EP0907361A1 - Verfahren zur messung von muskoloaponeurotischen fibromatosen (desmoide tumoren) - Google Patents

Verfahren zur messung von muskoloaponeurotischen fibromatosen (desmoide tumoren)

Info

Publication number
EP0907361A1
EP0907361A1 EP97906588A EP97906588A EP0907361A1 EP 0907361 A1 EP0907361 A1 EP 0907361A1 EP 97906588 A EP97906588 A EP 97906588A EP 97906588 A EP97906588 A EP 97906588A EP 0907361 A1 EP0907361 A1 EP 0907361A1
Authority
EP
European Patent Office
Prior art keywords
compound
formulation
desmoid
cells
raloxifene
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Withdrawn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
EP97906588A
Other languages
English (en)
French (fr)
Other versions
EP0907361A4 (de
Inventor
Maria L. Brandi
Francesco Tonelli
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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
Priority claimed from GBGB9603148.9A external-priority patent/GB9603148D0/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0907361A1 publication Critical patent/EP0907361A1/de
Publication of EP0907361A4 publication Critical patent/EP0907361A4/de
Withdrawn legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/4025Heterocyclic 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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the musculoaponeurotic fibromatoses are a group of nonmetastasizing, locally invasive dysplastic lesions of connective tissue. Included in this group are nodular fasciitis, plantar fibromatosis, and the lesions previously classified as desmoid tumors.
  • the invention provides methods for inhibiting musculoaponeurotic fibromatoses in mammals by administering to the mammal in need thereof of an effective amount of a compound of formula I.
  • R 1 and R 3 are independently hydrogen
  • R 2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof.
  • the current invention concerns the discovery that a select group of 2-phenyl-3-aroylbenzothiophene ⁇ (benzothiophene ⁇ ) , those of formula I, are useful for inhibiting musculoaponeurotic fibromatoses.
  • the methods of use provided by this invention are practiced by administering to a human in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit musculoaponeurotic fibromatoses.
  • a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof that is effective to inhibit musculoaponeurotic fibromatoses.
  • the term "inhibit” includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom or effect.
  • Raloxifene a compound of this invention wherein it is the hydrochloride salt of a compound of formula 1, R 1 and R 3 are hydrogen and R 2 is 1-piperidinyl, is a nuclear regulatory molecule.
  • Raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti-estrogen in that it blocked the ability of estrogen to activate uterine tissue and estrogen dependent breast cancers. Indeed, raloxifene does block the action of estrogen in some cells; however in other cell types, raloxifene activates the same genes as estrogen does and displays the same pharmacology, e . g. , osteoporosis, hyperlipidemia.
  • raloxifene has been referred to as an anti-estrogen with mixed agonist-antagonist properties.
  • the unique profile which raloxifene displays and differs from that of estrogen is now thought to be due to the unique activation and/or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed to the activation and/or suppression of genes by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen utilize and compete for the same receptor, the pharmacological outcome from gene regulation of the two is not easily predicted and is unique to each.
  • the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes.
  • the compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like.
  • the compounds used in the methods of the current invention can be made according to established procedures, such as those detailed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein.
  • the process starts with a benzo[b]thiophene having a 6-hydroxyl group and a 2- (4- hydroxyphenyl) group.
  • the starting compound is protected, acylated, and deprotected to form the formula I compounds. Examples of the preparation of such compounds are provided in the U.S. patents discussed above.
  • Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with C1 . -C 6 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro)methyl .
  • the compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1, 4-dioate, hexyne-1, 4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate,
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether or benzene.
  • the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
  • Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines.
  • Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamine and eyelo exylamine.
  • the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • compositions can be prepared by procedures known in the art.
  • the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; re ⁇ orption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate
  • the compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
  • the coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.
  • a compound of formula I required to inhibit musculoaponeurotic fibromatoses, or any other use disclosed herein, and according to this invention will depend upon the severity of the condition, the route of administration, and related factors that will be decided by the attending physician. Generally, accepted and effective daily doses will be from about 0.1 to about 1000 mg/day, and more typically from about 50 to about 200 mg/day. Such dosages will be administered to a subject in need thereof from once to about three times each day, or more often as needed to effectively inhibit musculoaponeurotic fibromatoses.
  • the compounds may be formulated as is known in the art for direct application to an area. Conventional forms for this purpose include ointments, lotions, pastes, jellies, sprays, and aerosols.
  • the percent by weight of a compound of the invention present in a topical formulation will depend on various factors, but generally will be from 0.5% to 95% of the total weight of the formulation, and typically 1-25% by weight.
  • the compo ⁇ itions can take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension.
  • compositions can contain pharmaceutically acceptable vehicles and adjuvants which are well known in the prior art. It is possible, for example, to prepare solutions using one or more organic solvent (s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvent ⁇ ⁇ uch as acetone, ethanol, isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanol”, polyglycols and polyethylene glycols, C 1 -C 4 alkyl esters of short-chain acids, preferably ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the name "Miglyol", isopropyl myristate, animal, mineral and vegetable oils and polysiloxanes.
  • organic solvent s
  • compositions according to the invention can also contain thickening agents such as cellulose and/or cellulose derivatives. They can also contain gums such as xanthan, guar or carob gum or gum arabic, or alternatively polyethylene glycols, bentones and montmorillonites, and the like.
  • the galenical forms chiefly conditioned for topical application take the form of creams, milks, gels, dispersions or microemulsions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, or alternatively the form of aerosol formulations in spray or foam form or alternatively in the form of a cake of soap.
  • Active ingredient means a compound of formula I.
  • Hard gelatin capsules are prepared using the following:
  • the ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules.
  • Silicone fluid 350 centistokes 1.7 Formulation 3 Raloxifene capsule
  • Raloxifene 50 Starch NF 150 Starch f lowable powder 397 Silicone fizid 350 centistokes 3 . 0
  • a tablet formulation is prepared using the ingredients below: Formulation fi : Tablets
  • the components are blended and compressed to form tablets,
  • tablets each containing 0.1 - 1000 mg of active ingredient are made up as follows:
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°-60° C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • Suspensions each containing 0.1 - 1000 mg of medicament per 5 mL dose are made as follows: Formulation 8: Suspensions
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • compositions are prepared:
  • Formulations 9-12 take the form of gels
  • Formulations 13, 14, 15, and 16 take the form of lotions
  • Formulations 17 and 18 take the form of sticks Desmoid tumors are rare non metastatic tumors of fibrous origin. Clinical correlates suggest that steroid hormones may have a role in the natural history of these tumors: it is predominantly seen in female patients of child-bearing age and regression of these tumors have been associated with menopause or with antiestrogen therapy. The aim of this work was to identify estrogen receptors in desmoid tumor primary cells, and to evaluate the effect of a compound of formula I on desmoid cells in primary culture.
  • FAP Familial Adenomatous Polyposis
  • Compound la is a compound of formula I wherein R 2 is pyrrolidino, and R 1 and R 3 are hydrogen.
  • Binding studies are performed using intact cells. Desmoid cells are plated on 6-well plates in growth medium (Coon's modified Ham's F12 supplemented with 10% FCS) . After 24 hours, the growth medium is substituted with steady state medium without phenol red, and cells are maintained in starvation for 24 hours. Then cells are incubated for one hour with 1 ml of medium without phenol red containing 25 mM HEPES and 0.5% EtOH (binding buffer) and increasing concentrations (0.05- 10 nM) of [ 3 H]17 ⁇ E2 with or without a 500-fold excess of unlabeled 17 ⁇ E2 and Compound Ia. After incubation, cells are washed two times with 800 ⁇ l of binding buffer and lysed with IN NaOH at
  • the pulverized tissue is homogenized with two 10-sec burst in a polytron homogenizer separated by a 30-sec cooling period in the following buffer: 10 mM Tris-HCl, 5 mM EDTA, 10 mM sodium molybdate, 10 mM dithiothreitol, 10% glycerol (v/v), pH 7.4.
  • the homogenate is centrifuged at 7000 g for 20 min and the pellet is discarded, the supernatant was recentrifuged at 105000 g for 60 min to obtain cytosol for estrogen receptor analysis. Cytosol is diluted to 1-2 mg protein/ml. Cytosol protein is determined according to the method of Bradford.
  • cytosol is incubated for 16 hr at 4°C over a concentration range of 0.05-5 nM of [ 3 H]17 ⁇ E 2 with or without a 500-fold excess of unlabeled 17 ⁇ E 2 and Compound Ia.
  • ER binding affinity and binding capacity are evaluated by Scatchard analysis.
  • Cells are plated on 6 well plates at a density of 8xl0 4 cell for well in growth medium. After 24 hours, the cells are stimulated in growth medium without phenol red supplemented with 0.1% DMF, 0.1% EtOH, and different concentrations of Compound Ia (2xl0" 5 M, 10 ⁇ 5 M, 5xl0 _6 M, 10 ⁇ 6 M) .
  • Cells are incubated six days, detached with trypsin/ethylenediamine tetracetic acid solution and then the growth is evaluated by counting to the microscope.
  • the same method is used for colon cancer primary fibroblasts cell line and for HCT8 cell line: this line is cultured in RPMI and incubated 4 days after stimulation.
  • Collagen type I in culture media and cell layers are measured using an enzyme-linked immunoassay (ELISA) . Briefly, cells are incubated for 24 hrs in supplement-free Coon's modified Ham F12 medium containing 50 ⁇ g/ml ascorbic acid and lOO ⁇ g/ml ⁇ aminopropionitryl fumarate.
  • ELISA enzyme-linked immunoassay
  • Culture media are harvested and appropriately diluted in 0.1 M carbonate/bicarbonate buffer (pH 9.6) and then used for coating the ELISA plates, overnight at 4°C ELISA plates are incubated 1.5 hrs at 37°C in PBS containing 5% of milk powder (PBS Blotto) to saturate non specific binding sites, 2 hrs at 37°C with PBS Blotto containing the specific polyclonal antibody, and 1.5 hrs at 37°C in PBS Blotto containing goat antirabbit IgG-alkaline phosphatase conjugated complex (Sigma Chemical Co., St. Louis, MO) .
  • Samples are then exposed to 10% diethanolamine (pH 9.8) with 50 ⁇ g/ml Mg++ and 1 mg/ml paranitrophenyl- phosphate as a substrate of alkaline phosphatase at room temperature.
  • Optical density is read at 405 nM, and concentrations calculated on the basis of the standard curve.
  • Cell monolayers are harvested in 0.5 N NaOH and sonicated to determine cellular Collagen type I.
  • Cell extracts are then diluted in 0.1 M carbonate/bicarbonate buffer (pH 9.6) and used for the coating of the ELISA plates. Standards and samples are assayed in triplicate. Results are expressed as ⁇ g protein/ ⁇ g cellular DNA. DNA content is spectrofluorimetrically measured.
  • Binding experiments are performed using [ 3 H]17 ⁇ E 2 as ligand in primary desmoid tumors cells and in frozen specimens of desmoid tumor.
  • Compound Ia is able to significantly inhibit desmoid cell proliferation at micromolar concentrations. In addition, at similar concentrations the compound inhibits the proliferation of epithelial and fibroblastic cells derived from human colon cancer.
  • Type I collagen production is also significantly reduced in desmoid cell in primary culture by the Compound la.
  • Comoound Ia (Mol/L) Cell x 10--4.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
EP97906588A 1996-01-29 1997-01-27 Verfahren zur messung von muskoloaponeurotischen fibromatosen (desmoide tumoren) Withdrawn EP0907361A4 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1077396P 1996-01-29 1996-01-29
US10773P 1996-01-29
GB9603148 1996-02-15
GBGB9603148.9A GB9603148D0 (en) 1996-02-15 1996-02-15 Methods of inhibiting musculoaponeurotic fibromatoses (desmoid tumors)
PCT/US1997/002287 WO1997026878A1 (en) 1996-01-29 1997-01-27 Methods of inhibiting musculoaponeurotic fibromatoses (desmoid tumors)

Publications (2)

Publication Number Publication Date
EP0907361A1 true EP0907361A1 (de) 1999-04-14
EP0907361A4 EP0907361A4 (de) 2002-05-02

Family

ID=26308707

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97906588A Withdrawn EP0907361A4 (de) 1996-01-29 1997-01-27 Verfahren zur messung von muskoloaponeurotischen fibromatosen (desmoide tumoren)

Country Status (11)

Country Link
EP (1) EP0907361A4 (de)
JP (1) JP2000503995A (de)
KR (1) KR19990082055A (de)
CN (1) CN1209746A (de)
AU (1) AU707675B2 (de)
CZ (1) CZ235398A3 (de)
EA (1) EA199800678A1 (de)
IL (1) IL125523A0 (de)
NO (1) NO983452L (de)
PL (1) PL328127A1 (de)
WO (1) WO1997026878A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2135195C1 (ru) * 1998-12-17 1999-08-27 Овсюк Валерий Григорьевич Способ получения материала, содержащего клетки предстательной железы, материал, содержащий клетки предстательной железы, и способы лечения фиброматоза матки, хронического простатита и нарушений мужской половой функции методом трансплантации
AU781168B2 (en) 2001-01-26 2005-05-12 Pfizer Products Inc. Method of treating certain cancers using an estrogen agonist/antagonist

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994017839A1 (en) * 1993-02-09 1994-08-18 Arch Development Corporation Method for the improvement of scar size and appearance
EP0652004A1 (de) * 1993-10-15 1995-05-10 Eli Lilly And Company Methode zur Behandlung von resistenten Neoplasmen
EP0664122A1 (de) * 1993-12-21 1995-07-26 Eli Lilly And Company Hemmung unvollständiger Gewebeheilung
US5457116A (en) * 1993-10-15 1995-10-10 Eli Lilly And Company Methods of inhibiting uterine fibrosis

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW366342B (en) * 1992-07-28 1999-08-11 Lilly Co Eli The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994017839A1 (en) * 1993-02-09 1994-08-18 Arch Development Corporation Method for the improvement of scar size and appearance
EP0652004A1 (de) * 1993-10-15 1995-05-10 Eli Lilly And Company Methode zur Behandlung von resistenten Neoplasmen
US5457116A (en) * 1993-10-15 1995-10-10 Eli Lilly And Company Methods of inhibiting uterine fibrosis
EP0664122A1 (de) * 1993-12-21 1995-07-26 Eli Lilly And Company Hemmung unvollständiger Gewebeheilung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9726878A1 *

Also Published As

Publication number Publication date
AU2124097A (en) 1997-08-20
EP0907361A4 (de) 2002-05-02
CZ235398A3 (cs) 1999-02-17
NO983452D0 (no) 1998-07-27
NO983452L (no) 1998-07-27
CN1209746A (zh) 1999-03-03
WO1997026878A1 (en) 1997-07-31
EA199800678A1 (ru) 1999-02-25
KR19990082055A (ko) 1999-11-15
IL125523A0 (en) 1999-03-12
AU707675B2 (en) 1999-07-15
PL328127A1 (en) 1999-01-18
JP2000503995A (ja) 2000-04-04

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