AU2008201150A1 - Prevention and treatment of gynecomastia or hot flashes - Google Patents

Prevention and treatment of gynecomastia or hot flashes Download PDF

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AU2008201150A1
AU2008201150A1 AU2008201150A AU2008201150A AU2008201150A1 AU 2008201150 A1 AU2008201150 A1 AU 2008201150A1 AU 2008201150 A AU2008201150 A AU 2008201150A AU 2008201150 A AU2008201150 A AU 2008201150A AU 2008201150 A1 AU2008201150 A1 AU 2008201150A1
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bone
use according
toremifene
subject
estrogen
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AU2008201150A
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Sharan Raghow
Mitchell S Steiner
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Oncternal Therapeutics Inc
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GTx Inc
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Priority claimed from AU2002356928A external-priority patent/AU2002356928B2/en
Priority claimed from AU2005202072A external-priority patent/AU2005202072B2/en
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Description

AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant: GTx, Inc.
Invention Title: PREVENTION AND TREATMENT OF GYNECOMASTIA OR HOT FLASHES The following statement is a full description of this invention, including the best method for performing it known to me/us: P53258 AU.2 PatlSetLFifng Applicatlon 2006-3-I0doc (B) 00 [0001] This invention relates to reducing the incidence, inhibition, suppression, prevention and treatment of gynecomastia and/or hot flashes such as in men suffering from prostate cancer.
00 BACKGROUND OF THE INVENTlON [0002] It is well established that the bone mineral density of males decrease with age. Decreased amounts of bone mneral content and density correlates with decreased bone srength and predspose to fracure. The molecular mechanisms underlying the plelotropic effects of sex-hormones In non-reproductive tissues are only beginning to be understood, but It is clear that physiologic concentrations of aangens and etrgens play an Important role in maintanng bone home throughout the fe-cycle. Consequently, when androgen or estrogen deprivation occurs, there is a resultant Increase In the rate of bone remodeling that tilts the balance of resorption and formation in the favor of resorption, contributing to an overall loss of bone mass. In males, the natural decline in sex-hormones at la 00 maturity (direct decline In androgens as well as lower levels of estrogens derived 0 from peripheral aromatization of androgens) is associated with the frailty of bones.
ci This effect is also observed in males who have been castrated.
[0003] Prostate cancer is one of the most frequently diagnosed noncutaneous cancers among men in the United States. One of the approaches to the treatment of prostate cancer is by androgen deprivation. The male sex hormone, Stestosterone, stimulates the growth of cancerous prostatic cells and, therefore, is the primary fuel for the growth of prostate cancer. The goal of androgen deprivation is to decrease the stimulation by testosterone of the cancerous prostatic cells.
oO Testosterone normally is produced by the testes in response to stimulation from a 0hormonal signal called luteinizing hormone (LH) which in turn Is stimulated by luteinizing-hormone releasing hormone (LH-RH). Androgen deprivation is accomplished either surgically by bilateral orchidectomy or chemically by LH-RH agonists (LHRH) with or without nonsteroidal antiandrogens.
[0004] Current studies suggest that early androgen deprivation in patients with micrometastatic disease may indeed prolong survival [Messing EM, et al (1999), N Engl J Med 34, 1781-1788; Newling (2001), Urology 58(Suppl 2A), 50-55].
Moreover, androgen deprivation is being employed in numerous new clinical settings, including neoadjuvant therapy prior to radical prostatectomy, long-term adjuvant therapy for patients at high risk for recurrence following radiation or surgery, neoadjuvant therapy for radiation, and treatment of biochemical recurrence following radiation or surgery [Carroll, at al (2001), Urology 58, 1-4; Horwitz EM, et al (2001), IntJRadiat OncolBlolPhy Mar 15;49(4), 947-56]. Thus, more prostate cancer patients have become candidates for and are being treated by androgen ablation. Moreover, these prostate cancer patients are being treated earlier and longer than in the past, which in some cases may be as long as 10 or more years of androgen deprivation therapy.
[0005] Unfortunately, androgen deprivation therapy is fraught with significant side effects, including hot flashes, gynecomastia, osteoporosis, decreased lean muscle 00 mass, depression and other mood changes, loss of libido, and erectile dysfunction [Stege R (2000), Prostate Suppl 10,38-42]. Consequently, N complications of androgen blockade now contribute significantly to the morbidity, Sand in some cases the mortality, of men suffering from prostate cancer.
S1[oooe] Given that more patients today are being treated by long-term androgen deprivation in men, new innovative approaches are urgently needed at both the Sbasic science and clinical levels to decrease the incidence of androgen- In deprivation induced side effects in men suffering from prostate cancer.
00 0O Os 3 00 SUMMARY OF THE INVENTION [0007] In one aspect the present invention relates to the use of toremifene and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof in the preparation of a composition for use in treating, reducing the incidence of, suppressing, or inhibiting hot flashes in a subject.
[0008] In an embodiment said toremifene is toremifene citrate.
00 [0009] In an embodiment said composition comprises a pharmaceutically Sacceptable carrier.
[0010] In an embodiment said composition is prepared in liquid form for intravenous, intraarterial, or intramuscular injection; in pellet form for subcutaneous implantation; in a liquid or solid form for oral administration; or for topical application.
[0011] In an embodiment said composition is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.
[0012] In an embodiment said subject is human, particularly a human male.
(0013] In an embodiment said male subject has received androgen deprivation therapy (ADT).
[0014] In a further aspect the present invention relates to the use of toremifene and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof in the preparation of a composition for use in treating, reducing the incidence of, suppressing, or inhibiting gynecomastia in a subject.
[0015] In an embodiment said toremifene is toremifene citrate.
00 O [0016] In an embodiment said composition comprises a pharmaceutically C" acceptable carrier.
[0017] In an embodiment said pharmaceutical composition is prepared in liquid form for intravenous, intraarterial, or intramuscular injection; in pellet form for subcutaneous implantation; in a liquid or solid form for oral administration; or for topical application.
[0018] In an embodiment said pharmaceutical composition is a pellet, a c-i 1o tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a (0 0cream, a suppository or a parenteral formulation.
[0019] In an embodiment said subject is human, particularly a human male.
[0020] In an embodiment said male subject has received androgen deprivation therapy (ADT).
00 BRIEF DESCRIPTION OF THE FIGURES [000211 The Present Invention will be understood and appreciated more fully from the following detailed desciption taken in conjunction with the appended figures which depict Figure 1: Effect of Toremifene on C-telopeptlde of rat collagen I (RatLaps
ELISA).
00 o0 Figure 2: Effect of Toremifene on serum osteocalcin levels. A) 10 and Sdays; B) 60 and 120 days.
DETAILED DESCRIPTION OF THE INVENTION [00022] Described herein are: 1) a method of treating androgen-deprivation i^ induced osteoporosis in a male subject suffering from prostate cancer 2) a method of preventing androgen-deprivation induced osteoporosis in a male subject suffering from prostate cancer; 3) a method of suppressing or Inhibiting Sandrogen-deprivation induced osteoporosis in a male subject suffering from prostate cancer; 4) a method of reducing the risk of developing androgen-deprivation induced osteoporosis in a male subject suffering from prostate cancer; 5) a method of treating androgen-deprivation induced loss of BMD in a male subject suffering from prostate cancer; 6) a method of preventing androgen-deprivation induced loss of BMD In a male subject suffering from prostate cancer; 7) a method of suppressing or inhibiting androgen-deprivation induced loss of BMD in a male subject suffering from prostate cancer; 8) a method of reducing the risk of developing androgen-deprivation induced loss of BMD in a male subject suffering from prostate cancer; 9) a method of treating androgen-deprivation induced bone fractures in a male subject suffering from prostate cancer; 10) a method of preventing androgen-deprivation induced bone fractures in a male subject suffering from prostate cancer; 11) a method of suppressing or inhibiting androgen-deprivation Induced bone fractures in a male subject suffering from prostate cancer; 12) a method of reducing the risk of developing androgen-deprivation Induced bone fractures in a male subject suffering from prostate cancer by administering to the subject an anti-estrogen agent and/or its analog, derivative, Isomer, metabolite, pharmaceuticaly acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
[00023 As provided herein, the results demonstrate that administration of an anti-estrogen, such as, for example, Toremffene, is bone sparing. This is determined by measuring the levels of bone-specific serum markers that indicate bone resorption and formation. Further, this invention demonstrates that an Santi-estrogen, such as, for example, Toremifene (and/or 17-?p -Estradiol), Increases bone mineral density.
C [00024] In one embodiment the anti-estrogen that treats, prevents, suppresses, inhibits or reduces the risk of developing androgen-deprivation Induced Sosteoporosis and/or loss of BMD is a selective estrogen receptor modulator (SERM) and/or its analog, derivative, isomer, metabolite, pharmaceutically.
acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination 0 thereof.
oO C [00025] In one embodiment, the SERMs that are encompassed by the present invention include, but are not limited to the following embodiments: triphenylalkylenes such as triphenylethylenes, which include Tamoxifen, Droloxifene, Toremifene, Idoxifene, Clomiphene, Enclomiphene and Zuclomiphene; benzothiphene derivatives such as Raloxifene and LY 353381; benzopyran derivatives such as EM 800 (SCH 57050) and its metabolite EM 652; naphthalene derivatives such as Lasofoxifene (CP 336,156); chromans such as Levormeloxfene or their analogs, derivatives, isomers, or metabolites thereof, or their pharmaceutically acceptable salts, esters, N-oxides, or mixtures thereof.
[0o002] Toremifene is an example of a triphenylalkylene compound described in US.
Patent Nos. 4,696,949 and 5,491,173 to Toivola et al., the disdosures of which.are incorporated herein by reference. The parenteral and topical administration to mammalian subjects of formulations containing Toremifene is described In U.S.
Patent No. 5,571,534 to Jalonen et al. and in U.S. Patent No. 5,605,700 to DeGregorio et al., the disclosures of which are incorporated herein by reference.
[00027] As contemplated herein, other embodiments of anti-estrogens that are encompassed by the present invention Include but are in no way limited to the following embodiments: Cycladiene, Merck Index, 10th ed. #3085 and U.S. Pat 0 No. 2,464,203 and U.S. Pat No. 2,465,505; Nafoxidine, USAN and USP Dictionary N of Drug Names, p. 327 (1983); CI-680, Unlisted Drugs, 28(10): 169(o) (1976); Cl-628, Unlisted Drugs, 26(7): 106(1) (1974); CN-55,945-27, or nitromifene citrate, Unlisted Drugs, 27(12): 194(n) (1975); R2323 or 13-ethyl-17a-ethynl- S17B-hydroxygon-4,9,1 1-trien-3-one, Unlisted Drugs, 23(3): 34(b) (1971); U-11,555A; U-11,100A; ICI-46,669 and ICI-46,474; all shown in L Terenlus, et al., S"Aspects on the Mode of Action of Antlestrogens and Antiprogestrogens," Hormones and Antagonists. Gynec. Invest. 3: 98; Diphenol hydrochrysene; erythro-MEA; and Park Davis CN-55,945; all disclosed in C. Geynet, et al., 0o "Estrogens and Antlestrogens," Hormones and. Antagonists. Gynec. Invest 3: 12-13 (1972); Allenolic acid and cyclofenyl, disclosed in C. Geynet, et al., c Hormones and Antagonists. Gynec. Invest. 3:17 (1972); Chlorotianisene, Merck Index, 10th ed., #2149; Ethamoxytriphetol, Merck Index, 10th ed., #3668; and Triparanol, Merck Index, 10th ed., #9541 and U.S. Pat. No. 2,914,562.
[00028] Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In osteoporotic patients, bone strength is abnormal, with a resulting increase in the risk of fracture. Osteoporosis depletes both the calcium and the protein collagen normally found in the bone, resulting in either.
abnormal bone quality or decreased bone density. Bones that are affected by osteoporosis can fracture with only a miner fall or injury that normally would not cause. a bone fracture. The fracture can be either in the form of cracking (as In a hip fracture) or collapsing (as in a compression fracture of the spine). The spine, hips, and wrists are common areas of osteoporosis bone fractures, although fractures can also occur in other skeletal areas.
oo00029] BMD is a measured calculation of the true mass of bone. The absolute amount of bone as measured by bone mineral density (BMD) generally correlates with bone strength and its ability to bear weight By measuring BMD, it is possible to predict fracture risk in the same manner that measuring blood pressure can help 0 predict the risk of stroke.
[00030] BMD in one embodiment can be measured by known bone-mineral content mapping techniques. Bone density of the hip, spine, wrist, or calcaneus may be C measured by a variety of techniques. The preferred method of BMD measurement is dual-energy x-ray densitometry (DXA). BMD of the hip, antero-posterior (AP) spine, lateral spine, and wrist can be measured using this technology.
t Measurement at any site predicts overall risk of fracture, but information from a specific site is the best predictor of fracture at that site. Quantitative computerized N tomography (QCT) is also used to measure BMD of the spine. See for example, S"Nuclear Medicine: "Quantitative Procedures". by Wahner H W, Dunn W L, CN Thorsen H C, et al, published by Toronto Little, Brown Co., 1983, (see pages 107-132). An article entitled "Assessment of Bone Mineral Part 1" appeared in the Journal of Nuclear Medicine, pp 1134-1141, (1984). Another article entitled "Bone Mineral Density of The Radius" appeared in Vol. 26, No. 11, (1985) Nov. Journal of Nuclear Medicine at pp 13-39. Abstracts on the use of gamma cameras for bone-mineral content measurements are S. Hoory et al, Radiology, Vol. 157(P), p. 87 (1985), and C. R. Wilson et al, Radiology, Vol. 157(P), p. 88 (1985).
[00031] The present invention provides a safe and effective method for treating, 00 preventing, suppressing, inhibiting or reducing the risk of developing androgen-deprivation induced osteoporosis and/or loss of BMD and is particularly useful for treating male subjects suffering from prostate cancer having an elevated risk of developing androgen-deprivation induced osteoporosis. In one Sembodiment, the male subject is a mammalian subject. In another embodiment, the male subject is a human subject.
V [00032] Furthermore, the anti-estrogens presented herein are effective at treating, suppressing or inhibiting osteopenia accompanied by bone loss. "Osteopenia" N refers to decreased calcification or density of bone. This is a term which 00 Sencompasses all skeletal systems in which such a condition is noted.
[00033] As contemplated herein, the present invention relates to the use of an anti-estrogen compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or combinations thereof for treating, preventing, suppressing, inhibiting or reducing the risk of developing andmgen-deprivation induced osteoporosis and/or loss of BMD.
Thus, in one embodiment, the methods of the present invention comprise administering an analog of the antiestrogen. In another embodiment, the methods of the present invention comprise administering a derivative of the anti-estrogen.
In another embodiment, the methods of the present invention comprise administering an isomer of the antiestrogen. In another embodiment, the methods of the present invention comprise administering.a metabolite of the anti-estrogen.
In another embodiment, the methods of the present invention comprise administering a pharmaceutically acceptable salt of the anti-estrogen. In another embodiment, the methods of the present invention comprise administering a pharmaceutical'product of the anti-estrogen. In another embodiment, the methods of the present invention comprise administering a hydrate of the anti-estrogen. In another embodiment, the methods of the present invention comprise administering an N-oxide of the anti-estrogen. In another embodiment, the methods of the present invention comprise administering any of a combination of an analog, -11r derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical oo product, hydrate or N-oxide of the anti-estrogen.
O
[00034] As defined herein, the term "isomer includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and Sanalogs, and the like.
[00035] In one embodiment, this invention encompasses the use of various optical In isomers of the anti-estrogen compound. It will be appreciated by those skilled in the art that the anti-estrogens of the present invention contain at least one chiral Scenter. Accordingly, the anti-estrogens used in the methods of the present 0 invention may exist in, and be isolated in, optically-active or racemic forms. Some N compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, .optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of androgen-related conditions described herein. In one embodiment, the anti-estrogens are the pure (R)-isomers. In another embodiment, the anti-estrogens are the pure (S)-isomers. In another embodiment, the anti-estrogens are a mixture of the and the isomers. In another embodiment, the anti-estrogens are a racemic mixture comprising an equal amount of the and the isomers. It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis,-or by chromatographic separation using a chiral stationary phase).
[00036] The invention Includes "pharmaceutically acceptable salts" of amino-substituted compounds with organic and inorganic adds, for example, citric acid and hydrochloric acid. The invention also includes N-oxides of the amino substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from the phenolic compounds by treatment with inorganic bases, for example, sodium..hydroxide. Also, esters of the phenolic compounds can be made with aliphatic and aromatic carboxylic adds, for example, -12acetic acid and benzoic acid esters.
00 N [00037] This invention further includes derivatives of the anti-estrogens. The term "derivatives" includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. In addition, this invention further includes C hydrates of the anti-estrogen compounds. The term "hydrate" Includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
O
[00ooo38] This invention further includes metabolites of the anti-estrogen compounds.
The term "metabolite" means any substance produced from another substance oO by metabolism or a metabolic process.
[00039] This invention further includes pharmaceutical products of the anti-estrogen compounds. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
[00040] In addition, the invention encompasses pure and isomers of the anti-estrogen compounds defined herein and mixtures thereof as well as pure (RR,SS)- and (RS,SR)-enantiomer couples and mixtures thereof.
Pharmaceutical Compositions [00041] In one embodiment, the methods of the present invention comprise administering a pharmaceutical composition comprising the anti-estrogen and/or its analog, derivative, isomer, metabolite- pharmaceutically acceptable salt; pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition is administered to a male subject suffering from prostate cancer for treating and/or preventing androgen-deprivation induced osteoporosis and/or loss of BMD; for suppressing or inhibiting androgen-deprivation induced osteoporosis and/or loss of BMD; and/or for reducing the risk of developing androgen-deprivation induced osteoporosis and/or loss of BMD in the male subject -13- [00042] As used herein, "pharmaceutical composition" means a "therapeutically effective amount" of the active ingredient, i.e. the anti-estrogen, together with a Spharmaceutically acceptable carrier or diluent. A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.
[00043] The pharmaceutical compositions containing the anti-estrogen can be Sadministered to a subject by any method known to a person skilled in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, Intraperitonealy, intraventricularly, N intracranially, intravaginally or intratumorally.
0 Ci [00044] In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a solid or a 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 and the like. In one embodiment of the present invention, the anti-estrogen compounds are formulated in a capsule. In accordance with this embodiment, the compositions of the present invention comprise, in addition to the anti-estrogen active compound and the inert carrier or diluent, a hard gelating capsule.
[00045] Further, in another embodiment, the pharmaceutical compositions are administered by intravenous, intraarterial, or intramuscular:injection.of a .liquid..
preparation. Suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment, the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for Intravenous administration. In another embodiment, the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration. In another embodiment, the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for Intramuscular administration.
-14- 00 O [00046] Further, in another embodiment, the pharmaceutical compositions are N administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, the anti-estrogen N agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are prepared and applied as solutions, suspensions, or emulsions in 0 a physiologically acceptable diluent with or without a pharmaceutical carrier.
10 [00047] Further, in another embodiment, the pharmaceutical compositions are I administered as a suppository,. for example a rectal suppository or a urethral suppository. Further, in another embodiment, the pharmaceutical compositions are NC administered by subcutaneous implantation of a pellet In a further embodiment, the pellet provides for controlled release of anti-estrogen agent over a period of time.
[00048] In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp.
317-327; see generally ibid).
[00049) As used herein "pharmaceutically acceptable carriers or diluents" are well known to those skilled in the art The carrier or diluent:may be a solid carrier or diluent for solid formulations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
[00050] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g.
corn starch, pregeletanized starch), a sugar lactose, mannitol, sucrose, dextrose), a cellulosic material microcrystalline cellulose), an acrylate (e.g.
polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
0 [000511 For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, Salcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or Ssynthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
cN [00052] Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or oO 0 intramuscular injection) include sodium chloride solution, Ringer's dextrose, N dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles indude fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Examples are stenle liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid caniers, particularly for injectable solutions. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
[00053] In addition, the compositions may further comprise binders acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,.hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents comstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers Tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants sodium lauryl sulfate), permeation enhancers, solubilizing agents glycerol, polyethylene glycerol), anti-oxidants ascorbic acid, sodium metabisuffite, butylated hydroxyanisole), stabilizers OO hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing 0 agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), c sweeteners aspartame, citric acid), preservatives Thimerosal, benzyl alcohol, parabens), lubricants stearic acd, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids colloidal silicon dioxide), plasticizers diethyl phthalate, triethyl citrate), emulsifiers carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings poloxamers or Spoloxamines), coating and film forming agents ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
0o [00064] In one embodiment, the pharmaceutical compositions provided herein are Scontrolled-release compositions, i.e. compositions in which the anti-estrogen compound is released over a period of time after administration. Controlled- or sustained-release compositions include formulation in lipophilic depots fatty acids, waxes, oils). In another embodiment, the composition is an immediate-release composition, i.e. a composition in which all of the anti-estrogen compound is released immediately after administration.
[00055] In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit Ref.
Biomed. Eng. 14:201 (1987);:Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, the brain, thus requiring only a fraction of the systemic dose (see, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled-release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
-17- [0005e] The compositions may also include incorporation of the active material into 0 or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, c-I unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubility, stability, rate of in vivo c- release, and rate of in vivo clearance.
([ooo57] Also comprehended by the invention are particulate compositions coated with polymers poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled C to ligands of tissue-specific receptors.
0oo S[0oo0058] Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline. The modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981; Newmark et al., 1982; and Katre et al., 1987). Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound.
As a result, the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently:orin-lower doses than with the unmodified compound.
[00059] The preparation of pharmaceutical compositions which contain an active component is well understood in the art, for example by mixing, granulating, or tablet-forming processes. The active therapeutic ingredient is often mixed with exclplents which are pharmaceutically acceptable and compatible with the active ingredient For oral administration, the anti-estrogen agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with -18- 00 additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, C and converted by customary methods into suitable forms for administration, such c as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. For parenteral administration, the anti-estrogen agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other.
[00060] An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include 00 the acid addition salts (formed with the free amino groups of the polypeptide or Santibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
[00061] For use in medicine, the salts of the anti-estrogens are pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention With a-solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
[000ooo] As defined herein, "contacting" means that the anti-estrogen compound of the present invention is introduced into a sample containing the enzyme in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the antiestrogen 19to the enzyme. Methods for contacting the samples with the anti-estrogen or other 00 specific binding components are known to those skilled in the art and may be Sselected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art S[ooo0063] In another embodiment, the term "contacting" means that the anti-estrogen compound of the present invention is introduced into a subject receiving treatment, and the anti-estrogen compound is allowed to come in contact with the androgen receptor in vivo.
C [00064] As used herein, the term "treating" includes preventative as well as disorder 0 remitative treatment As used herein, the terms "reducing", "suppressing" and C "inhibiting" have their commonly understood meaning of lessening or decreasing.
As used herein, the term "progression" means increasing in scope or severity, advancing, growing or becoming worse. As used herein, the term "recurrence" means the return of a disease after a remission.
[00065] As used herein, the term "administering" refers to bringing a subject in contact with an anti-estrogen compound of the present invention. As used herein, administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of living organisms, for example humans. In one embodiment, the present invention encompasses administering the compounds of the present invention to a subject.
[0006] In one embodiment, the methods of the present invention comprise administering an anti-estrogen compound as the sole active ingredient However, also encompassed within the scope of the present invention are methods for hormone therapy, for treating prostate cancer, for delaying the progression of prostate cancer, and for preventing and/or treating the recurrence of prostate cancer, which comprise administering the anti-estrogen compounds in combination with one or more therapeutic agents. These agents include, but are not limited to: LHRH analogs, reversible antiandrogens (such as bicalutamide or flutamide), additional anti-estrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase 00 0 inhibitors, progestins, selective androgen receptor modulators (SARMS) or agents Sacting through other nuclear hormone receptors.
[00087] Thus, in one embodiment, the methods of the present invention include Cl using compositions and pharmaceutical compositions comprising an anti-estrogen, in combination with an LHRH analog. In another embodiment, the methods of the Spresent invention include using compositions and pharmaceutical compositions comprising an anti-estrogen, in combination with a reversible antiandrogen. In another embodiment, the methods of the present invention include using c compositions and pharmaceutical compositions comprising an anti-estrogen, in Scombination with an additional anti-estrogen. In another embodiment, the methods Cl of the present invention include using compositions and pharmaceutical compositions comprising an anti-estrogen, in combination with an anticancer drug.
In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising an anti-estrogen, in combination with a 5-alpha reductase inhibitor. In another embodiment, the methods of the present invention include using compositions and'pharmaceutical compositions comprising an anti-estrogen, in combination with an aromatase inhibitor. In another embodiment, the methods of the present invention Include using compositions and pharmaceutical compositions comprising an anti-estrogen, in combination with a progestin. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising- an anti-estrogen, in, combination with a SARM. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising an anti-estrogen, in combination with an agent acting through other nuclear hormone receptors.
-21- 00 ooo0068 Various embodiments of dosage ranges are contemplated by this invention.
N The dosage may be in the range of 1-80 mg/day. The dosage may be in the range of 5-80 mg/day. In another embodiment the dosage is in the range of 35-66 mg/day. In another embodiment the dosage is in the range of 20-60 mg/day. In another embodiment the dosage is in the range of 40-60 mg/day. In another embodiment the dosage is in a range of 45-60 mg/day. In another embodiment 0 the dosage is in the range of 15-25 mg/day. In another embodiment the dosage Sis in the range of 55-65 mg/day. In one embodiment, the dosage is 20 mg/day. In another embodiment, the dosage is 40 mg/day. In another embodiment, the OO dosage is 60 mg/day.
00 I [0006os] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.
EXPERIMENTAL DETAILS SECTION EXAMPLE 1 Effect of Toremifene on bone turnover in human male sublects [00070] In a Phase Ila clinical trial to determine whether Toremifene has chemopreventive activity against prostate cancer, 18 men with high-grade prostatic intraepithelial neoplasia (HGPIN) were treated with 60mg/d of Toremifene for 4 months. At Day 120 there was a significant reduction from baseline in serum calcium (mean -0.12, p=0.005) and at both day 60 and day 120, alkaline phosphatase was significantly decreased compared to baseline (mean=-18.7 at Day 60 and -21.0 at Day 120, and p<0.001 for both visits).
[00071] These clinical data demonstrate that the anti-estrogen Toremifene showed estrogenic effects on bone favorably affecting bone tumover markers in men.
EXAMPLE 2: EFFECT OF TOREMIFENE ON BONE IN MALE RATS 00 0 Drug Delivery System N [00072] The test article, positive control and placebo were delivered by ALZA pumps manufactured by Durect Corporation (Cupertino, CA). Pumps were implanted in a subcutaneous pocket using appropriate surgical technique. The pumps N employed in this study deliver a continuous rate of drug over a 30-day period with Toremifene formulated to release 1.8 mg/day (2 mL pump) and 17- P -Estradiol 0 (positive control) is released at 70 pg/day. Data provided by the manufacturer of the pumps validates the constant rate of drug delivery over a 28 day period, and suggests that the constant rate can be expected for several additional days.
OO Animals were anesthetized and pump replacement was performed for each dosage group on days 31, 61, and 91 to provide drug administration over a 120 day period.
CI Every animal on study had a pellet implanted to control for potential confounding variables associated with surgery for implantation.
Study Groups: [00073] Adult male Sprague-Dawley rats (14-weeks old at start of study), weighing approximately 0.35 kg, were used in the experiments. This study employed five test groups of 12 rats. Treatment groups represent placebo control (castrated and sham operated), 17-p-estradiol (castrated) and Toremifene (castrated and sham operated). 5 animals from each treatment group were sacrificed at day 60 and day 120 and bone metabolism markers were measured and bone were harvested for biomechanical strength and density testing.
Table 1. Treatment groups for Effects of Toremifene on Bone -23- 3 Toremifene (1.75 5 mg/day) 4 Toremifene (1.75 5 120 mg/day) Estradlol (0.07 5 mg/day) 6 Estradlol (0.07 5 120 mg/day) 7 Placebo control 5 8 Placebo control 5 120 9 Toremifene (1.75 5 mg/day) 10 Toremifene (1.75 5 120 mg/day) O0 00
O
0 Observations: [00074] Clinical Observations: Cage-side observations were made and recorded once weekly (daily cage checks note any exceptions). Effects on vital functions were observed. Any animals found moribund or presenting with signs of acute toxicity were anesthetized by an intramuscular ketamine/xylazine (87/13) injection and euthanized by abdominal aorta exsanguinations.
[00075] Body Weight Body weights were taken in triplicate and averaged once per week.
[00076] Sacrifices were made at 60 and 120-days. Each sacrifice Involved 5 rats from each treatment group, and 2 rats at 30, 60, 90, and 120 days to verify drug in plasma (refer to Table 1 for group allocation to treatment and sacrifice). Animals were anesthetized by an injection of ketamine/xylazine (87/13) and sacrificed by abdominal aorta exsanguinations. Blood collected at exsanguinations was processed to collect serum.
-24- (0007 Bone remodeling was assessed per serum markers to analyze bone resorption and bone formation of treatment rats. The tests listed in Table 2 indicate the bone remodeling category and the amounts of serum required for analysis. Serum chemistry analysis of blood calcium, phosphorus, bilirubin and creatinine levels, and bone-specific alkaline phosphatase, were performed at AniLytics, Inc. (Gaithersburg, MVD).
Table 2. Assays for serum markers of bone remodeling In mouse Remodeling Teats Run Test Supplier Minimum Serum Category Required Bone Formation Rat-MID Osteocalcin OSTEOMETER 20u1
ELISA
Chemistry Analysis of AniLytics, Inc. 70u1 Calcium, Phosphorus, Bilflrubin, Creatine Bone Spec. AnlLytics, Inc. soul Phosphatase Bone Resorption Serum CrossLaps One OSTEOMETER 20u1 Step EUSA (Deoxy)Pydinollne METRA Croaslink In srm RatTRAP ELISA SBA Sciences Soul (tartrate-reslstant Acid
P)
.0 (000781 Specimen collection Included femoral bones In addition to blood. Blood was processed for "serum. Serum was aliquoted and frozen at -8 0 C until analysis.
Serum tests were performed at GTx, Inc. for osteocalcin levels (bone formation marker) and o-telopeptide (bone resorption marker). After the femur was removed from each animal, it was stripped of extraneous tissue, and stored at -200C until blomechanical strength and bone mineral density analysis.
RANDOMIZATIONIASSIGNMENT TO GROUPS: [00079] Prior to study, 10 groups were randomized to treatments, then sixty (60) 12 O week-old rats were ordered, ear-tagged and weighed by the Manager of Animal N Resources. Sixty animals were then randomized to the 10 treatment groups of 6 Sanimals each. An ANOVA was performed to establish the presence or absence of significant difference in body weight (within 10% of average body weight is acceptable). The population was already restricted and could not be restricted further. If there was a significant difference, it was duly noted, but changes in Sassignment were not made. Bone parameters were not normalized to body weight Values for bone parameters are reported as absolute and evaluated based on group means compared to the appropriate controls.
00
COMPOUNDS
[oooeo] Test Article 1: Identification: Toremifene Description: White crystalline powder, that is extracted from Toremifene tablets as active ingredient.
[00081] Test Article 2 (Positive Control): Identification: 17-p-Estradiol (Sigma Aldrich, for laboratory research use).
EXAMPLE3 EFFECT OF TOREMIFENE ON BONE DENSITY AND SERUM MARKERS FOR BONE REMODELING IN MALE RATS [00082] The purpose of this study is to determine whether administration of Toremifene to mature male rats is bone sparing as can presently be measured by the levels of bone-specific serum markers that indicate bone resorption and formation (where 17-p-Estradiol is used as a positive control). The effect of -26- Toremifene (and 17-p -Estradiol) on androgen deprivation-induced bone loss was 0 also determined through bone density and mechanical strength testing.
[00083] Its well established that the bone mineral density of males, similar to that of females, decreases with age. Decreased amounts of bone mineral content and c density correlates with decreased bone strength, and predisposes to fracture. The molecular mechanism underlying the pleiotropic effects of sex-hormones in non-reproductive tissues are only beginning to be understood, but it is clear that tt physiologic concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout the life-cycle. Consequently, when C androgen and/or estrogen deprivation occurs, there is a resultant increase in the 00 Srate of bone remodeling that tilts the balance of resorption and formation in the C favor of resorption contributing to the overall loss of bone mass. In males, the natural decline in sex-horrnone at maturity (direct decline in androgens as well as lower levels of estrogens derived from peripheral aromatization of androgens) is associated with the frailty of bones. This effect is also observed in males who have been castrated. Previous studies demonstrate in mice that pharmacological therapy with selective estrogen receptor modulator (SERM) compounds in androgen deficient males has a positive effect on bone mineral density and that bone can be maintained or even increased (Broulik, Horm Metab Res, 2000; 32: 181-184). It is suggested that in humans, this intervention would halt the onset of osteoporosis or at least reduce its severity. Importantly, recent human data indicates that estrogen loss in elderly males is more critical for short-term bone changes than.loss of androgens. It is believed that the selective estrogen receptor modulator Toremifene (trade name is Acapodene T M and generic name is toremifene) will have similar bone-building properties when compared with other nonsteroidal anti-estrogens Tamoxtfene, (Broulik, Horm Metab Res, 2000; 32: 181-184), and will be a clinically useful drug for preventing osteoporosis and maintaining bone density in aging males. The model used herein is an orchidectomy model, which is an experimental model used to mimic the type of androgen deprivation that would be caused by, for example, LHRH agonist therapy in prostate cancer.
-27- 00 0 MATERIALS AND METHODS C Study Design [00084] Male Sprague-Dawley rats (Harlan Sprague Dawley) were placed on study at 14-weeks of age. They were randomized and divided into five treatment groups: vehicle only (placebo, or P) after sham operation, vehicle only after orchidectomy (Orx), Toremifene (5 mg/kg/day) after sham-operation, and Toremifene after In orchidectomy, and 17-p-estradiol (0.5 mg/kg/day) after orchidectomy. Test articles were delivered subcutaneously by Alzet pumps. Pumps were re-implanted every C 10 30 days until the end of the study. Five to six animals from each group were 00 oO 0 sacrificed after 60 and 120 days of treatment, and femurs were harvested, stipped C from soft tissue and muscle, and stored individually in polypropylene vials at until analysis of bone density and mechanical strength testing. Additionally, serum was collected on days 15, 30, 60, 90 and 120, to measure markers of bone metabolism and to perform serum chemistry.
[00085] After collection, serum was divided into 3 aliquots and stored at -80C until analysis. 125 1d for serum biochemistry performed by AniLytics, Gaithersburg, MD (Bone-Specific Alkaline Phosphatase, Calcium, Phosphorus, Creatinine and Bilirubin). 100 jl for serum Rat Osteocalcin ELISA and Serum RatLaps EUSA for C-terminal telopeptides determination. The rest of the collected serum was left for repeated test if necessary.
[00086] Bones were stripped from soft tissue and muscles and stored Individually in 15 ml vials at -80 C, until further testing.
Analysis of Bone Turnover Markers from Rat Serum Serum RatLaps ELISA, Osteometer BioTech AIS, Denmark [00087] The assay was performed in duplicates, each 20 pl of serum as well as standards and control. Briefly, 100 pl of Biotinylated RatLaps Antigen was -28incubated 30 min in each well, strips were washed and 20 p1 of Standard, Control 0 and unknown samples were added to appropriate wells, followed by 100 pi of c primary antibody (polyclonal Ab raised against a synthetic peptide EKSQDGGR specific for a part of the C-terminal telopeptide alphal chain of rat type I collagen).
After overnight incubation at 4 C, the wells were washed and 100 pi of Peroxidase N_ conjugated Goat anti-Rabbit IgG Antibody was added to each well and incubated min. After washing the strips 100 pI of the Chromogenic Substrate Solution was Sadded to each well, and after 15 min the reaction was stopped and the absorbance was measured at 450 nm. The means of the duplicate absorbance determination were calculated, and a standard curve was constructed using 4-parametric logistic O curve fit. Sample RatLaps concentrations were determined by interpolation.
C Rat Osteocalcin EIA, Biomedical Technologies, MA [00088] This assay is specific for rat Osteocalcin and both carboxylated and decarboxylated rat Osteocalcin are recognized. A monoclonal antibody against the N-terminal region of Osteocalcin is bound to the polystyrene wells. The assay was performed in duplicates. 100 pi of standards, control and 1 to 20 diluted samples were added to appropriate wells and incubated overnight at 4 C. After washing the strips, 100 pI of Goat polyclonal antibody of high specificity for C-terminus of rat Osteocalcin was added and incubated 60 min at 37 C. After washing, 100 pi of Donkey.anti-goat IgG peroxidase conjugated antibody was added and incubated min at 22 C. The wells were washed and a mix of TMB and peroxide solution was added and incubated 30 min at 22 C in the dark. The reaction was stopped, and the absorbance was measured at 450 nm. A standard curve was constructed using 4-parametric logistic curve fit. Sample osteocalcin concentrations were determined by interpolation.
Bone Analysis Methodology Peripheral Quantitative Computed Tomography (pQCT) [00089] Right femurs were subjected to pQCT analysis using a Stratec XCT-RM with -29associated software (Stratec Medizintechnik GmbH, Pforzhelm, Germany.
oO Software version 5.40 Femurs were scanned at two sites, 20% and 50% of the Stotal femoral length measured from the distal femur. The position was verified Susing scout views, and scan results from two 0.5 mm slices perpendicular to the long axis of the femur shaft were recorded.
Mechanical Testing S[00090] Using a Material Testing System (Model 5501R Instron Corp., Canton, MA), two types of mechanical testing were performed on the right femur. The load and extension curves were collected by the machine software (Meriln II, Instron Corp.).
OO All tests were conducted using a 5 kN load cell at a constant loading rate of 6 mm/min. The general applications of the tests were as described in Tumer and C Burr (Bone, 1993; 14: 595-608) and Ke et al (Bone, 1998; 23, 249-255).
Compression Test of the Distal Femur [00091] A compression test was used to determine the mechanical properties of the distal femur. The distal femur test specimen was obtained by removing a 3 mm segment directly proximal to the distal condyle using a slow speed diamond saw with constant saline irrigation. An electronic caliper was used to measure the average anterior/posterior diameter medial/lateral diameter and height (h) of the bone. The extrinsic parameters, maximal load stiffness and energy were obtained from the load and extension durve. The following intrinsic parameters were calculated from the measured values: Cross sectional area (CSA) (n a b) Ultimate Strength Fu CSA; Elastic modulus (CSA Toughness W (CSA h).
RESULTS/DISCUSSION
Analysis of Serum Markers of Bone Turnover 100092] Bone turnover markers have been demonstrated as an effective, validated tool for the clinical scientist to monitor bone activity. Ultimately, the data of greatest consequence to evaluate novel therapeutics aimed at osteoporosis treatment and
O
0 prevention is a demonstrated improvement in the quality of bone Itself. However, O because changes in bone turnover markers correlate well with bone strength Stesting, in the present study we analyzed C-telopeptide and osteocalcin levels for interim analysis and supplementary data to support of the effectiveness of C treatment SC-telopeptlde of Type I collagen: [00093] As demonstrated in Figure 1, C-telopeptide levels in orchidectomized animals were slightly Increased by 22 and 9.5% over the placebo 15 and 30 day 0 groups, respectively, indicating that, after castration, bone resorptive activity is Sincreased and type I collagen is being degraded, with fragments containing the C. cross-linked molecules released into the blood. Further, treatment of orchidectomized animals with toremifene and the positive control, 17-p-estradiol, reduced the C-telopeptide levels to at or below control values (i.e.
unorchidectomized, placebo-treated animals), with the 30 day treatment trending to significance for the 17-p-estradiol group.
[000941 Because toremifene and 17-p-estradiol decrease the level of C-telopeptide in the serum, the data indicate that these agents are acting to prevent the resorption of bone induced by androgen deprivation.
Osteocalcin: [00095] Similar to other published literature, Applicants found that osteocalcin levels were Increased by castration. Toremlfene significantly reduced the osteocalcin levels in castrated animals to Intact control levels (p<0.05 at 15 days, and p<0.02 at 30 days, Figure 2A). The increase in osteocalcin levels were most pronounced days after castration, although Toremifene and 17-p-estradiol continued to significantly reduce osteocalcin levels to below that of intact control rats for up to 120 days (Figure 2B). These results indicate that the rate of bone formation in males is upregulated following orchidectomy to compensate for increased resorptive activity. 17-p-Estradiol, and the selective estrogen receptor modulator -31toremifene, stabilize the bone resorption and formation processes, hence o0 decreasing overall osteocalcin levels that are detectable in serum.
O
Biomechanical Analysis of Bone [00096] Androgen deficiency, induced by castration, has been used as a model of male osteoporosis. In this model, most of the bone loss occurs in cancellous bone. To further understand the effects of toremifene on bone mineral density and mechanical strength, bones were harvested upon completion of the in-life study i' phase and sent to SkeleTech (Bothell, WA) for testing. All bones were thawed in physiological saline prior to analysis. Statistical analysis was performed using SAS l software (SAS Institute, Cary, NC). One-way analysis of variance (group) was 0 performed. Individual group differences were ascertained with Dunnett's procedure using treatment group 2 (Castrated Placebo) as the reference group. A p value of 0.05 was considered significant Where appropriate, a p value of 0.1 is noted as a trend (when the treatment results are in the direction of the positive control).
Distal Right Femur Cancellous pQCT: [00097] Total bone mineral content and density were lower, though not statistically significant, in Orx animals when compared to Sham-operated animals. Both Toremifene and 17-p-Estradiol treatment appeared to reduce total bone area and increase total bone mineral density. Cancellous bone mineral content and density in Orx animals were 34% less than Sham-operated animals. Toremifene partially prevented this decrease whereas 17-p-Estradiol was able to fully prevent this cancellous bone loss. None of the parameters produced statistically significant differences from the Orx group due to the small sample size and the large variations in the measured results. The results are summarized in Table 3.
Table 3: Summary of the Distal Right Femur Cancellous pQCT -32- 00 Treatment content Area Denaity Content Area Density Gop(mg/mm) (nimn) (mg/cm 8 (mg/mm) (mm 2 (mg/cm') Shm11.7 17.41 66827 1.85 7.83 209.72 ri(n =6) 0.89 0.97 32.81 0.43 0.44 52.17 PI x nsn.9 n.m 0 0 5 1 1 61 1 Meon 11.07 17.38 839.50 1.08 7.82 138.38 Cx .E.M 0512 470 02 0.7 31.88 (n C. 050 12 470 022 .0Me*~ n.a. n.a. n.m. na.
00Mean 10.69 15.98 689.74 1.13 7.18 157.56 Cx+ EM Toremttene .M 0.48 0.67 21.95 0.22 0.30 3Z.77 (n n.8 n.9 nxm n-s nxs n.s ri .05 1_ Mean 11.01 15.95 590.74 1.52 7.17 210.28 Cx .E.M EST 0.76 0.98 28.68 0.50 0.44 62.69 (n 5) nxm n.s n.s ns n.s n.s p<0.05 vs. TG2.
n.s. not significant fl.e. nlot applicable Compression Test of the Distal Femur: [00098] Mechanical strength was tested at the distal femur, a site rich in canclloJs, bone. Maximumn load, stiffness, ultimate strength, and elastic modulus were lower in Orx animals when compared to Sham-operated animals. roremiffene treatment of Onc animals improved various parameters to a level that was 'better. than Sham-operated animals. 17-*Estradiol treatment showed statistically significant improvements In these parameter values. Cross-sectional area was decreased in toremifene and I 7-p-EstradioI -treated Onc animals as expected from pQCT data.
The results are summarized in Table 3.
Table 4: Summary of the Distal Right Femur Compression Test -33- Lod Ult. .1mkate Elastic oughnes GSA ftIht Treatment Madu Stnt Modulus ca- Greup (Ni/im) I(Wn) (N~mm) (MPa) j(MJ/mm') (mm 2 (mm) Sham 420.04 13400.22 43.10 18.96 481.38 0.82 22.32 3.13 S.D. 123.75 94.4.50 113.09 5.868 152.38 10.18 1.84 10.14 C n.s. n.s. n.e. n.e. n.s. n.s. n.s. n.s.
Cx (n 388.80 2538.96. 49.97 16.73 341.02 10.88 23.19 3.141 S.D. 70.43 887.58 18.45 13.33 109.52 0.23 1.28 0.10 0.0 n.e. n.e. n.e. In.e. n.e. n.a. n.a. na Toremifene0.6 230 .1 (n 1487.01 13858.71 1 69 22.13 5 79.07 __086 21.0__1 S.D. 126.89 11303.58 17.07 8 .34 211.70 0.30 1.43 0.15 P<n.s. n.s. Inae n.e. n.s. n.e. fl.s.
EST
1.5 813.81 4842.87 58.28 31.2 753.44 0.98 19.75 3.08 S.D. 72.10 740.18 18.39 4.78 138.97 10.34 1.14 0.12 P n.s. n.e. ne p<0.05 vs. TG2.
n.s. not significant n.a. not applicable
SUMMARY
(000991 Androgen deficiency model resulted In animals that had Increased levels of the bone resorption marker C-telopeptide as well as osteocalcin In serum.
Treatment with toremifene and I 7-p.-estradiol significantly reduced the levels of these serum markers following castration. Further, androgen deficiency resulted in a 34% loss of cancellous bane mineral content and density. importantly, the use of toremifene partially prevented this loss. As predicted, estrogen was Very effective in preventing cancellous bone loss due to androgen deficiency.
Additionally, the compression test of the distal femur showed improved strength parameters in orchidectomized groups treated with toremifene, and statistically 0o 0 significant improvements with estrogen treatment. These measurements are cpartially correlated with total bone mineral density at that site. In conclusion, the data presented herein suggests that the selective estrogen receptor modulator toremffene would have a positive effect for bone improvement in men undergoing c l androgen-deprivation therapy for prostate cancer.
[00100] In the claims which follow and in the preceding description of the o invention, except where the context requires otherwise due to express language Sor necessary implication, the word "comprise" or variations such as "comprises" cN or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
[00101] It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Claims (16)

1. Use of toremifene and/or its analog, derivative, isomer, metabolite, G pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof in the preparation of a composition for use in treating, reducing the incidence of, suppressing, or inhibiting hot flashes in a subject.
2. The use according to claim 1, wherein said toremifene is toremifene citrate. S 00
3. The use according to claim 1, wherein said composition comprises a Spharmaceutically acceptable carrier.
4. The use according to claim 1, said composition is prepared in liquid form for intravenous, intraarterial, or intramuscular injection; in pellet form for subcutaneous implantation; in a liquid or solid form for oral administration; or for topical application.
The use according to claim 4, wherein said composition is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.
6. The use according to claim 1, wherein said subject is human
7. The use according to claim 6, wherein said human subject is male.
8. The use according to claim 7, wherein said male subject has received androgen deprivation therapy (ADT).
9. Use of toremifene and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof in the preparation of a composition for use in treating, reducing the incidence of, suppressing, or inhibiting gynecomastia in a subject.
The use according to claim 9, wherein said toremifene is toremifene citrate. 00
11. The use according to claim 9, wherein said composition comprises a pharmaceutically acceptable carrier.
12. The use according to claim 9, wherein said pharmaceutical composition is prepared in liquid form for intravenous, intraarterial, or intramuscular Sinjection; in pellet form for subcutaneous implantation; in a liquid or solid form for oral administration; or for topical application. C o10
13. The use according to claim 12, wherein said pharmaceutical composition 00 0is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a 0 gel, a cream, a suppository or a parenteral formulation.
14. The use according to claim 9, wherein said subject is human.
The use according to claim 14, wherein said human subject is male.
16. The use according to claim 16, wherein said male subject has received androgen deprivation therapy (ADT).
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