EP0927029A4 - Novel methods - Google Patents

Novel methods

Info

Publication number
EP0927029A4
EP0927029A4 EP97942388A EP97942388A EP0927029A4 EP 0927029 A4 EP0927029 A4 EP 0927029A4 EP 97942388 A EP97942388 A EP 97942388A EP 97942388 A EP97942388 A EP 97942388A EP 0927029 A4 EP0927029 A4 EP 0927029A4
Authority
EP
European Patent Office
Prior art keywords
cardiovascular disease
compound
formula
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.)
Withdrawn
Application number
EP97942388A
Other languages
German (de)
French (fr)
Other versions
EP0927029A1 (en
Inventor
Jeremy N Bradbeer
Maxime Gowen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0927029A1 publication Critical patent/EP0927029A1/en
Publication of EP0927029A4 publication Critical patent/EP0927029A4/en
Withdrawn legal-status Critical Current

Links

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

Definitions

  • the present invention relates to therapeutic agents that are tissue selective estrogen agonist/antagonist compounds that have been found to be useful in the treatment and prevention of cardiovascular disease in postmenopausal women.
  • This invention provides a method for the prevention and treatment of cardiovascular disease in postmenopausal women without having an overt uterotrophic effect, or promoting an increased risk of breast cancer or causing an increased incidence of vaginal bleeding and breast tenderness
  • the method comprises administering to a human in need thereof an effective amount of a compound of formula I
  • X represents 3- or 4- lodo or bromo and the R-* and Rr symbols, which may be the same or different, represent Cj-3 alkyl, especially methyl or ethyl, groups or R 1 - represents a hydrogen atom and R2 a C1.3 alkyl group or R-- and R2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, typically having 5 or 6 ring atoms, especially a pyrrolidmo, pipendino, 4- methylpipe ⁇ dino or morpholino group, and their pharmaceutically acceptable acid addition salts
  • the present invention is a therapeutic method for preventing and treating cardiovascular disease in postmenopausal women with a group of compounds that have been previously prepared and evaluated as effective in the treatment of estrogen receptor-positive breast cancer These compounds are described in formula I above and in U S. patent 4,839,155
  • the preferred compound for the described method of treatment is
  • Such compounds are known to bind to the estrogen receptor and to cause either estrogen agonist or antagonist effects depending on the tissue bemg studied
  • a beneficial effect on cardiovascular disease would be produced by estrogen agonist effects on the liver ( to alter the hpid profile and levels of fibinogen)
  • estrogen agonist effects on the arterial wall may also contribute to a reduction in the risk of cardiovascular disease.
  • cardiovascular disease refers to atherosclerotic cardiovascular diseases such as myocardial infarction, stroke, angina, intermittent claudication transient blindness, transient lschemic attacks (TIA) and peripheral vascular disease.
  • the method of this invention is useful in producing a plasma lipid profile that is associated with a reduced risk of atherosclerosis and a reduction of raised LDL cholesterol levels Additionally this method is useful in producing a reduction of other independent cardiovascular risk factors such as plasma fibnnogen levels and serum levels of lp(a).
  • the ability to reduce the risk of cardiovascular disease is assessed by studies of the effect of idoxifene a number of different risk factors for cardiovascular disease in postmenopausal women. These include different parameters of the pid profile and levels of coagulation and fib ⁇ nolysis markers.
  • the compounds of the instant invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carner(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or colonng agent
  • a suitable liquid carner(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or colonng agent
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical car ⁇ er(s) routinely used for prepa ⁇ ng solid formulations Examples of such earners include magnesium stearate, starch, lactose, sucrose and cellulose
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule: alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carner(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • a suitable pharmaceutical carner(s) for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • the compounds of the instant invention and their pharmaceutically acceptable salts which are active when administered parenterally can be formulated as solutions or suspensions.
  • a composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrro done, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrro done, lecithin, arachis oil or sesame oil.
  • the solution can be lyophi sed and then reconstituted with a suitable solvent just prior to administration
  • a typical suppository composition comprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats
  • a typical transdermal formulation comprises a conventional aqueous or non- aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane
  • the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts
  • Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting and bodying agents, as for example, polyethylene glycols, antibacterial components such as quaternary ammonium compounds; buffering ingredients such as alkali metal chloride, antioxidants such as sodium metabisulfite, and other conventional ingredients such as sorbitan monolaurate
  • the composition is in unit dose form.
  • Doses of the compounds of the instant invention in a pharmaceutical dosage unit will be an efficacious, 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 in need of treatment or prevention of cardiovascular disease is or in the lowering of plasma cholesterol from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion
  • Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound Lower dosages are used generally for parenteral administration
  • Oral administration is used when safe, effective, and convenient for the patient
  • An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below
  • sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatmg solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Abstract

A novel method for treating cardiovascular disease in postmenopausal women is described. Idoxifene is the preferred compound.

Description

NOVEL METHODS
Field of the Invention
The present invention relates to therapeutic agents that are tissue selective estrogen agonist/antagonist compounds that have been found to be useful in the treatment and prevention of cardiovascular disease in postmenopausal women.
Background of the Invention
The decrease in estrogen that occurs at the menopause is an important etiological factor in the increased incidence of cardiovascular disease in postmenopausal women. Estrogen therapy after the menopause has been shown to have beneficial effects on a number of independent risk factors for cardiovascular disease including serum levels of LDL-cholesterol and poprotein (a) (lp(a)) and plasma levels of fibnnogen. For references please see Levenson J et al, ( 1995), Artenoscler Thromb Vase 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 Chn Med 123, 837-841. These effects may explain in part the epideiruological observations that estrogen therapy causes a reduction in the incidence of cardiovascular disease. However unopposed estrogen given alone increases the risk of endometnal cancer and may also be associated with an increased risk of breast cancer. For these reasons and because of troublesome side effects (pπncipally breast tenderness and vaginal bleeding) few women continue HRT for long enough to benefit from the cardioprotective effects. An ideal therapy would retain the desirable cardiovascular effects of estrogen without having the unwanted effects on reproductive tissues. Consequently, efforts have been made to identify compounds that have tissue-selective estrogen agonist or antagonist properties. Such tissue selective effects could produce the beneficial effects of estrogen on risk factors for cardiovascular disease without the unwanted effects in breast and uteπne tissue.
Summary of the Invention
This invention provides a method for the prevention and treatment of cardiovascular disease in postmenopausal women without having an overt uterotrophic effect, or promoting an increased risk of breast cancer or causing an increased incidence of vaginal bleeding and breast tenderness The method comprises administering to a human in need thereof an effective amount of a compound of formula I
wherein X represents 3- or 4- lodo or bromo and the R-* and Rr symbols, which may be the same or different, represent Cj-3 alkyl, especially methyl or ethyl, groups or R1- represents a hydrogen atom and R2 a C1.3 alkyl group or R-- and R2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, typically having 5 or 6 ring atoms, especially a pyrrolidmo, pipendino, 4- methylpipeπdino or morpholino group, and their pharmaceutically acceptable acid addition salts
Detailed Description of the Invention
The present invention is a therapeutic method for preventing and treating cardiovascular disease in postmenopausal women with a group of compounds that have been previously prepared and evaluated as effective in the treatment of estrogen receptor-positive breast cancer These compounds are described in formula I above and in U S. patent 4,839,155
The preferred compound for the described method of treatment is
(E)- l-[2-[4-[ l-(4-lodophenyl)-2-phenyl- l-butenyl]phenoxy]pyrrolιdιne
Such compounds are known to bind to the estrogen receptor and to cause either estrogen agonist or antagonist effects depending on the tissue bemg studied A beneficial effect on cardiovascular disease would be produced by estrogen agonist effects on the liver ( to alter the hpid profile and levels of fibinogen) However estrogen agonist effects on the arterial wall may also contribute to a reduction in the risk of cardiovascular disease.
The term "cardiovascular disease" refers to atherosclerotic cardiovascular diseases such as myocardial infarction, stroke, angina, intermittent claudication transient blindness, transient lschemic attacks (TIA) and peripheral vascular disease. The method of this invention is useful in producing a plasma lipid profile that is associated with a reduced risk of atherosclerosis and a reduction of raised LDL cholesterol levels Additionally this method is useful in producing a reduction of other independent cardiovascular risk factors such as plasma fibnnogen levels and serum levels of lp(a).
The ability to reduce the risk of cardiovascular disease is assessed by studies of the effect of idoxifene a number of different risk factors for cardiovascular disease in postmenopausal women. These include different parameters of the pid profile and levels of coagulation and fibπnolysis markers.
Three different doses of idoxifene (2.5, 5 and lOmg/day) were compared with placebo in a study of three months duration m postmenopausal women. Changes in the levels of different lipid parameters, fibnnogen and other coagulation/fibπnolysis parameters were measured before and after treatment. The results of this study are described below All changes are descnbed as percentage change from the baseline value. Statistically significant differences from placebo are designated by the following notation: *=p<0.01 , **=p<0.001.
Placebo 2.5 5.0 10.0
Total chol 0.5(1.1) -0.9(1.1) -4.2(1.2)* -98(1.1)**
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)
HDLLDL 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) triεlvcendes 1.3(3.8) 1.8(3.9) -3.2 (3.6) 3.8(3.8)
Fibnnogen 5.8 (3.0) -17(2.4) -83(3 n* -16.9(2.4)**
D-dimer 00(31) 47(43) -21 (2.7) -71 (2.7)
Factor VII 54(2.4) -10.1 (24)** -96(21)** -111 (16)** In the same study the incidence of vaginal bleeding and breast tenderness was reduced compared to placebo and there were no cases of histologically defined endometnal hyperplasia in idoxifene treated patients as compared to one case in the placebo cohort
These results show that in humans idoxifene is able to produce the desired beneficial effects of estrogen on cardiovascular risk factors without the undesirable effects on reproductive tissues. The compounds of the instant invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carner(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or colonng agent A composition in the form of a tablet can be prepared using any suitable pharmaceutical carπer(s) routinely used for prepaπng solid formulations Examples of such earners include magnesium stearate, starch, lactose, sucrose and cellulose A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule: alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carner(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
The compounds of the instant invention and their pharmaceutically acceptable salts which are active when administered parenterally (i.e by injection of infusion) can be formulated as solutions or suspensions.
A composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrro done, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophi sed and then reconstituted with a suitable solvent just prior to administration
A typical suppository composition comprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats
A typical transdermal formulation comprises a conventional aqueous or non- aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane
For topical administration, the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting and bodying agents, as for example, polyethylene glycols, antibacterial components such as quaternary ammonium compounds; buffering ingredients such as alkali metal chloride, antioxidants such as sodium metabisulfite, and other conventional ingredients such as sorbitan monolaurate
Preferably the composition is in unit dose form. Doses of the compounds of the instant invention in a pharmaceutical dosage unit will be an efficacious, 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 in need of treatment or prevention of cardiovascular disease is or in the lowering of plasma cholesterol from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound Lower dosages are used generally for parenteral administration Oral administration is used when safe, effective, and convenient for the patient
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention
Example 1
An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below Ingredients Amounts (E)- 1 -[2-[4-[ I -(4-lodophenyl)-2-phenyl- 1 -butenyl] phenoxyjpyrrolidine 100 mg magnesium stearate 10 mg lactose 100 mg
Example 2 The sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatmg solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
ingredients Amounts
(E)- l-[2-[4-[l-(4-lodophenyl)-2-phenyl- 1 -butenyl] phenoxylpyrrolidine 75 mg calcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4 mg stearic acid 2 mg
Eχι ample 3
(E)-l-[2-[4-[ l-(4-lodophenyl)-2-phenyl-l-butenyl]phenoxy]pyrrolidme, 50 mg, is dispersedin 25 ml of normal saline to prepare an injectable preparation.

Claims

What is claimed is
1 A method of treating and preventing postmenopausal cardiovascular disease in women which compnses 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)-l-
[2-[4-[ 1 -(4-lodophenyl)-2-phenyl- 1 -butenyl]phenoxy ]pyrrolιdιne
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 I 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)-l-[2-
[4-[ 1 -(4-lodophenyl)-2-phenyl- 1 -buteπyl]phenoxy]pyrrolιdme.
6. A use according to Claim 4 wherein the disease is myocardial or stroke.
EP97942388A 1996-09-06 1997-09-03 Novel methods Withdrawn EP0927029A4 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US2543996P 1996-09-06 1996-09-06
US25439P 1996-09-06
US5066697P 1997-06-24 1997-06-24
US50666P 1997-06-24
PCT/US1997/015475 WO1998009619A1 (en) 1996-09-06 1997-09-03 Novel methods

Publications (2)

Publication Number Publication Date
EP0927029A1 EP0927029A1 (en) 1999-07-07
EP0927029A4 true EP0927029A4 (en) 2001-06-13

Family

ID=26699738

Family Applications (2)

Application Number Title Priority Date Filing Date
EP97940773A Withdrawn EP0929216A4 (en) 1996-09-06 1997-09-03 Method of treating post menopausal diseases, including osteoporosis
EP97942388A Withdrawn EP0927029A4 (en) 1996-09-06 1997-09-03 Novel methods

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP97940773A Withdrawn EP0929216A4 (en) 1996-09-06 1997-09-03 Method of treating post menopausal diseases, including osteoporosis

Country Status (16)

Country Link
EP (2) EP0929216A4 (en)
JP (2) JP2002515046A (en)
KR (2) KR20000068473A (en)
CN (2) CN1236299A (en)
AR (1) AR008155A1 (en)
AU (2) AU4409797A (en)
BR (2) BR9711676A (en)
CA (2) CA2264943A1 (en)
CO (2) CO4920218A1 (en)
CZ (1) CZ76699A3 (en)
IL (1) IL128645A0 (en)
NO (2) NO991096L (en)
PL (2) PL332038A1 (en)
TR (2) TR199900504T2 (en)
TW (1) TW411273B (en)
WO (2) WO1998009519A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
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

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WO1996040098A2 (en) * 1995-06-07 1996-12-19 Neorx Corporation Prevention and treatment of cardiovascular pathologies with tamoxifen analogues
EP0843999A1 (en) * 1996-11-15 1998-05-27 Pfizer Inc. Use of estrogen agonists/antagonists for the manufacture of a medicament in the treatment of atherosclerosis independent of a lipid lowering effect

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Publication number Priority date Publication date Assignee Title
WO1996040098A2 (en) * 1995-06-07 1996-12-19 Neorx Corporation Prevention and treatment of cardiovascular pathologies with tamoxifen analogues
EP0843999A1 (en) * 1996-11-15 1998-05-27 Pfizer Inc. Use of estrogen agonists/antagonists for the manufacture of a medicament in the treatment of atherosclerosis independent of a lipid lowering effect

Non-Patent Citations (3)

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Title
GRAINGER D J ET AL: "TAMOXIFEN DECREASES THE RATE OF PROLIFERATION OF RAT VASCULAR SMOOTH-MUSCLE CELLS IN CULTURE BY INDUCING PRODUCTION OF TRANSFORMING GROWTH FACTOR BETA", BIOCHEMICAL JOURNAL,GB,PORTLAND PRESS, LONDON, vol. 294, no. 1, 15 August 1993 (1993-08-15), pages 109 - 112, XP002061173, ISSN: 0264-6021 *
GRAINGER D J ET AL: "TAMOXIFEN: TEACHING AN OLD DRUG NEW TRICKS?", NATURE MEDICINE,US,NATURE PUBLISHING, CO, vol. 2, no. 4, 1 April 1996 (1996-04-01), pages 381 - 385, XP000604987, ISSN: 1078-8956 *
See also references of WO9809619A1 *

Also Published As

Publication number Publication date
CO4920218A1 (en) 2000-05-29
NO991096D0 (en) 1999-03-05
EP0927029A1 (en) 1999-07-07
KR20000068473A (en) 2000-11-25
CZ76699A3 (en) 1999-08-11
AU4409797A (en) 1998-03-26
BR9711681A (en) 1999-08-24
WO1998009619A1 (en) 1998-03-12
TR199900506T2 (en) 1999-07-21
AR008155A1 (en) 1999-12-09
EP0929216A1 (en) 1999-07-21
NO991096L (en) 1999-03-05
JP2002515047A (en) 2002-05-21
BR9711676A (en) 1999-08-24
TR199900504T2 (en) 1999-06-21
CA2264775A1 (en) 1998-03-12
AU4247397A (en) 1998-03-26
PL332278A1 (en) 1999-08-30
PL332038A1 (en) 1999-08-16
JP2002515046A (en) 2002-05-21
NO991097L (en) 1999-03-05
CN1236299A (en) 1999-11-24
CN1236313A (en) 1999-11-24
IL128645A0 (en) 2000-01-31
CA2264943A1 (en) 1998-03-12
KR20000068472A (en) 2000-11-25
TW411273B (en) 2000-11-11
CO5070658A1 (en) 2001-08-28
EP0929216A4 (en) 2001-04-04
NO991097D0 (en) 1999-03-05
WO1998009519A1 (en) 1998-03-12

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