WO1998025627A1 - 17α-DIHYDROEQUILENIN FOR USE AS A MEDICAL ANTIOXIDANT - Google Patents
17α-DIHYDROEQUILENIN FOR USE AS A MEDICAL ANTIOXIDANT Download PDFInfo
- Publication number
- WO1998025627A1 WO1998025627A1 PCT/US1997/022155 US9722155W WO9825627A1 WO 1998025627 A1 WO1998025627 A1 WO 1998025627A1 US 9722155 W US9722155 W US 9722155W WO 9825627 A1 WO9825627 A1 WO 9825627A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dihydroequilenin
- free radical
- pharmaceutically acceptable
- sulfate ester
- disease
- Prior art date
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
- A61K31/56—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
- A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
-
- 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
Definitions
- Biologically generated free radicals have been implicated in a large number of disease states.
- the survival of aerobic organisms in an oxygen environment involves a complicated interplay between the biological generation of these very reactive chemical species and the ability of the organism to control them (Del Maestro RF, Acta Phy Scan Suppl. 492:153-68 (1980)).
- This interplay between the host organism and biologically generated free radicals results in profound biochemical alterations which culminate in cellular injury and death of the organism.
- the accumulated products of free radical reactions result in some of the large number of disease conditions which have been suggested to result, in part, from cellular injury induced by an increased flux of intracellular free radicals.
- These include, but are not limited to cancers, cardiovascular disease, central nervous system disorders, bone disease, aging, Alzheimer's dementia, inflammatory disorders, rheumatoid arthritis, autoimmune diseases, respiratory distress and emphysema.
- Oxidation and the use of antioxidants is also important for the treatment of numerous inflammatory disease states.
- Rheumatoid arthritis is the most common chronic inflammatory disease.
- Epidemiological studies reveal a prevalence rate of classical and definite RA between 0.3 and 1.5 percent.
- Joint disease with chronic persistent inflammation is accompanied by the formation of H2O2 in the inflamed rheumatoid joint.
- oxygen free radicals are also produced, especially by polymorphonuclear leukocytes (PMN) and macrophages. In any chronic or acute inflammatory disease, PMN and macrophages will produce both O2 " and H2O2.
- Tuberculosis, psoriasis, systemic lupus erythematosus, other autoimmune diseases, and adult respiratory distress syndrome can also be mentioned as inflammatory diseases with oxidation as a contributor, and many others can be added to this list.
- Antioxidants have been suggested to be protective against breast cancer and other cancers including those of the brain and liver, as well as to protect against cardiovascular disease and osteoporosis (Wiseman H, Free Radical Res 21(3): 187-94 (1994)). They have been demonstrated to protect model and cellular membranes including the nuclear membrane against potentially carcinogenic free radical intermediates and the products of lipid peroxidation. Severe complications associated with atherosclerosis and its common incidence have focused attention on prevention and therapy of this vascular disease state, possibly through their ability to protect low density lipoproteins (LDL) against oxidative damage (Steinberg D, N Engl J of Med 14:915-924 (1989)).
- LDL low density lipoproteins
- this invention provides a method of treating or inhibiting free radical induced disease states by administering an antioxidant amount of 17 ⁇ -dihydroequilenin or its pharmaceutically acceptable salt of the 3-sulfate ester, to a mammal in need thereof.
- this invention provides a process for treating free radical reactions with enzymes, ion channels, structural proteins and membrane lipids in a mammal, which comprises administering 17 ⁇ - dihydroequilenin or a pharmaceutically acceptable sulfate ester salt thereof, as a sacrificial substrate, in an amount sufficient to selectively react with and inhibit free radical reaction with the patients enzymes, ion channels, structural proteins or membrane lipids.
- antioxidant therapy is indicated to be warranted are with cancers, central nervous system disorders, bone disease, aging, inflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, respiratory distress, emphysema, prevention of reperfusion injury, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, adult respiratory distress syndrome, central nervous system trauma and stroke.
- treating covers treatment of an existing condition, ameliorating the condition, or providing palliation of the condition and inhibiting includes inhibiting or preventing the progress or development of the condition.
- Pharmaceutically acceptable salts of 17 ⁇ -dihydroequilenin 3-sulfate ester include, but are not limited to, the alkali metal salts, alkaline earth metal salts, ammonium salts, alkylamine salts containing 1-6 carbon atoms or dialkylamine salts containing 1-6 carbon atoms in each alkyl group.
- the antioxidant properties of 17 ⁇ -dihydroequilenin were established in a standard pharmacological test procedure that measured the ability to inhibit the formation of oxidatively modified low density lipoprotein (LDL) induced by exposure to either Cu++ ions or cultured endothelial cells (Parthasarathy S, Proc Natl Acad Sci USA 86:1046-1050 (1989)) by the TBARS (thiobarbituric acid reactive substances) method for analysis of free aldehydes (Yagi K., Biochem Med 15:212-216 (1976)).
- LDL low density lipoprotein
- 17 ⁇ -Dihydroequilenin when tested at a concentration of 25nM was able to extend the lag phase in the formation of conjugated dienes in human LDL by 28%.
- T 50 and T max were extended by 31% and 30%, respectively.
- estrone at 25 nM increased all parameters by only 7-10%.
- 17 ⁇ -Dihydroequilenin at 25 nM had a marked inhibitory effect on the formation of conjugated dienes in human HDL. It extended the lag phase by 299%.
- T 50 and T ma! . were extended by 134% and 118%, respectively.
- Estrone at the same concentration effected the formation of conjugated dienes in HDL by extending the lag phase by 20% , T 50 by 38% and T max by 46%.
- 17 ⁇ -Dihydroequilenin at 25 nM had no effect on the lag phase in the formation of conjuagted dienes in human plasma. However, it did extend the T 50 and T max by 19% and 32%, respectively, indicating that although it did not effect the initiation of oxidation it has slowed its rate. Estrone in this system also had no effect on the lag phase, and only a 5% and 10% effect on its T 50 and T max , repectively.
- porcine aortic endothelial cells were exposed to LDL that had been modified as above, by exposure to Cu++ in the presence and absence of 17 ⁇ -dihydroequilenin. Oxidized LDL has been demonstrated to be cytotoxic to endothelial cells, and this process has also been strongly implicated in the atherogenic process. Subsequent to a 24 hr incubation of the cells with the treated LDL, an MTT assay was performed to assess cytotoxicity (Hansen MB, J Immu Methods 119:203-210 (1989)). This test procedure assesses the percent of cells that are viable (live) in a given assay.
- 17 ⁇ -dihydroequilenin and the pharmaceutically acceptable salts of its sulfate ester are therefore useful as antioxidants, and in the treatment or inhibition of free radical induced disease states.
- the antioxidants of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
- the pharmaceutical carrier may be solid or liquid.
- a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
- the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
- the compounds of this invention can also be administered orally either in liquid or solid composition form.
- the antioxidants of this invention may be administered rectally in the form of a conventional suppository.
- the antioxidants of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
- the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
- the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
- the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
- Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
- a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermiable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
- the antioxidants of this invention may be employed as a solution, cream, or lotion by formulation with pharmaceutically acceptable vehicles containing 0.1 - 5 percent, preferably 2%, of active compound which may be administered to a fungally affected area.
- the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 ⁇ g/kg - 500 ⁇ g/kg. Treatment will generally be initiated with small dosages less than the optimum dose of the compound.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU54644/98A AU743519B2 (en) | 1996-12-09 | 1997-12-05 | 17alpha-dihydroequilenin for use as a medical antioxidant |
IL13006997A IL130069A0 (en) | 1996-12-09 | 1997-12-05 | 17alpha-dihydroequilenin for use as a medical antioxidant |
BR9714382-0A BR9714382A (en) | 1996-12-09 | 1997-12-05 | 17alpha-dihydroequiline for use as a medical antioxidant |
NZ336341A NZ336341A (en) | 1996-12-09 | 1997-12-05 | 17alpha-dihydroequilenin or salts of 17alpha-dihydroequilenin-3-sulfate ester for use as a medical antioxidant |
CA002272089A CA2272089A1 (en) | 1996-12-09 | 1997-12-05 | 17.alpha.-dihydroequilenin for use as a medical antioxidant |
HU0000570A HUP0000570A3 (en) | 1996-12-09 | 1997-12-05 | Use of 17 alpha-dihydroequilenin for producing pharmaceutical compositions for the treatment of free radical induced disease states |
EP97948610A EP0946182A1 (en) | 1996-12-09 | 1997-12-05 | 17$g(a)-DIHYDROEQUILENIN FOR USE AS A MEDICAL ANTIOXIDANT |
JP52680598A JP2001506629A (en) | 1996-12-09 | 1997-12-05 | 17α-dihydroequilenin for use as a medical antioxidant |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76263496A | 1996-12-09 | 1996-12-09 | |
US08/762,634 | 1996-12-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998025627A1 true WO1998025627A1 (en) | 1998-06-18 |
Family
ID=25065657
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/022155 WO1998025627A1 (en) | 1996-12-09 | 1997-12-05 | 17α-DIHYDROEQUILENIN FOR USE AS A MEDICAL ANTIOXIDANT |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0946182A1 (en) |
JP (1) | JP2001506629A (en) |
KR (1) | KR20000069346A (en) |
CN (1) | CN1239890A (en) |
AR (1) | AR010336A1 (en) |
AU (1) | AU743519B2 (en) |
BR (1) | BR9714382A (en) |
CA (1) | CA2272089A1 (en) |
HU (1) | HUP0000570A3 (en) |
IL (1) | IL130069A0 (en) |
NZ (1) | NZ336341A (en) |
WO (1) | WO1998025627A1 (en) |
ZA (1) | ZA9711053B (en) |
Cited By (2)
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 |
WO2003039555A2 (en) * | 2001-11-07 | 2003-05-15 | Max-Delbrück-Centrum für Molekulare Medizin | Agents for treating lesions of the nervous system |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4338314C1 (en) * | 1993-11-10 | 1995-03-30 | Jenapharm Gmbh | Pharmaceutical preparations for the prophylaxis and therapy of radical-mediated cell damage |
-
1997
- 1997-12-05 KR KR1019997005048A patent/KR20000069346A/en not_active Application Discontinuation
- 1997-12-05 WO PCT/US1997/022155 patent/WO1998025627A1/en not_active Application Discontinuation
- 1997-12-05 BR BR9714382-0A patent/BR9714382A/en not_active IP Right Cessation
- 1997-12-05 IL IL13006997A patent/IL130069A0/en unknown
- 1997-12-05 AR ARP970105739A patent/AR010336A1/en unknown
- 1997-12-05 NZ NZ336341A patent/NZ336341A/en unknown
- 1997-12-05 CA CA002272089A patent/CA2272089A1/en not_active Abandoned
- 1997-12-05 EP EP97948610A patent/EP0946182A1/en not_active Ceased
- 1997-12-05 HU HU0000570A patent/HUP0000570A3/en unknown
- 1997-12-05 AU AU54644/98A patent/AU743519B2/en not_active Ceased
- 1997-12-05 CN CN97180446A patent/CN1239890A/en active Pending
- 1997-12-05 JP JP52680598A patent/JP2001506629A/en active Pending
- 1997-12-09 ZA ZA9711053A patent/ZA9711053B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4338314C1 (en) * | 1993-11-10 | 1995-03-30 | Jenapharm Gmbh | Pharmaceutical preparations for the prophylaxis and therapy of radical-mediated cell damage |
Non-Patent Citations (3)
Title |
---|
KAUFFMAN ET AL: "selective estrogen receptor modulators", DRUG NEWS AND PERSPECTIVES, vol. 8, no. 9, 1995, pages 531 - 539, XP002055053 * |
TANG ET AL: "superior and distinct antioxidant effects of selected estrogen metabolites on lipid peroxidation", METAB CLIN EXP, vol. 45, no. 4, April 1996 (1996-04-01), pages 411 - 414, XP002055052 * |
WASHBURN ET AL: "a conjugated equine estrogen with differential effects on uterine weight and plasma cholesterol in the rat", AMER. J. OBST. GYNECOL., vol. 169, 1993, pages 251 - 256, XP002058586 * |
Cited By (3)
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 |
WO2003039555A2 (en) * | 2001-11-07 | 2003-05-15 | Max-Delbrück-Centrum für Molekulare Medizin | Agents for treating lesions of the nervous system |
WO2003039555A3 (en) * | 2001-11-07 | 2003-10-16 | Max Delbrueck Centrum | Agents for treating lesions of the nervous system |
Also Published As
Publication number | Publication date |
---|---|
JP2001506629A (en) | 2001-05-22 |
ZA9711053B (en) | 1999-06-09 |
AU5464498A (en) | 1998-07-03 |
IL130069A0 (en) | 2000-02-29 |
NZ336341A (en) | 2002-02-01 |
BR9714382A (en) | 2000-05-16 |
AR010336A1 (en) | 2000-06-07 |
KR20000069346A (en) | 2000-11-25 |
EP0946182A1 (en) | 1999-10-06 |
CA2272089A1 (en) | 1998-06-18 |
AU743519B2 (en) | 2002-01-31 |
CN1239890A (en) | 1999-12-29 |
HUP0000570A3 (en) | 2000-12-28 |
HUP0000570A2 (en) | 2000-10-28 |
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