TW200536555A - Treating symptoms of androgen deprivation - Google Patents

Abstract

This invention provides: (1) a method of treating androgen-deprivation induced osteoporosis and/or bone fractures and/or loss of Bone Mineral Density (BMD) in a male subject suffering from prostate cancer; (2) a method of preventing androgen-deprivation induced osteoporosis and/or bone fractures and/or loss of Bone Mineral Density (BMD) in a male subject suffering from prostate cancer; (3) a method of suppressing or inhibiting androgen-deprivation induced osteoporosis and/or bone fractures and/or loss of BMD in a male subject suffering from prostate cancer; and (4) a method of reducing the risk of developing androgen-deprivation induced osteoporosis and/or bone fractures and/or loss of BMD in a male subject suffering from prostate cancer, by administering to the subject a pharmaceutical composition comprising an anti-estrogen agent and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof as described herein.

Description

.200536555 IX. Description of the invention: [Number of households of the genus genus Zygophyllum spp., Field of invention _ The present invention relates to the reduction of androgen loss-induced osteoporosis and / or in men with prostate cancer5. Incidence of bone rupture and / or loss of bone mineral density (BMD), its inhibition, suppression, prevention, and treatment. More specifically, the present invention relates to a method for treating, preventing, suppressing, suppressing, or reducing the risk of developing androgen-induced osteoporosis and / or cranial rupture and / or BMD loss in men with prostate cancer. A method comprising administering an anti-estrogen agent and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicines to male patients with top 10 adenocarcinomas Product, hydrate, N-oxide, or any combination thereof. ϋ 前 # 支 冬 袭 3 BACKGROUND OF THE INVENTION It has been well established that 'the bone mineral density of men decreases with age. The decrease in bone mineral content and density is related to the reduction of bone anxiety 'and is susceptible to fractures. The molecular mechanism underlying the role of sexual hormones in non-reproductive tissues is only just beginning to be understood, but ㈣ it is obvious that 'physiological concentrations of androgens and estrogen are maintained throughout the life cycle π In terms of aggregate stability, the system plays an important role. Therefore, when androgen or estrogen loss occurs, 'there is an increase in the rate of bone anxiety modification', which is to skew the balance between wear and formation and is beneficial to consumption and expansion and promotes the overall loss of bone mass. Among men, the natural decline of sexual hormones in the mature period (direct decline of androgens, and lower levels of androgens, derived from d: 200536555 androgen's peripheral aromatization) is accompanied by bone weakness. This effect has also been found in castrated men. Adenocarcinoma is one of the most commonly diagnosed non-skin cancers in American men. One of the treatments for stigma adenocarcinoma is through androgen loss. The male sex hormone, fluorenone, stimulates the growth of cancerous prostate cells and is therefore the main fuel for prostate cancer growth. The purpose of androgen loss is to reduce the irritation of cancer cells by prostatic cancer cells. Testosterone is normally produced by testes in response to a stimulus from a hormone message called luteinizing hormone (LH), which in turn is stimulated by luteinizing hormone releasing hormone (LH_RH). Androgen loss is achieved either by bilateral levectomy or chemically by LH-RH activator (LHRH), with or without the use of nonsteroidal antiandrogen substances. Current studies point to early androgen loss in patients with micrometastasis and prolonged survival consistently [Messing EM et al., (1999), # 厶 7 34, 178H788; Newllng (2001), 58 (Supplementary Edition 2A), 50-55]. Furthermore, androgen loss is being used in many novel clinical devices, including new adjuvant therapy before radical prostatectomy, and long-term adjuvant therapy for patients who are at high risk of recurrence after radiation or surgery, New adjuvant therapies for radiation, and 20 treatments for biochemical recurrence after radiation or surgery [C_n et al. (Fan), Zhe 58, 14; η㈣ ^ tank A, (2QQ \), Int J Radiat Oncol Biol Phy Mar \ 5, 49 (4), 947-56]. As a result, more patients with prostate cancer have become candidates for androgen resection and are being treated. Furthermore, these patients with prostate cancer are treated earlier and longer than in the past, and in some cases may be as long as androgen deprivation treatment of 200536555 or more years. Unfortunately, androgen loss therapy systems are full of significant side effects, including heat's flashes, female-like breast milk, osteoporosis, reduced carcass mass, depression and other mood changes, loss of libido and erectile dysfunction [Stege R ( 2000), 5M, 38.42]. Therefore, the complications of androgen suppression currently contribute significantly to the incidence of men with prostate cancer, and in some cases their mortality. β With more patients now undergoing long-term androgen loss treatment, osteoporosis has become a clinically important side effect in men with androgen loss in prostate cancer. Loss of bone mineral density (BMD) occurs in most patients who have been treated with androgen loss for 6 months. Novel and innovative approaches at both the basic science and clinical levels are urgently needed to reduce the incidence of androgen-induced osteoporosis in men with prostate cancer. 15 [Cosmetics]% Summary of the invention The present invention relates to a method for treating androgen loss-induced osteoporosis in a male patient with prostate cancer. The method includes administering an anti-estrogen to the patient. And / or its analogs, derivatives, isomers, metabolism 20 products, pharmaceutically acceptable salts, pharmaceutical products, hydrates, oxidized oxides, or any combination thereof, in an amount effective in the patient Treatment of androgen-induced osteoporosis. This "Ming Department" relates to a method for preventing androgen loss-induced osteoporosis in male patients with prostate cancer. The method includes administering 200536555 to an anti-estrogen: vegetal agent and / or the like. , Derivatives, isomers, metabolites, musically acceptable salts, medicinal products, hydrates, oxides, or any combination of these steps' in an amount effective to prevent androgen-induced Osteoporosis. 5 The present invention relates to a method for suppressing or inhibiting androgen loss-induced osteoporosis in male patients with prostate cancer, the method comprising administering an anti-estrogen agent and / or the like to the patient , Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N · oxyl 10 15 compounds, or any combination thereof, in an amount effective to suppress or inhibit male sex in the patient Osteoporosis induced by hormone loss. The present invention relates to a method for reducing the risk of developing osteoporosis in male patients with prostate cancer, the method comprising administering an anti-estrogen and / or its analogue to the patient ' Derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products 'hydrates, N_ oxides, or any combination of these steps' in an amount effective to reduce the development of androgen-induced bone in this patient The danger of osteoporosis. This "Yueshiguanfang"-a method of treating androgen loss-induced BMD loss in male patients with prostate cancer, the method comprising administering an anti-estrogen agent and / or the like to the patient, Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, n-oxides, or their compounds, and you know what to do! It can effectively treat androgens in this patient The present invention relates to a method for preventing androgen loss-induced BMD loss in male patients with prostate cancer. The method includes administering 20 200536555 anti-estrogens to the patient and / or An analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, medicinal substance, hydrate, N_oxide, or any combination thereof, in an amount effective to prevent male sex in the patient Hormone loss-induced bone loss. 5 The present invention relates to a method for suppressing or inhibiting androgen loss-induced BMD loss in male patients with prostate cancer. This method includes administering anti-estrogen to the patient Agent / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, team oxides, or any combination thereof, in an amount effective to depress or Inhibits bone loss caused by 10 androgen loss.

The present invention relates to a method for reducing the risk of developing androgen-induced loss in male patients with prostate cancer, which method comprises administering to the patient an anti-estrogen agent and / or its analogs and derivatives , Isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N · oxides, or any combination thereof, the amount of which can effectively reduce the development of androgen-induced bone loss in the patient Of danger. The present invention relates to a method for treating androgen loss-induced bone rupture in a male patient with prostate cancer. The method includes administering an anti-estrogenic agent and / or an analog or derivative thereof to the patient. , Isomers, 20 metabolic products, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N • oxides, or any combination thereof, in an amount effective to treat androgen-induced bone loss in the patient rupture. The present invention relates to a method for preventing androgen loss-induced bone rupture in a male patient with prostate cancer, which method comprises administering 200536555 an anti-estrogen agent and / or its analog, derivative, The steps of the isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates, N-oxides, or any combination thereof, are in amounts effective to prevent androgen-induced bone rupture in the patient. 5 The present invention relates to a method for suppressing or inhibiting androgen loss-induced osteosynthesis in male patients with prostate cancer, which method comprises administering an anti-estrogen agent and / or the like to the patient , Derivatives, isomers, metabolites' pharmaceutically acceptable salts, medicinal products, hydrates, N-oxidized 10 15 20 compounds or any combination thereof, in an amount effective to suppress or inhibit in the patient Rupture of bones caused by androgen loss. The present invention relates to a method for reducing the risk of developing androgen-induced bone fracture rupture in patients with prostate cancer m. This method includes administering an anti-estrogen agent and / or its analogues and derivatives to the patient. 'Isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, μ compounds or any combination of these steps' in an amount effective to reduce the development of androgen-induced bone rupture in the patient Danger. In a specific embodiment, the anti-estrogens are _selections and _ hormone receptor modulators (SERMs). In another specific embodiment, the anti-estrogen is tribenzylethylene. In another specific embodiment, the anti-estrogen is toremifene. The present invention provides a safe and effective method for treating, preventing, suppressing, inhibiting or reducing the development of androgen-induced The risk of osteoporosis and / or loss of BMD 'and is particularly useful for treating male patients with prostate cancer who have a high risk of developing androgen-induced osteoporosis and / or lion loss) 0 0 200536555. BRIEF DESCRIPTION OF THE DRAWINGS The present invention is described in more detail below, and is accompanied by the accompanying drawings for a better understanding and understanding. The diagram depicts: 5 Figure 1: Tolimidine for rat collagen I C-tail peptide effect (RatLaps ELISA). Figure 2. The effect of tolimidine on serum bone calcium content. Eight days and percent days, B) 60 and 120 days. I [Solution method; 3 ίο Detailed description of the preferred embodiment The present invention provides: 1) a method for treating androgen-induced osteoporosis in male patients with prostate cancer; 2) an A method for preventing androgen-induced osteoporosis in male patients with prostate cancer; 3) a method for suppressing or inhibiting androgen 15-induced osteoporosis in male patients with prostate cancer; 4) A method for reducing the risk of developing androgen-induced osteoporosis in male patients with prostate cancer, 5)-a method of treating androgen-induced BMD loss in male patients with prostate cancer Methods; 6) A method of preventing androgen loss-induced BMD loss in male patients with prostate cancer; 7) A method of suppressing or inhibiting androgen loss-induced BMD loss in male patients with top 20 adenocarcinoma Methods of BMD loss, 8)-a method of reducing the risk of developing androgen-induced BMD loss in male patients with prostate cancer; 9) a method of treating males in male patients with prostate cancer Method for bone loss-induced rupture of hormones; 10) A method for preventing androgen loss-induced bones in male patients with prostate cancer ⑤ 11 200536555 Each method for rupture of bones; 11)-A method for males with prostate cancer A method of suppressing or inhibiting androgen-induced bone fracture in patients; 12) A method of reducing the risk of developing androgen-induced bone fracture rupture in male patients with prostate cancer by treating the disease Patients are administered antiestrogens and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof. As provided herein, the results confirm that anti-estrogens, such as the administration of torimidine, are bone-controlled. It is measured by measuring the amount of bone-specific serum markers that indicate bone loss and formation. Furthermore, the present invention has confirmed that anti-estrogens, such as tolimidine (and / or 17-々-estradiol), increase bone mineral density. In a specific embodiment, treating, preventing, suppressing, inhibiting or reducing the risk of developing androgen-induced osteoporosis and / or BMD loss is a selective estrogen receptor modulation and / or 15 Analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates, phenols, or any combination thereof. In a specific embodiment, the SERM systems covered by the present invention include, but are not limited to, the following specific examples: Triphenylenes, such as triphenylethyl feminine, which include tamoxifen, Droloxifene, Torifine (emifene), Idoxifene, Clomiphene, Encomiphene, and Zucolene ZUCl0miphene; Benz0thiphene derivatives, such as Ralox (fal) and LY353381; Benzopipe derivatives, such as EM_ (SCH57050) and its metabolite EM652 Naphthalene derivatives, such as 12 200536555, such as Lasofoxifene (CP336, 156); bite _ (chr〇mans), such as Levormeloxifene, or its analogs, derivatives, isopropyl Or metabolites, or pharmaceutically acceptable salts, esters, sense oxides, or mixtures thereof. 5 Toremifene is an example of a diphenyl diphenyl compound described in U.S. Patent Nos. 4,696,949 and 5,491,173 to Toivola et al., The disclosures of which are incorporated herein by reference. Parenteral and topical administration of formulations containing tolimide in mammalian patients is described in U.S. Patent No. 5,571,534 to Jalonen et al. And U.S. Patent No. 10 to DeGregorio et al. No. 5,605,700, the disclosure of which is incorporated herein by reference. As intended herein, other specific examples of anti-estrogens covered by the present invention include, but are by no means limited to, the following specific examples: Kolaxian (匸 乂 (: 1 & (^ 116) ,] \ ^ 1 ^ 1 <: Index, 10th edition # 3085 and US Patent No. 2,464,203 and US Patent No. 2,465,505; Nafoxidine, USAN and USP Drug Names Dictionary, page 327 (1983 ); CI-680, unlisted drug, 28 (10): 169 (0) (1976); CI-628, unlisted drug 26 (7): 106 (1) (1974): CN-55,945-27, or Nitromifene citrate, unlisted drug 27 (12): 194 (n) (1975); R2323 or 13-ethyl 20 -17a-ethoxy-17B-adenyl gonad-4,9 Same as 11-Mistress-3-S, unlisted drugs 23 (3): 34 (b) (1971); MER-25; U-11? 555A; U-ll? 100A; ICI-46,669 and ICI-46,474; All are shown in L. Terenius et al., "In aspects of the mode of action of antiestrogens and antiprogestins", Hormones and Antagonists, Gynec.] Nvest. 3: 98; 2 g Diphenol hydrochrysene; 13 200536555 Red-MEA; and Park Davis CN-55,945; all Revealed in C. Geynet et al., "Estrogens and Anti-Estrogens" Hormones and Antagonists, Gynec. Invest. 3: 12-13 (1972); Acrylic Acids and Cyclophenyls, Revealed In C. Geynet et al., Hormones and Antagonists, Gynec. Invest. 3: 17 (1972); Tri-p-methoxyphenyl chloride 5-ethylene, Merck Index, 10th edition, # 2149; Ethamoxytriphetol ), Merck Index, 10th Edition, # 3668; and Triphenyl Ethanol, Merck Index, 10th Edition, # 9541 and U.S. Patent 2,914,562. Osteoporosis is a systemic skeletal disease characterized by low bone mass and degeneration of bone tissue, It is accompanied by increased bone fragility and susceptibility to fractures. In osteoporosis patients, bone strength is abnormal, with an increased risk of fractures. Osteoporosis is normally found in Both calcium and protein collagen in bones are depleted, resulting in either abnormal bone quality or reduced bone density. Bones affected by osteoporosis may fracture, but have only minor depressions or injuries, which usually do not cause the bone 15 to rupture. This fracture can be in the form of a crack (such as on a hip fracture) or a collapse (such as on a vertebral compression fracture). The vertebrae, hips, and wrists are common areas of osteoporotic bone rupture, but fractures can also occur in other skeletal areas. BMD is a measure of the true bone mass. The absolute bone mass when measured by the bone mineral density (BMD) is generally related to the strength of the bone and its ability to carry weight. By measuring BMD, fracture risk can be predicted in the same way that blood pressure can help predict the risk of stroke. In a specific embodiment, BMD can be measured by a mapping technique of known bone mineral content. The bone density of the hip, vertebra, wrist, or calcaneus can be measured by various techniques. The preferred method of BMD measurement is dual energy x-ray optical density analysis (DXA). BMD of hip, anterior and posterior (AP) vertebrae, lateral vertebrae and wrists can be measured using this technique. Metrics at any location predict the overall risk of a fracture, but information from a particular location is the 5 best predictors of a fracture at that location. Quantitative computerized local X-ray examination (QCT) is also used to measure the BMD of vertebrae. See, for example, '' Nuclear Medicine: '' Quantitative Procedures', edited by Wahner HW, Dunn W L, Thorsen H C, et al., Published by Toronto Little, Brown Corporation, 1983 (see pages 107-132). One paper titled "Assessment of Bone Minerals Part 1" appeared in the Journal of Nuclear Medicine, pp. 1134-1141 10 (1984). Another paper titled "Bone Mineral Density of Radius" The thesis appears in Volume 26, Issue 11, November 1985, Nuclear Medicine Journal, pages 13-39. An abstract on the use of the T camera for the measurement of bone mineral content is (a) S. Hoory et al., Radiology, Vol. 157 (P), p. 87 (1985), and (b) C. R. Wilson et al., Radiology, Vol. 157 (P), p. 88 (1985). 15 The present invention provides a safe and effective method for treating, preventing, suppressing, suppressing or reducing the risk of developing androgen-induced osteoporosis and / or BMD loss, and is particularly useful for treating prostate cancer, and Male patients at high risk of developing androgen-induced osteoporosis. In one embodiment, the male patient is a mammalian patient. In another embodiment, the male patient is a male patient For human patients. Furthermore, the anti-estrogens proposed in this article, for the treatment It is effective to suppress or inhibit bone disease accompanied by bone loss. "Bone disease" refers to reducing the calcification or density of bones. This is a term covering all skeletal systems in which such symptoms are found. 15 ⑤ 200536555 / this article So: t'm 者 'The present invention relates to anti-estrogen compounds, immortals, organisms, isomers, metabolites, pharmaceutical products, hydrates, N · oxides or combinations thereof. For the prevention, To suppress, inhibit or reduce the development of androgen 5 porosity and / in the use of moon shells / such as loss of risk. Therefore, in the first specific implementation 1, the method of the invention includes the administration of an analogue of anti-estrogen. In the other-item 罝In the embodiment t, the method of the present invention includes administering an anti-estrogen charm. In another embodiment, the method of the present invention includes administering an anti-estrogen isomer 10: ^ ㉟ specific implementation In the example, the method of the present invention includes administering an anti-estrogen & H. In the specific embodiment, the method of the present invention includes pharmacological administration of several estrogen, and the salt of the present invention, de M accepts. In another Specific embodiment r: Anti-estrogens pharmaceutical products. In another specific embodiment, the present invention in one embodiment, the present = administration of anti-hormone hydrate. In another 15 "method includes the administration of anti-estrogens N-Oxidation Table-Analogs, street organisms, and methods in another specific embodiment include anti-estrogen salts, isomers, metabolites, pharmaceutically acceptable ', hydrates, or N-oxidation Any combination of things. As defined herein, the term "isomers" refers to structures and analogues, "Qianfang, Meixianyi 20", etc., Ά, structures and analogues, conformational isomers and analogues. In a specific embodiment, the use of various optical isomers, A is used to cover the use of anti-hormone compounds. Those skilled in the art should understand that the anti-estrogens of the present invention contain at least _ In this method, the private hormones used in the present invention can exist and be isolated into optical activity or elimination] 6 200536555 Γ formula. Some compounds can also show polymorphism. It should be understood that , Ben =: _ spin, optically active, polymorphic or stereoisomeric forms ^ ⑺ riding style has properties that can be used to treat the androgen-related 'Chia' described in this article. Yu-specific implementation, anti-estrogens It is a pure ⑻ · 10 15 isomer. In another specific embodiment, the anti-estrogen line is a pure (S) _ structure. In another specific embodiment, the anti-estrogen line is A mixture of tadpoles and tadpoles. In another specific embodiment, the anti-estrogens are The "mixture" contains equal amounts of the (R) and hydrazone isomers. It is known in this art how to prepare optically active forms (for example, by recrystallization technology through analysis of racemic forms) by synthesis from optically active starting materials (Synthesis by palladium, or by chromatography using palladium stationary phase). The present invention includes "pharmaceutically acceptable salts of amine-substituted compounds and organic and inorganic acids (such as citric acid and hydrochloric acid), . The invention also includes N-oxides of the amine substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with an inorganic base, such as sodium hydroxide. Esters of phenolic compounds can also be made of aliphatic and aromatic carboxylic acids, such as acetic acid and benzoates. The invention further includes derivatives of anti-estrogens. "Derivatives," includes, but is not limited to, ether derivatives, acid derivatives, amidine derivatives, ester derivatives 20, etc. In addition, the present invention further includes hydrates of anti-estrogenic compounds. The term includes, but is not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, etc. The present invention further includes metabolites of anti-estrogen compounds. The term "metabolites" means to consist of another substance Any substance produced by metabolism or 17 200536555 metabolic process. The present invention further includes a medicinal product of an anti-estrogen compound. "Medicinal product" means a composition (medical composition) suitable for medical use, as defined herein . In addition, the present invention encompasses the pure (Z)-and (E) -isomers of anti-estrogen compounds as defined herein, and mixtures thereof, and pure (RR, SS) _ and (rs, sr). Isomer pairs, and mixtures thereof. Medical music composition formula; in a specific embodiment, the method of the present invention comprises administering 10 pieces of a medicine group which contains anti-estrogen and / or its analogs, derivatives, isomers, metabolites, Pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-

Danger of BMD loss.

20 It is possible to administer any of the anti-cancer, transmucosal, intradermal, and anti-estrogen-containing pharmaceutical compositions known to this artist by heat, which can be administered to patients by any method, such as parenteral , Right, percutaneous, intramuscular, intravenous, etc.] 2005200555 Indoor, internal, intravaginal, or swollen. In a specific embodiment, the pharmaceutical composition is administered in the form of hydration, so They are formulated in a form suitable for oral administration, that is, as a solid or liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils. In the hair of the day-item specific _ towel, anti-estrogen compound

Style, intraperitoneal style, intratumoral style. The system is formulated in a capsule.粝 M + T5 a —— — / According to this specific embodiment, the composition of the present invention contains hard 10 gelatin capsules in addition to the anti-estrogen active compound and an inert carrier or diluent. Furthermore, in another embodiment, the composition is administered by intravenous, intraarterial or intramuscular injection of a liquid preparation. Suitable liquid formulations include baths, suspensions, dispersions, emulsions, oils, and the like. In a specific embodiment, the pharmaceutical composition is administered intravenously, so it is formulated into a form suitable for intravenous administration. In another embodiment, the pharmaceutical composition is administered intra-arterially, and is therefore formulated to be suitable for intra-arterial administration. In another embodiment, the pharmaceutical composition is administered intramuscularly, so it is formulated into a form suitable for intramuscular administration. Furthermore, in another specific embodiment, the pharmaceutical composition is administered to the surface of the body in a local manner, so it is formulated into a form suitable for local administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, an anti-estrogen agent or a physiologically acceptable derivative thereof, such as salts, esters, N-oxides, etc., is made into a solution in a physiologically acceptable diluent, Suspensions or emulsions, with or without pharmaceutical carriers, and coated with 19 200536555. Furthermore, in another specific embodiment, the t-drug composition is administered as a test agent, for example, silk nucleus, and in another specific embodiment, the medicinal composition is obtained by using Subcutaneous implants are administered. In another specific implementation project, the column granules were used for the controlled release of anti-estrogens over a period of time. In another specific embodiment, the 'active compound may be vesicles, especially microlipids, to be transmitted (see Langer, 2: 1 533 (199 ()), Treat et al., Microlipids are used in infectious diseases and Cancer Therapy 10, Lopez-Berestein and Fidler (eds.) Uss, New York, ed. Secret Pages (1989); Lopez_Berestein, op. Cit., 3i7_327; see cit. Formula, used in this article, a pharmaceutically acceptable carrier or diluent, is known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for a solid formulation, or a liquid carrier or diluent for a liquid formulation, or a mixture thereof. Solid carriers or diluents include, but are not limited to, gums, corn flour (eg corn starch, pre-gelatinized corn flour), sugars (eg lactose, mannitol, dextrose, dextrose), cellulosic materials (eg microcrystalline Cellulose), acrylic acid vinegar (such as methyl 20 polyacrylate ^ calcium carbonate, magnesium oxide, talc or mixtures thereof. For liquid formulations, pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions Liquids, emulsions, or oils. Examples of non-aqueous solvents are glycerol + ethylene glycol and injectable organic esters, such as ethyl oleate. Aqueous carriers include 7jc, alcoholic / solution, emulsion, or suspension Including saline ⑤ 20 200536555 and buffered media. Examples of oils are petroleum, animal, plant or synthetic origin such as peanut oil, soybean oil, Shi Guangyou, olive oil, sunflower oil and cod liver oil. 10 15 20 f enteral vehicle (For subcutaneous, intravenous, intra-arterial or intramuscular injections, it includes emulsified sodium solution, Ringer's dextrose, dextrose and sodium carbonate, Ringer's and non-volatile oils. Intravenous vehicle Including fluids and nutritional supplements Substances, electrolyte supplements, such as those based on Ringer's dextrose, and the like. Examples are sterile liquids, such as water and oils, with or without interface: sex agents, and other pharmacologically acceptable Accepted adjuvants. In general, water, saline, dextrose and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are the preferred liquid carriers, especially for injectable solutions. Examples of oils are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and cod liver oil. In addition, these compositions may further include a binder (such as gum arabic, Corn flour, gelatin, carbohydrates, ethyl cellulose, guar gum, propylcellulose, propyl cellulose, povidone), disintegrating agents (such as corn flour, glutinous potato) Powder, alginic acid, dioxin, cross-linked methylcellulose sodium, knife cross-linked powellone, guar gum, sodium triacetate), buffers with various positive values and ionic strength (such as tin (Acetate, phosphonate), additives, such as Such as albumin or gelatin to prevent absorption to the surface, cleaning agents (such as Dingen's Tween80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (such as sodium lauryl sulfate), penetration enhancers, Solubilizers (e.g. glycerol, polyethylene glycol), antioxidants (e.g. ascorbic acid, sodium metabisulfite, butylated hydroxytoluene), stabilizers (e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose), Tackifiers (such as carbon polymers, colloidal silica, ethyl cellulose, ⑤ 21 200536555 guar), sweeteners (such as aspartame, phenylalanine, citric acid), preservatives (such as thimerosal , Chicken alcohol, p-phenylene sulfonate), lubricants (such as stearic acid, stearic acid ballast, polyethylene glycol, sodium lauryl sulfate), flow aids (such as silicon dioxide), Plasticizers (such as diethyl phthalate, 5 triethyl citrate), emulsifiers (such as carbon polymers, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (such as polyoxygen Polymer or polyoxyamine), coatings and film formers (e.g. ethyl Cellulose, acrylate, polymethacrylate) and / or adjuvant. • In a specific embodiment, the pharmaceutical composition provided herein is a controlled release composition ' meaning ' wherein the anti-estrogen compound is released after administration for a period of time. Controlled or sustained release compositions include formulations in parental products such as fatty acids, kansas, and oils. In another embodiment, the composition is an immediate release composition, that is, a composition in which all anti-estrogen compounds are released immediately after administration. In yet another specific embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, this medication can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, microfilaments, or other modes of administration. In the specific example of a yoke, a pump can be used (see Langer, ibid. · Sefton, CRC Cnt. Ref · Biomed · Eng 14: 2010987); Buchwald et al., 88 · 507 ( 1980), Saudek et al., N. Engl J. Med. 321: 574 (1989)). 20 In another embodiment, a polymeric substance may be used. In yet another specific embodiment, the controlled release system can be placed close to the target of treatment, meaning the brain, so only a fraction of the system dose is needed (see, e.g., G〇ds〇n, subject to The medical application of controlled release is the same as in the previous source, volume 2, page ": 丨".% 4 ". Other release-releasing systems are discussed in the review of Langer (Scie)] ce249. · D 200536555 1527- 1533 (1990)). These compositions may also include active substances incorporated into or on microparticle formulations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, etc., or on liposomes, microemulsions , Cells, monolayer or multilayer vesicles, pseudo red blood cells or spheroids. This composition will affect the physical state, solubility, stability, in vivo release rate and in vivo clearance rate. Also encompassed by the present invention are microparticle compositions that have been coated with a polymer (such as a polyoxymer or polyoxyamine), and are coupled to antibodies to target tissue-specific receptors, ligands, or antigens or are coupled to Tissue-specific receptor ligand compounds.10 Also encompassed by the present invention Compounds modified by covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyethylene Alcohol, polyvinyl tetrahydropyrrolidone or polyproline. It is known that modified compounds, after intravenous injection, show in the blood that they are substantially longer than their corresponding unmodified compounds by about 15 years. (Abuchowski et al., 1981; Newmark et al. 51 982; and Katre et al., 1987). This modification can also increase the solubility of the compound in aqueous solution, eliminate aggregation, and strengthen the physical and chemical stability of the compound, and It greatly reduces the immunogenicity and reactivity of the compound. Therefore, the desired biological activity in vivo can be administered to this polymer-compound by adding 20 less or less than the dose of the unmodified compound. The preparation of pharmaceutical compositions containing active ingredients is well known in the art, such as by mixing, granulating, or tablet forming methods. Active therapeutic ingredients are often used in combination with pharmacy Acceptable excipients compatible with the active ingredients. For oral administration, the anti-estrogens or their physiologically acceptable 23 d 200536555 derivatives, such as salts, vinegars, N-oxides Etc., mixed with additives commonly used in this project, such as vehicles, stabilizers or inert diluents, and converted into appropriate dosage forms by conventional methods, such as tablets, coated tablets, hard or soft gelatin capsules, water Alcoholic or oily suspensions. For parenteral administration, Series 5 converts anti-estrogens or their physiologically acceptable derivatives, such as salts, vinegars, N-oxides, into solutions, Suspensions or emulsions, if desired, use conventional materials suitable for this purpose, such as solubilizers or other substances. The active ingredient can be formulated into the composition in the form of a neutralized pharmaceutically acceptable salt. Pharmaceutically acceptable salts, including acid addition salts (formed with the free amine group of 10 molecules of a polypeptide or antibody), are associated with inorganic acids, such as hydrochloric acid or fulvic acid, or organic acids, such as acetic acid, oxalic acid, tartaric acid , Phenylglycolic acid and the like. Salts formed from free state europium can also be derived from inorganic tests, such as H-ammonium, dance, or iron hydroxides, and organic tests, such as isopropylamine, trimethylamine, 2-Acetoethanol, histidine, and Prolu Caine and so on. 15 20 For medical use, antiestrogens are pharmaceutically acceptable salts. However, other salts can be used in the preparation of a compound according to the invention or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of a compound according to the present invention, a solution of an acceptable acid, such as hydrochloric acid, sulfuric acid , Methane ~ acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. The meaning of contact in this article means that the anti-estrogen compound of the present invention is introduced into a sample containing an enzyme and placed in a test tube, flask, tissue culture, wafer, array, plate, microplate, capillary, or the like And incubated at a temperature and time sufficient to allow the binding of anti-estrogen to the enzyme. The method of contacting the sample with anti-estrogens or other specific binding components is known to those skilled in the art, and can be selected according to the type of test proposal to be operated. The cultivation method is also standard 'and is known to those skilled in the art. In another embodiment, the term "contacting" means introducing an anti-estrogen compound of the present invention into a treated patient and allowing the anti-estrogen compound to contact the androgen receptor in vivo.

10 The term " treatment " as used herein includes both preventive and palliative treatment. The terms "reduced," "depressed," and "inhibited," as used herein, have the meaning of reducing or decreasing as they are generally understood. significance. As used in this article, progress, a 5th department thinks that the stomach increases in scope or severity, advances, grows or becomes worse. The term "recurrence" as used herein means the recovery of the disease after it has been alleviated. The term "administration" as used herein refers to bringing a patient into contact with an anti-estrogen compound of the present invention. Herein The drug used in the application can reach 15% in vitro, which means in a test tube, or in vivo, which means in living cells such as human cells or tissues. In a specific embodiment, the present invention is The administration of a compound of the present invention to a patient is covered. In a specific embodiment, the method of the present invention comprises the administration of an anti-estrogen compound as a separate active ingredient. However, it is also encompassed within the scope of the present invention. A method for treating, treating prostate cancer, delaying the progression of prostate cancer, and preventing and / or treating the recurrence of prostate cancer, includes administering anti-hormonal compounds and using one or more therapeutic agents. These agents include, but are not limited to: LHRH Analogs, reversible anti-androgen substances (such as hcalmamide or flutamide), other anti-estrogens, anti-25 200536555 cancer drugs, 5-α Protoenzyme inhibitors, aromatase inhibitors, luteal preparations, selective androgen receptor modulators (SARMS), or agents acting through other nuclear hormone receptors. Therefore, in a specific embodiment, the method of the present invention includes The combination 5 is used with a pharmaceutical composition, which comprises an anti-estrogen, and an LHRH analog is used in combination. In another specific embodiment, the method of the present invention includes using the composition and a pharmaceutical composition, which contains an anti-estrogen, and is used in combination. Reversible anti-androgenic substance. In another specific embodiment, the method of the present invention includes using a composition and a pharmaceutical composition comprising an anti-estrogen and using another anti-estrogen. In another embodiment In the method of the present invention, the method comprises using a composition and a pharmaceutical composition comprising an anti-estrogen and using an anticancer drug together. In another specific embodiment, the method of the present invention comprises using the composition and a pharmaceutical composition comprising an anti-estrogen Estrogen and a 5-alpha reductase inhibitor. In another embodiment, the method of the present invention comprises using a composition and a pharmaceutical composition comprising an anti- Hormones, 15 and the use of aromatase inhibitors. In another embodiment, the method of the present invention includes the use of a composition and a pharmaceutical composition comprising an anti-estrogen and a corpus luteum preparation. In another embodiment The method of the present invention comprises using a composition and a pharmaceutical composition comprising an anti-estrogen and using SARM in combination. In another specific embodiment, the method of the present invention comprises using the composition and a pharmaceutical composition 20 comprising an anti-estrogen And combined with an agent that acts through other nuclear hormone receptors. Various specific examples of dosage ranges are intended to be included in the present invention. This dosage may be in the range of -80 mg / day. This dosage may be in the range of 5 In the range of -80 mg / day. In another specific embodiment, the dose is in the range of 35-66 mg 26 d 200536555 / day. In another specific embodiment, θ w W A, the dosage is in the range of 20-60 mg / day. In another specific example, such as 眚 and 五, the dose is in the range of 40-60 pen grams per day. In another presentation, each August ugly shellfish, examples, this dose is in the range of 45-60 mg / day. In another example, Wu Yue Dou Guan, this dose is in the range of 15-25 mg / day. In another specific embodiment, this agent

The 10 amount is in the range of 55-65 mg / day. In a specific embodiment, the dosage is 20 mg / day. In another embodiment, the dose is 40 mg / day. In another embodiment, the dose is 60 mg / day. The following examples are presented to more fully illustrate the preferred embodiments of the present invention. But 'should never be interpreted as limiting the broad scope of the invention. EXPERIMENTAL DETAILS_ Example 1 J: Mass Conversion 15 Does Pantolimide have chemopreventive activity against prostate cancer?

In the phase Ila clinical trial, 18 men with advanced prostate intraepithelial neoplasia (ie Qing) were treated with 60 mg / day of toriphene for 4 months. On day 120, there was a significant decrease from baseline in serum calcium (mean _〇a, P.) ', and on day 60 and day 120, alkaline phosphatase was 20% above baseline, Lines were significantly reduced ('average = _18 7 on day 60 and _21 · 0 on day 120 and p < 0.01 for two probes). In these clinical series ", the anti-estrogens torimidene show hormonal effects on M 'in the male towel. It is a favorable transition marker in male towels. For sex mice 27 200536555 Drug delivery system A Ma Shuang 4 No positive control group and comfort The agent was delivered by the ALZA pump, which was manufactured by Durect Corporation (Cupertm0, CA). These fruits were implanted into a subcutaneous pouch using appropriate surgical techniques. I, used in this study, was delivered 5 Continuous rate of drug, over 3G days, of which 1.8 mg / day (2 liter pump) of torimidine was formulated, while diol (positive control group) was released at 70 μg / day The data provided by the pump manufacturer confirmed the constant rate of drug delivery. Over a 28-day period, iU determined that this constant rate could last another few days. The animals were anesthetized, and the dose groups were identified on pages 31 and 61. And 91 for 10 days, the pump was replaced by a pump to provide drug administration, which lasted for 120 days. Each animal in the study had a human implanted spherule to control possible confounding variables associated with implantation surgery. Research Groups: History of Adult Males Spfague_Dawley A white rat (M week old at the beginning of Study 5) 'weighs approximately 035 kg and was used in the experiment. This study used five groups of 12 rats each. The treatment group Denotes placebo control group (castration dependent operation), 17_π alcohol (castration) and torimidine (castration and simulated operation). Makes $ animals from each treatment group on days 60 and 12G Sacrifice time, and measure epiphyseal metabolic markers, and collect 20 bones for biomechanical strength and density testing. 200536555 Table 1. The effects of torimidine on bones in the treatment group

Observation: Torimidine (mg / day). Lotion. Clinical observation: Perform side observation of the cage and record it once a week (daily cage inspection, note any exceptions). Observe the effect on life function. Any animal found to be dying or showing signs of acute toxicity is anesthetized by tritiated toluidine, 87/13) injection, and pelvically anesthetized by bleeding from the abdominal aorta: every Monday: owe, three times of body weight And averaged. Yu Di 60 and 120 angels made their sacrifice. Each sacrifice involved 5 rats from each treatment group and 2 rats at ㈣, 60, 90, and ⑽ days to confirm the blood drug (refer to the table! Group configuration for treatment and sacrifice) ). The animals were anesthetized by the main injection of methamphetamine, and the sacrifice of blood was sacrificed. Blood collected in the bloodletting site is processed to collect serum. Skeletal modification was evaluated based on serum markers to analyze bone loss and bone formation in treated rats. The tests listed in Table 2 show the type of bone modification and the amount of serum required for analysis. Serum chemical analysis of calcium, phosphorus, bilirubin and creatinine in blood, and bone-specific test potacinase was performed in AniLytics (Gaithersburg, MD). Table 2. Serum Marker Detection in Skeleton Modification in Rats Modification Type Test Operation Test Providers Minimum Serum Bone Formation Rats-MID Bone Calcium ELISA OSTEOMETER 20 μl Ma, Structure, Bilirubin, Creatine Chemistry Analysis of AniLytics '70 microliters of bone specific monophosphatase AniLytics' 50 microliters of bone loss serum cross-single-step ELISA OSTEOMETER 20 microliters of serum (deoxy) pyridoline cross-linked METRA 25 microliters of RatTRAP ELISA (tartrate resistance Acid P) SBA Sciences 50 microliter samples were collected, including femoral bones in addition to blood. Process the blood to provide serum. The serum was divided into several aliquots and chilled at -80 ° C; east until analysis. 10 Serum tests were performed at GTx to provide bone calcium content (marker for bone formation) and 0-tail peptide (marker for bone loss). After the femur was removed from each animal, it was stripped of external tissue and stored at -20 ° C until analysis of biomechanical strength and bone mineral density. Randomization / Assignment of Groups: 15 Prior to the study, 10 groups of treatment groups were randomly assigned, and then sixty (60) 12-week-old white rats were designated by the animal resource manager with ears marked and weighed. Sixty animals were then randomly divided into 10 treatment groups with 6 animals each. Application ⑤ 30 200536555 ANOVA ’was performed to establish the presence or absence of significant differences in body weight (acceptable within 1G% of average body weight). This group of individuals is already restricted and cannot be further restricted. If there is a significant attribution, it is of course pointed out, but the change in assignment has not been implemented. „Parameter pairs are normalized for body weight. The values of bone loss are reported on the basis of values, and the average surface is evaluated and compared with the appropriate control group. Compound Test Object 1: 10 Identification Name: Torimidine Description ·· White crystalline powder, sexual ingredients. It is extracted from tormiphene tablets and used as a living test object 2 (positive control group). · Distinguished name · 17 ^ · estradiol ⑸ ⑽ ⑽, laboratory research use ) Example 3 15 The effect of phen on labeling ~ ~ The purpose of this study was to determine the dose of torimidene in mature male mice = whether it is ready-made for scallops, which is currently available through bone-specific- Serum markers were measured, and the markers were indicative of bone loss and formation (of which 17 festradiol was used as a positive control group). The effect of tormiphene sculpting = alcohol) on bone loss caused by hormonal loss has also been determined through the test of bone density and mechanical strength. ^ Left & Well established is ‘Men ’s bone mineral density, similar to women, decreases with age. The reduction in bone mineral content and density is related to a decrease in bone strength of 20 200536555 and is susceptible to fractures. In non-reproductive tissues, the molecular mechanisms underlying the role of pro-multi-organisms in sexual hormones are only just beginning to be understood, but it is obvious that the physiological concentrations of androgens and estrogen throughout the life cycle, In order to maintain the sexuality, I played 5 important angles. Therefore, when the loss of androgen and / or estrogen occurs, there may be an increase in the rate of bone and bone modification. It is because the depletion and formation of the deflection are skewed, which is beneficial to the loss and promotes the overall loss of bone mass. Among men, the natural decline of sexual hormones during maturity (direct decline of androgens, and lower levels of estrogen, derived from the aromatization of the androgen's periphery) is accompanied by 10 weaknesses in the bone pathway. This immortal was also found in a male towel that had been castrated. FiE was first studied in mice. In androgen-deficient men, pharmacological treatment with selective estrogen receptor modulator (SERM) compounds has a positive effect on bone mineral density, and the bone can be treated by Maintain or even increase (Broulk, Gram, 2000; 32: 181-184). It states that in humans, such interventions can stop or at least reduce the severity of the development of osteoporosis. Importantly, ‘Recent human data shows that estrogen loss in older men ’s towels is more important than short-term changes in bone mass. Xianxin Selective Hormone Receptor Modifiers Tolimide (brand name A (: __ τM, and the general name is torimide), when combined with other non-steroidal anti-estrogens (such as tamoxifen) (丁 amoxlfen) Instruct him, give me secrets, 2_ '· 32: 184))%, will have properties similar to bone establishment, and will be clinically useful fun to prevent aging men Osteoporosis and keep bone ~ mountain. The mode used in this article is the cystectomy mode, which is a conventional mode using ...: pseudo- 隹 hormone loss type, which is caused by, for example, ⑤ 32 200536555 LHRH activator therapy in prostate cancer Cause. Materials and Methods Study Design A 14-week-old male Sprague-Dawley rat 5 (Harlan SpragueDawley) was placed on the study. It was randomly divided into five treatment groups: only vehicle after the simulated operation (placebo or P), only vehicle after the cystectomy (Orx), torimidine (5 mg / kg / day) after the simulated operation, And torimidine after testicular resection, and 17-yS-estradiol (0.5 mg / kg / day) after testectomy. The test article was delivered subcutaneously by an Alzet pump. 10 Re-implant the pump every 30 days until the end of the study. After 60 and 120 days of treatment, five to six animals from each group were sacrificed, femurs were collected, soft tissues and muscles were stripped, and individually stored in polypropylene vials at -80 ° C until bones Analysis of density and mechanical strength tests. In addition, serum was collected on days 15, 30, 60, 90, and 120 to measure markers of bone metabolism and perform blood chemistry. After collection, the serum was divided into 3 aliquots and stored at -80 ° C until analysis. 125 μl for serum biochemistry, performed by AniLytics, Gaithersburg, MD (bone-specific alkaline phosphatase, calcium, phosphorus, creatinine, and bilirubin). 100 μl was used for serum rat bone calcium ELISA and serum RatLaps ELISA, 20 for C-terminal tail peptide determination. The remaining sera collected were kept for repeated tests if necessary. The bones were stripped of soft tissue and muscle and stored individually in 15 ml vials at -80 ° C until further testing. 33 200536555 Analysis of osteoporotic markers from rat serum Serum RatLaps ELISA, Osteometer BioTech A / S, Denmark This test was repeated with 20 microliters each of serum and standards and controls. Briefly, 100 microliters of biotinylated RatLaps antigen was incubated in each well for 5 minutes, the slats were washed, and 20 microliters of standard, control, and unknown samples were added to the appropriate wells, followed by 100 microliters. Original antibody (for multiple strains of Ab produced by the synthetic peptide EKSQDGGR, the synthetic peptide is specific for a part of the α-chain of the C-terminal tail peptide of type I collagen of rats). After overnight incubation at 4 ° C, the wells were washed and 100 microliters of peroxidase-conjugated goat anti-rabbit IgG antibody was added to 10 wells and incubated for 60 minutes. After the slats were washed, 100 microliters of the chromogen receiving solution was added to each well, and after 15 minutes, the reaction was stopped and the absorbance was measured at 450 nm. Calculate the average of the repeated absorbance measurements and use the 4-parameter calculation curve to fit the standard curve. The sample RatLaps concentration was measured by interpolation.

15 Rat Bone Calcium EIA, Biomedical Technology, MA This test is specific to rat bone calcium and identifies carboxylated and decarboxylated rat bone calcium. Monoclonal antibodies to the osteocalcin N-terminal region were bound to polystyrene wells. This test is repeated. Add 100 μl of standard, control, and 1 to 20 diluted samples to the appropriate wells and incubate overnight at 4 ° C 20. After washing the slats, 100 microliters of goat polyclonal antibodies specific for the C-terminus of rat bone calcium were added and cultured at 37 ° C for 60 minutes. After washing, 100 microliters of donkey anti-goat IgG peroxidase conjugate antibody was added and incubated at 22 ° C for 60 minutes. The wells were washed, and a mixture of TMB and peroxide solution was added and incubated at 22 ° C for 30 minutes in the dark. The reaction time should be stopped and the absorbance measured at 450 nm. A 4-parameter calculation of the curve fit was used to establish a standard curve. The bone calcium concentration of the sample was measured by interpolation. Osteoanalysis method Peripheral quantitative local X-ray examination (pQCT) 5 The right femur was subjected to pQCT analysis using Stratec XCT-RM (Stratec Medizintechnik GmbH, Pforzheim, Germany. Software version 5.40C) with associated software. The femur was scanned at two locations, 20% and 50% of the total femoral length, as measured from the peripheral femur. This position was confirmed using a scout view, and the results of the scans obtained from two 0.5 mm sections perpendicular to the long axis of the femoral axis were recorded. Mechanical Testing Two types of mechanical tests were performed on the right femur using a material testing system (Model 5501R, Instron, Canton, MA). The load and tensile curves were collected by mechanical software (Merlinll, Instron). All tests were performed using a 5kN 15 load sensor at a constant load rate of 6 mm / min. The general application of these tests is as described in Turner and Burr (Bone, 1993; 14: 595-608) and Ke et al. Koone, 1998; 23,249-255). Compression test of peripheral femur Compression test is used to determine the mechanical properties of peripheral femur. Peripheral femur test 20 was obtained using a slow diamond saw with constant saline infusion by removing a 3 mm segment directly adjacent to the peripheral condyle. Use an electronic caliper to measure the average front / back diameter (a), middle / lateral straight (b), and height (h) of the bone. The external parameters, maximum load (Fi0, rigidity (S), and energy (W) are derived from the load and tensile curves. The following intrinsic parameters are calculated from the measured values: Crossing surface 35 200536555 Area (CSA > (π * a * b) / 4; Ultimate strength (σ > Fu / CSA; Elastic modulus (E) 2 S / (CSA / h); Toughness (T > W / (CSA * h). Results / Discussion Analysis of converted serum markers5 Bone conversion markers have been shown to be used by clinical scientists to monitor bone activity

-An effective confirmation tool. Fundamentally, the data for evaluating the maximum results of novel therapeutic agents for the treatment and prevention of osteoporosis are tangible improvements in the quality of the bone itself. However, because the changes in bone conversion markers are well correlated with bone strength testing, in this study, we analyzed C. tail peptides and system content in order to provide mid-term analysis and supplementary data to Effectiveness of supportive care. C-tail peptide of type I collagen: 15 20 As explained in Figure 1, the C · tail content in the testis-excision animals slightly increased, which exceeded the placebo 15 and 3G days. With 9 5%, the bone loss activity system was increased after castration, and collagen was being degraded, and the fragments containing the cross-linked molecules were released into human blood. Furthermore, the use of tormiphene to treat animals that had undergone testicular resection and that of the i7m group in the positive control group reduced the C. content by up to 10% ("placent-treated animals that had not been subjected to testectomy). For the 17 | estradiol group, it tends to be very significant. Since torimidine and 1 7-yS • Carved i, the data show that bone loss in these agents is used. Alcohol will reduce the C-tail Peptide in serum to prevent androgen-induced 36 200536555 Bone Calcium: Similar to other published literature, applicants have found that the bone calcium content is increased by castration. Torimide is significantly reduced in castrated animals Bone calcium content reached the original control content (p &lt; 0.05 at 15 days and 5 p &lt; 0.02 at 30 days, Figure 2A). The increase in bone calcium content was most significant 15 days after castration, but only Remiphene and 17-/ 5-estradiol continued to significantly reduce bone calcium content to less than the control rat that remained intact for 120 days (Figure 2B). These results show that after the testicle removal, in males The bone formation rate is adjusted upwards to compensate for the increased consumption Activity. 17- / S-estradiol and selective estrogen receptor 10-portion torimidene will stabilize bone loss and formation, thus reducing the overall bone calcium content that can be measured in serum. Biomechanical analysis of bones due to castration-induced androgen deficiency has been used as a model for male osteoporosis. In this model, most of the bone wastage is in the 15-bone of bone sponge. To learn more about Torrey Mifephene has effects on bone mineral density and mechanical strength, so bones were collected at the end of the life study period and sent to SkeleTech (Bothell, WA) for testing. Prior to analysis, all bones were thawed in physiological saline. Statistical analysis It was performed using SAS software (SAS Institute, Cary, NC). One-way analysis of variance (group) was performed. Individual group differences 20 were determined using Dunnett's program, using treatment group 2 (castration + placebo) as reference Group. P-value <0.05 is considered significant. Where appropriate, p-value <0.1 is indicated as a trend (when the treatment results are in the direction of the positive control group). Peripheral right Bone sponge PQCT: When compared with simulated manipulation animals, the total bone mineral content in Orx animals is 37 ⑤ 200536555, which is lower in content and density, but is not statistically significant. Torimide and 71 diol The treatments have shown that the total bone area is reduced, and the total bone mineral density is increased. The bone mineral content and density of bone sponge in 0rx animals are lower than those of simulated manipulation animals. 4 /. Partial prevention of torimidine This reduction, however, although the diol month b is 70 Wang P; $ · This is the Xiao sponge cotton bone loss. There is no statistically significant difference between the parameter and the group, which is due to the small sample size, and Caused by large deviations in the measurement results. The results are summarized in Table 3.

Table 3: Descriptive treatment of peripheral j femur bone sponge pQCT Total bone content Total bone area Total bone density Trabecular content Trabecular area Trabecular density group (mg / mm) (mm2) (mg / cm3) (mg / mm) (mm2) (mg / cm3) 11.47 17.41 658.27 1.65 7.83 209.72 Simulation (n = 6) S.E.M. 0.89 0.97 32.81 0.43 0.44 52.17 P &lt; 0. 05 nsnsnsnsnsns average 11.07 17.38 639.50 1.08 7.82 138.38 Cx (n = 5) S. Ε · Μ. 0.50 1.26 47.07 0.22 0.57 31.88 P <0.05 nananananana Cx + average 10.69 15.96 669.74 1.13 7.18 157.56 Torimine SEM 0.48 0.67 21.95 0.22 0.30 32.77 Ul-D; P &lt; 0.05 nsnsnsnsnsns Γγ ± average 11.01 15.95 690.74 1.52 7.17 210.28 Τ EST (η-5) S · E · M. 0.76 0.98 26.68 0.50 0.44 62.69 P &lt; 0 · 05 nsnsnsnsnsnsns ρ &lt; 0 · 05 Not applicable for TG2 · 10 ns = Not significant 38 ⑧ 200536555 Compression test of the femur of the grass ·· The mechanical strength is adjusted at the position of the peripheral femoral towel 1 in the cotton-bone-added bone of Nakata. 5: Bomb: hour, maximum load, rigid , (Iv) the ultimate strength, such as in lower animals. Add tormiphene treatment to animals, 2 good fortunes, depending on the material of the model. ηι 二 二 智 treatment 'shows a statistically significant improvement in these parameter values. As expected from the data, the cross-sectional area of the plate decreased with the addition of torimidine and 17, diol treatment. The results are summarized in Table 4.

0.18 1.64 0.14 10 ρ &lt; 0.05

467.01 3856.7 1 $ 6.96 22.13 579.07 0.86 21.30 .15 + Recipe 5 CX Tommy i 125.89 1 303.56 17.07 6.34 21 1.70 0.30 1.43 • 15

200536555 P &lt; 0.05. For TG2. • n.s, not significant N / A Abstract 5 Androgen deficiency mode will cause animals to have increased content of bone in serum. Mass loss markers C-tail peptide and bone calcium. After castration, treatment with torimidine and 17- / 3-, although diol, will significantly reduce the content of these serum markers. In addition, androgen deficiency can cause 34% of bone mineral content and density in bone sponges. Importantly, the use of torimidine will partially prevent this loss. As predicted by the 10 ', hormonal hormones are extremely effective in preventing bone sponge loss due to androgen deficiency. In addition, the compression test of the peripheral femur showed an improved intensity in the resection group treated with toriphene and Erbi Pill, but it was statistically significantly improved with steroid treatment. These measures are related in part to the total bone mineral density at that location. All in all, the data presented here indicate that the selection of the 15 sex hormone receptor modulator torimidene has a positive effect on bone improvement in men who are treated with androgen deprivation for prostate cancer. • It should be clear to those skilled in the art that the present invention is not limited to what has been specifically illustrated and described above. [Brief description of the drawings] 20 The present invention is described in detail above, and is accompanied by the accompanying drawings for a better understanding and understanding. The drawing depicts: Figure 1 · Tolimidine for rats The role of collagen tail peptide (RatLapsEUSA). Figure 2 Torium, the effect on serum bone content. a) Du Deng Tian; b) Yi and Yu Tian. [Description of Symbols of Main Components] (None) 40

Claims (1)

200536555 10. Scope of patent application: 1. A composition for treating hot flash sensation induced by androgen loss in male individuals with prostate cancer, reducing carcass quality, loss of sexual desire or erectile dysfunction, which comprises a selective estrogen Receptor modulators (SERMs) and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof. 2. The composition as claimed in claim 1, wherein the anti-estrogen is triphenylethyl. 3. A composition for treating hot flash sensation induced by androgen loss in a male individual with prostate cancer, reducing the mass of carcass, loss of libido or erectile dysfunction, comprising a torimidine and / or an analog thereof, Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof. 4. The composition as claimed in any one of claims 1 to 3, wherein the pharmaceutical composition is administered intravenously, intra-arterially or intramuscularly, whereby the pharmaceutical composition is injected as a liquid To a body; administered subcutaneously, whereby a plaque system containing the pharmaceutical composition is implanted in a body; administered orally, whereby the pharmaceutical composition is administered in liquid or solid form The individual; or administered topically, whereby the pharmaceutical composition is applied to the skin surface of the individual. 4]