV1 by protons instead of blocking it). Examples of such antagonists supported by animal studies are A-1165901 and AMG7905. Experience has shown that these antagonists can be very effective in treating hot flashes by both blocking thermal discomfort (by blocking the thermal mode of TRPV1 activation) and reducing body temperature (by enhancing proton activation).

[0061] Example 3 experiment Hot flashes are currently considered to be the normal reaction of abnormal (easily occurring) cutaneous vasodilation.However, similar vasodilation often occurs in both male and female non-estrogen deficient individuals under many circumstances, for example, in warm environments, after exposure to cold, after eating spicy food, during difficult work, during sexual intercourse, when people are embarrassed or angry, and in countless other situations.In some embodiments, general feeling of hot discomfort (thermal discomfort) can be associated with hot flashes.

[0062] Thermal sensation is mediated by thermo-TRP channels. There are six major thermosensory channels in the skin and in the neurons that innervate it: TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, and TRPM3. TRPV1 channels are abundant in pain fibers and have a temperature threshold of approximately 41°C in vitro, but there is strong evidence that the threshold is low in vivo and that many bioactive substances can affect this threshold. In one embodiment, estrogen depletion / deficiency also leads to a TRPV1-mediated increase in thermal pain in the skin and general thermal discomfort. TRPV1 is activated by temperature, protons, or capsaicin (Garami A, et al. J Neurosci 30: 1435-1440, 2010). Temperature activation is important for thermal discomfort.

[0063] These findings constitute the basis for promoting thermoneutral TRPV1 antagonists (i.e., TRPV1 antagonists that induce neither hyperthermia nor hypothermia), i.e., TRPV1 antagonists that do not block the proton mode of activation and therefore do not cause hyperthermia, but block the thermal mode, as new drugs for treating hot flashes.

[0064] Example 4 TRPV1 antagonists eliminate the thermal discomfort characteristic of hot flashes and related postmenopausal symptoms - Methods animal: Experiments were performed on the day of the first surgery (day 0) in adult female Wistar rats (Envigo) weighing 240-280 g. Rats were housed three per cage in a standard "show box." The room was maintained at 24 ± 2°C on a 12:12-h light / dark cycle (lights on at 6 AM). All protocols were approved by the Institutional Animal Care and Use Committee.

[0065] protocol: On day 0, each rat underwent bilateral ovariectomy or sham surgery, with or without the simultaneous implantation of a miniature data logger into the abdominal cavity for body temperature measurement. On day 7, ovariectomized rats were subcutaneously implanted with capsules containing either estradiol or vehicle, and sham-operated rats were implanted with vehicle-containing capsules. On days 6–15, rats were habituated to the experimental apparatus and procedures. Rats were enrolled between days 16–20 (Experiments 1–3) or between days 13–20 (Experiment 4), and each rat was used in two experiments. Thermal discomfort was tested in one of two tests: a test of cold-seeking induced by ambient warming in a thermal gradient apparatus (cold-seeking test; Experiments 1–3) or a test of warm sucrose intake cessation induced by an increase in internal body temperature (sucrose intake cessation test; Experiment 4). Some ovariectomized rats were treated with TRPV1 antagonists (capsazepine, A1165442, or SB366791) or vehicle before testing. After the experiment (day 21), each rat used in experiments 1–3 was euthanized, and the uterus was removed and weighed to confirm the completeness of the ovariectomy and the effectiveness of the estradiol replacement procedure.

[0066] experiment: The goal of Experiment 1 was to determine whether ovariectomy enhances cold-seeking behavior after heat exposure and whether this enhancement, if it occurs, is estradiol-dependent. The following groups of rats were tested: OVX Vehicle (ovariectomized rats given vehicle via implanted capsules); Sham-Operated Vehicle (sham-operated rats given vehicle via capsules); and OVX Estradiol (ovariectomized rats given estradiol via capsules).

[0067] The goal of Experiment 2 was to determine whether capsazepine attenuates the expression of excessive cold-seeking behavior in ovariectomized rats. Rats assigned to this experiment were treated with capsazepine or its vehicle by oral gavage 30 minutes before heat exposure. The following groups of rats were tested: OVX Vehicle + Capsazepine (ovariectomized rats given vehicle via implanted capsules and pretreated with capsazepine by oral gavage); OVX Vehicle + Vehicle (ovariectomized rats given vehicle via capsules and pretreated with vehicle by gavage); and OVX Estradiol + Vehicle (ovariectomized rats given estradiol via capsules and pretreated with vehicle by gavage).

[0068] The goal of Experiment 3 was to determine whether A1165442 attenuates the expression of excessive cold-seeking behavior caused by ovariectomy. This experiment was performed exactly as in Experiment 2, except that rats were pretreated with A1165442 instead of capsazepine.

[0069] The goal of Experiment 4 was to determine whether ovariectomized, heat-exposed rats would consume less sucrose solution when placed in a warm environment (40°C) compared with a cold environment (27°C), and whether this decrease was estradiol-dependent and could be attenuated by SB366791. Rats were treated with SB366791 or its vehicle by oral gavage 20 minutes before heat exposure. The following groups were tested: OVX Vehicle + SB366791 (ovariectomized rats given vehicle via an implanted capsule and pretreated with SB366791 by oral gavage); OVX Vehicle + Vehicle (ovariectomized rats given vehicle via a capsule and pretreated with vehicle by gavage); and OVX Estradiol + Vehicle (ovariectomized rats given estradiol via a capsule and pretreated with vehicle by gavage).

[0070] Surgery: Ovariectomy and Data Logger Implantation. Ovariectomy was performed under anesthesia with an intraperitoneal injection of a mixture of ketamine (55.6 mg / kg), acepromazine maleate (1.1 mg / kg), and xylazine (5.6 mg / kg). Antibiotic protection was provided by intramuscular enrofloxacin (1.1 mg / kg). Buprenorphine (50 μg / kg) was administered subcutaneously for postoperative analgesia. A laparotomy (upper half of the flank) was first performed on the left side, and the left ovary was exposed by retracting the periovarian fat pad. The fallopian tube was ligated with its surrounding tissue and severed distal to the ligature. The ovaries were removed, and the uterine horn was returned to the abdominal cavity. The surgical wound was closed first with the peritoneum and muscle, followed by the skin layer. The same surgical procedure was performed on the right side to remove the right ovary. For sham oophorectomy, the same procedure was performed bilaterally, except that the fallopian tubes were not ligated or cut and the ovaries were not removed.

[0071] Estradiol capsule implantation. For hormone replacement, two 20-mm-long Silastic capsules (Dow Corning) containing 17-estradiol (Sigma Aldrich; 180 μg / ml in sesame oil) or sesame oil were implanted subcutaneously through a small incision in the interscapular region under isofluorane (3%) anesthesia.

[0072] test: Cold exploration test. Rats were placed in the pathway of the thermal gradient device and allowed to move freely for 2 hours to select their preferred ambient temperature. They were then subjected to a mild heat exposure in which they were confined to the warm zone of the device (31°C) for 10 minutes. After removing the restraining device, the rats were again allowed to move freely and select their preferred thermal environment. Their preferred ambient temperature was recorded for 10 minutes.

[0073] Sucrose cessation test. On the day of testing, rats in individual cages were placed in an environmental chamber and exposed to heat (32.5°C) for 10 minutes. A 0.1 ml measuring glass burette, thermally insulated with a gel sleeve, was introduced into each cage. Each burette was fitted with a stainless steel spout and filled with 0.3 M sucrose solution at either 27°C or 40°C. Sucrose solution consumption was recorded for 15 minutes.

[0074] Drugs and drug administration: Three TRPV1 antagonists were tested: capsazepine (Cayman Chemical; 40 mg / kg, Experiment 2), A1165442 (MedChem Express; 100 mg / kg, Experiment 3), and SB366791 (Tocris Bioscience; 10 mg / kg, Experiment 4). All compounds were dissolved in a solution containing 30% propylene glycol and 30% ethanol in saline (capsazepine) or water (A1165442 and SB366791). Working solutions were prepared immediately before the experiment at the following concentrations: 40 mg / ml (capsazepine), 100 mg / ml (A1165442), and 10 mg / ml (SB366791). All compounds and their vehicles were administered orally (by gavage, 0.1 ml / kg).

[0075] Thermal Gradient Apparatus: The thermal gradient apparatus used has been described elsewhere (Almeda et al., 2006; Wanner et al., 2017). Briefly, the apparatus consists of six 200 cm long aluminum tracks. At each end, all tracks share a common aluminum wall separating them from a larger tank; the tank at the "warm" end of the track is filled with water heated by two electrical units (PolyScience) to maintain the air temperature within this end of the track at 36.0 °C. The tank at the "cold" end is constantly perfused with 10% ethylene glycol by an external circulating cooling / heating pump (PolyScience) to maintain the air temperature within this end of the track at 14.0 °C. In this setup, all tracks have a common, approximately linear longitudinal temperature gradient of 0.1 °C / cm. Rats are placed in the apparatus, one per track, and are free to move within their tracks to select their preferred ambient temperature. The position of each rat was tracked by a video camera (Panasonic Model WV-CP280, Matsushita Electric Industrial Co., Ltd.), and ambient temperature was recorded at multiple points by thermocouples connected to a multichannel temperature data acquisition system (Omega TempScan). The position data were converted to desired ambient temperature data using a linear regression equation derived from the temperature measured by the thermocouples and the thermocouple positions.

[0076] Data Analysis: All data are expressed as mean ± SE. Preferred ambient temperature and sucrose intake data were analyzed by two-way repeated measures ANOVA followed by Fisher's or Newman-Keuls multiple comparison test, as appropriate. Uterine weight data were analyzed by one-way ANOVA followed by Fisher's test. The significance level was set at P = 0.05.

[0077] Example 5 TRPV1 antagonists eliminate thermal discomfort characteristic of hot flashes and related postmenopausal symptoms - Results In Experiment 1, ovariectomized rats exhibited significantly stronger cold-seeking behavior than sham-operated rats after gradual heat exposure (Figure 1), indicating that after ovariectomy, rats more readily express thermal discomfort after gradual heat exposure and attempt to cool themselves by moving toward a cooler environment. Estradiol blocked this effect (Figure 1), thus demonstrating that the increased tendency for cold-seeking in ovariectomized rats is estradiol-dependent. The completeness of ovariectomy and the effectiveness of the estradiol replacement procedure were confirmed by uterine weight data: ovariectomy reduced weight to 0.13 ± 0.01 g compared to 0.40 ± 0.02 g in sham-operated rats (P < 0.001), whereas estradiol replacement restored uterine weight in ovariectomized rats to 0.42 ± 0.02 g (P < 0.001).

[0078] In Experiment 2 (Figure 2) and Experiment 3 (Figure 3), TRPV1 antagonists (capsazepine and A1165442, respectively) strongly attenuated the cold-seeking behavior induced by heat exposure in ovariectomized rats. These data indicate that thermal discomfort, which is easily induced in ovariectomized rats by mild heat exposure, can be treated / attenuated by TRPV1 antagonists. The completeness of the ovariectomy and the effectiveness of the estradiol replacement procedure were confirmed by uterine weight data (not shown).

[0079] In Experiment 4, after gradual heat exposure, ovariectomized rats without estradiol replacement (Figure 4, Panel A) consumed significantly less sucrose when the sucrose solution was warm (40°C) compared with cold (27°C). These data indicate that ovariectomized rats attempted to avoid thermal discomfort by limiting sucrose consumption when associated with increased internal body temperature. Estradiol replacement (Figure 4, Panel B) strongly attenuated this temperature-elevation avoidance effect: after the same heat exposure, ovariectomized rats treated with estradiol did not significantly reduce the amount of sucrose solution consumed when the solution temperature was increased from 27°C to 40°C. These data indicate that the avoidance of internal body temperature elevated by gradual heat exposure in ovariectomized rats is estradiol-dependent and can be attenuated by the TRPV1 antagonist (SB366791, Figure 4, Panel C) used in this experiment.

[0080] Cumulatively, these data demonstrate that mild heat exposure induces thermal discomfort in ovariectomized rats, manifested by active search for a cooler environment and avoidance of elevated internal temperatures. This discomfort is estradiol-dependent and is a characteristic feature of hot flashes and related postmenopausal symptoms. TRPV1 antagonists (capsazepine, A1165442, and SB366791) treat this thermal discomfort.

[0081] The various methods and techniques described above provide many ways to implement the present invention. Of course, it should be understood that not all described objectives or advantages may be achieved in accordance with any particular embodiment described herein. Thus, for example, one skilled in the art will understand that a method may be implemented in a manner that achieves or optimizes an advantage or advantages taught herein without necessarily achieving other objectives or advantages that may be taught or suggested herein. Various advantageous and disadvantageous alternatives are described herein. It should be understood that some preferred embodiments specifically include one, another, or several advantageous features, while other preferred embodiments specifically exclude one, another, or several disadvantageous features, while other preferred embodiments specifically mitigate an adverse feature of the present invention by including one, another, or several advantageous features.

[0082] Moreover, one skilled in the art will understand the applicability of various features from different embodiments. Similarly, the various elements, features, and steps described above, as well as other known equivalents for each such element, feature, or step, can be mixed and matched by one skilled in the art to practice methods in accordance with the principles described herein. Some of the various elements, features, and steps are specifically included, while others are specifically excluded, in various embodiments.

[0083] While the present invention has been disclosed with respect to particular embodiments and examples, those skilled in the art will appreciate that the present invention extends to other alternative embodiments and / or uses and modifications and equivalents beyond those specifically disclosed.

[0084] Many variations and alternative elements have been disclosed in the embodiments of the present invention. Further variations and alternative elements will be apparent to those skilled in the art. Among these variations are, but are not limited to, the selection of components for the compositions of the present invention and the diseases and other clinical conditions that may be diagnosed, prognosed, or treated thereby. Various embodiments of the present invention can specifically include or exclude any of these variations or elements.

[0085] In some embodiments, numbers expressing quantities, concentrations, reaction conditions, and the like of components and other characteristics used to describe and claim particular embodiments of the invention should be understood to be modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. The numerical values ​​set forth in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0086] In some embodiments, the terms "a," "an," and "the," and similar references, as used in the context of describing particular embodiments of the invention (particularly in the context of the particular claims that follow), can be interpreted to include both the singular and the plural. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise stated, each separate value is incorporated herein as if individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise stated or clearly contradicted by context. The use of any and all examples provided with respect to particular embodiments herein, or exemplary language (e.g., "such as"), is intended merely to better elucidate the invention and does not limit the scope of the invention as claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0087] The categorization of alternative elements or embodiments of the invention disclosed herein should not be construed as limiting. Members of each group may be referred to and claimed individually or in any combination with other group members or other elements found herein. One or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is considered to include the group as modified herein, and thus satisfies the written description of all Markush groups used in the appended claims.

[0088] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations on these preferred embodiments will become apparent to those of skill in the art upon reading the foregoing description. Those skilled in the art will be able to employ such variations as appropriate, and it is contemplated that the invention may be practiced otherwise than as specifically described herein. Accordingly, many aspects of the invention include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0089] Additionally, throughout this specification, various references have been made to patents and printed publications. Each of the above cited literature and printed publications is individually incorporated herein by reference in its entirety.

[0090] Finally, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that can be used may be within the scope of the invention. Thus, by way of example, and not of limitation, alternative configurations of the invention can be utilized in accordance with the teachings herein. Therefore, embodiments of the invention are not limited to that precisely as shown and described.

Claims

1. A composition for treating hot flashes in a subject, comprising a therapeutically effective amount of a transient receptor potential channel subfamily V member 1 (TRPV1) blocker or a salt thereof, The TRPV1 blocker or its salt has the following structure: Or the salt, or Or that salt A composition having the following characteristics.

2. The composition according to claim 1, wherein the treatment of hot flashes includes suppressing, inhibiting, and / or reducing the risk thereof of thermal discomfort.

3. A composition for improving, reducing, or preventing hot flash-related thermal discomfort in a subject requiring treatment for hot flashes, comprising a therapeutically effective amount of a transient receptor potential channel subfamily V member 1 (TRPV1) blocker or a salt thereof, The TRPV1 blocker or its salt has the following structure: Or the salt, or Or that salt A composition having the following characteristics.

4. The composition according to any one of claims 1 to 3, wherein the target is female.

5. A composition according to any one of claims 1 to 4, wherein the target is menopausal.

6. A composition according to any one of claims 1 to 5, wherein the subject is estrogen deficiency.

7. The composition according to any one of claims 1 to 6, wherein the composition is a pellet, tablet, capsule, liquid, suspension, spray, emulsion, elixir, gel, cream, patch, ointment, suppository, and / or parenteral formulation.

8. The composition according to any one of claims 1 to 7, wherein the composition is administered topically to a subject, and / or as a patch, ointment, and / or spray.

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