CN1239892A - Use of equilenin as antioxidant - Google Patents

Use of equilenin as antioxidant Download PDF

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Publication number
CN1239892A
CN1239892A CN97180448A CN97180448A CN1239892A CN 1239892 A CN1239892 A CN 1239892A CN 97180448 A CN97180448 A CN 97180448A CN 97180448 A CN97180448 A CN 97180448A CN 1239892 A CN1239892 A CN 1239892A
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CN
China
Prior art keywords
equilenin
disease
salt
pharmaceutical salts
free radical
Prior art date
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Pending
Application number
CN97180448A
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Chinese (zh)
Inventor
S·J·阿德曼
D·H·普罗兹勒克
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Wyeth LLC
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American Home Products Corp
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Publication of CN1239892A publication Critical patent/CN1239892A/en
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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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Abstract

This invention provides a method of using equilenin or a pharmaceutically acceptable salt of equilenin-3-sulfate ester as an antioxidant.

Description

(.+-.)-Equilenin. is as the purposes of antioxidant
Background of invention
The equal congener of free radical of Sheng Chenging and numerous disease biologically, the survival of aerobe in aerobic environment relates to complex interactions (Del Maestro RF between these biologies that have active chemical group generations and their ability of BIOLOGICAL CONTROL, Acta Phy ScanSuppl.492:153-68 (1980)), this interaction between host living beings and the free radical that biologically generates has caused the biochemistry variation of the profundity that damage and death with biological cell is termination.The product of radical reaction accumulation has caused numerous disease, these diseases have been considered to partly result from the interior free radical flux of cell that increases and the cell injury of bringing out, and these diseases include but is not limited to cancer, cardiovascular disease, central nervous system disorder, bone disease, aging, Alzheimers, inflammation, rheumatoid arthritis, autoimmune disease, respiratory distress and emphysema.
Getting in touch of free radical damage and numerous disease widely reported; comprise enzyme; ion channel; many cell component of structural protein and membrane lipid all are potential target (Rice-Evans C of living radical; Mol Aspects of Med 13 (1): 1-111 (1992)); the antioxidant that is in appropriate site can limit this infringement; can influence a series of cell function and cause pathological changes and final cell death with the radical reaction of these potential targets; the antioxidant status that is in the potential reaction site can limit this infringement, and antioxidant is at protection DNA; protein (comprising lipoprotein) and membrane lipid avoid playing an important role in the oxidative damage.
There is strong evidence proof free radical damage to cause many chronic health problems, for most of human diseasess, oxidant by endogenous generation is accessory to initial stage lysis, but oxidative damage has increased the weight of the damage at initial stage, the infringement of organ when for example, reperfusion injury can be defined as showing effect the recovery blood flow after betiding ischemia.Although be essential, the formation of oxygen recovery having increased oxidant in injured tissues has also temporarily worsened this damage, and (UraizeeA, Circulaton 75 (6): 1237-1248 (1987)).Guanieri has described the minimizing lipid peroxidation increase (Biochim-Biophys-ACTA718 (2): 157-164 (1982)) along with reoxygenation then of antioxidant defence in the anoxia cardiac muscle.In reperfusion injury, because adhesion and activate neutrophilic leukocyte, cause producing superoxides after the ischemia in the inflammatory reaction of endothelial injury site.In many different clinical settings, also increased the generation of oxygen-derived free radicals in the liver.In viral hepatitis and chronic active hepatitis, accumulated the macrophage that a large amount of quilts stimulate in the liver, they produce free radical, owing to often increased the generation by the free radical of cytochrome P-450 mediation in the liver, a large amount of deleterious chemical substances cause the hepatogenotoxicity damage.The generation that can conclude the ferrum catalysis hydroxyl that discharges from ferritin is mechanism (Lee WM, the N Eng J of Med that many hepatopathies are easily sent out; Review is (1995) P.1118).
The use of oxidation and antioxidant also is very important for the treatment of many inflammation diseases, and rheumatoid arthritis (RA) is modal chronic inflammatory disease, and epidemiological study shows that standard and clear and definite RA prevalence rate are between 0.3% and 1.5%.Chronic persistence IJD is attended by H in the rheumatoid joint of inflammation 2O 2Generation, during inflammation, polymorphonuclear leukocyte (PMN) and macrophage also especially produce oxygen-derived free radicals.In any chronic or acute inflammation disease, PMN and macrophage can produce O 2 -And H 2O 2Tuberculosis, psoriasis, systemic lupus erythematosus (sle), other autoimmune disease and adult respiratory distress syndrome also can be called as follows the inflammatory diseases of oxidation as principal element, and many other diseases also can be listed in these ranks.
In central nervous system's (CNS) wound and apoplexy (for example ischemia) field, the generation of oxygen-derived free radicals and lipid peroxidation process have also become the focus that research worker is paid close attention to.Many researchs provide a large amount of evidences to prove the reaction ((Hall ED, J-Neurotrauma 9 (Suppl.l): S165-S172 (1992)) that exists free radical and lipid peroxidation in damage or ischemic CNS.
Advised the anti-breast carcinoma of antioxidant protectability and anti-other cancer (comprising the brain cancer and hepatocarcinoma), and protectiveness anti-cardiovascular disease and osteoporosis ((Wiseman H, Free Radical Res21 (3): 187-94 (1994)).Verified these antioxidant protection models and cell membrane (comprising nuclear membrane) are to resist possibility carcinogenic free radical intermediate and lipid peroxidation product.People have concentrated on the attention of the serious syndrome relevant with atherosclerosis and its common sickness rate and can prevent and treat (Steinberg D, N Engl J of Med 14:915-924 (1989)) on this angiopathy by the ability that antioxidant protection low density lipoprotein, LDL (LDL) avoids oxidative damage.
Invention is described
The invention provides the (.+-.)-Equilenin. of antioxidant amounting or its 3-sulfuric ester pharmaceutical salts are fed the mammal that needs with treatment or suppress the method for the disease of free yl induction.Inference according to this, the invention provides and handle free radical and enzyme in the mammal, ion channel, the method of structural protein and membrane lipid reaction, this method comprises (.+-.)-Equilenin. or its medicinal sulfuric acid that feeds as sacrificing substrate, present in an amount at least sufficient to optionally and enzyme with the patient, ion channel, the radical reaction of structural protein and membrane lipid reaction also suppresses free radical and patient's enzyme, ion channel, the reaction of structural protein and membrane lipid wherein determines with the guaranteed concrete disease of antioxidant therapy it is cancer, central nervous system disorder, the bone disease, old and feeble, inflammation, peripheral vascular disease, rheumatoid arthritis, autoimmune disease, respiratory distress, emphysema, prevent perfusion injury again, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus (sle), adult respiratory distress syndrome, central nervous system trauma and apoplexy.
As purposes of the present invention, handle and to comprise existing treatment of diseases, improve disease or palliate a disease, suppress to comprise and suppress or prophylactic development or diffusion.
(.+-.)-Equilenin. 3-sulfuric ester pharmaceutical salts comprises (but being not limited to this) alkali metal salt, alkali salt, ammonium salt, contain the alkylamine salt of 1-6 carbon atom or contain the dialkyl group amine salt of 1-6 carbon atom in alkyl group separately.
The pharmacology method of testing of employing standard is determined the performance of (.+-.)-Equilenin. antioxidant, and this method is measured it to by being exposed to Cu by the free aldehyde (Yagi K., BiochemMed 15:212-216 (1976)) of TBARS (thiobarbituricacid active substance) methods analyst ++The inhibition ability of the formation of the low density lipoprotein, LDL of inductive oxidative deformation (LDL) in ion or the endothelial cells cultured (Parthasarathy S, Proc Natl Acad Sci USA 86:1046-1050 (1989)).
The result who obtains with the pharmacology method of testing of this standard shows that (.+-.)-Equilenin. is effective LDL oxidation reaction inhibitor, promptly suppresses to reach 99%, at Cu ++Obtain the IC of 0.119 μ M and 0.19 μ M in ion mediation and the oxidation mediation of porcine aorta endotheliocyte respectively 50Value.By relatively, in the oxidation method of testing of porcine aorta endotheliocyte mediation, the resulting IC of estrone 50Value is 0.56 μ M.Can prove also that with this method of testing (.+-.)-Equilenin. is effective HDL and blood plasma oxidation retarder, the IC that obtains 50The s value is respectively 0.047 μ M and 0.062 μ M.
The (.+-.)-Equilenin. antioxidant properties is also estimated by its kinetic effect, and this kinetic effect relates at Cu ++There are LDL, the HDL of generation down and the oxidation of blood plasma, promptly have been used to induce standard technique (Esterbauer H, the Ann NY Acad Sci 1989 of LDL degeneration; 570:254-267, Huber LA, Free Rad Res Comms 1990; 8:167-173, VossenRcrm, Lipids 1993; 8:857-861, Jialal I, J Lipid Res1992; 33:899-906).The following parameters of following the tracks of the formation estimation of conjugated diene (main initial stage lipid peroxide) with spectrophotography is: period of delay or T Min: oxidation begins the used time; T 50: form two used times of diene of 50% conjugation; And T Max: reach the used time of maximum oxidation.
Concentration is to prolong period of delay 30% during (.+-.)-Equilenin. that 25nM is tried can form in the conjugated diene of human LDL.T 50And T MaxAll prolong 21%.In same test, the estrone of 25nM only increases all parameter 7-10%.The (.+-.)-Equilenin. of 25nM has the effect of the conjugated diene formation of the human HDL of obvious inhibition, and it prolongs 282% of period of delay.T 50And T MaxProlong 120% and 105% respectively.The estrone of same concentrations by prolong period of delay 20%, T 5038% and T MaxThe conjugated diene of 46% couple of HDL forms and works.Prolong period of delay 3% during the (.+-.)-Equilenin. of 25nM can form in the conjugated diene of human plasma, prolong T respectively 50And T Max21% and 31%, though this has just indicated it to the almost not effect of oxidation initial stage, it has reduced its speed.Estrone in this system is to also not having effect period of delay, for T 50And T MaxEffect only be respectively 5% and 10%.
For further proving the antioxygenic property of (.+-.)-Equilenin., carry out two additional standard pharmacology testing procedures with cultured cells.In first testing procedure, (.+-.)-Equilenin. exist or non-existent situation under, with the LDL of labelled with radioisotope ( 125I-LDL) (McFarlaneAS, In:Munro HN, Allison JB, eds.Mammalian ProteinMetabolism.Vol.l.New York:Academic Press 297-341 (1964)) places Cu ++Middle degeneration.Next step places processing with expressing J774 macrophage in conjunction with the scavenger lipoprotein receptor of oxidative deformation LDL 125Among the I-LDL.This result of the test shows: in the presence of (.+-.)-Equilenin., and the Cu of oxidation ++-the LDL that handles in conjunction with reducing by 60% and 37% (being respectively 2.5 and 0.25 μ M (.+-.)-Equilenin .), by relatively, the estrone of same concentrations reduces the combination of 39% and 0% oxidation LDL respectively.Because the LDL of oxidation is considered to facilitate strongly the growth of spongiocyte and atherosclerotic plaque by macrophage combination and metabolism, therefore, this minimizing LDL oxidation and be attached to subsequently that effect on the scavenger receptor is considered to be highly profitable.
In second testing procedure, (PAEC) places LDL with the porcine aorta endotheliocyte, and this LDL is as above-mentioned by placing the Cu that is with or without under the (.+-.)-Equilenin. situation ++In and degeneration.The LDL that has proved oxidation has cytotoxicity and this process and atherosclerosis to endotheliocyte very strong association.After the LDL incubated cell of handling 24 hours, carry out the MTT test to estimate cytotoxicity (HanSen MB, J Immu Methods 119:203-210 (1989)).This assay method is made an appraisal to the percentage rate of living cells in the give test.In this test, 25 μ g/ml LDL of oxidation when placing no chemical compound to exist in cell, only 2% cell survival gets off afterwards.Contrast with it is placed at cell the Cu under (.+-.)-Equilenin. (the .25 μ M) existence subsequently ++Among the LDL that handles, the percentage rate of survivaling cell is 100% or bigger afterwards.Other chemical compound of testing in identical test is to protection effect minimum (17 beta estradiols=11% survival of PACE; 1,3,5,7-estratetraen-3-ol-17-one=4% survival; Estrone=37% survival).The result of this method of testing proves: there is the LDL no cytotoxicity of modification down in (.+-.)-Equilenin., therefore, these data with above-mentioned by the TBARS method prove consistent by the degeneration of (.+-.)-Equilenin. inhibited oxidation.
The result who obtains based on these method of testings, the pharmaceutical salts of (.+-.)-Equilenin. and its sulfuric ester can be used for treating or suppressing the disease of free yl induction as antioxidant, described pharmaceutical salts such as alkali metal salt, alkali salt, ammonium salt, contains the alkylamine salt of 1-6 carbon atom or contain the dialkyl group amine salt of 1-6 carbon atom in alkyl group separately.
Antioxidant of the present invention can be mixed with pure or prepare administration with pharmaceutical carrier, and the route of administration of dissolubility by chemical compound and chemical property, selection and the pharmacology of standard put into practice to determine the ratio of carrier.Pharmaceutical carrier can be solid or liquid.
Solid carrier can comprise one or more materials, and this material also can play correctives, lubricant, solubilizing agent, suspending agent, filler, fluidizer, compression aid, binding agent or tablet disintegrant; Solid carrier also can be the encapsulate material.In powder, carrier is the solid of segmentation, and this solid mixes with the active component of segmentation.In tablet, active component and the carrier with required compression property are with suitable mixed and be pressed into required shape and size.Preferred powder and tablet contain to the active component that reaches 99%.Suitable solid carrier comprises calcium phosphate, magnesium stearate, Talcum, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Liquid-carrier is used to prepare solution, suspension, Emulsion, syrup, elixir and pressurized compositions.Active component can be dissolved in or be suspended in the medicinal fluid carrier, in water, organic solvent, both mixture or medicinal oil or fat, liquid-carrier can contain other suitable medical additive, as solubilizing agent, emulsifying agent, buffer, antiseptic, sweeting agent, correctives, suspending agent, thickening agent, pigment, viscosity-controlling agent, stabilizing agent or Osmolyte regulator.Oral and the suitable example of liquid-carrier parenteral comprises that water (partly contains additive as above, as cellulose derivative, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising MHA and polyhydroxy-alcohol) and their derivant, lethicins and oil (as the Oleum Cocois and the Oleum Arachidis hypogaeae semen of rectification) as ethylene glycol.For parenteral, carrier also can be an oils and fats, as ethyl oleate and Semen Myristicae isopropyl acid ester.The sterile liquid carrier is used for the compositions of the sterile liquid form of parenteral, can be halogenated hydrocarbon or other medicinal propellant for the liquid-carrier of pressurized compositions.
The composition of liquid medicine of sterile solution or suspension can use by for example intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can intravenously administrable, and chemical compound of the present invention also can be with the form oral administration of liquid or solid compositions.
Antioxidant of the present invention can conventional suppository the form per rectum feed, for by sucking or be blown into administration in intranasal or the bronchus, antioxidant of the present invention can be mixed with aqueous solution or partially aqueous solution, it can be used with the form of aerosol, The compounds of this invention also can feed by the transdermal sheet percutaneous that contains reactive compound and carrier, described carrier for reactive compound be inert, for skin be nontoxic, and can the medicament general of transmission be adsorbed onto in the blood flow by skin.Carrier can be taked various ways, as cream and ointment, paste, gel and closing device.Cream and ointment can be the thick liquid or the semisolid Emulsion of oil-in-water type or water-in-oil type, and the paste that dispersive adsorptivity powder is formed in oil that contains active component or hydrophilic petroleum also is suitable for.Also can utilize multiple closing device that active component is discharged in the blood flow, contain active component, have or the semipermeable membrane of DNAcarrier free reservoir or contain the substrate of active component as covering, other closing device sees in the document.
In addition, by being mixed with the preparation that contains 0.1-5% (preferred 2%) reactive compound with pharmaceutical excipient, antioxidant of the present invention can be used as solution, cream or washing liquid and uses the zone that imposes on the fungus effect.
The concrete object that required dosage is treated with used concrete compositions, route of administration, the seriousness that presents symptom and quilt changes, the result who obtains based on standard pharmacology method of testing, the daily dose of the reactive compound of design should be 0.02 μ g/kg-500 μ g/kg, by the low dose of begin treatment with the optimal dose that is less than chemical compound.Then, increase dosage to the optimum efficiency that reaches under the treatment environment; The pharmacists can determine the exact dose of oral, parenteral, intranasal or intraperitoneal administration according to the experience of each object of treatment, preferred pharmaceutical compositions is a unit dosage form, for example, and tablet or capsule, in this form, compositions is subdivided into the unit dose that contains the appropriate amount active component; Unit dosage forms can be packaged compositions, for example, is packaged powder, can be medicine bottle, ampoule, pre-filled syringe or the sachets that contains liquid.Unit dosage form can be for example capsule or tablet itself, maybe can be any described compositions of suitable quantity under the packaged form.

Claims (4)

1. suppress or treat the method for the disease of free yl induction, this method is for to be used for the mammal of needs with the (.+-.)-Equilenin. of antioxidant amounting or the pharmaceutical salts of (.+-.)-Equilenin .-3-sulfuric ester.
2. the process of claim 1 wherein that the pharmaceutical salts of (.+-.)-Equilenin .-3-sulfuric ester is alkali metal salt, alkali salt, ammonium salt, contains the alkylamine salt of 1-6 carbon atom or contain the dialkyl group amine salt of 1-6 carbon atom in each alkyl group.
3. need to suppress the method that free radical and enzyme, ion channel, structural protein and membrane lipid react in the mammal of corresponding treatment, this method comprises to be used as the (.+-.)-Equilenin. of sacrificing substrate or the pharmaceutical salts of (.+-.)-Equilenin .-3-sulfuric ester, present in an amount at least sufficient to optionally with the radical reaction of enzyme, ion channel, structural protein and the membrane lipid reaction of described mammal and suppress free radical and the reaction of the enzyme of described mammal, ion channel, structural protein and membrane lipid.
4. the method that suppresses the endogenous free radical relevant with following advancing of disease, described disease is a cancer, central nervous system disorder, Alzheimer, the bone disease, old and feeble, inflammation, peripheral vascular disease, rheumatoid arthritis, autoimmune disease, respiratory distress, emphysema, prevent perfusion injury again, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus (sle), adult respiratory distress syndrome, central nervous system trauma and apoplexy, or the damage in filling process again, this method comprises the pharmaceutical salts of using (.+-.)-Equilenin. or (.+-.)-Equilenin .-3-sulfuric ester.
CN97180448A 1996-12-10 1997-12-05 Use of equilenin as antioxidant Pending CN1239892A (en)

Applications Claiming Priority (2)

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US76257996A 1996-12-10 1996-12-10
US08/762,579 1996-12-10

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EP (1) EP0944391A1 (en)
JP (1) JP2001506628A (en)
KR (1) KR20000069412A (en)
CN (1) CN1239892A (en)
AR (1) AR010344A1 (en)
AU (1) AU743586B2 (en)
BR (1) BR9714384A (en)
CA (1) CA2272087A1 (en)
HU (1) HUP0000569A3 (en)
IL (1) IL130071A0 (en)
NZ (1) NZ336343A (en)
TW (1) TW466115B (en)
WO (1) WO1998025626A1 (en)
ZA (1) ZA9711052B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271221B1 (en) * 1996-12-10 2001-08-07 American Home Products Corporation Use of equilenin as an antioxidant
DE19915576A1 (en) 1999-03-30 2000-10-05 Jenapharm Gmbh New equilenine derivatives, useful as antioxidative estrogenic hormonal steroids for e.g. prophylactic geriatrics in women and men
CA2466928A1 (en) * 2001-12-10 2003-07-03 Yansheng Du Treatment of neurodegenerative and cardiovascular disorders
CN108958639B (en) 2017-05-19 2021-07-06 华邦电子股份有限公司 Flash memory storage device

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* Cited by examiner, † Cited by third party
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US4154820A (en) * 1976-02-23 1979-05-15 Akzona Incorporated Compositions containing alkali metal sulfate salts of conjugated estrogens and antioxidants as stabilizers
EP0240717A3 (en) * 1986-03-04 1990-05-16 Board of Regents of the University of Nebraska Prevention of mammary carcinoma
US4937238A (en) * 1986-03-04 1990-06-26 The Board Of Regents Of The University Of Nebraska Prevention of mammary carcinoma
US5545635A (en) * 1995-05-23 1996-08-13 Eli Lilly And Company Inhibiting bone loss with equilenin

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ZA9711052B (en) 1999-06-09
CA2272087A1 (en) 1998-06-18
NZ336343A (en) 2000-11-24
KR20000069412A (en) 2000-11-25
TW466115B (en) 2001-12-01
WO1998025626A1 (en) 1998-06-18
HUP0000569A3 (en) 2000-11-28
JP2001506628A (en) 2001-05-22
AU5370798A (en) 1998-07-03
HUP0000569A2 (en) 2000-10-28
AR010344A1 (en) 2000-06-07
IL130071A0 (en) 2000-02-29
AU743586B2 (en) 2002-01-31
EP0944391A1 (en) 1999-09-29

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