WO2000041700A1 - Utilisation d'oestrogenes et de delta-gonadiene-21-ol-3,20-diones dans le traitement ou la prevention de maladies degeneratives du cerveau - Google Patents

Utilisation d'oestrogenes et de delta-gonadiene-21-ol-3,20-diones dans le traitement ou la prevention de maladies degeneratives du cerveau Download PDF

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Publication number
WO2000041700A1
WO2000041700A1 PCT/DK2000/000020 DK0000020W WO0041700A1 WO 2000041700 A1 WO2000041700 A1 WO 2000041700A1 DK 0000020 W DK0000020 W DK 0000020W WO 0041700 A1 WO0041700 A1 WO 0041700A1
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Prior art keywords
estrogen
formula
compound
phenyl
receptor modulator
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PCT/DK2000/000020
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English (en)
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René DE BEUN
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Novo Nordisk A/S
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Priority to AU20923/00A priority Critical patent/AU2092300A/en
Publication of WO2000041700A1 publication Critical patent/WO2000041700A1/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of a combination of estrogens or SERMs with delta- gonadien-21-ol-3,20-diones for the treatment of patients suffering from cerebral degenerative disorders, e.g. Alzheimer's disease, and prophylaxis hereof.
  • the present invention also embraces pharmaceutical compositions and kits comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • AD Alzheimer's disease
  • AD is perhaps the most important of all the degenerative diseases because of its frequent occurrence and devastating nature.
  • AD is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement and emotional stability that gradually leads to profound mental deterioration and provocatively death.
  • AD is the most common cause of progressive mental failure (dementia) in the elderly and is believed to represent the fourth most common medical cause of death in the United States.
  • the disease is currently estimated to affect about two to three million individuals in the United States alone.
  • many of the degenerative nervous system diseases, including AD progress uninfluenced by any therapeutic measures.
  • the outstanding pathologic feature is death and disappearance of nerve cells in the cerebral cortex.
  • AD Alzheimer's disease consists of intraneuronal accumulations of filamentous material in the form of loops, coils, or tangled masses referred to as Alzheimer neurofibrillar tangles. Their exact nature is currently under active investigations, but the neuropathologic evidence strongly suggests that these fibrillar masses of amyloidogenic nature are of major importance in bringing about the death of the neurons.
  • the second histopathologic change that characterizes AD is the presence of intracortical clusters of thickened neuronal processes, both axons and dendrites.
  • AP amyloidogenic proteins
  • CSF cerebrospinal fluid
  • choline acetyltransferase the key enzyme required for the synthesis of acetylcholine
  • the major source of the neocortical cholinergic innervation is a group of neurons situated in the basal part of the forebrain just beneath the corpus striatum, the nucleus basalis of Meynert. This nucleus is a site of major neuronal loss and of frequent Alzheimer neurofibrillar tangles. Thus, impairment of cholinergic transmission may play a part in the clinical expression of the disease.
  • attempted therapy with cholinomimetic agents have been largely unsuccessful.
  • estrogen influences cholinergic function through a stimulation of choline acetyltransferase (Kaufman H et al., Brain Res 453:389, 1988) and that it also increases the binding sites of hypothalamic nicotinic acetylcholine receptors (Morley BJ et al., Brain Res 278:262, 1983). Furthermore, it has been suggested that low dose estrogen replacement therapy may have a beneficial effect on AD (Okura T et al., Menopause 1 :125, 1994).
  • compositions and methods that are useful in the treatment or prophylaxis of degenerative cerebral disorders including Alzheimer's disease.
  • compositions that lack or has decreased undesirable side effects of estrogen(s) and/or progesterone(s).
  • One object of the present invention is to provide compositions in one dosage form which can effectively be used in the treatment or prophylaxis of cerebral degenerative disorders, e.g. Alzheimer's disease.
  • Another object of the present invention is to provide compositions, method of treatment or kits exhibiting a synergistic effect.
  • a further object of the present invention is to provide compositions, method of treatment or kits exhibiting no substantial side effects, such as high level of coronary heart disease events.
  • the present invention is based in part on the discovery that a representative combination of an estrogen or estrogen receptor modulator and a compound of formula I
  • R ⁇ R 2 and R 3 independently of each other are C 1-12 alkyl, in the form of 21 R or 21S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, is effective against cerebral degenerative disorders, e.g. Alzheimer's disease, inter alia in mice or rats e.g. Fisher rats or Wistar rats.
  • the combination of an estrogen or estrogen receptor modulator and a compound of formula I shows a synergistic effect in treatment of cerebral degenerative disorders and/or a synergistic effect on side-effects, such as cardiovascular disorders, eg. lowering lipids.
  • the invention relates to a method of treating or preventing cerebral degenerative disorders, preferably Alzheimer's disease, which method comprises administering to a subject an effective amount of an estrogen or estrogen receptor modulator in combination with an effective amount of a compound of formula I
  • Ri , R 2 and R 3 independently of each other are C 1-12 alkyl, in the form of 21 R or 21 S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat or prevent cerebral degenerative disorders.
  • the invention in a second aspect relates to a kit containing a treatment for cerebral degenerative disorders comprising a) an effective amount of an estrogen or estrogen receptor modulator and a pharmaceutically acceptable carrier in a first unit dosage form; b) an effective amount of a compound of formula I
  • R ⁇ R 2 and R 3 independently of each other are C 1-12 alkyl, in the form of 21R or 21S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • the invention relates to a use of an estrogen or estrogen receptor modulator in combination with an effective amount of a compound of formula I
  • R ⁇ R 2 and R 3 independently of each other are C 1-12 alkyl, in the form of 21 R or 21 S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing cerebral degenerative disorders.
  • composition such as a pharmaceutical composition, comprising an estrogen or estrogen receptor modulator and a compound of formula I
  • R 1f R 2 and R 3 independently of each other are C 1-12 alkyl, in the form of 21R or 21S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the estrogen or estrogen receptor modulator and the compound of formula I is administered simultaneously in one dosage form, preferably orally as a tablet or capsule or as a transdermal patch.
  • the estrogen or estrogen receptor modulator and the compound of formula I is administered substantially simultaneously.
  • R 2 and R 3 are independently of each other a C 1-6 alkyl, such as C 1- alkyl, preferably methyl.
  • the compound of formula I is selected from
  • the estrogen is selected from 17-beta- estradiol and esters thereof, ethinylestradiol, estriol (trihydroxyestrin), estrone, conjugated estrogens (eg. Premarin), sodium estrone sulfate, 8(9)-dehydroestradiol derivatives, 17alfa- dihydroequilin, equilenin, 17alfa-dihydroequilenin, esterified estrogens, and equilin, prefera- bly 17-beta-estradiol and esters thereof, ethinylestradiol, and conjugated estrogens.
  • Each of these estrogens is individually considered an embodiment of the invention.
  • the estrogen receptor modulator is selected from droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, idoxifene, centchroman, levor- meloxifene, Cis-6-(4-fluoro-phenyl)-5-[4-2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8- tetrahydronaphthalene-2-ol; (-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8- tetrahydronaphthalene -2-ol; Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8- tetrahydronaphthalene -2-ol; Cis-1-[6'-pyrrolidino
  • the effective amount of an estrogen or estrogen receptor modulator is from 0.00001 to 1000 mg/day, such as 0.01 to 2.5 mg/day and the effective amount of a compound of formula I is from 0.00001 to 1000 mg/day, such as 0.01 to 1.0 mg/day.
  • the estrogen or estrogen receptor modulator and the compound of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • acid-addition salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Each of these salts is individually considered an embodiment of the invention.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the C 1-12 -alkyl, C 1-6 -alkyl or C 1- -alkyl groups specified above are intended to include those alkyl or alkylene groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl and their corresponding divalent moieties, such as ethylene.
  • Examples of branched alkyl are isopropyl, sec-butyl, tert-butyl, isopentyl, and isohexyl and their corresponding divalent moieties, such as isopropyl- ene.
  • Examples of cyclic alkyl are C 3 . 6 -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their corresponding divalent moieties, such as cyclopropylene.
  • compositions and kits of the present invention are useful within human and veterinary medicine, for example, in the treatment or prophylaxis of patients suffering from cerebral degenerative disorders, e.g. Alzheimer's disease.
  • the estrogens or estrogen receptor modulators and compounds of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc.
  • the estrogen or estrogen receptor modulator and compound of formula I are prepared in a form suitable for oral administration, such as a tablet or capsule, that is either a tablet or capsule containing both the estrogen or estrogen receptor modulator and compound of formula I in one dosage form, or a tablet or capsule containing the estrogen or estrogen receptor modulator in one dosage form and a tablet or capsule containing the compound of formula I in another dosage form.
  • a pharmaceutically acceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet.
  • Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like.
  • compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • Pharmaceutical compositions containing the estrogen or estrogen receptor modulator and the compound of formula I may be administered one or more times per day or week.
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against cerebral degenerative disorders, e.g. Alzheimer's disease. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • a typical oral dose will contain a nontoxic dosage range of from about 0.0001 to about 100 mg/kg patient per day of the estrogen or estrogen receptor modulator.
  • a suitable oral dose of a compound of formula I is from 0.0001 to 100 mg/kg patient per day.
  • preferred dosages are from 0.001 to 50 mg, in particular 0.01 to 10 mg, more preferred 0.05 to 5 mg, most preferred 0.3 to 2.0 mg estrogen, eg. 17-beta-estradiol or conjugated equine estrogens, continuously combined with 10-14 days of 0.0001 to 10 mg, preferred 0.001 to 10 mg, in particular 0.01 to 5 mg, most preferred 0.05 to 0.5 mg of compound of formula I, eg. a compound of formula II.
  • preferred dosages are from 0.001 to 50 mg, in particular 0.01 to 10 mg, more preferred 0.05 to 5 mg, most preferred 0.3 to 2.0 mg estrogen, eg. 17-beta-estradiol or conjugated equine estrogens, continuously combined with 0.0001 to 10 mg, preferred 0.001 to 10 mg, in particular 0.01 to 5 mg, most preferred 0.05 to 0.5 mg of compound of formula I, eg. a compound of formula II, continuously.
  • a typical transdermal dose will contain a nontoxic dosage range of from about 0.00001 to about 100 mg/kg patient per day of the estrogen or estrogen receptor modulator.
  • a suitable transdermal dose of a compound of formula I is from 0.00001 to 100 mg/kg patient per day.
  • preferred dosages are from 0.0001 to 50 mg, in particular 0.001 to 1 mg, more preferred 0.01 to 0.5 mg, most preferred 0.02 to 0.1 mg estrogen, eg. 17-beta-estradiol or conjugated equine estrogens, continuously combined with 10-14 days of 0.0001 to 10 mg, preferred 0.001 to 1 mg, in particular 0.01 to 0.5 mg, most preferred 0.05 to 0.4 mg of compound of formula I, eg. a compound of formula II.
  • preferred dosages are from 0.0001 to 50 mg, in particular 0.001 to 1 mg, more preferred 0.01 to 0.5 mg, most preferred 0.02 to 0.1 mg estrogen, eg. 17-beta- estradiol or conjugated equine estrogens, continuously combined with 0.0001 to 10 mg, preferred 0.001 to 1 mg, in particular 0.01 to 0.5 mg, most preferred 0.05 to 0.4 mg of compound of formula I, eg. a compound of formula II, continuously.
  • Subject or patient is intended to mean mammals, in particular humans, such as women in the menopause or postmenopausal women.
  • Treatment as used herein is intended to include profylactic treatment and palliative treatment.
  • compositions containing an estrogen or estrogen receptor modulator and a compound of formula I may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implantation. Implants are formulated to provide release of active compound over the desired period of time, which can be up to several years. Controlled- release formulations are disclosed by, for example, Sanders et al., J.Pharm.Sci. 73 (1964), 1294 - 1297, 1984. Controlled-release formulations are also disclosed by U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorporated herein by reference.
  • the present invention relates to the prevention or treatment of cerebral degenerative disorders, e.g. Alzheimer's disease by treatment with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form.
  • the kit includes two separate pharmaceutical compositions: in one embodiment an estrogen and a delta4,9-gonadiene-21-ol-3,20-dione of formula I; and in another embodiment an estrogen receptor modulator and a delta4,9- gonadiene-21-ol-3,20-dione of formula I.
  • the kit includes container means for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit in- dudes directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g. oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the pack- aging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relative of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • estrogen or “estrogens” has its conventional meaning and comprises estrogen and estrogen derivatives such as 17-beta-estradiol and esters thereof, ethinylestradiol, estriol (trihydroxyestrin), estrone, conjugated estrogens e.g. disclosed in US Patent nos 2,720,483 and 2,565,115, in particular premarin cf.
  • SERMs Selective estrogen receptor modulators
  • SERMs which previously were characterised as estrogen antagonists/partial agonists on their basis of their binding to the estrogen receptor alpha, act as full estrogen agonists in bone.
  • SERM takes into account the fact that the activity of these agents is tissue selective and they cannot be definitely labeled as agonsists or antagonists but only as modulators of the estrogen receptor until their actions in specific tissues have been evaluated (Gustafsson, Current Opin Chem Biol 1998; 2:508- 511).
  • SERM serotonin receptor modulators
  • droloxifene raloxifene
  • tamoxifen 4-hydroxy-tamoxifen
  • idoxifene centchroman
  • the present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection.
  • the chemist of ordinary skill in the art will recognize that certain compounds related to this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included within the present invention.
  • Some of the compounds related to the present invention have assymethc carbon atoms and are enantiomers or diastereomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se. Such methods may be chromatografy and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound, eg. alcohol, separating the diastereomers and converting, eg. hydrolyzing, the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered a part of this invention.
  • an appropriate optically active compound eg. alcohol
  • Conjugated estrogens may be obtained following the process described in US 2,720,483 or US 2,565,115, which are incorporated herein by reference.
  • a tablet contains a conjugated estrogen (0,6mg) and a compound of formula II (2,4 mg) formulated with pharmaceutically acceptable carriers to provide a medicament for oral administration according to conventional methods.
  • the formulation further include the following diluents, fillers, emulsifiers, preservatives, buffers and/or excipients, that is calcium phosphate tribasic, calcium sulfate, canauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylen glycol, sucrose, povidone, titanium dioxide and red ferric oxide.
  • One skilled in this art may formulate the tablet composition in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., Easton, PA, 1990.
  • the separation wall contained a doorway in the middle, measuring 8.5 x 7 cm (w x h). Both compartments (25 x 21 cm) in the shuttle-box had a grid floor that (compartment-wise) could be electrified by a shock-scrambler. Both compartments were equipped with a cue light and a cue beeper. A fan mounted on the back-wall of the shuttle-box provided ventilation and masking noise. For a given subject, all sessions required to complete an AA study took place in the same shuttle-box. After each session, the animals were returned to their respective home cages and transported to the animal quarters.
  • CS multisensory conditioned stimulus
  • the offset of the CS (af- ter 5 sec) initiated the onset of the unconditioned stimulus (UCS), a 220 V- 0.2 mA electrical shock delivered through the grid floor.
  • the UCS was terminated after 2 sec.
  • the CS-UCS sequence was repeated 40 times within a session.
  • the length of the inter-trial intervals was random (in steps of 1 sec), with a mean value of 15 sec, and with the lower- and upper-limit set at 10 and 20 sec, respectively. Session duration was variable and, dependent on the be- havior of the animal, between 15 and 20 min. Measurements:
  • - Avoidance The number of crossings (+ latency time) to the other 'safe' compartment within 5 sec after onset of the CS (i.e., before the onset of the UCS). In that case the animals did not receive a shock.
  • - Escape The number of crossings (+ latency time) to the other 'safe' compartment within 2 sec after onset of the UCS (i.e., after the offset of the CS, but before the offset of the UCS). In that case the animals did receive a shock, which varied in duration (somewhere in between 0 and 2 sec).
  • mice Male db/db mice were used as a model for type 2 diabetes.
  • the db mouse is of
  • the homozy- gotic db/db mouse is characterized by obesity, hyperphagia, hyperinsulinemia and hyperglycemia. As with most other conditions of hyperinsulinemia, the insulin response to glucose eventually becomes impaired leading ultimately to severe glucose intolerance Due to these phenotypic characteristics this mouse model is recognized as a model of type 2 diabetes.
  • the animals used in these studies were 13 weeks of age and at a time point of hyperinsu- linemia and severe hyperglycemia with modest hypertriglyceridemia. All animal procedures were conducted according to Novo Nordisk A/S Animal Care approved protocols, and the experiments were done in compliance with internal animal welfare and national guidelines.
  • the animals were allowed to adapt to the laboratory conditions for 2 weeks prior to the ex- perimental procedure. Normal chow and tap water were freely available in the home cages throughout the studies. A normal 12 h/12 h light/dark regime was operative (lights on at 06.00 hours) and room temperature was held between 20-23° C.

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Abstract

L'invention concerne l'utilisation d'une combinaison d'oestrogènes ou de SERM et de delta-gonadiène-21-ol-3,20-diones dans le traitement de patients atteints de maladies dégénératives du cerveau, telles que la maladie d'Alzheimer, et dans la prévention de ces maladies.
PCT/DK2000/000020 1999-01-18 2000-01-17 Utilisation d'oestrogenes et de delta-gonadiene-21-ol-3,20-diones dans le traitement ou la prevention de maladies degeneratives du cerveau WO2000041700A1 (fr)

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AU20923/00A AU2092300A (en) 1999-01-18 2000-01-17 Use of estrogens and delta-gonadien-21-ol-3,20-diones in the treatment or prophylaxis of cerebral degenerative disorders

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DKPA199900050 1999-01-18
DKPA199900050 1999-01-18

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056892A2 (fr) * 2001-01-19 2002-07-25 The Brigham And Women's Hospital, Inc. Procedes de traitement de troubles neurologiques
WO2002069976A2 (fr) * 2001-03-02 2002-09-12 Stem Cell Therapeutics Inc. Augmentation de cellules souches neurales induite par une hormone ovarienne
WO2002069975A1 (fr) * 2001-03-02 2002-09-12 Stem Cell Therapeutics Inc. Utilisation d'un oestrogene pour induire l'augmentation du nombre de cellules souches neurales
WO2003084521A2 (fr) * 2002-04-03 2003-10-16 Wyeth Traitement hormonal substitutif
WO2003092699A1 (fr) * 2002-04-29 2003-11-13 Wyeth Utilisation d'oestrogenes conjugues en combinaison avec de la trimegestone dans une therapie de remplacement hormonal
WO2003097069A1 (fr) * 2002-05-17 2003-11-27 Wyeth Trimegestone et oestrogenes pour le traitement de troubles post-menauposiques
JP2005530791A (ja) * 2002-05-17 2005-10-13 ワイス 結合型エストロゲンとトリメゲストンの組み合わせを用いたホルモン補充療法

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WO1998004246A2 (fr) * 1996-07-26 1998-02-05 American Home Prod Contraceptif oral

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WO1998004246A2 (fr) * 1996-07-26 1998-02-05 American Home Prod Contraceptif oral

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A.R. GENAZZANI.: "Menopause and the central nervous system: intervention options", MATURITAS,, vol. 31, 1999, pages 103 - 110, XP002928707 *
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056892A2 (fr) * 2001-01-19 2002-07-25 The Brigham And Women's Hospital, Inc. Procedes de traitement de troubles neurologiques
WO2002056892A3 (fr) * 2001-01-19 2002-10-31 Brigham & Womens Hospital Procedes de traitement de troubles neurologiques
WO2002069976A2 (fr) * 2001-03-02 2002-09-12 Stem Cell Therapeutics Inc. Augmentation de cellules souches neurales induite par une hormone ovarienne
WO2002069975A1 (fr) * 2001-03-02 2002-09-12 Stem Cell Therapeutics Inc. Utilisation d'un oestrogene pour induire l'augmentation du nombre de cellules souches neurales
WO2002069976A3 (fr) * 2001-03-02 2003-05-15 Stem Cell Therapeutics Inc Augmentation de cellules souches neurales induite par une hormone ovarienne
WO2003084521A2 (fr) * 2002-04-03 2003-10-16 Wyeth Traitement hormonal substitutif
WO2003084521A3 (fr) * 2002-04-03 2004-04-08 Wyeth Corp Traitement hormonal substitutif
WO2003092699A1 (fr) * 2002-04-29 2003-11-13 Wyeth Utilisation d'oestrogenes conjugues en combinaison avec de la trimegestone dans une therapie de remplacement hormonal
WO2003097069A1 (fr) * 2002-05-17 2003-11-27 Wyeth Trimegestone et oestrogenes pour le traitement de troubles post-menauposiques
JP2005530791A (ja) * 2002-05-17 2005-10-13 ワイス 結合型エストロゲンとトリメゲストンの組み合わせを用いたホルモン補充療法

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