US20100317635A1 - Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators - Google Patents

Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators Download PDF

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Publication number
US20100317635A1
US20100317635A1 US12/791,174 US79117410A US2010317635A1 US 20100317635 A1 US20100317635 A1 US 20100317635A1 US 79117410 A US79117410 A US 79117410A US 2010317635 A1 US2010317635 A1 US 2010317635A1
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United States
Prior art keywords
group
acid
estrogen receptor
receptor modulator
selective estrogen
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Abandoned
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US12/791,174
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English (en)
Inventor
Fernand Labrie
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Endorecherche Inc
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Endorecherche Inc
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Application filed by Endorecherche Inc filed Critical Endorecherche Inc
Priority to US12/791,174 priority Critical patent/US20100317635A1/en
Priority to TW099119438A priority patent/TWI612044B/zh
Priority to CA2765446A priority patent/CA2765446A1/en
Priority to MX2011013689A priority patent/MX338290B/es
Priority to AU2010262722A priority patent/AU2010262722A1/en
Priority to EP20158118.8A priority patent/EP3682880A1/en
Priority to ARP100102137A priority patent/AR077119A1/es
Priority to CA2893236A priority patent/CA2893236A1/en
Priority to CN201710016998.8A priority patent/CN107468695A/zh
Priority to MA34540A priority patent/MA33434B1/fr
Priority to KR1020177034988A priority patent/KR20170138584A/ko
Priority to CN2010800271605A priority patent/CN102458404A/zh
Priority to SG10201705761YA priority patent/SG10201705761YA/en
Priority to KR1020217012518A priority patent/KR20210048609A/ko
Priority to KR1020197006112A priority patent/KR20190025752A/ko
Priority to EP17151727.9A priority patent/EP3178480A1/en
Priority to EP10788551.9A priority patent/EP2442807A4/en
Priority to SG10201912379PA priority patent/SG10201912379PA/en
Priority to CN201410386309.9A priority patent/CN104352504A/zh
Priority to KR1020147011740A priority patent/KR20140070650A/ko
Priority to KR1020157034399A priority patent/KR20150141195A/ko
Priority to EA201200016A priority patent/EA201200016A1/xx
Priority to KR1020197021846A priority patent/KR20190090088A/ko
Priority to PCT/CA2010/000898 priority patent/WO2010145010A1/en
Priority to SG2012000410A priority patent/SG177497A1/en
Priority to KR1020177017880A priority patent/KR20170078879A/ko
Priority to KR1020127001215A priority patent/KR20120097470A/ko
Priority to JP2012515300A priority patent/JP2012530074A/ja
Priority to NZ597583A priority patent/NZ597583A/en
Priority to KR1020207026222A priority patent/KR20200108505A/ko
Priority to KR1020167015258A priority patent/KR20160072269A/ko
Assigned to ENDORECHERCHE, INC. reassignment ENDORECHERCHE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LABRIE, FERNAND
Publication of US20100317635A1 publication Critical patent/US20100317635A1/en
Priority to IL216963A priority patent/IL216963A/en
Priority to CL2011003172A priority patent/CL2011003172A1/es
Priority to HK15104344.8A priority patent/HK1204550A1/xx
Priority to US13/875,027 priority patent/US10342805B2/en
Priority to JP2014025183A priority patent/JP2014088442A/ja
Priority to JP2015223062A priority patent/JP2016029101A/ja
Priority to IL248245A priority patent/IL248245A0/en
Priority to JP2018189078A priority patent/JP2018203785A/ja
Priority to US16/418,591 priority patent/US20190269696A1/en
Priority to US16/418,651 priority patent/US11452731B2/en
Abandoned legal-status Critical Current

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Definitions

  • the present invention relates to a new treatment for hot flushes, vasomotor symptoms, and night sweats in women.
  • the treatment includes the administration of a precursor of sex steroids in combination with a selective estrogen receptor modulator (SERM) for reducing the risk of acquiring breast or endometrial cancer.
  • SERM selective estrogen receptor modulator
  • the invention also provides kits and pharmaceutical compositions for practicing the foregoing combination. Administration of the foregoing combination to patients reduces or eliminates the incidence of hot flushes, vasomotor symptoms, night sweats, and sleep disturbance. Moreover, the risk of acquiring breast cancer and/or endometrial cancer is believed to be reduced for patients receiving this combination therapy.
  • Additional benefits such as reduction of the likelihood or risk of acquiring osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, Alzheimer's disease, loss of cognition, loss of memory, insomnia, cardiovascular diseases, insulin resistance, diabetes, and obesity (especially abdominal obesity) are also provided.
  • estrogens are believed to decrease the rate of bone loss while androgens have been shown to build bone mass by stimulating bone formation.
  • Hormone replacement therapy e.g., administration of estrogens
  • Progestins are frequently used to counteract the endometrial proliferation and the risk of endometrial cancer induced by estrogens.
  • Use of estrogens, androgenic compounds and/or progestins for treatment, or for prophylactic purposes, for a wide variety of symptoms and disorders suffer from a number of weaknesses. Treatment of females with androgenic compounds may have the undesirable side effect of causing certain masculinising side effects. Also, administering sex steroids to patients may increase the patient's risk of acquiring certain diseases. Female breast cancer, for example, is exacerbated by estrogenic activity.
  • kits and pharmaceutical compositions suitable for use in the above methods are packaged with directions for using the contents thereof for reducing or eliminating the incidence of symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats.
  • the invention provides a method of reducing or eliminating the incidence of hot flushes, vasomotor symptoms, night sweats, and sleep disturbance, said method comprising administering to patient in need of said elimination or reduction, a therapeutically effective amount of a precursor of sex steroids or prodrug thereof in association with administering to said patient a therapeutically effective amount of a selective estrogen receptor modulator or an antiestrogen or prodrug thereof.
  • the sex steroid precursor is selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androst-5-ene-3 ⁇ ,17 ⁇ -diol, 4-androstene-3,17-dioneo, and a prodrug of any of the foregoing additional agents.
  • the invention provides additional beneficial effects or reduces the risk of acquiring a condition selected from the group consisting of osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, Alzheimer's disease, insulin resistance, diabetes, loss of muscle mass, obesity, said beneficial effects being obtained by administering to patient in need of said beneficial effects, a therapeutically effective amount of a precursor of sex steroids or prodrug thereof in association with administering to said patient a therapeutically effective amount of a selective estrogen receptor modulator or prodrug thereof.
  • the invention provides a pill, a tablet, a capsule, a gel, a cream, an ovule, or a suppository comprising:
  • the invention provides a kit comprising a first container containing a pharmaceutical formulation comprising a therapeutically effective amount of at least one sex steroid precursor or a prodrug thereof; and said kit further comprising a second container containing a pharmaceutical formulation comprising a therapeutically effective amount of at least one selective estrogen receptor modulator or an antiestrogen or prodrug thereof.
  • the invention pertains to a method of treating or reducing the incidence of hot flushes, vasomotor symptoms, night sweats, and sleep disturbance by increasing levels of a sex steroid precursor selected from the group consisting of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), androst-5-ene-3 ⁇ ,17 ⁇ -diol (5-diol) and 4-androstene-3,17-dione in a patient in need of said treatment or said reduction, and further comprising administering to said patient a therapeutically effective amount of a selective estrogen receptor modulator (SERM) as part of a combination therapy.
  • DHEA dehydroepiandrosterone
  • DHEA-S dehydroepiandrosterone-sulfate
  • SERM selective estrogen receptor modulator
  • Pure SERM means that the SERM does not have any estrogenic activity in breast and endometrial tissues at physiological or pharmacological concentrations.
  • the invention provides a kit comprising a first container containing a therapeutically effective amount of at least one precursor of sex steroids and further comprising a second container containing a therapeutically effective amount of at least one selective estrogen receptor modulator.
  • the invention provides, in one container, a pharmaceutical composition comprising:
  • the invention provides a method of reducing or eliminating the incidence of symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats, said method comprising administering to a patient in need of said elimination or reduction, (i) a therapeutically effective amount of a sex steroid precursor or prodrug thereof in association with (ii) a therapeutically effective amount of a selective estrogen receptor modulator or an antiestrogen or prodrug of either.
  • the invention provides a pharmaceutical composition for reducing or eliminating symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats, comprising:
  • the invention provides a kit for reducing or eliminating symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats, comprising (i) a first container having therein a at least one sex steroid precursor or a prodrug thereof; (ii) a second container having therein a at least one selective estrogen receptor modulator, or an antiestrogen or prodrug of either of the foregoing; and (iii) instructions for using the kit for the reduction or elimination of at least one symptom selected from the group consisting of hot flushes, vasomotor symptoms and night sweats.
  • compounds administered to a patient “in association with” other compounds are administered sufficiently close to administration of said other compound that a patient obtains the physiological effects of both compounds simultaneously, even though the compounds were not administered in close time proximity.
  • compounds are administered as part of a combination therapy they are administered in association with each other.
  • Preferred selective estrogen receptor modulators discussed herein are preferably used in combination with preferred sex steroid precursors dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androst-5-ene-3 ⁇ ,17 ⁇ -diol, or 4-androstene-3,17-dione, especially dehydroepiandrosterone.
  • the estrogen replacement therapy is commonly used in postmenopausal women to prevent and treat diseases due to the menopause, namely osteoporosis, hot flushes, vaginal dryness, coronary heart disease (Cummings 1991) but presents some undesirable effects associated with chronic estrogen administration.
  • diseases due to the menopause namely osteoporosis, hot flushes, vaginal dryness, coronary heart disease (Cummings 1991)
  • Cummings 1991 the perceived increased risk for uterine and/or breast cancer (Judd, Meldrum et al., 1983; Colditz, Hankinson et al., 1995) generated by estrogen is the major disadvantage of this therapy.
  • the authors of the present invention have found that the addition of a selective estrogen receptor modulator (SERM) to precursors of sex steroids administration suppresses these undesirable effects.
  • SERM selective estrogen receptor modulator
  • SERMs alone have little or no beneficial effects on some menopausal symptoms like hot flushes and sweats.
  • the applicant believes that the addition of a precursor of sex steroids to SERM treatment of menopausal symptoms reduces or even eliminates hot flushes and sweats. It is important to note that hot flushes and sweats are the first manifestations of menopause and the acceptation or non-acceptation of menopausal treatment by patients is usually dependent upon the success or non-success in the reduction of hot flushes and sweats.
  • a selective estrogen receptor modulator is a compound that either directly or through its active metabolite functions as an estrogen receptor antagonist (“antiestrogen”) in breast tissue, yet provides estrogenic or estrogen-like effect on bone tissue and on serum cholesterol levels (i.e. by reducing serum cholesterol).
  • antiestrogen an estrogen receptor antagonist
  • Non-steroidal compounds that function as estrogen receptor antagonists in vitro or in human or rat breast tissue is likely to function as a SERM.
  • steroidal antiestrogens tend not to function as SERMs because they tend not to display any beneficial effect on serum cholesterol.
  • Non-steroidal antiestrogens we have tested and found to function as SERMs include EM-800, EM-652.HCl, Raloxifene, Tamoxifen, 4-hydroxy-Tamoxifen, Toremifene, 4-hydroxy-Toremifene, Droloxifene, LY 353 381, LY 335 563, GW-5638, Lasofoxifene, bazedoxifene (TSE 424; WAY-TSE 424; WAY 140424; 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]-2-(4-hydro-xyphenyl)-3-methyl-1H-indol-5-ol), Pipendoxifene (ERA 923; 2-(4-hydroxyphenyl)-3-methyl-1-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-1H-indol-5-ol
  • SERMs do not react in the same manner and may be divided into two subclasses: “pure SERMs” and “mixed SERMs”.
  • some SERMs like EM-800 and EM-652.HCl do not have any estrogenic activity in breast and endometrial tissues at physiological or pharmacological concentrations and have hypocholesterolemic and hypotriglyceridemic effects in the rat.
  • These SERMS may be called “pure SERMs”.
  • the ideal SERM is a pure SERM of the type EM-652.HCl because of its potent and pure antiestrogenic activity in the mammary gland.
  • This second series of SERMs may be called “mixed SERMs”.
  • the unwanted estrogenic activities of these “mixed SERMs” may be inhibited by addition of pure “SERMs” as shown in FIGS. 5 and 6 in vitro tests and in FIG. 7 in an in vivo test of breast cancer. Since human breast carcinoma xenografts in nude mice are the closest available model of human breast cancer, we have thus compared the effect of EM-800 and Tamoxifen alone and in combination on the growth of ZR-75-1 breast cancer xenografts in nude mice.
  • SERMs of the invention act as pure antiestrogens in breast, uterine, and endometrial tissues because SERMs have to counteract potential side-effects of estrogens, particularly those formed from the exogenous precursors of sex steroids which can increase the risk of cancer in these tissues.
  • benzopyran derivatives of the invention having the absolute configuration 2S at position 2 is more suitable than its racemic mixture.
  • optically active benzopyran antiestrogens having 2S configuration are disclosed to treat estrogen-exacerbated breast and endometrial cancer and these compounds are shown to be significantly more efficient than racemic mixtures (See FIGS. 1-5 of U.S. Pat. No. 060,503).
  • the enantiomer of 2S configuration being difficult to be industrially obtained as a pure state, the applicant believes that less than 10%, preferably less than 5% and more preferably less than 2% by weight of contamination by the 2R enantiomer is preferred.
  • FIG. 1 shows the effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 ⁇ g, orally, once daily) alone or in combination for 9 months on serum triglyceride (A) and cholesterol (B) levels in the rat. Data are expressed as the means ⁇ SEM. **: P ⁇ 0.01 experimental versus respective control.
  • FIG. 2 shows the effect of 37-week treatment with increasing doses (0.01, 0.03, 0.1, 0.3, and 1 mg/kg) of EM-800 or Raloxifene administered on total serum cholesterol levels in the ovariectomized rat. Comparison is made with intact rats and ovariectomized animals bearing an implant of 17 ⁇ -estradiol (E 2 ); ** p ⁇ 0.01, experimental versus OVX control rats.
  • FIG. 3 shows: A) Effect of increasing doses of DHEA (0.3 mg, 1.0 mg or 3.0 mg) administered percutaneously twice daily on average ZR-75-1 tumor size in ovariectomized (OVX) nude mice supplemented with estrone. Control OVX mice receiving the vehicle alone are used as additional controls. The initial tumor size was taken as 100%. DHEA was administered percutaneously (p.c.) in a 0.02 ml solution of 50% ethanol-50% propylene glycol on the dorsal skin. B) Effect of treatment with increasing doses of DHEA or EM-800 (a SERM of the present invention) alone or in combination for 9.5 months on ZR-75-1 tumor weight in OVX nude mice supplemented with estrone. **, p ⁇ 0.01, treated versus control OVX mice supplemented with estrone.
  • DHEA 0.3 mg, 1.0 mg or 3.0 mg
  • FIG. 4 shows the effect of increasing oral doses of the antiestrogen EM-800 (15 ⁇ g, 50 ⁇ g or 100 ⁇ g) (B) or of percutaneous administration of increasing doses of DHEA (0.3, 1.0 or 3.0 mg) combined with EM-800 (15 ⁇ g) or EM-800 alone (A) for 9.5 months on average ZR-75-1 tumor size in ovariectomized (OVX) nude mice supplemented with estrone. The initial tumor size was taken as 100%. Control OVX mice receiving the vehicle alone were used as additional controls.
  • OVX ovariectomized
  • Estrone was administered subcutaneously at the dose of 0.5 ⁇ g once daily while DHEA was dissolved in 50% ethanol—50% propylene glycol and applied on the dorsal skin area twice daily in a volume of 0.02 ml. Comparison is also made with OVX animals receiving the vehicle alone.
  • FIG. 5 shows the effect of increasing concentrations of EM-800, (Z)-4-OH-Tamoxifen, (Z)-4-OH-Toremifene and Raloxifene on alkaline phosphatase activity in human Ishikawa cells.
  • Alkaline phosphatase activity was measured after a 5-day exposure to increasing concentrations of indicated compounds in the presence or absence of 1.0 nM E 2 .
  • the data are expressed as the means ⁇ SEM of four wells. When SEM overlaps with the symbol used, only the symbol is shown (Simard, Sanchez et al., 1997).
  • FIG. 6 shows the blockade of the stimulatory effect of (Z)-4-OH-Tamoxifen, (Z)-4-OH-Toremifene, Droloxifene and Raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human Ishikawa carcinoma cells.
  • Alkaline phosphatase activity was measured after a 5-day exposure to 3 or 10 nM of the indicated compounds in the presence or absence of 30 or 100 nM EM-800.
  • the data are expressed as the means ⁇ SD of eight wells with the exception of the control groups were data are obtained from 16 wells (Simard, Sanchez et al., 1997).
  • FIG. 7 shows that the stimulatory effect of Tamoxifen on the growth of human breast cancer ZR-75-1 xenografts is completely blocked by simultaneous administration of EM-652.HCl.
  • EM-652.HCl by itself, in agreement with its pure antiestrogenic activity has no effect on tumor growth in the absence of Tamoxifen.
  • FIG. 8 shows the comparison of the effects of standard ERT (estrogen) or HRT (estrogen+progestin) and the combination of dehydroepiandrosterone and the SERM Acolbifene on parameters of menopause.
  • the addition of Acolbifene to dehydroepiandrosterone will counteract the potentially negative effect of estrogen formed from dehydroepiandrosterone.
  • FIG. 9 shows sections of rat mammary gland
  • FIG. 10 shows sections of rat endometrium
  • FIG. 11 shows the effect on uterine weight of increasing concentrations of EM-652.HCl, Lasofoxifene (free base; active and inactive enantiomers) and Raloxifene administered orally for 9 days to ovariectomized mice simultaneously treated with estrone. *p ⁇ 0.05, **p ⁇ 0.01 versus E 1 -treated control.
  • FIG. 12 shows the effect on vaginal weight of increasing concentrations of EM-652.HCl, Lasofoxifene (free base; active and inactive enantiomers) and Raloxifene administered orally for 9 days to ovariectomized mice simultaneously treated with estrone. **p ⁇ 0.01 versus E 1 -treated control.
  • FIG. 13 shows the effect on uterine weight of 1 ⁇ g and 10 ⁇ g of EM-652.HCl, Lasofoxifene (free base; active and inactive enantiomers) and Raloxifene administered orally for 9 days to ovariectomized mice. **p ⁇ 0.01 versus OVX control.
  • FIG. 14 shows the effect on vaginal weight of 1 ⁇ g and 10 ⁇ g of EM-652.HCl, Lasofoxifene (free base; active and inactive enantiomers) and Raloxifene administered orally for 9 days to ovariectomized mice. **p ⁇ 0.01 versus OVX control.
  • FIG. 15 shows the effect of 12-month treatment with dehydroepiandrosterone (DHEA) alone or in combination with Flutamide or EM-800 on trabecular bone volume in ovariectomized rats. Intact animals are added as additional controls. Data are presented as mean ⁇ SEM ** p ⁇ 0.01 versus OVX Control.
  • DHEA dehydroepiandrosterone
  • FIG. 16 shows the effect of 12-month treatment with dehydroepiandrosterone (DHEA) alone or in combination with Flutamide or EM-800 on trabecular number in ovariectomized rats. Intact animals are added as additional controls. Data are presented as mean ⁇ SEM ** p ⁇ 0.01 versus OVX Control.
  • DHEA dehydroepiandrosterone
  • FIG. 17 shows proximal tibia metaphyses from intact control (A), ovariectomized control (B), and ovariectomized rats treated with DHEA alone (C) or in combination with Flutamide (D) or EM-800 (E).
  • D Flutamide
  • E EM-800
  • FIG. 21 shows the effects of antiestrogens on categories of response. Effect of a 161-day administration of 7 antiestrogens, on the category of response of human ZR-75-1 breast tumors in ovariectomized nude mice. Complete regression identifies those tumors that were undetectable at the end of treatment; partial regression corresponds to the tumors that regressed ⁇ 50% of their original size; stable response refers to tumors that regressed ⁇ 50% or progressed ⁇ 50%; and progression indicates that they progressed more than 50% compared with their original size. Antiestrogens were administered orally once daily at the dose of 50 ⁇ g/mouse under estrone stimulation obtained with subcutaneous 0.5-cm silastic implants containing 1:25 ratio of estrone and cholesterol.
  • FIG. 22 shows the effects of antiestrogen on categories of response. Effect of a 161-day administration of 7 antiestrogens, on the category of response of human ZR-75-1 breast tumors in ovariectomized nude mice. Complete regression identifies those tumors that were undetectable at the end of treatment; partial regression corresponds to the tumors that regressed ⁇ 50% of their original size; stable response refers to tumors that regressed ⁇ 50% or progressed ⁇ 50%; and progression indicates that they progressed more than 50% compared with their original size. Antiestrogens were administered orally once daily at the dose of 200 ⁇ g/mouse in absence of estrogen stimulation.
  • FIG. 23 shows the effects of antiestrogen on categories of response. Effect of a 161-day administration of the antiestrogens Tamoxifen, EM-652.HCl (Acolbifene) and the combination of Tamoxifen and EM-652.HCl, on the category of response of human ZR-75-1 breast tumors in ovariectomized nude mice. Complete regression identifies those tumors that were undetectable at the end of treatment; partial regression corresponds to the tumors that regressed ⁇ 50% of their original size; stable response refers to tumors that regressed ⁇ 50% or progressed ⁇ 50%; and progression indicates that they progressed more than 50% compared with their original size. Antiestrogens were administered orally once daily at the dose of 200 ⁇ g/mouse in absence of estrogen stimulation.
  • FIG. 24 shows the effect of a daily dose of DHEA or placebo on mean number of moderate to severe hot flushes during 16 weeks of treatment (*, p ⁇ 0.05 DHEA versus placebo).
  • FIG. 25 shows the treatment with a daily 50 mg dose of DHEA or placebo on mean number of all hot flushes (mild, moderate and severe) during 16 weeks of treatment (*, p ⁇ 0.05 DHEA versus placebo).
  • Hormone replacement therapy is used in postmenopausal women for the acute symptoms arising from estrogen deficiency, particularly hot flushes and night sweats, and for the long term prevention of osteoporosis and possibly cardiovascular disease. While progestins are effective at protecting the uterus from the stimulatory effects of long term estrogen exposure, it carries its own side effects, in particular dysfunctional uterine bleeding (Archer et al., 1999). This is a frequent side effect and a common reason for women to prematurely stop hormone replacement therapy within the first 6-12 months.
  • the present invention is thus based upon the recent progress achieved in our understanding of sex steroid physiology in men and women (Labrie, 1991; Labrie et al., 1992a; Labrie et al., 1992b; Labrie et al., 1994; Labrie et al., 1995a; Luu-The et al., 1995a; Labrie et al., 1997a; Labrie et al., 1997b; Labrie et al., 1997c; Labrie et al., 1997d) and the recognition that women, at menopause, are not only deprived from estrogens activity due to a declining ovarian activity, but have already been submitted for a few years to a decreasing exposure to androgens. In fact, normal women produce an amount of androgens equivalent to two thirds of the androgens secreted in men (Labrie et al., 1997a).
  • DHEA and especially DHEA-S which are converted into potent androgens and/or estrogens in peripheral tissues.
  • Plasma DHEA-S levels in adult and women are 500 times higher than those of testosterone and 10,000 times higher than those of estradiol, thus providing a large supply of substrate for the formation of androgens and/or estrogens.
  • the local synthesis and action of sex steroids in peripheral target tissues has been called intracrinology (Labrie et al., 1988; Labrie, 1991).
  • DHEA and DHEA-S in human sex steroid physiology are illustrated by the estimate that approximately 50% of total androgens in adult men derive from these adrenal precursor steroids (Labrie et al., 1985; Bélanger et al., 1986; Labrie et al., 1993), while, in women, our best estimate of the intracrine formation of estrogens in peripheral tissues is in the order of 75% before menopause and close to 100% after menopause (Labrie, 1991).
  • DHEA is known to prevent the development (Luo et al., 1997) and to inhibit the growth (Li et al., 1993) of dimethylbenz(a)anthracene mammary tumors in the rat. DHEA, in addition, inhibits the growth of human breast cancer xenografts in nude mice (See example 1 and Couillard et al., 1998). Thus, contrary to estrogens and progestins which exert stimulatory effects, DHEA is expected to inhibit both the development and the growth of breast cancer in women.
  • DHEA administration is on the circulating levels of the glucuronide derivatives of the metabolites of DHT, namely ADT-G and 3 ⁇ -diol-G, these metabolites being produced locally in the peripheral intracrine tissues which possess the appropriate steroidogenic enzymes to synthesize DHT from the adrenal precursors DHEA and DHEA-S and, thereafter, to further metabolize DHT into inactive conjugates (Labrie, 1991; Labrie et al., 1996).
  • This local biosynthesis and action of androgens in target tissues eliminates the exposure of other tissues to androgens and thus minimizes the risks of undesirable masculinizing or other androgen-related side effects.
  • the same applies to estrogens although we feel that a reliable parameter of total estrogen secretion (comparable to the glucuronides for androgens) is not yet available.
  • Androgens are known to play a role in women's arousability, pleasure as well as intensity and ease of orgasm. Androgens are also involved in the neurovascular smooth muscle response of swelling and increased lubrication (Basson, 2004). Estrogens affect the vulval and vaginal congestive responses. Since estrogens also affect mood, they have an influence on sexual interest (Basson, 2004). It should be remembered that DHEA is transformed into both androgens and estrogens in the vagina (Sourla et al., 1998) (Berger et al., 2005)
  • DHEA DHEA
  • androgen therapy is successful in reducing hot flushes in hypogonadal men (De Fazio et al., 1984) and in menopausal transition in women (Overlie et al., 2002).
  • androgens has been found to be effective in relieving hot flushes in women who had unsatisfactory results with estrogen alone (Sherwin and Gelfand, 1984). Hot flushes are one of the main reasons women initially seek HRT therapy, and estrogen is very effective at alleviating this symptom.
  • DHEA-S and DHEA have, in fact, been found in patients with breast cancer (Zumoff et al., 1981) and DHEA has been found to exert antioncogenic activity in a series of animal models (Schwartz et al., 1986; Gordon et al., 1987; Li et al., 1993). DHEA has also been shown to have immuno modulatory effects in vitro (Suzuki et al., 1991) and in vivo in fungal and viral diseases (Rasmussen et al., 1992), including HIV (Henderson et al., 1992). On the other hand, a stimulatory effect of DHEA on the immune system has been described in postmenopausal women (Casson et al., 1993).
  • estrogen replacement therapy requires the addition of progestins to counteract the endometrial proliferation induced by estrogens while both estrogens and progestins could increase the risk of breast cancer (Bardon et al., 1985; Colditz et al., 1995).
  • ERT estrogen
  • HRT hormonal replacement therapy
  • the index of sebum secretion was 79% increased after 12 months of DHEA therapy with a return to pretreatment values 3 months after cessation of treatment.
  • DHEA administration stimulated vaginal epithelium maturation in 8 out of 10 women who had a maturation value of zero at the onset of therapy while a stimulation was also seen in the three women who had an intermediate vaginal maturation before therapy.
  • the estrogenic stimulatory effect observed in the vagina was not found in the endometrium which remained completely atrophic in all women after 12 months of DHEA treatment (Labrie et al., 1997c).
  • the present data clearly indicate the beneficial effects of DHEA therapy in postmenopausal women through its transformation into androgens and/or estrogens in specific intracrine target tissues without significant side effects.
  • the absence of stimulation of the endometrium by DHEA eliminates the need for progestin replacement therapy, thus avoiding the fear of progestin-induced breast cancer.
  • the observed stimulatory effect of DHEA on bone mineral density and the increase in serum osteocalcin, a marker of bone formation are of particular interest for the prevention and treatment of osteoporosis and indicate a unique activity of DHEA on bone physiology, namely on bone formation while, ERT and HRT can only reduce the rate of bone loss.
  • estrogen improves synapse formation on dendritic spines in the hippocampi of oophorectomized rats (Mc Ewen and Alves, 1999, Monk and Brodatz, 2000). Moreover, estrogen improves cerebral blood flow and glucose metabolism and it may act as an antioxidant ((Mc Ewen and Alves, 1999; Monk and Brodatz, 2000; Gibbs and Aggamal, 1998). Estrogen has also been found to prevent B-Amyloid 1-42 from inducing a rise in intracellular calcium and from causing mitochondrial damage (Chen et al., 2006, Morrison et al., 2006).
  • the present invention is based upon the recent progress achieved in our understanding of sex steroid physiology in women and the recognition that women, at menopause, are not only deprived from estrogen due to the arrest of estrogen secretion by the ovaries, but have already been submitted for a few years to a decreasing exposure to androgens.
  • normal women produce an amount of androgens equivalent to two thirds of the androgens secreted in men (Labrie et al., 1997a).
  • the pool of androgens in women decreases progressively from the age of 30 years in parallel with the decrease in the serum concentration of DHEA and DHEA-S (Labrie et al., 1997b).
  • SERMs in accordance with the invention, may be administered in the same dosage as known in the art, even where the art uses them as antiestrogens instead of as SERMs.
  • SERMs have also a beneficial effect on hypertension, insulin resistance, diabetes, and obesity (especially abdominal obesity).
  • SERMs many of which preferably have two aromatic rings linked by one to two carbon atoms, are expected to interact with the estrogen receptor by virtue of the foregoing portion of the molecule that is best recognized by the receptor.
  • Preferred SERMs have side chains which may selectively cause antagonistic properties in breast and usually uterine tissues without having significant antagonistic properties in other tissues.
  • the SERMs may desirably functions as antiestrogens in the breast while surprisingly and desirably functioning as estrogens (or providing estrogen-like activity) in bone and in the blood (where concentrations of lipid and cholesterol are favorably affected).
  • the favorable effect on cholesterol and lipids translates to a favorable effect against atherosclerosis which is known to be adversely, affected by improper levels of cholesterol and lipids.
  • Hot flushes, cardiovascular symptoms, Alzheimer's disease, loss of cognitive functions and insomnia involve certainly estrogen receptors situated in the nervous central system. Probably, low levels of estrogens in the brain, can explain at least in part, these conditions. Exogenous estrogens and particularly those (i.e. estradiol) formed by the administration of sex steroid precursors can pass through the brain barrier and bind to the estrogen receptor to restore the normal estrogenic action. On the other hand, SERMs of the invention, and more particularly those of Acolbifene family, cannot pass through the brain barrier as shown in example 8.
  • DHEA can provide both estrogens and androgens in the brain according to physiological needs.
  • EM-652 to sex steroid precursor blocks the stimulatory effect of formed estrogens on the mammary gland and uterus while, in other tissues, EM-652 will exert its own beneficial effect, for example on the bone, where it partially reverses the effect of ovariectomy on bone mineral density.
  • Preferred SERMs or antiestrogens discussed herein relate: (1) to all diseases stated to be susceptible to the invention; (2) to both therapeutic and prophylactic applications; and (3) to preferred pharmaceutical compositions and kits.
  • a patient in need of treatment or of reducing the risk of onset of a given disease is one who has either been diagnosed with such disease or one who is susceptible of acquiring such disease.
  • the preferred dosage of the active compounds (concentrations and modes of administration) of the invention is identical for both therapeutic and prophylactic purposes.
  • the dosage for each active component discussed herein is the same regardless of the disease being treated (or of the disease whose likelihood of onset is being reduced).
  • dosages herein refer to weight of active compounds unaffected by pharmaceutical excipients, diluents, carriers or other ingredients, although such additional ingredients are desirably included, as shown in the examples herein.
  • Any dosage form (capsule, pill, tablet, injection or the like) commonly used in the pharmaceutical industry is appropriate for use herein, and the terms “excipient”, “diluent”, or “carrier” include such nonactive ingredients as are typically included, together with active ingredients in such dosage forms in the industry.
  • typical capsules, pills, enteric coatings, solid or liquid diluents or excipients, flavorants, preservatives, or the like may be included.
  • All of the active ingredients used in any of the therapies discussed herein may be formulated in pharmaceutical compositions which also include one or more of the other active ingredients. Alternatively, they may each be administered separately but sufficiently simultaneous in time so that a patient eventually has elevated blood levels or otherwise enjoys the benefits of each of the active ingredients (or strategies) simultaneously.
  • one or more active ingredients are to be formulated in a single pharmaceutical composition.
  • a kit is provided which includes at least two separate containers wherein the contents of at least one container differs, in whole or in part, from the contents of at least one other container with respect to active ingredients contained therein.
  • Combination therapies discussed herein also include use of one active ingredient (of the combination) in the manufacture of a medicament for the treatment (or risk reduction) of the disease in question where the treatment or prevention further includes another active ingredient of the combination in accordance with the invention.
  • the invention provides the use of a SERM in the preparation of a medicament for use, in combination with a sex steroid precursor in vivo, in the treatment of any of the diseases for which the present combination therapy is believed effective (i.e. hot flushes, sweat, irregular menstruation, and any symptoms related to menopause).
  • Estrogens are well-known to stimulate the proliferation of breast epithelial cells and cell proliferation itself is thought to increase the risk of cancer by accumulating random genetic errors that may result in neoplasia (Preston Martin et al., 1990). Based on this concept, antiestrogens have been introduced to prevent breast cancer with the objective of reducing the rate of cell division stimulated by estrogens.
  • FIGS. 3 and 4 show that DHEA, by itself, at the doses used, causes a 50 to 80% inhibition of tumor growth while the near complete inhibition of tumor growth achieved with a low dose of the antiestrogen was not affected by DHEA.
  • BMD bone mineral density
  • reduced bone mineral density is not the only abnormality associated with reduced bone strength. It is thus important to analyze the changes in biochemical parameters of bone metabolism induced by various compounds and treatments in order to gain a better knowledge of their action.
  • DHEA did not affect the urinary hydroxyproline/creatinine ratio, a marker of bone resorption.
  • no effect of DHEA could be detected on daily urinary calcium or phosphorus excretion (Luo et al., 1997).
  • EM-800 decreased the urinary hydroxyproline/creatinine ratio by 48% while, similarly to DHEA, no effect of EM-800 was seen on urinary calcium or phosphorus excretion.
  • EM-800 moreover, had no effect on serum alkaline phosphatase activity, a marker of bone formation while DHEA increased the value of the parameter by about 75% (Luo et al., 1997).
  • trabecular bone volume of the tibia increased from 4.1 ⁇ 0.7% in ovariectomized rats to 11.9 ⁇ 0.6% (p ⁇ 0.01) with DHEA alone while the addition of EM-800 to DHEA further increased trabecular bone volume to 14.7 ⁇ 1.4%, a value similar to that found in intact controls ( FIG. 15 ).
  • FIG. 17 illustrates the increase in trabecular bone volume in the proximal tibia metaphysis induced by DHEA in ovariectomized treated animals (C) compared to ovariectomized controls (B), as well as the partial inhibition of the stimulatory effect of DHEA after the addition of Flutamide to DHEA treatment (D).
  • D Flutamide to DHEA treatment
  • administration of DHEA in combination with EM-800 resulted in a complete prevention of the ovariectomy-induced osteopenia (E), the trabecular bone volume being comparable to that seen in intact controls (A).
  • hydroxyproline released during collagen degradation is not reutilized in collagen synthesis, it is a useful marker of collagen metabolism or osteoclastic bone resorption.
  • the urinary hydroxyproline/creatinine ratio decreased from 11.7 ⁇ 1.2 •mol/mmol in OVX controls to 7.3 ⁇ 1.0 •mol/mmol (p ⁇ 0.05) in DHEA-treated rats (Table 2).
  • the administration of FLU completely prevented the inhibitory effect of DHEA on this parameter while EM-800 had no statistically significant influence on the effect of DHEA.
  • the bone loss observed at menopause in women is believed to be related to an increase in the rate of bone resorption which is not fully compensated by the secondary increase in bone formation.
  • the parameters of both bone formation and bone resorption are increased in osteoporosis and both bone resorption and formation are inhibited by estrogen replacement therapy.
  • the inhibitory effect of estrogen replacement on bone formation is thus believed to result from a coupled mechanism between bone resorption and bone formation, such that the primary estrogen-induced reduction in bone resorption entrains a reduction in bone formation (Parfitt, 1984).
  • Cancellous bone strength and subsequent resistance to fracture do not only depend upon the total amount of cancellous bone but also on the trabecular microstructure, as determined by the number, size, and distribution of the trabeculae.
  • the loss of ovarian function in postmenopausal women is accompanied by a significant decrease in total trabecular bone volume (Melsen et al., 1978; Vakamatsou et al., 1985), mainly related to a decrease in the number and, to a lesser degree, in the width of trabeculae (Weinstein and Hutson, 1987).
  • the invention contemplates pharmaceutical compositions which include the SERM and the sex steroid precursor in a single composition for simultaneous administration.
  • the composition may be suitable for administration in any traditional manner including but not limited to oral administration, subcutaneous injection, intramuscular injection or percutaneous administration.
  • a kit is provided wherein the kit includes one or more SERM and sex steroid precursor in separate or in one container.
  • the kit may include appropriate materials for oral administration, e.g. tablets, capsules, syrups and the like and for transdermal administration, e.g., ointments, lotions, gels, creams, sustained release patches and the like.
  • the active ingredients of the invention may be formulated and administered in a variety of ways. When administered together in accordance with the invention, the active ingredients may be administered simultaneously or separately.
  • Active ingredient for transdermal or transmucosal is preferably from 0.01% to 1%, DHEA or 5-diol.
  • the active ingredient may be placed into a vaginal ring or a transdermal patch having structures known in the art, for example, structures such as those set forth in E.P. Patent No. 0279982 or in an intravaginal cream, gel, ovule, or suppository.
  • the active compound When formulated as an ointment, lotion, gel, cream, ovule, or suppository or the like, the active compound is admixed with a suitable carrier which is compatible with human skin or mucosa and which enhances transdermal or transmucosal penetration of the compound through the skin or mucosa.
  • suitable carriers are known in the art and include but are not limited to Klucel H F and Glaxal base. Some are commercially available, e.g., Glaxal base available from Glaxal Canada Limited Company. Other suitable vehicles can be found in Koller and Buri, S.T.P. Pharma 3(2), 115-124, 1987.
  • the carrier is preferably one in which the active ingredient(s) is (are) soluble at ambient temperature at the concentration of active ingredient that is used.
  • the carrier should have sufficient viscosity to maintain the inhibitor on a localized area of skin or mucosa to which the composition has been applied, without running or evaporating for a time period sufficient to permit substantial penetration of the precursor through the localized area of skin or mucosa and into the bloodstream where it will cause a desirable clinical effect.
  • the carrier is typically a mixture of several components, e.g. pharmaceutically acceptable solvents and a thickening agent.
  • a mixture of organic and inorganic solvents can aid hydrophylic and lipophylic solubility, e.g. water and an alcohol such as ethanol.
  • the active compound When formulated as an ovule or a vaginal suppository or the like, the active compound is admixed with a suitable carrier which is compatible with human vaginal mucosa.
  • suitable carriers are hard fats (mixture of glycerides of saturated fatty acids), particularly Witepsol, and specially Witepsol H-15 base (available from Medisca, Montreal, Canada). Any other lipophilic base such as Fattibase, Wecobee, cocoa butter, theobroma oil or other combinations of Witepsol bases could used.
  • DHEA dehydroepiandrosterone
  • the carrier may also include various additives commonly used in ointments, lotions and suppositories and well known in the cosmetic and medical arts.
  • various additives commonly used in ointments, lotions and suppositories and well known in the cosmetic and medical arts.
  • fragrances, antioxidants, perfumes, gelling agents, thickening agents such as carboxymethylcellulose, surfactants, stabilizers, emollients, coloring agents and other similar agents may be present.
  • SERM or antiestrogenic compound and the sex steroid precursor can also be administered, by the oral route, and may be formulated with conventional pharmaceutical excipients, e.g. spray dried lactose, microcrystalline cellulose, and magnesium stearate into tablets or capsules for oral administration.
  • conventional pharmaceutical excipients e.g. spray dried lactose, microcrystalline cellulose, and magnesium stearate into tablets or capsules for oral administration.
  • the active substances can be worked into tablets or dragee cores by being mixed with solid, pulverulent carrier substances, such as sodium citrate, calcium carbonate or dicalcium phosphate, and binders such as polyvinyl pyrrolidone, gelatin or cellulose derivatives, possibly by adding also lubricants such as magnesium stearate, sodium lauryl sulfate, “Carbowax” or polyethylene glycol.
  • solid, pulverulent carrier substances such as sodium citrate, calcium carbonate or dicalcium phosphate
  • binders such as polyvinyl pyrrolidone, gelatin or cellulose derivatives
  • lubricants such as magnesium stearate, sodium lauryl sulfate, “Carbowax” or polyethylene glycol.
  • taste-improving substances can be added in the case of oral administration forms.
  • plug capsules e.g. of hard gelatin, as well as closed soft-gelatin capsules comprising a softener or plasticizer, e.g. glycerin.
  • the plug capsules contain the active substance preferably in the form of granulate, e.g. in mixture with fillers, such as lactose, saccharose, mannitol, starches, such as potato starch or amylopectin, cellulose derivatives or highly dispersed silicic acids.
  • the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethylene glycols.
  • the lotion, ointment, gel or cream should be thoroughly rubbed into the skin so that no excess is plainly visible, and the skin should not be washed in that region until most of the transdermal penetration has occurred preferably at least 4 hours and, more preferably, at least 6 hours.
  • a transdermal patch may be used to deliver precursor in accordance with known techniques. It is typically applied for a much longer period, e.g., 1 to 4 days, but typically contacts active ingredient to a smaller surface area, allowing a slow and constant delivery of active ingredient.
  • transdermal drug delivery systems that have been developed, and are in use, are suitable for delivering the active ingredient of the present invention.
  • the rate of release is typically controlled by a matrix diffusion, or by passage of the active ingredient through a controlling membrane.
  • the device may be any of the general types known in the art including adhesive matrix and reservoir-type transdermal delivery devices.
  • the device may include drug-containing matrixes incorporating fibers which absorb the active ingredient and/or carrier.
  • the reservoir may be defined by a polymer membrane impermeable to the carrier and to the active ingredient.
  • a transdermal device In a transdermal device, the device itself maintains active ingredient in contact with the desired localized skin surface. In such a device, the viscosity of the carrier for active ingredient is of less concern than with a cream or gel.
  • a solvent system for a transdermal device may include, for example, oleic acid, linear alcohol lactate and dipropylene glycol, or other solvent systems known in the art. The active ingredient may be dissolved or suspended in the carrier.
  • a transdermal patch may be mounted on a surgical adhesive tape having a hole punched in the middle.
  • the adhesive is preferably covered by a release liner to protect it prior to use.
  • Typical material suitable for release includes polyethylene and polyethylene-coated paper, and preferably silicone-coated for ease of removal.
  • the release liner is simply peeled away and the adhesive attached to the patient's skin.
  • Bannon et al. describe an alternative device having a non-adhesive means for securing the device to the skin.
  • SERM antiestrogen and sex steroid precursor be administered in a manner and at a dosage sufficient to allow blood serum concentration of each to obtain desired levels.
  • concentration of the SERM is maintained within desired parameters at the same time that sex steroid precursor concentration is maintained within desired parameters
  • DHEA DHEA
  • DHEA-S and analogs discussed below are also especially effective for the reasons stated below.
  • a selective estrogen receptor modulator of the invention has a molecular formula with the following features: a) two aromatic rings spaced by 1 to 2 intervening carbon atoms, both aromatic rings being either unsubstituted or substituted by a hydroxyl group or a group converted in vivo to hydroxyl; and b) a side chain possessing an aromatic ring and a tertiary amine function or salt thereof.
  • One preferred SERM of the invention is Acolbifene:
  • Acolbifene (also called EM-652.HCl; EM-1538) is the hydrochloride salt of the potent antiestrogen EM-652. It is disclosed in U.S. Pat. No. 6,710,059 B1.
  • Another preferred SERM is Lasoxifene (Oporia; CP-336,156; ( ⁇ )-cis-(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol, D-( ⁇ )-tartrate salt) (available from Pfizer Inc., USA).
  • SERM is Bazedoxifene (TSE 424; WAY-TSE 424; WAY 140424; 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol, acetate) developed by Wyeth Ayers (USA) and disclosed in JP10036347 (American home products corporation) and approved in USA for the prevention of postmenopausal osteoporosis and non-steroidal estrogen derivatives described in WO 97/32837.
  • SERMs of the invention include Tamoxifen ((Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine) (available from Zeneca, UK), Toremifene ((Z)-2-[4-(4-Chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine) available from Orion, Finland, under the trademark Fareston or Schering-Plough), Droloxifene ((E)-3-[1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]phenol) and, from Eli Lilly and Co., USA: Raloxifene ([2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone hydrochloride),
  • SERMs are Idoxifene ((E)-1-[2-[4-[1-(4-Iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl]pyrrolidine) (SmithKline Beecham, USA), Levormeloxifene (3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman) (Novo Nordisk, A/S, Denmark) which is disclosed in Shalmi et al.
  • SERM used as required for efficacy, as recommended by the manufacturer, can be used. Appropriate dosages are known in the art. Any other non steroidal antiestrogen commercially available can be used according to the invention. Any compound having activity similar to SERMs (example: Raloxifene can be used).
  • SERMs administered in accordance with the invention are preferably administered in a dosage range between 0.01 to 10 mg/kg of body weight per day (preferably 0.05 to 1.0 mg/kg), with 5 mg per day, especially 10 mg per day, in two equally divided doses being preferred for a person of average body weight when orally administered, or in a dosage range between 0.003 to 3.0 mg/kg of body weight per day (preferably 0.015 to 0.3 mg/ml), with 1.5 mg per day, especially 3.0 mg per day, in two equally divided doses being preferred for a person of average body weight when parentally administered (i.e. intramuscular, subcutaneous or percutaneous administration).
  • the SERMs are administered together with a pharmaceutically acceptable diluent or carrier as described below.
  • One preferred antiestrogen of the invention is fulvestrant (Faslodex; ICI 182 7807 ⁇ -[9-(4,4,5,5,5-pentafluoro-pentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17 ⁇ -diol) which is intramuscularly administered with the dosage of 250 mg per month available from AstraZeneca Canada Inc., Mississauga, Ontario, Canada.
  • DHEA steroid dehydroepiandrosterone
  • mice received daily subcutaneous injections of 0.5 ⁇ g estrone (an estrogenic hormone) immediately after ovariectomy.
  • EM-800 (15, 50 or 100 ⁇ g) was given orally once daily.
  • DHEA was applied twice daily (total dose 0.3, 1.0 or 3.0 mg) to the dorsal skin either alone or in combination with a 15 ⁇ g daily oral dose of EM-800. Changes in tumor size in response to the treatments were assessed periodically in relation to the measurements made on the first day. At the end of the experiments, tumors were dissected and weighed.
  • DHEA and EM-800 independently suppressed the growth of estrone-stimulated ZR-75-1 mouse xenograft tumors in nude mice.
  • Administration of DHEA at the defined doses does not alter the inhibitory effect of EM-800.
  • ZR-75-1 human breast cancer cells were obtained from the American Type Culture Collection (Rockville, Md.) and routinely cultured as monolayers in RPMI 1640 medium supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 100 IU penicillin/ml, 100 ⁇ g streptomycin/ml, and 10% fetal bovine serum, under a humidified atmosphere of 95% air/5% CO 2 at 37° C. as described (Poulin and Labrie, 1986; Poulin et al., 1988). Cells were passaged weekly after treatment with 0.05% trypsin: 0.02% EDTA (w/v). The cell cultures used for the experiments described in this report were derived from passage 93 of the cell line ZR-75-1.
  • mice Female homozygous Harlan Sprague-Dawley (nu/nu) athymic mice (28- to 42-day-old) were obtained from HSD (Indianapolis, Ind., USA). Mice were housed in vinyl cages with air filter tops in laminar air flow hoods and maintained under pathogen-limited conditions. Cages, bedding, and food were autoclaved before use. Water was autoclaved, acidified to pH 2.8, and provided ad libitum.
  • mice were bilaterally ovariectomized (OVX) one week before tumor cell inoculation under anesthesia achieved by intraperitoneal injection of 0.25 ml/animal of Avertin (amylic alcohol: 0.8 g/100 ml 0.9% NaCl; and tribromo ethanol: 2 g/100 ml 0.9% NaCl).
  • Avertin anlic alcohol: 0.8 g/100 ml 0.9% NaCl
  • tribromo ethanol 2 g/100 ml 0.9% NaCl
  • All animals except those in the control OVX group, received daily subcutaneous injections of 0.5 ⁇ g estrone (E 1 ) in 0.2 ml of 0.9% NaCl 5% ethanol 1% gelatin.
  • DHEA was administered percutaneously twice daily at the doses of 0.3, 1.0 or 3.0 mg/animal applied in a volume of 0.02 ml on the dorsal skin area outside the area of tumor growth.
  • DHEA was dissolved in 50% ethanol 50% propylene glycol.
  • EM-800 ((+)-7-pivaloyloxy-3-(4′-pivaloyloxyphenyl)-4-methyl-2-(4′′-(2′′′-piperidinoethoxy)phenyl)-2H-benzopyran), was synthesized as described earlier (Gauthier et al., J. Med. Chem. 40: 2117-2122, 1997) in the medicinal chemistry division of the Laboratory of Molecular Endocrinology of the CHUL Research Center. EM-800 was dissolved in 4% (v/v) ethanol 4% (v/v) polyethylene glycol (PEG) 600 1% (w/v) gelatin 0.9% (w/v) NaCl.
  • PEG polyethylene glycol
  • Statistical significance of the effects of treatments on tumor size was assessed using an analysis of variance (ANOVA) evaluating the effects due to DHEA, EM-800, and time, and repeated measures in the same animals performed at the initiation and at the end of the treatment (subjects within group factor).
  • the repeated measures at time 0 and after 9.5 months of treatment constitute randomized blocks of animals. The time is thus analyzed as a within-block effect while both treatments are assessed as between-block effects. All interactions between main effects were included in the model.
  • the significance of the treatment factors and of their interactions was analyzed using the subjects within group as the error term. Data were log-transformed.
  • the hypotheses underlying the ANOVA assumed the normality of the residuals and the homogeneity of variance.
  • a posteriori pairwise comparisons were performed using Fisher's test for least significant difference. Main effects and the interaction of treatments on body weight and organ weight were analyzed using a standard two-way ANOVA with interactions. All ANOVAs were performed using SAS program (SAS Institute, Cary, N.C., USA). Significance of differences was declared using a 2-tailed test with an overall level of 5%. Categorical data were analyzed with a Kruskall-Wallis test for ordered categorical response variables (complete response, partial response, stable response, and progression of tumor). After overall assessment of a treatment effects, subsets of the results presented in Table 4 were analyzed adjusting the critical p-value for multiple comparisons. The exact p-values were calculated using StatXact program (Cytel, Cambridge, Mass., USA). Data are expressed as means ⁇ standard error of the mean (SEM) of 12 to 15 mice in each group.
  • human ZR-75-1 tumors increased by 9.4-fold over 291 days (9.5 months) in ovariectomized nude mice treated with a daily 0.5 ⁇ g subcutaneously administered dose of estrone while in control OVX mice who received the vehicle alone, tumor size was decreased to 36.9% of the initial value during the course of the study.
  • the tumor size reductions achieved with the three EM-800 doses are not significantly different between each other. As illustrated in FIG.
  • tumor weight at the end of the 9.5-month study was decreased from 1.12 ⁇ 0.26 g in control E 1 -supplemented OVX mice to 0.08 ⁇ 0.03 g, 0.03 ⁇ 0.01 g and 0.04 ⁇ 0.03 g in animals treated with the daily 15 ⁇ g, 50 ⁇ g, and 100 ⁇ g doses of EM-800, respectively (P ⁇ 0.0001 at all doses of EM-800 vs E 1 supplemented OVX).
  • the antiestrogen EM-800 at the daily oral dose of 15 ⁇ g, caused a 87.5% inhibition of estrone-stimulated tumor growth measured at 9.5 months.
  • the addition of DHEA at the three doses used had no significant effect on the already marked inhibition of tumor size achieved with the 15 ⁇ g daily dose of the antiestrogen EM-800 ( FIG. 4B ).
  • Stable responses were measured at 12.5%, 21.4%, 20.0%, and 13.3% in the control E 1 -supplemented mice and in the three groups of animals who received the above-indicated doses of DHEA, respectively.
  • the rates of complete, partial and stable responses were measured at 68.8%, 6.2%, and 18.8%, respectively, while progression was seen in only 6.2% of tumors (Table 3).
  • estrone-stimulated uterine weight was decreased from 132 ⁇ 8 mg in control estrone-supplemented mice to 49 ⁇ 3 mg, 36 ⁇ 2 mg, and 32 ⁇ 1 mg (P ⁇ 0.0001 at all doses vs control) with the daily oral doses of 15 ⁇ g, 50 ⁇ g, or 100 ⁇ g of EM-800 (overall P ⁇ 0.0001), respectively.
  • vaginal weight was then reduced to 23 ⁇ 1 mg, 15 ⁇ 1 mg, and 11 ⁇ 1 mg following treatment with the daily 15 ⁇ g, 50 ⁇ g or 100 ⁇ g doses of EM-800, respectively (overall p and pairwise P ⁇ 0.0001 at all doses vs. control).
  • vaginal weight was measured at 22 ⁇ 1 mg, 25 ⁇ 2 mg and 23 ⁇ 1 mg, respectively (N.S. for all groups versus 15 ⁇ g EM-800).
  • EM-800 decreased uterine weight in estrone-supplemented OVX animals to a value not different from that of OVX controls while vaginal weight was reduced to a value below that measured in OVX controls (P ⁇ 0.05).
  • DHEA probably due to its androgenic effects, partially counteracted the effect of EM-800 on uterine and vaginal weight.
  • Step A BF 3 .Et 2 O, toluene; 100° C.; 1 hour.
  • Step C 3,4-dihydropyran, p-toluenesulfonic acid monohydrate, ethyl acetate; 25° C. under nitrogen, 16 hours, and then crystallization in isopropanol.
  • Step G (1S)-(+)-10-camphorsulfonic acid, acetone, water, toluene, room temperature, 48 hours.
  • Step HH 95% ethanol, 70° C., then room temperature 3 days.
  • Step HHR Recycling of mother liquor and wash of step HH (S)-10-camphorsulfonic acid, reflux; 36 hours, then room temperature for 16 hours.
  • Toluene (6.5 L) was removed from the solution by distillation at atmospheric pressure. Dimethylformamide (6.5 L) and 1,8-diazabicyclo[5,4,0]undec-7-ene (110.5 g, 0.726 mole) were added. The solution was agitated for about 8 hours at room temperature to isomerize the chalcone 8 to chromanone 9 and then added to a mixture of water and ice (8 L) and toluene (4 L). The phases were separated and the toluene layer washed with water (5 L). The combined aqueous washes were extracted with toluene (3 ⁇ 4 L).
  • the mixture was stirred for 2 hours and then added the saturated ammonium chloride solution (2 L) and toluene (4 L) and agitated for five minutes.
  • the phases were separated and the aqueous layer extracted with toluene (2 ⁇ 4 L).
  • the combined toluene extracts were washed with dilute hydrochloric acid until the solution became homogenous and then with brine (3 ⁇ 4 L).
  • the toluene solution was finally concentrated at atmospheric pressure to 2 L. This solution was used directly in the next step.
  • mice Female BALB/c mice (BALB/cAnNCrlBR) weighing 18-20 g were obtained from Charles-River, Inc. (St-Constant, Quebec, Canada) and housed 5 per cage in a temperature (23 ⁇ 1° C.)—and light (12 h light/day, lights on at 7:15)—controlled environment. The mice were fed rodent chow and tap water ad libitum. The animals were ovariectomized (OVX) under Isoflurane anesthesia via bilateral flank incisions and randomly assigned to groups of 10 animals. Ten mice were kept intact as controls.
  • OVX ovariectomized mice
  • tested compounds namely EM-652.HCl, lasofoxifene (as free base; active and inactive enantiomers) and raloxifene, were administered orally by gavage once daily at doses of 1, 3 or 10 ⁇ g/animal for 9 days, starting 2 days after ovariectomy.
  • TSE 424 was administered orally by gavage once daily at doses of 1, 3, 10 or 30 ⁇ g/animal for 9 days, starting 2 days after ovariectomy.
  • estrone E 1 , 0.06 ⁇ g, s.c.
  • EM-652.HCl administered at the daily oral doses of 1 ⁇ g, 3 ⁇ g, and 10 ⁇ g caused respective 24%, 48%, and 72% inhibitions of estrone-stimulated uterine weight (p ⁇ 0.01 for all doses versus control) while raloxifene administered at the same doses caused respective 6% (NS), 14% (p ⁇ 0.01) and 43% (p ⁇ 0.01) inhibitions of this parameter.
  • Lasofoxifene (as free base) had no inhibitory effect at the lowest dose used while it caused respective 25% (p ⁇ 0.01) and 44% (p ⁇ 0.01) inhibitions of estrone-stimulated uterine weight at the daily doses of 3 ⁇ g and 10 ⁇ g.
  • the inactive enantiomer of lasofoxifene exerted no inhibitory effect on this parameter at any dose used.
  • EM-652.HCl When compounds were administered alone (in the absence of estrone) to ovariectomized mice at the daily oral doses of 1 ⁇ g and 10 ⁇ g, EM-652.HCl had no significant stimulatory effect on uterine weight at both doses used, while treatment with 10 ⁇ g of lasofoxifene and raloxifene caused respective 93% (p ⁇ 0.01) and 85% (p ⁇ 0.01) stimulations of uterine weight ( FIG. 13 ), thus indicating an estrogenic effect of these latter compounds on this parameter. Similarly, EM-652.HCl exerted no significant stimulatory effect on vaginal weight ( FIG.
  • TSE 424 administered at the daily oral doses of 1 ⁇ g, 3 ⁇ g, 10 ⁇ g or 30 ⁇ g caused respective 12% (NS), 47%, 74%, and 94% inhibitions of estrone-stimulated uterine weight (p ⁇ 0.01 for the three highest doses versus E 1 -control).
  • the daily oral administration of TSE 424 led to respective 16% (NS), 56% (p ⁇ 0.01) and 93% (p ⁇ 0.01) inhibitions of vaginal weight at the 3 ⁇ g, 10 ⁇ g, and 30 ⁇ g doses.
  • TSE 424 had no significant stimulatory effect on uterine and vaginal weight at both doses used (Table 4).
  • BMD of the lumbar spine was 10% lower in OVX control animals than in intact controls (p ⁇ 0.01).
  • estradiol and EM-652.HCl alone prevented lumbar spine BMD loss by 98% (p ⁇ 0.01) and 65% (p ⁇ 0.05), respectively, while the combined treatment with E 2 and EM-652.HCl prevented the OVX-induced decrease in lumbar spine BMD by 61% (p ⁇ 0.05).
  • DHEA serum alkaline phosphatase activity
  • ALP activity was increased from 73 ⁇ 6 IU/L in OVX control animals to 224 ⁇ 18 IU/L, 290 ⁇ 27 IU/L, 123 ⁇ 8 IU/L and 261 ⁇ 20 IU/L (all p ⁇ 0.01) in DHEA-, DHEA+EM-652.HCl-, DHEA+E 2 - and DHEA+E 2 +EM-652.HCl-treated animals, respectively, thus suggesting a stimulatory effect of DHEA on bone formation (Table 7).
  • EM-652.HCl In addition to the preventive effects on bone loss, the administration of EM-652.HCl, TSE 424, Lasofoxifene, GW 5638, DHEA and E 2 exerts some beneficial effects on total body fat percentage and serum lipids. After three months of ovariectomy, total body fat was increase by 22% (p ⁇ 0.05; Table XXX 6). The administration of EM-652.HCl completely prevented the OVX-induced fat percentage increase while the addition of DHEA and/or E 2 to the SERM led to fat percentage values below those observed in intact control animals.
  • OTAL FAT CHOLESTEROL LP TREATMENT (%) (mmol/L) (IU/L) 1) Intact 24.0 ⁇ 1.5* 2.01 ⁇ 0.11** 39 ⁇ 2** OVX 29.2 ⁇ 1.5 2.46 ⁇ 0.08 73 ⁇ 6 OVX + E 2 19.5 ⁇ 2.5** 1.37 ⁇ 0.18** 59 ⁇ 4 OVX + EM-652.HCl 23.2 ⁇ 1.4** 0.87 ⁇ 0.04** 91 ⁇ 6* OVX + 20.4 ⁇ 1.4** 0.96 ⁇ 0.07** 92 ⁇ 5* EM-652.HCl + E 2 OVX + DHEA 17.3 ⁇ 1.5** 1.59 ⁇ 0.10** 224 ⁇ 18** OVX + DHEA + 18.0 ⁇ 1.1** 0.65 ⁇ 0.06** 290 ⁇ 27** EM-652.HCl OVX + DHEA + E 2 15.8 ⁇ 1.3** 1.08 ⁇ 0.08** 123 ⁇ 8** OVX + D
  • OTAL FAT HOLESTEROL LP TREATMENT (%) (mmol/L) (IU) 1) Intact 25.5 ⁇ 1.8** 2.11 ⁇ 0.11** 33 ⁇ 2* OVX 35.7 ⁇ 1.6 2.51 ⁇ 0.09 60 ⁇ 6 OVX + Premarin 28.2 ⁇ 1.8** 1.22 ⁇ 0.07** 49 ⁇ 3 OVX + EM-652.HCl 27.7 ⁇ 1.4** 0.98 ⁇ 0.06** 78 ⁇ 4 OVX + EM-652.HCl + 25.7 ⁇ 2.2** 1.10 ⁇ 0.07** 81 ⁇ 6 Premarin OVX + TSE 424 28.0 ⁇ 1.8** 1.15 ⁇ 0.05** 85 ⁇ 6 OVX + TSE 424 + 25.7 ⁇ 1.7** 1.26 ⁇ 0.14** 98 ⁇ 22** Premarin OVX + Lasofoxifene 24.1 ⁇ 1.3** 0.60 ⁇ 0.02** 116 ⁇ 9** OVX + Lasofoxifene +
  • One hundred twenty-six rats were randomly distributed between 9 groups of 14 animals each as follows: 1) Intact control; 2) OVX control; 3) OVX+EM-652.HCl (2.5 mg/kg); 4) OVX+TSE-424 (EM-4803, 2.5 mg/kg); 5) OVX+ERA-923 (EM-3527, 2.5 mg/kg); 6) OVX+dehydroepiandrosterone (DHEA; 80 mg/kg); 7) OVX+DHEA+EM-652.HCl; 8) OVX+DHEA+TSE-424; 9) OVX+DHEA+ERA-923.
  • Bone mineral density of the distal femoral metaphysis was decreased by 10% after 5 weeks of ovariectomy (Table 9).
  • the human Ishikawa cell line derived from a well differentiated endometrial adenocarcinoma was kindly provided by Dr. Erlio Gurpide, The Mount Sinai Medical Center, New York, N.Y.
  • the Ishikawa cells were routinely maintained in Eagle's Minimum Essential Medium (MEM) containing 5% (vol/vol) FBS (Fetal Bovine Serum) and supplemented with 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 0.1 mM non-essential amino acids solution.
  • MEM Eagle's Minimum Essential Medium
  • FBS Fetal Bovine Serum
  • Cells were plated in Falcon T75 flasks at a density of 1.5 ⁇ 10 6 cells at 37° C.
  • EFBM estrogen-free basal medium
  • DMEM Dulbecco's Modified Eagle's Medium
  • Cells were then harvested by 0.1% pancreatin (Sigma) and 0.25 mM HEPES, resuspended in EFBM and plated in Falcon 96, well flat-bottomed microtiter plates at a density of 2.2 ⁇ 10 4 cells/well in a volume of 100 ⁇ l and allowed to adhere to the surface of the plates for 24 h. Thereafter, medium was replaced with fresh EFBM containing the indicated concentrations of compounds in a final volume of 200 ⁇ l. Cells were incubated for five days, with a medium change after 48 h.
  • pancreatin Sigma
  • HEPES 0.25 mM HEPES
  • microtiter plates were inverted and growth medium was decanted.
  • the plates were rinsed with 200 ⁇ l by well of PBS (0.15M NaCl, 10 mM sodium phosphate, pH 7.4). PBS was then removed from the plates while carefully leaving some residual PBS, and the wash procedure was repeated once.
  • the buffered saline was then decanted, and the inverted plates were blotted gently on a paper towel. Following replacement of the covers, the plates were placed at ⁇ 80° C. for 15 min followed by thawing at room temperature for 10 min.
  • Dose-response curves as well as IC 50 values were calculated using a weighted iterative nonlinear squares regression.
  • MCF-7 human breast cancer cells were obtained from the American Type Culture Collection # HTB 22 at passage 147 and routinely grown in phenol red-free Dulbecco's Modified Eagle's-Ham's F12 medium, the supplements mentioned above and 5% FBS.
  • the MCF-7 human breast adenocarcinoma cell line was derived from the pleural effusion of a Caucasian 69-year-old female patient. MCF-7 cells were used between passages 148 and 165 and subcultured weekly
  • Cells in their late logarithmic growth phase were harvested with 0.1% pancreatin (Sigma) and resuspended in the appropriate medium containing 50 ng bovine insulin/ml and 5% (v/v) FBS treated twice with dextran-coated charcoal to remove endogenous steroids.
  • Cells were plated in 24-well Falcon plastic culture plates (2 cm 2 /well) at the indicated density and allowed to adhere to the surface of the plates for 72 h. Thereafter, medium was replaced with fresh medium containing the indicated concentrations of compounds diluted from 1000 ⁇ stock solutions in 99% redistilled ethanol in the presence or absence of E 2 .
  • Control cells received only the ethanolic vehicle (0.1% EtOH, v/v). Cells were incubated for the specified time intervals with medium changes at 2- or 3-day intervals. Cell number was determined by measurement of DNA content.
  • Dose-response curves as well IC 50 values were calculated using a weighted iterative nonlinear least-squares regression. All results are expressed as means ⁇ SEM.
  • the objective of this example was to compare the agonistic and antagonistic effects of EM-652.HCl and six other oral antiestrogens (SERMs) on the growth of the well-characterized estrogen-sensitive ZR-75-1 breast cancer xenografts in ovariectomized nude mice.
  • SERMs oral antiestrogens
  • ZR-75-1 human breast cancer cells were obtained from the American Type Culture Collection (Rockville, Md.) and cultured in phenol red-free RPMI-1640 medium. The cells were supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 100 IU penicillin/ml, 100 ⁇ g streptomycin/ml, and 10% (v/v) fetal bovine serum and incubated under an humidified atmosphere of 95% air/5% CO2 at 37° C. Cells were passaged weekly and harvested at 85-90% confluence using 0.083% pancreatin/0.3 mM EDTA.
  • mice Homozygous female nu/nu Br athymic mice (28- to 42-day old) were obtained from Charles River, Inc. (Saint-Constant, Québec, Canada). The mice (5 per cage) were housed in vinyl cages equipped with air filter lids, which were kept in laminar airflow hoods and maintained under pathogen-limiting conditions. The photoperiod was 12 hours of light and 12 hours of darkness (lights on at 07:15). Cages, bedding and food (Agway Pro-Lab R-M-H Diet #4018) were autoclaved before use. Water was autoclaved and provided ad libitum. Bilateral ovariectomy was performed under isoflurane-induced anesthesia.
  • E 2 estradiol
  • E 2 implants were prepared in 1 cm-long Silastic tubing (inside diameter: 0.062 inch; outside diameter: 0.095 inch) containing 0.5 cm of a 1:10 (w/w) mixture of estradiol and cholesterol.
  • 2 ⁇ 10 6 ZR-75-1 (passage 93) cells were inoculated subcutaneously in 0.1 ml of RPMI-1640 medium+30% Matrigel on both flanks of each ovariectomized (OVX) mouse through a 2.5-cm-long 22-gauge needle.
  • the E 2 implants were replaced in all animals by estrone-containing implants of the same size (E1:chol, 1:25, w:w). Randomization and treatments were started one week later.
  • mice bearing ZR-75-1 tumors of an average area of 24.4 ⁇ 0.4 mm2 were randomly assigned to 17 groups (with respect to tumor size), each containing 15 mice (total of 29 or 30 tumors).
  • the 17 groups included two control groups (OVX and OVX+Estrone), seven groups supplemented with an estrone implant and treated with an antiestrogen and eight other groups that received an antiestrogen alone.
  • the estrone implants were then removed from the animals in the ovariectomized control group (OVX) and in groups that were to receive the antiestrogen alone. Estrone-containing implants in the nine other groups were changed thereafter every 6 weeks.
  • EM-652 ⁇ HCl, raloxifene, droloxifene, idoxifene and GW 5638 were synthesized in the medicinal chemistry division of the Oncology and Molecular Endocrinology Research Center. Tamoxifen was purchased from Plantex (Netanya, fran ⁇ l) while toremifene citrate was purchased from Orion (Espoo, Finland). Under estrone stimulation, the antiestrogens were given at the daily oral dose of 50 ⁇ g (2 mg/kg, on average) suspended in 0.2 ml of 0.4% (w/v) methylcellulose. In the absence of estrone stimulation, animals were treated with 200 ⁇ g (8 mg/kg on average) of each antiestrogen once daily by the oral route.
  • tumor area (mm2) was calculated using the formula: L/2 ⁇ W/2 ⁇ .
  • the area measured on the first day of treatment was taken as 100%.
  • estrogen-responsive tissues such as the uterus and vagina
  • the uteri were prepared to evaluate endometrial thickness by image analysis performed with Image Pro-Plus (Media Cybernetics, Maryland, USA). In brief, uteri were fixed in 10% formalin and embedded in parafin. Hematoxylin- and eosin-stained sections of mice uteri were analyzed. Four images per uterus (2 per uterine horn) were analyzed. Mean epithelial cell height was measured in all animals of each group.
  • Tumor response was assessed at the end of the study or at death of each animal, if it occurred during the course of the experiment. In this case, only data of mice that survived for at least half of the study (84 days) were used in the tumor response analysis. In brief, complete regression identifies those tumors that were undetectable at the end of the experiment; partial regression corresponds to the tumors that regressed ⁇ 50% of their original size; stable response refers to tumors that regressed ⁇ 50% or progressed ⁇ 50%; and progression refers to tumors that progressed ⁇ 50% compared with their original size.
  • the change in total tumors surface areas between day 1 and day 161 were analyzed according to an ANOVA for repeated measurements.
  • the model included the treatment, time, and time-treatment interaction effects plus the term to account for the strata at randomization.
  • the significance of the different treatments effects at 161 days was thus tested by the time-treatment interaction.
  • Analysis of the residuals indicated that the measurements on the original scale were not fitted for analysis by an ANOVA nor any of the transformations that were tried. The ranks were therefore selected for the analyses.
  • the effect of the treatments on the epithelial thickness was assessed by a one-way ANOVA including also the strata at randomization.
  • a posteriori pairwise comparisons were performed using least square means statistics.
  • the overvall type 1 error rate (a) was controlled at 5% to declare significance of the differences. All calculations were performed using Proc MIXED on the SAS Software (SAS Institute, Carry, N.C.).
  • Estrone alone caused a 707% increase in ZR-75-1 tumor size during the 23 week-treatment period ( FIG. 18 ).
  • Administration of the pure antiestrogen EM-652 ⁇ HCl at the daily oral dose of 50 ⁇ g to estrone-stimulated mice completely prevented tumor growth. In fact, not only tumor growth was prevented but after 23 weeks of treatment, tumor size was 26% lower than the initial value at start of treatment (p ⁇ 0.04). This value obtained after treatment with EM-652 ⁇ HCl was not statistically different from that observed after ovariectomy alone (OVX) where tumor size decreased by 61% below initial tumor size. At the same dose (50 ⁇ g) and treatment period, the six other antiestrogens did not decrease initial average tumor size.
  • Tumors in these groups were all significantly higher than the OVX control group and to the EM-652 ⁇ HCl-treated group (p ⁇ 0.01).
  • 23 weeks of treatment with droloxifene, toremifene, GW 5638, raloxifene, tamoxifen and idoxifene led to average tumor sizes 478%, 230%, 227%, 191%, 87% and 86% above pretreatment values, respectively ( FIG. 18 ).
  • the height of the endometrial epithelial cells was measured as the most direct parameter of agonistic and antagonistic effect of each compound in the endometrium.
  • EM-652 ⁇ HCl inhibited the stimulatory effect of estrone on epithelial height by 70%.
  • the efficacy of the six other antiestrogens tested were significantly lower (p ⁇ 0.01).
  • droloxifene, GW 5638, raloxifene, tamoxifen, toremifene and idoxifene inhibited estrone stimulation by 17%, 24%, 26%, 32%, 41% and 50%, respectively. (Table 12).
  • EM-652 ⁇ HCl and droloxifene were the only compounds tested that did not significantly increase the height of epithelial cells (114% and 101% of the OVX control group value, respectively).
  • Tamoxifen (155%), toremifene (135%) and idoxifene (176%) exerted a significant stimulation of uterine epithelial height (p ⁇ 0.01 vs OVX control group).
  • Raloxifene (122%) and GW 5638 (121%) also exerted a statistically significant stimulation of uterine epithelial height (p ⁇ 0.05 vs OVX control group (Table 12).
  • the agonistic and antagonistic effects of each antiestrogen measured on uterine and vaginal weight were in accordance with the pattern observed on uterine epithelium thickness (Data not shown).
  • Example 8 shows the radioactivity in brain of rats following single oral dose of 14 C-EM-800 (20 mg/kg), a SERM of the present invention.
  • values for the blood, plasma, liver (Table 13) and uterus from each of these animals were included.
  • Tissue Distribution and Excretion of Radioactivity Following a Single Oral Dose of 14 C-EM-800 (20 mg/2 ml/kg) to Male and Female Long-Evans Rats were included.
  • radioactivity in the brain was 412 lower than in liver, 21 times lower than in the uterus, 8.4 times lower that in the blood and 13 times lower than in plasma. Since an unknown proportion of total brain radioactivity is due to contamination by blood radioactivity, the values shown in Table X 1 for brain radioactivity are an overestimate of the level of 14 C (EM-800)-related radioactivity in the brain tissue itself. Such data suggest that the level of the antiestrogen in the brain tissue is too low, to counteract the effect of exogenous estrogen. It is important to note that some of the radioactivity detected in the brain tissue may be due to residual blood in the tissue (Table 14). Additionally, the radiochemical purity of the 14 C-EM-800 used for this study was minimally 96.25%.
  • the primary endpoint was the change from Baseline in the weekly frequency of moderate to severe hot flushes at Week 16, after four months of treatment.
  • the objectives also included the change from Baseline in the weekly frequency of all hot flushes and the change from Baseline in the weekly weighted severity score.
  • the secondary endpoints were the safety evaluation of DHEA as well as quality of life.
  • the response endpoint is the patient's paper diary which was filled in daily to specify the number and type of hot flushes as follows:
  • the hot flush diary began as a Screening diary for two weeks prior to randomization whereby patients had to complete the diary daily, recording the number and severity of hot flushes. The patients had to record an average of 50 or more moderate or severe hot flushes per week over the two-week period to be eligible (i.e., at least 100 hot flushes documented on the two week Screening diary).
  • the patient completed eight, two-week hot flush diaries upon beginning study medication.
  • the diaries had to be filled out on a daily basis.
  • the first diary was completed over the first two weeks and be returned on the two week visit.
  • the second two-week diary was completed over the next two weeks of the first four week treatment period and was returned at the four week visit.
  • two two-week diaries for hot flushes were collected.
  • Diary and blinded medication began on the same day (ie, on day 1. The patient began recording hot flushes when she woke up on the same day she planned to begin taking the study medication).
  • the number of moderate to severe hot flushes decreased from 70.7 ⁇ 4.5 per week at screening to 50.1 ⁇ 5.7 at week 4 (N.S. US placebo), 40.2 ⁇ 6.1 at week 8, 34.7 ⁇ 5.8 at week 12 (p ⁇ 0.05 vs placebo) and 32.2 ⁇ 5.8 at week 16 (p ⁇ 0.0.5 vs placebo).
  • Placebo cause a 32.9% decrease compared to 54.5% for DHEA.
  • the present data demonstrated the efficacy of 50 mg DHEA treatment for alleviating vasomotor symptoms as assessed by the significant decrease in the total number of moderate to severe hot flushes or all hot flushes, as well as by the significant reduction of the hot flush weekly severity weighted score.
  • the primary objective of that study was measurement of the maturation value of the vaginal epithelial cells following daily intravaginal application of DHEA. Forty postmenopausal women were randomized to receive a daily dose of one ovule of the following DHEA concentrations: 0.0%, 0.5% (6.5 mg of DHEA/ovule), 1.0% (13 mg of DHEA/ovule) or 1.8% (23.4 mg of DHEA/ovule) for 7 days. The systemic bioavailability of DHEA and its metabolites were also measured.
  • the maturation index increased by 107% (p ⁇ 0.01), 75% (p ⁇ 0.05) and 150% (p ⁇ 0.01) in the 0.5%, 1.0% and 1.8% DHEA groups, respectively ( FIG. 26 ).
  • Vaginal pH decreased from 6.29 ⁇ 0.21 to 5.75 ⁇ 0.27 (p ⁇ 0.05), 6.47 ⁇ 0.23 to 5.76 ⁇ 0.22 (p ⁇ 0.01) and 6.53 ⁇ 0.25 to 5.86 ⁇ 0.28 (p ⁇ 0.05), respectively in the 0.5%, 1.0% and 1.8% DHEA groups ( FIG. 27 ). No change of vaginal pH was observed in the placebo group.
  • the present data show that the intravaginal administration of DHEA permits to rapidly achieve the beneficial effects against vaginal atrophy without significant changes of serum estrogens, thus avoiding the increased risk of breast cancer associated with the current intravaginal or systemic estrogenic formulations and adding the local benefits on all the layers of the vagina of the recently recognized androgenic component of DHEA action in this tissue.
  • compositions utilizing preferred active SERM Acolbifene (EM-652.HCl; EM-1538) and preferred active sex steroid precursor dehydroepiandrosterone (DHEA, Prasterone).
  • active SERM Acolbifene EM-652.HCl; EM-1538
  • DHEA preferred active sex steroid precursor dehydroepiandrosterone
  • Other compounds of the invention or combination thereof may be used in place of (or in addition to) Acolbifene or dehydroepiandrosterone.
  • concentration of active ingredient may be varied over a wide range as discussed herein.
  • the amounts and types of other ingredients that may be included are well known in the art.
  • composition for orally administration (capsules) Weight % (by weight of Ingredient total composition) Acolbifene 5.0 DHEA 10.0 Lactose hydrous 70.0 Starch 4.8 Cellulose microcrystalline 9.8 Magnesium stearate 0.4
  • composition for orally administration tablettes
  • Weight % by weight of Ingredient total composition
  • Topical administration (cream) Weight % (by weight of Ingredient total composition) DHEA 1.0 Acolbifene 0.2 Emulsifying Wax, NF 18.0 Light mineral oil, NF 12.0 Benzyl alcohol 1.0 Ethanol 95% USP 33.8 Purifed water, USP 34.0
  • Vaginal administration Vaginal suppository or ovule Weight % (by weight of Ingredient total composition) DHEA 0.25 to 2.0 Acolbifene 0.25 to 3.0 Witepsol H-15 base 95.0 to 99.5
  • DHEA suppositories were prepared using Witepsol H-15 base (Medisca, Montreal, Canada). Any other lipophilic base such as Hard Fat, Fattibase, Wecobee, cocoa butter, theobroma oil or other combinations of Witepsol bases could used.
  • Preferred SERMs are EM-800, and Acolbifene
  • kits utilizing preferred active SREM Acolbifene, preferred antiestrogen Faslodex and preferred active a sex steroid precursor DHEA are several kits utilizing preferred active SREM Acolbifene, preferred antiestrogen Faslodex and preferred active a sex steroid precursor DHEA.
  • concentration of active ingredient may be varied over a wide range as discussed herein.
  • the amounts and types of other ingredients that may be included are well known in the art.
  • the SERM and sex steroid precursor are orally administered Non-Steroidal Antiestrogen composition for oral administration (capsules)
  • Magnesium stearate 0.4 +DHEA composition for oral administration (Gelatin capsule) DHEA 25.0 Lactose hydrous 27.2 Sodium Starch Glycolate 20.0 Microcrystalline Cellulose, Colloidal 27.2 Silicon Dioxide, Silica Colloidal Anhydrous and Light Anhydrous Silicic Acid Colloidal Silicon Dioxide 0.1
  • SERMs may be substituted for Acolbifene in the above formulations, as well as other sex steroid precursors may be substituted for DHEA. More than one SERM or more than one sex steroid precursor may be included in which case the combined weight percentage is preferably that of the weight percentage for the single sex steroid precursor or single SERM given in the examples above.
  • the SERM is orally administered and the sex steroid precursor is intra vaginally administered SERM composition for oral administration (capsules)
  • DHEA suppositories were prepared using Witepsol H-15 base (Medisca, Montreal, Canada). Any other lipophilic base such as Hard Fat, Fattibase, Wecobee, cocoa butter, theobroma oil or other combinations of Witepsol bases could used.
  • the SERM and the sex steroid precursor are intra vaginally administered Vaginal suppository DHEA 0.25 to 2.0 Witepsol H-15 base 98 to 99.75 +Vaginal suppository Acolbifene 0.3 to 3.0 Hard Fat 97.0 to 99.7
  • Acolbifene suppositories were prepared using Hard Fat (Witepsol). Any other bases such as Fattibase, Wecobee, cocoa butter, theobroma oil or other combinations of Hard Fat could be used.
  • the SERM is orally administered and the sex steroid precursor is percutaneously administered SERM composition for oral administration (capsules)
  • Acolbifene 5.0 Lactose hydrous 80.0 Starch 4.8 Cellulose microcrystalline 9.8 Magnesium stearate 0.4 +sex steroid precursor composition for oral administration (gel)
  • DHEA 2.0 Caprylic-capric Triglyceride (Neobee M-5) 5.0 Hexylene Glycol 15.0 Transcutol (diethyleneglycol monomethyl ether) 5.0 Benzyl alcohol 2.0 Cyclomethicone (Dow corning 345) 5.0 Ethanol (absolute) 64.0 Hydroxypropylcellulose (1500 cps) (KLUCEL) 2.0 or Sex steroid precursor composition for oral administration (cream) Formulation EM-760-48-1.0% Cyclometicone 5.0% Light mineral oil 3.0% 2-ethylhexyl stearate 10.0% Cutina E
  • the antiestrogen is intramuscularly administered and sex steroid precursor is orally administered
  • Commercially available steroidal Antiestrogen Faslodex + DHEA composition for oral administration (Gelatin capsule) Weight % (by weight of Ingredient total composition) DHEA 25.0 Lactose hydrous 27.2 Sodium Starch Glycolate 20.0 Microcrystalline Cellulose, Colloidal 27.2 Silicon Dioxide, Silica Colloidal Anhydrous and Light Anhydrous Silicic Acid Colloidal Silicon Dioxide 0.1 Magnesium stearate 0.5
  • SERMs may be substituted for Acolbifene in the above formulations, as well as other sex steroid inhibitors may be substituted for DHEA.
  • More than one SERM or more than one precursor may be included in which case the combined weight percentage is preferably that of the weight percentage for the single precursor or single SERM given in the examples above.

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US12/791,174 US20100317635A1 (en) 2009-06-16 2010-06-01 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
TW099119438A TWI612044B (zh) 2009-06-16 2010-06-15 以性類固醇前驅物組合選擇性雌激素受體調節物治療熱潮紅、血管舒縮症狀及夜汗之技術
KR1020167015258A KR20160072269A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 안면 홍조, 혈관 운동성 증상 및 도한증의 치료
KR1020157034399A KR20150141195A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 알츠하이머병, 인지 상실, 기억 상실 및 치매의 치료
PCT/CA2010/000898 WO2010145010A1 (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
SG2012000410A SG177497A1 (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
EP20158118.8A EP3682880A1 (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
ARP100102137A AR077119A1 (es) 2009-06-16 2010-06-16 Tratamiento de sofocos, sintomas vasomotores y sudores nocturnos con precursores de esteroides sexuales en combinacion con moduladores selectivos del receptor de estrogenos. composicion farmaceutica. conjunto de elementos.
CA2893236A CA2893236A1 (en) 2009-06-16 2010-06-16 Treatment of alzheimer's disease, loss of cognition, memory loss and dementia with sex steroid precursors in combination with selective estrogen receptor modulators
CN201710016998.8A CN107468695A (zh) 2009-06-16 2010-06-16 以性类固醇前体组合选择性雌激素受体调节物治疗热潮红、血管舒缩症状及夜汗的技术
MX2011013689A MX338290B (es) 2009-06-16 2010-06-16 Tratamiento de enfermedad de alzheimer, perdida de cognición, perdida de memoria y demencia con precursores de esteroides sexuales en conbinación con moduladores selectivos del receptor de estrógenos.
KR1020177034988A KR20170138584A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 안면 홍조, 혈관 운동성 증상 및 도한증의 치료
CN2010800271605A CN102458404A (zh) 2009-06-16 2010-06-16 以性类固醇前驱物组合选择性雌激素受体调节物治疗热潮红、血管舒缩症状及夜汗的技术
SG10201705761YA SG10201705761YA (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
KR1020217012518A KR20210048609A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 안면 홍조, 혈관 운동성 증상 및 도한증의 치료
KR1020197021846A KR20190090088A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 안면 홍조, 혈관 운동성 증상 및 도한증의 치료
EP17151727.9A EP3178480A1 (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
EP10788551.9A EP2442807A4 (en) 2009-06-16 2010-06-16 TREATMENT OF HEAT BURSTS, VASOMOTOR SYMPTOMS AND NOCTURNED SWEATERS BY SEXUAL STEROID PRECURSORS IN COMBINATION WITH STROGEN RECEPTOR SELECTIVE MODULATORS
SG10201912379PA SG10201912379PA (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
CN201410386309.9A CN104352504A (zh) 2009-06-16 2010-06-16 以性类固醇前体组合选择性雌激素受体调节物治疗热潮红、血管舒缩症状及夜汗的技术
KR1020147011740A KR20140070650A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 안면 홍조, 혈관 운동성 증상 및 도한증의 치료
CA2765446A CA2765446A1 (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
EA201200016A EA201200016A1 (ru) 2009-06-16 2010-06-16 Лечение приливов, вазомоторных симптомов и ночной потливости с помощью предшественников половых стероидов в комбинации с избирательными (селективными) модуляторами эстрогеновых рецепторов
KR1020197006112A KR20190025752A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 알츠하이머병, 인지 상실, 기억 상실 및 치매의 치료
MA34540A MA33434B1 (fr) 2009-06-16 2010-06-16 Traitement de bouffées de chaleur, de symptômes vasomoteurs et de sueurs nocturnes par des précurseurs de stéroïdes sexuels en combinaison avec des modulateurs sélectifs du récepteur de l'oestrogène
AU2010262722A AU2010262722A1 (en) 2009-06-16 2010-06-16 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
KR1020177017880A KR20170078879A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 알츠하이머병, 인지 상실, 기억 상실 및 치매의 치료
KR1020127001215A KR20120097470A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 안면 홍조, 혈관 운동성 장애 및 도한증의 치료
JP2012515300A JP2012530074A (ja) 2009-06-16 2010-06-16 性ステロイド前駆体と選択的エストロゲン受容体モジュレーターとの組み合わせによるホットフラッシュ、血管運動症状及び寝汗の治療
NZ597583A NZ597583A (en) 2009-06-16 2010-06-16 Treatment of alzheimer’s disease, loss of cognition, memory loss and dementia with sex steroid precursors in combination with selective estrogen receptor modulators
KR1020207026222A KR20200108505A (ko) 2009-06-16 2010-06-16 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 알츠하이머병, 인지 상실, 기억 상실 및 치매의 치료
IL216963A IL216963A (en) 2009-06-16 2011-12-13 Preparations containing a sex steroid precursor with a variety of estrogen receptor receptors and their uses
CL2011003172A CL2011003172A1 (es) 2009-06-16 2011-12-15 Composicion farmaceutica que comprende a) un excepiente, b) al menos un precursor de esteroides sexuales, c) al menos un modulador selectivo del receptor de estrogenos o una antiestrogeno y no contiene una progestina y/o un estrogeno; kit farmaceutico; y uso para reducir o eliminar sofocos, sintomas vasomotores y sudores nocturnos.
HK15104344.8A HK1204550A1 (en) 2009-06-16 2012-08-24 Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
US13/875,027 US10342805B2 (en) 2009-06-16 2013-05-01 Treatment of Alzheimer's disease, loss of cognition, memory loss and dementia with sex steroid precursors in combination with selective estrogen receptor modulators
JP2014025183A JP2014088442A (ja) 2009-06-16 2014-02-13 性ステロイド前駆体と選択的エストロゲン受容体モジュレーターとの組み合わせによるアルツハイマー病、認知機能の喪失、記憶喪失及び痴呆症の治療
JP2015223062A JP2016029101A (ja) 2009-06-16 2015-11-13 性ステロイド前駆体と選択的エストロゲン受容体モジュレーターとの組み合わせによるホットフラッシュ、血管運動症状及び寝汗の治療
IL248245A IL248245A0 (en) 2009-06-16 2016-10-09 Preparations containing a sex steroid precursor with a selective estrogen receptor variety and uses thereof
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9018244B2 (en) 2011-12-16 2015-04-28 Olema Pharmaceuticals, Inc. Benzopyran compounds, compositions and uses thereof
US10519143B2 (en) 2016-03-25 2019-12-31 Luoxin Pharmaceutical (Shanghai) Co., Ltd. Substituted-indole-compounds as estrogen receptor down-regulators
US10548903B2 (en) 2014-03-10 2020-02-04 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM
US10881650B2 (en) 2007-08-10 2021-01-05 Endorecherche, Inc. Pharmaceutical compositions

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
EP2734193B1 (en) * 2011-07-19 2015-05-20 Pantarhei Bioscience B.V. Tablet containing dehydroepiandrosterone (dhea)
AU2012351942B2 (en) 2011-12-14 2017-07-06 Seragon Pharmaceuticals, Inc. Fluorinated estrogen receptor modulators and uses thereof
WO2013134311A1 (en) * 2012-03-07 2013-09-12 Ligand Pharmaceuticals, Inc. Steroid hormone and cholesterol pathways as one unified homestatic system
WO2014008159A1 (en) * 2012-07-03 2014-01-09 The University Of North Carolina At Chapel Hill Selective estrogen receptor degraders for treatment of tamoxifen resistant tumors
WO2014203129A1 (en) 2013-06-19 2014-12-24 Olema Pharmaceuticals, Inc. Combinations of benzopyran compounds, compositions and uses thereof
WO2014203132A1 (en) 2013-06-19 2014-12-24 Olema Pharmaceuticals, Inc. Substituted benzopyran compounds, compositions and uses thereof
CN103739456A (zh) * 2013-12-03 2014-04-23 镇江圣安医药有限公司 2-（对-（（z-4-氯-1,2-二苯基-1-丁烯基）苯氧基）乙醇的新型衍生物及其应用
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WO2017201508A1 (en) 2016-05-20 2017-11-23 Azure Biotech, Inc. Vaginal delivery systems containing selective estrogen receptor modulator (serm) and uses thereof
SG11202002105WA (en) 2017-09-11 2020-04-29 Atossa Therapeutics Inc Methods for making and using endoxifen
CN111212631A (zh) * 2017-09-11 2020-05-29 阿托莎医疗公司 局部用组合物和治疗方法
WO2022203097A1 (ko) * 2021-03-24 2022-09-29 디어젠 주식회사 스트레스 과립의 조절제인 atxn2를 제어하여 tdp-43 단백질의 과잉생산을 억제하는 중추신경계질환의 예방 및 치료 조성물

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3742951A (en) * 1971-08-09 1973-07-03 Alza Corp Bandage for controlled release of vasodilators
US3797444A (en) * 1971-04-19 1974-03-19 H Stubbs Towing guide
US4568343A (en) * 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
US4624665A (en) * 1984-10-01 1986-11-25 Biotek, Inc. Method of transdermal drug delivery
US4666441A (en) * 1985-12-17 1987-05-19 Ciba-Geigy Corporation Multicompartmentalized transdermal patches
US5064654A (en) * 1989-01-11 1991-11-12 Ciba-Geigy Corporation Mixed solvent mutually enhanced transdermal therapeutic system
US5071644A (en) * 1990-08-07 1991-12-10 Mediventures, Inc. Topical drug delivery with thermo-irreversible gels
US5071657A (en) * 1983-09-12 1991-12-10 Schering Aktiengesellschaft Device for transdermal administration of active medicinal agents
US5135480A (en) * 1986-07-10 1992-08-04 Elan Transdermal Limited Transdermal drug delivery device
US5154922A (en) * 1988-12-01 1992-10-13 Schering Corporation Compositions for transdermal delivery of estradiol
US5162037A (en) * 1988-04-01 1992-11-10 Whitson Laboratories, Inc. Magnetically influenced homeopathic pharmaceutical formulations, methods of their preparation and methods of their administration
US5776923A (en) * 1993-01-19 1998-07-07 Endorecherche, Inc. Method of treating or preventing osteoporosis by adminstering dehydropiandrosterone
WO2000074684A1 (en) * 1999-06-04 2000-12-14 The General Hospital Corporation Pharmaceutical formulations for treating postmenopausal and perimenopausal women, and their use
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US20020198179A1 (en) * 2000-01-28 2002-12-26 Endorecherche, Inc. Selective estrogen receptor modulators in combination with estrogens
US6710059B1 (en) * 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
US20070270394A1 (en) * 2004-10-20 2007-11-22 Endorecherche, Inc. Sex steroid precursor alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
US20090054383A1 (en) * 2007-08-10 2009-02-26 Endorecherche, Inc. Pharmaceutical compositions

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US60503A (en) 1866-12-18 Improvement in olaips foe gluing the tips on billiard cues
CA1254514A (en) 1984-06-29 1989-05-23 Eugene Roberts Method for promoting nerve regeneration
US4725439A (en) 1984-06-29 1988-02-16 Alza Corporation Transdermal drug delivery device
US4816258A (en) 1987-02-26 1989-03-28 Alza Corporation Transdermal contraceptive formulations
US5707983A (en) 1990-08-29 1998-01-13 Humanetics Corporation Treatment of alzheimer's disease and modulation of immune system with Δ5-androstenes
US5292730A (en) * 1990-08-29 1994-03-08 Humanetics Corporation Modulation of immune system with Δ5-androstenes
US6060503A (en) 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
DE69433994T2 (de) 1993-01-19 2005-09-22 Endorecherche Inc., Ste-Foy Therapeutische verwendungen und verabreichungsysteme von dehydroepiandrosteron
AU6513196A (en) 1995-07-11 1997-02-10 Ansaldo Volund A/S A stirling machine
IL124882A0 (en) 1996-01-11 1999-01-26 Novo Nordisk As Use of 3, 4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms
US5883118A (en) 1996-01-11 1999-03-16 Nova Nordisk A/S Prostatic carcinoma
EP0873119A1 (en) 1996-01-11 1998-10-28 Novo Nordisk A/S Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer
US5747059A (en) 1996-01-11 1998-05-05 Novo Nordisk A/S Atrophy of skin/mucous membrane
US5726202A (en) 1996-01-11 1998-03-10 Novo Nordisk A/S Benign prostatic hypertrophy
WO1997032837A1 (fr) 1996-03-06 1997-09-12 Sumitomo Pharmaceuticals Co., Ltd. Derives estrogenes non steroidiens
SK281737B6 (sk) 1996-04-19 2001-07-10 American Home Products Corporation 2-fenylindolové zlúčeniny, farmaceutický prostriedok s ich obsahom a ich použitie
TW397821B (en) 1996-04-19 2000-07-11 American Home Produits Corp 3-[4-(2-phenyl-indole-1-ylmethyl)-phenyl]-acrylamides and 2-phenyl-1-[4-(amino-1-yl-alk-1-ynyl)-benzyl]-1H-indol-5-ol as well as pharmaceutical compositions of estrogenic agents thereof
US6150381A (en) 1998-06-09 2000-11-21 R.J. Reynolds Tobacco Company Methods of treating microbial infection and therapeutic formulations therefor
TR200100063T2 (tr) * 1998-06-11 2001-05-21 Endorecherche, Inc Androst-5-en-3ß,17ß-diol için farmasötik kompozisyonlar ve kullanımlar
WO2001026651A2 (en) * 1999-10-14 2001-04-19 Endorecherche, Inc. Selective estrogen receptor modulators in the treatment or reduction of the risk of acquiring hypertension, cardiovascular diseases, and insulin resistance
GB0000313D0 (en) 2000-01-10 2000-03-01 Astrazeneca Uk Ltd Formulation
US20040198706A1 (en) * 2003-03-11 2004-10-07 Carrara Dario Norberto R. Methods and formulations for transdermal or transmucosal application of active agents
AU2003223754B2 (en) * 2002-04-30 2007-08-16 Merck Sharp & Dohme Corp. 4-azasteroid derivatives as androgen receptor modulators
RU2005113238A (ru) 2002-10-01 2006-01-20 Дайниппон Фармасьютикал Ко., Лтд. (JP) Спиросоединения, содержащие их лекарственные композиции и промежуточные соединения указанных соединений
US20040121991A1 (en) 2002-12-20 2004-06-24 Araneo Barbara A. Dehydroepiandrosterone (DHEA) congeners for prevention and/or treatment of ulcers
TW200526684A (en) * 2003-11-21 2005-08-16 Schering Corp Anti-IGFR1 antibody therapeutic combinations
UA85862C2 (uk) 2004-01-22 2009-03-10 Елі Ліллі Енд Компані Селективні модулятори рецепторів естрогену для лікування вазомоторних симптомів
JP2008504263A (ja) * 2004-06-23 2008-02-14 メルク　エンド　カムパニー　インコーポレーテッド エストロゲン受容体モジュレーター
US20070248590A1 (en) 2005-12-02 2007-10-25 Sirtris Pharmaceuticals, Inc. Modulators of CDC2-like kinases (CLKS) and methods of use thereof
CN101489563A (zh) 2006-07-06 2009-07-22 拜耳先灵医药股份有限公司 用于避孕和预防先天性畸形风险的药物制剂
AU2012204083C1 (en) 2007-08-10 2015-02-05 Myriel Pharmaceuticals, Llc DHEA compositions for treating menopause
US9744177B2 (en) 2014-03-10 2017-08-29 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3797444A (en) * 1971-04-19 1974-03-19 H Stubbs Towing guide
US3742951B1 (ko) * 1971-08-09 1982-11-23
US3742951A (en) * 1971-08-09 1973-07-03 Alza Corp Bandage for controlled release of vasodilators
US5071657A (en) * 1983-09-12 1991-12-10 Schering Aktiengesellschaft Device for transdermal administration of active medicinal agents
US4624665A (en) * 1984-10-01 1986-11-25 Biotek, Inc. Method of transdermal drug delivery
US4568343A (en) * 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
US4666441A (en) * 1985-12-17 1987-05-19 Ciba-Geigy Corporation Multicompartmentalized transdermal patches
US5135480A (en) * 1986-07-10 1992-08-04 Elan Transdermal Limited Transdermal drug delivery device
US5162037A (en) * 1988-04-01 1992-11-10 Whitson Laboratories, Inc. Magnetically influenced homeopathic pharmaceutical formulations, methods of their preparation and methods of their administration
US5154922A (en) * 1988-12-01 1992-10-13 Schering Corporation Compositions for transdermal delivery of estradiol
US5064654A (en) * 1989-01-11 1991-11-12 Ciba-Geigy Corporation Mixed solvent mutually enhanced transdermal therapeutic system
US5071644A (en) * 1990-08-07 1991-12-10 Mediventures, Inc. Topical drug delivery with thermo-irreversible gels
US5776923A (en) * 1993-01-19 1998-07-07 Endorecherche, Inc. Method of treating or preventing osteoporosis by adminstering dehydropiandrosterone
US6670346B1 (en) * 1998-06-11 2003-12-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
WO2000074684A1 (en) * 1999-06-04 2000-12-14 The General Hospital Corporation Pharmaceutical formulations for treating postmenopausal and perimenopausal women, and their use
US6710059B1 (en) * 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
US20030065008A1 (en) * 2000-01-28 2003-04-03 Endorecherche, Inc. Selective estrogen receptor modulators in combination with estrogens
US20030040510A1 (en) * 2000-01-28 2003-02-27 Endorecherche, Inc. Selective estrogen receptor modulators in combination with estrogens
US20020198179A1 (en) * 2000-01-28 2002-12-26 Endorecherche, Inc. Selective estrogen receptor modulators in combination with estrogens
US20070270394A1 (en) * 2004-10-20 2007-11-22 Endorecherche, Inc. Sex steroid precursor alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
US20090054383A1 (en) * 2007-08-10 2009-02-26 Endorecherche, Inc. Pharmaceutical compositions
US20120322778A1 (en) * 2007-08-10 2012-12-20 Endorecherche, Inc. Pharmaceutical compositions

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Structure-Activity Relationship and Drug Design." Remington's Pharmaceutical Sciences (Sixteenth Edition). Mack Publishing, 1980, pages 420-425. *
Adelson et al. Treatment of hot flushes in breast and prostate cancer. Expert Opin. Pharmacother. 2005, 6(7): 1095-1106. *
Barton et al (Supportive Cancer Therapy, 2006; 3(2):91-97) (Year: 2006) *
Berge et al. "Pharmaceutical Salts." Journal of Pharmaceutical Sciences, 66(1); 1977:1-19. *
Berger et al. Effects of dehydroepiandrosterone, premarin and acolbifene on histomorphology and sex steroid receptors in the rat vagina. Journal of Steroid Biochemistry & Molecular Biology, 96, 2005, 201-215. *
Liu et al. Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem. Res. Toxicol. 2005, 18, 174-182. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10881650B2 (en) 2007-08-10 2021-01-05 Endorecherche, Inc. Pharmaceutical compositions
US9018244B2 (en) 2011-12-16 2015-04-28 Olema Pharmaceuticals, Inc. Benzopyran compounds, compositions and uses thereof
US10548903B2 (en) 2014-03-10 2020-02-04 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM
US10519143B2 (en) 2016-03-25 2019-12-31 Luoxin Pharmaceutical (Shanghai) Co., Ltd. Substituted-indole-compounds as estrogen receptor down-regulators

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