CA2264943A1 - Novel methods - Google Patents
Novel methods Download PDFInfo
- Publication number
- CA2264943A1 CA2264943A1 CA002264943A CA2264943A CA2264943A1 CA 2264943 A1 CA2264943 A1 CA 2264943A1 CA 002264943 A CA002264943 A CA 002264943A CA 2264943 A CA2264943 A CA 2264943A CA 2264943 A1 CA2264943 A1 CA 2264943A1
- Authority
- CA
- Canada
- Prior art keywords
- cardiovascular disease
- formula
- compound
- effects
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A novel method for treating cardiovascular disease in postmenopausal women is described. Idoxifene is the preferred compound.
Description
WO 98/09619101520253035CA 02264943 1999-03-05PCT/US97/15475NVL DSFigld of the InventionThe present invention relates to therapeutic agents that are tissue selectiveestrogen agonist/antagonist compounds that have been found to be useful in thetreatment and prevention of cardiovascular disease in postmenopausal women.Background of the InventionThe decrease in estrogen that occurs at the menopause is an importantetiological factor in the increased incidence of cardiovascular disease inpostmenopausal women. Estrogen therapy after the menopause has been shown tohave beneï¬cial effects on a number of independent risk factors for cardiovasculardisease including serum levels of LDL-cholesterol and lipoprotein (a) (lp(a)) andplasma levels of fibrinogen. For references please see Levenson J et al. (1995),Arterioscler Thromb Vasc Biol, 15, 1263-1268. Kroon et al (1994), Thomb Hemost,71, 420-423. Ettinger B (1990) Obstet Gynecol Clinics of North America, 17, 741-757. Mendoza S et al (1994) J Lab Clin Med 123, 837-841. These effects mayexplain in part the epidemiological observations that estrogen therapy causes areduction in the incidence of cardiovascular disease. However unopposed estrogengiven alone increases the risk of endometrial cancer and may also be associated withan increased risk of breast cancer. For these reasons and because of troublesomeside effects (principally breast tenderness and vaginal bleeding) few womencontinue HRT for long enough to benefit from the cardioprotective effects. An idealtherapy would retain the desirable cardiovascular effects of estrogen without havingthe unwanted effects on reproductive tissues. Consequently, efforts have been madeto identify compounds that have tissueâselective estrogen agonist or antagonistproperties. Such tissue selective effects could produce the beneficial effects ofestrogen on risk factors for cardiovascular disease without the unwanted effects inbreast and uterine tissue.Summg 9f the InventionThis invention provides a method for the prevention and treatment ofcardiovascular disease in postmenopausal women without having an overtuterotrophic effect, or promoting an increased risk of breast cancer or causing anincreased incidence of vaginal bleeding and breast tenderness. The methodcomprises administering to a human in need thereof an effective amount of acompound of formula I-1-CA 02264943 1999-03-05WO 98/09619 PCTIUS97/15475(1)wherein X represents 3- or 4- iodo or bromo and the R1 and R2 symbols, which may5 be the same or different. represent C 1-3 alkyl, especially methyl or ethyl, groups orR1 represents a hydrogen atom and R2 a C 1_3 alkyl group or R1 and R2 togetherwith the nitrogen atom to which they are attached represent a saturated heterocyclicgroup, typically having 5 or 6 ring atoms, especially a pyrrolidino, piperidino, 4-methylpiperidino or morpholino group, and their pharmaceutically acceptable acid10 addition salts.Detailed Description of the InventionThe present invention is a therapeutic method for preventing and treatingcardiovascular disease in postmenopausal women with a group of compounds that15 have been previously prepared and evaluated as effective in the treatment of estrogenreceptor-positive breast cancer. These compounds are described in formula I aboveand in U.S. patent 4,839,155.The preferred compound for the described method of treatment isOK0 O "O OI(E)- l-{2-[4-[ l-(4-lodophenyl)-2-phenyl-1-butenyl]phenoxy]pyrrolidine20Such compounds are known to bind to the estrogen receptor and to cause25 either estrogen agonist or antagonist effects depending on the tissue being studied.A beneficial effect on cardiovascular disease would be produced by estrogen agonist-3-10152025WO 98109619CA 02264943 1999-03-05PCTIUS97/15475effects on the liver ( to alter the lipid proï¬le and levels of fibinogen). Howeverestrogen agonist effects on the arterial wall may also contribute to a reduction in therisk of cardiovascular disease.The term "cardiovascular disease" refers to atherosclerotic cardiovasculardiseases such as myocardial infarction, stroke. angina. intermittent claudicationtransient blindness. transient ischernic attacks (TIA) and peripheral vascular disease.The method of this invention is useful in producing a plasma lipid profile that isassociated with a reduced risk of atherosclerosis and a reduction of raised LDLcholesterol levels Additionally this method is useful in producing a reduction ofother independent cardiovascular risk factors such as plasma fibrinogen levels andserum levels of lp(a).The ability to reduce the risk of cardiovascular disease is assessed by studiesof the effect of idoxifene a number of different risk factors for cardiovascular diseasein postmenopausal women. These include different parameters of the lipid profileand levels of coagulation and fibrinolysis markers.Three different doses of idoxifene (2.5. 5 and 10mg/day) were comparedwith placebo in a study of three months duration in postmenopausal women.Changes in the levels of different lipid parameters, fibiinogen and othercoagulation/ï¬brinolysis parameters were measured before and after treatment. Theresults of this study are described below. All changes are described as percentagechange from the baseline value. Statistically significant differences from placeboare designated by the following notation: *=p<0.01, **=p<0.001.Placebo 2.5 5.0 10.0Total chol 0.5 (1.1) -0.9 (1.1) -4.2 (1.2)* -9.8 (l.l)**LDL-chol 1.3 (1.5) -1.3 (2.0) -4.7 (1.7)* -15.2 (1.6)**HDL-chol 2.4 (1.4) 2.7 (1.5) -1.4 (1.5) 0.8 (1.7)HDL/LDL ratio 2.2 (1.6) 7.1 (2.6) 5.2 (2.1) 21.7 (3.1)**lipoprotein (a) 5.0 (3.0) -2.0 (6.0) 1.0 (4.0) -6.0 (4.0)triglycerides 1.3 (3.8) 1.8 (3.9) -3.2 (3.6) 3.8 (3.8)Fibrinogen 5.8 (3.0) -1.7 (2.4) -8.3 (3.l)* -16.9 (2.4)**Dâdimer 0.0 (3.1) 4.7 (4.3) -2.1 (2.7) -7.1 (2.7)Factor VII 5.4 (2.4) -10.1(2.4)** -9.6 (2.1)** -11.1 (l.6)**-3-W0 98/09619l0I520253035CA 02264943 1999-03-05PCT/US97/15475In the same study the incidence of vaginal bleeding and breast tendernesswas reduced compared to placebo and there were no cases of histologically deï¬nedendometrial hyperplasia in idoxifene treated patients as compared to one case in theplacebo cohort.These results show that in humans idoxifene is able to produce the desiredbeneï¬cial effects of estrogen on cardiovascular risk factors without the undesirableeffects on reproductive tissues.The compounds of the instant invention and their pharmaceuticallyacceptable salts which are active when given orally can be formulated as liquids. forexample syrups. suspensions or emulsions. tablets, capsules and lozenges.A liquid formulation will generally consist of a suspension or solution of thecompound or pharmaceutically acceptable salt in a suitable liquid carrier(s) forexample, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol,oils, or water with a suspending agent. preservative, ï¬avoring or coloring agent.A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solid formulations. Examplesof such carriers include magnesium stearate. starch, lactose, sucrose and cellulose.A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example. pellets containing the active ingredient canbe prepared using standard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using any suitablepharmaceutical carrier(s). for example aqueous gums. celluloses, silicates or oils andthe dispersion or suspension then filled into a soft gelatin capsule.The compounds of the instant invention and their pharmaceuticallyacceptable salts which are active when administered parenterally (i.e. by injection ofinfusion) can be formulated as solutions or suspensions.A composition for parenteral administration will generally consist of asolution or suspension of the active ingredient in a sterile aqueous carrier orparenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone.lecithin. arachis oil or sesame oil. Alternatively, the solution can be lyophilised andthen reconstituted with a suitable solvent just prior to administration.A typical suppository composition comprises a compound of the instantinvention or a pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent such as polymeric-4-WO 98/09619 â1015202530CA 02264943 1999-03-05PCT/US97/ 15475glycols. gelatins or coca butter or other low melting vegetable or synthetic waxes orfats.A typical transderrnal formulation comprises a conventional aqueous or non-aqueous vehicle. for example. a cream. ointment lotion or paste or in the form of amedicated plaster. patch or membrane.For topical administration, the pharmaceutical compositions adapted includesolutions, suspensions, ointments. and solid inserts. Typical pharmaceuticallyacceptable carriers are, for example, water. mixtures of water and waterâmisciblesolvents such as lower alkanols or vegetable oils. and water solubleophthalmologically acceptable nonâtoxic polymers, for example, cellulosederivatives such as methyl cellulose. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving, wetting andbodying agents. as for example, polyethylene glycols; antibacterial components suchas quaternary ammonium compounds; buffering ingredients such as alkali metalchloride; antioxidants such as sodium rnetabisulfite; and other conventionalingredients such as sorbitan monolaurate.Preferably the composition is in unit dose form. Doses of the compounds ofthe instant invention in a pharmaceutical dosage unit will be an efï¬cacious, non-toxic quantity selected from the range of .01 - 200 mg/kg of active compound,preferably .1 - 100 mg/kg. The selected dose is administered to a human patient inneed of treatment or prevention of cardiovascular disease is or in the lowering ofplasma cholesterol from 1-6 times daily, orally, rectally, topically, by injection. orcontinuously by infusion. Oral dosage units for human administration preferablycontain from 10 to 500 mg of active compound. Lower dosages are used generallyfor parenteral administration. Oral administration is used when safe, effective. andconvenient for the patient.No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.Example lAn oral dosage form for administering orally active Formula (1) compoundsis produced by screening, mixing and filling into hard gelatin capsules theingredients in proportions, for example, as shown below.CA 02264943 1999-03-05WO 98/09619 PCT/US97/ 15475Ingredients Amounts(E)-1-[2-[4-[l-(4-lodophenyl)-2-phenyl-1-butenyl]phenoxyjpyrrolidine 100 mgmagnesium stearate 10 mg5 lactose 100 mgExample 2The sucrose calcium sulfate dihydrate and orally active Formula (1)compounds are mixed and granulated with a 10% gelating solution. The wetl0 granules are screened, dried. mixed with the starch, talc and stearic acid, screenedl5and compressed into a tablet.Ingredients Amounts(E)- l-[2-[4-[1-(4-lodophenyl)-2-phenyl- l-butenyl]phenoxy]pyrrolidine 75 mgcalcium sulfate dihydrate , 100 mgsucrose 15 mgstarch 8 mgtalc 4 mg20 steanc acid 2 mgExa e 3(E)-l-[2-[4-[1-(4-lodophenyl)-2-phenyl-l-butenyl]phenoxy]pyrrolidine, 50mg, is dispersedin 25 ml of normal saline to prepare an injectable preparation.
Claims (6)
1. A method of treating and preventing postmenopausal cardiovascular disease in women which comprises administering to a subject in need thereof an effective amount of a compound of formula I.
2 A method according to Claim 1 wherein the compound of formula I is (E)-1-[2-[4-[1-(4-lodophenyl)-2-phenyl-1-butenyl]phenoxy]pyrrolidine.
3. A method according to Claim 1 wherein the postmenopausal cardiovascular disease is myocardial infarction or stroke.
4. The use of a compound of formula 1 in the manufacture of a medicament for use in the treatment of cardiovascular disease in women.
5. A use according to Claim 4 wherein the compound of formula I is (E)-1-[2-[4-[1-(4-lodophenyl)-2-phenyl-1-butenyl]phenoxy]pyrrolidine.
6. A use according to Claim 4 wherein the disease is myocardial or stroke.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2543996P | 1996-09-06 | 1996-09-06 | |
US60/025,439 | 1996-09-06 | ||
US5066697P | 1997-06-24 | 1997-06-24 | |
US60/050,666 | 1997-06-24 | ||
PCT/US1997/015475 WO1998009619A1 (en) | 1996-09-06 | 1997-09-03 | Novel methods |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2264943A1 true CA2264943A1 (en) | 1998-03-12 |
Family
ID=26699738
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002264943A Abandoned CA2264943A1 (en) | 1996-09-06 | 1997-09-03 | Novel methods |
CA002264775A Abandoned CA2264775A1 (en) | 1996-09-06 | 1997-09-03 | Method of treating post menopausal diseases, including osteoporosis |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002264775A Abandoned CA2264775A1 (en) | 1996-09-06 | 1997-09-03 | Method of treating post menopausal diseases, including osteoporosis |
Country Status (16)
Country | Link |
---|---|
EP (2) | EP0927029A4 (en) |
JP (2) | JP2002515047A (en) |
KR (2) | KR20000068472A (en) |
CN (2) | CN1236299A (en) |
AR (1) | AR008155A1 (en) |
AU (2) | AU4247397A (en) |
BR (2) | BR9711681A (en) |
CA (2) | CA2264943A1 (en) |
CO (2) | CO5070658A1 (en) |
CZ (1) | CZ76699A3 (en) |
IL (1) | IL128645A0 (en) |
NO (2) | NO991097D0 (en) |
PL (2) | PL332038A1 (en) |
TR (2) | TR199900506T2 (en) |
TW (1) | TW411273B (en) |
WO (2) | WO1998009619A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998034608A1 (en) * | 1997-02-11 | 1998-08-13 | Novo Nordisk A/S | Methods for treatment or prophylaxis of menopausal symptoms |
GB9827121D0 (en) * | 1998-12-09 | 1999-02-03 | Orion Corp | Agent for lowering endothelin levels |
DE19905961A1 (en) * | 1999-02-12 | 2000-08-17 | Stefan Neubauer | Use of estrogens to treat cardiac insufficiency and left ventricular dysfunction following myocardial infarction |
US6528681B2 (en) * | 2000-04-05 | 2003-03-04 | Bristol-Meyers Squibb Pharma Company | Halogenated triphenylethylene derivatives as selective estrogen receptor modulators |
IL145876A0 (en) | 2000-10-17 | 2002-07-25 | Pfizer Prod Inc | Methods and kits for improving vascular health |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2196003A (en) * | 1986-09-11 | 1988-04-20 | Nat Res Dev | Iodo-and bromo-tamoxifen derivatives |
KR100326962B1 (en) * | 1992-09-15 | 2002-12-02 | 메렐 파마슈티칼스 인크. | Tamoxifen-Non Metabolic Clomiphene Analog for Treatment of Tolerant Tumor |
US6197789B1 (en) * | 1995-06-07 | 2001-03-06 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
US5681835A (en) * | 1994-04-25 | 1997-10-28 | Glaxo Wellcome Inc. | Non-steroidal ligands for the estrogen receptor |
US5604248A (en) * | 1994-05-05 | 1997-02-18 | Eli Lilly And Company | Method for minimizing the uterotrophic effect of tamoxifen and tamoxifen analogs |
US5470883A (en) * | 1994-05-23 | 1995-11-28 | Stromberg; Brent V. | Method of treating peripheral vasoconstriction with tamoxifen citrate |
HN1996000101A (en) * | 1996-02-28 | 1997-06-26 | Inc Pfizer | COMBINED THERAPY FOR OSTEOPOROSIS |
US6069175A (en) * | 1996-11-15 | 2000-05-30 | Pfizer Inc. | Estrogen agonist/antagonists treatment of atherosclerosis |
-
1997
- 1997-08-29 AR ARP970103968A patent/AR008155A1/en unknown
- 1997-09-03 TR TR1999/00506T patent/TR199900506T2/en unknown
- 1997-09-03 CA CA002264943A patent/CA2264943A1/en not_active Abandoned
- 1997-09-03 BR BR9711681A patent/BR9711681A/en not_active Application Discontinuation
- 1997-09-03 PL PL97332038A patent/PL332038A1/en unknown
- 1997-09-03 IL IL12864597A patent/IL128645A0/en unknown
- 1997-09-03 JP JP51283898A patent/JP2002515047A/en active Pending
- 1997-09-03 WO PCT/US1997/015475 patent/WO1998009619A1/en not_active Application Discontinuation
- 1997-09-03 TR TR1999/00504T patent/TR199900504T2/en unknown
- 1997-09-03 AU AU42473/97A patent/AU4247397A/en not_active Abandoned
- 1997-09-03 KR KR1019997001860A patent/KR20000068472A/en not_active Application Discontinuation
- 1997-09-03 AU AU44097/97A patent/AU4409797A/en not_active Abandoned
- 1997-09-03 EP EP97942388A patent/EP0927029A4/en not_active Withdrawn
- 1997-09-03 CZ CZ99766A patent/CZ76699A3/en unknown
- 1997-09-03 KR KR1019997001861A patent/KR20000068473A/en not_active Application Discontinuation
- 1997-09-03 CN CN97199492A patent/CN1236299A/en active Pending
- 1997-09-03 CN CN97199493A patent/CN1236313A/en active Pending
- 1997-09-03 WO PCT/US1997/015474 patent/WO1998009519A1/en not_active Application Discontinuation
- 1997-09-03 PL PL97332278A patent/PL332278A1/en unknown
- 1997-09-03 BR BR9711676A patent/BR9711676A/en not_active Application Discontinuation
- 1997-09-03 EP EP97940773A patent/EP0929216A4/en not_active Withdrawn
- 1997-09-03 JP JP51283798A patent/JP2002515046A/en active Pending
- 1997-09-03 CA CA002264775A patent/CA2264775A1/en not_active Abandoned
- 1997-09-04 CO CO97051289A patent/CO5070658A1/en unknown
- 1997-09-04 CO CO97051287A patent/CO4920218A1/en unknown
- 1997-12-11 TW TW086112930A patent/TW411273B/en active
-
1999
- 1999-03-05 NO NO991097A patent/NO991097D0/en not_active Application Discontinuation
- 1999-03-05 NO NO991096A patent/NO991096L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
AU4409797A (en) | 1998-03-26 |
BR9711681A (en) | 1999-08-24 |
EP0929216A1 (en) | 1999-07-21 |
NO991097L (en) | 1999-03-05 |
WO1998009519A1 (en) | 1998-03-12 |
TW411273B (en) | 2000-11-11 |
CO4920218A1 (en) | 2000-05-29 |
NO991096D0 (en) | 1999-03-05 |
AU4247397A (en) | 1998-03-26 |
EP0929216A4 (en) | 2001-04-04 |
BR9711676A (en) | 1999-08-24 |
JP2002515046A (en) | 2002-05-21 |
CN1236299A (en) | 1999-11-24 |
CA2264775A1 (en) | 1998-03-12 |
IL128645A0 (en) | 2000-01-31 |
CZ76699A3 (en) | 1999-08-11 |
PL332278A1 (en) | 1999-08-30 |
PL332038A1 (en) | 1999-08-16 |
AR008155A1 (en) | 1999-12-09 |
EP0927029A1 (en) | 1999-07-07 |
CN1236313A (en) | 1999-11-24 |
TR199900506T2 (en) | 1999-07-21 |
KR20000068473A (en) | 2000-11-25 |
JP2002515047A (en) | 2002-05-21 |
EP0927029A4 (en) | 2001-06-13 |
KR20000068472A (en) | 2000-11-25 |
WO1998009619A1 (en) | 1998-03-12 |
CO5070658A1 (en) | 2001-08-28 |
NO991097D0 (en) | 1999-03-05 |
TR199900504T2 (en) | 1999-06-21 |
NO991096L (en) | 1999-03-05 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |