EP1178831A1 - Methode de traitement combinee mettant en oeuvre un inhibiteur d'aromatase et un autre compose biologiquement actif - Google Patents

Methode de traitement combinee mettant en oeuvre un inhibiteur d'aromatase et un autre compose biologiquement actif

Info

Publication number
EP1178831A1
EP1178831A1 EP00917084A EP00917084A EP1178831A1 EP 1178831 A1 EP1178831 A1 EP 1178831A1 EP 00917084 A EP00917084 A EP 00917084A EP 00917084 A EP00917084 A EP 00917084A EP 1178831 A1 EP1178831 A1 EP 1178831A1
Authority
EP
European Patent Office
Prior art keywords
antineoplastic
amount
effective
agent
aromatase inhibitor
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Withdrawn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
EP00917084A
Other languages
German (de)
English (en)
Inventor
Enrico Di Salle
Tiziana Zaccheo
Michele Tedeschi
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.)
Pfizer Italia SRL
Original Assignee
Pharmacia Italia SpA
Pharmacia and Upjohn SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia Italia SpA, Pharmacia and Upjohn SpA filed Critical Pharmacia Italia SpA
Publication of EP1178831A1 publication Critical patent/EP1178831A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method of treatment of human breast cancer and in particular to combination therapy involving administration of an aromatase (estrogen synthetase) inhibitor in combination with mono-or-polichemotherapy with cytotoxic agents.
  • aromatase estrogen synthetase
  • aromatase (estrogen synthetase) inhibitors which inhibit the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the prototype antiestrogen, tamoxifen is now largely used in the adjuvant systemic therapy of localized breast cancer (i.e., systemic therapy given at the time of primary local treatment in the absence of demonstrated metastasis) and in the treatment of the advanced (metastatic) breast cancer.
  • resistance to tamoxifen occurs, due to: 1) the intrinsic estrogenic effect of tamoxifen (i.e., partial estrogen agonism); 2) the formation of tamoxifen' s estrogenic metabolites; 3) the stimulation by tamoxifen and its metabolites of a mutated ER; 4) the growth of estrogen independent tumor cells.
  • some concerns are now being considered in the use of tamoxifen in the early disease, due to the increased risk of endometrial cancer.
  • aromatase inhibitors One of such new antihormonal treatment modality of breast cancer is represented by the aromatase inhibitors.
  • the ovarian aromatase is the main source of circulating estrogens.
  • adipose tissue is considered to be the main site for estrogen synthesis.
  • aromatase activity has been shown in the breast tissue, including the tumor itself. Therefore, the very high levels of intratumoral estrogens in comparison to the circulating estrogens are due to the local estrogen synthesis through the aromatase enzyme.
  • aromatase inhibitors including the steroidal derivatives exemestane and formestane, and the non- steroidal derivatives aminoglutethimide, vorozole, fadrozole, letrozole, anastrozole and YM511 (K.M. Susaki et al. J. Steroid. Biochem. Molec. Biol. 58, 189-194, 1996).
  • Many clinical trials have shown that these compounds represent an effective second- line treatment for metastatic breast cancer refractory to tamoxifen.
  • these compounds are being clinically evaluated in the adjuvant setting, either alone or combined with tamoxifen, and as first-line treatment of the metastatic disease.
  • cytotoxic compounds generally used in the polychemotherapy of breast cancer or under clinical evaluation belong to various classes including:
  • Topoisomerase II inhibitors such as the antracyclines doxorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Antimicrotubule agents such as the taxanes paclitaxel and docetaxel, and the vinka alkaloids vinblastine and vinorelbine.
  • Alkylating agents such as cyclophosphamide, ifosfamide and melphalan and the alkycycline derivative PNU-159548 (C. Geroni et al., Proc. Am. Assoc. Cancer Res.
  • Antineoplastic antimetabolites such as 5-fluorouracil, capecitabine, gemcitabine, methotrexate and edatrexate.
  • Topoisomerase I inhibitors such as topotecan, irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound Al in
  • breast cancer remains one of the leading causes of morbidity and mortality in women.
  • early-stage disease is now frequently cured by surgical intervention and adjuvant hormonal and/or chemotherapy, the prognosis for women with advanced or with metastatic disease remains poor.
  • a median survival of only 2-3 years has been consistently reported over the last 20 years, in spite of the introduction of novel agents. Therefore, in advanced breast cancer patients, palliation of symptoms remains one of the primary objectives of treatment, and maintaining a reasonable quality of life is of paramount importance.
  • Hormonal therapy is often the treatment of choice in such patients.
  • currently hormonal treatments of breast cancer cause, in patients not selected on the basis of their receptor status, only a maximal response rate of 30- 35%.
  • the median duration of response is 1 to 2 years and is influenced by the site of disease. If a patient's cancer responds to hormonal therapy but later progressed, the cancer may respond again to a second hormonal therapy, but the response rate decreases and the duration of response become shorter. Eventually, nearly all breast cancers become refractory to hormonal manipulation and the patients are candidates for cytotoxic chemotherapy. Chemotherapy is more toxic than hormonal therapy, therefore is in general reserved for patients refractory to hormonal treatment or in patients with extensive visceral involvement, or if the tumor is growing rapidly. Combination chemotherapy is generally more effective than single agent treatment. However, only 15% of patients have a complete remission, the duration of the response is limited, all the tumors become resistant to chemotherapy and the patients die.
  • a major goal in breast cancer therapy is to develop new treatment modalities in order to increase tumor response and survival. Accordingly, it would be desirable to have a drug combination modality having improved action than currently used treatment modalities. Ideally such combination should have increased efficacy, e.g. by providing both a better controlling of breast tumor growth and a longer duration of action, while resulting in less toxic side-effects, thus allowing administration of lower dosage levels of chemotherapeutic agent.
  • an aromatase inhibitor antitumor agent i.e. a compound which inhibits the formation of estrogens by inhibiting the enzyme aromatase.
  • the present invention provides the use of an antineoplastic agent in the manufacture of a pharmaceutical composition for treatment of breast cancer, the treatment additionally comprising administration of at least one pharmaceutical composition comprising an aromatase inhibitor, in amounts effective to produce a superadditive antitumor effect.
  • the present invention also provides a product containing (a) an antineoplastic agent and (b) an aromatase inhibitor, in amounts effective to produce a superadditive antitumor effect, as a combined preparation for simultaneous, separate or sequential use in breast cancer therapy in humans.
  • the antineoplastic agent and the aromatase inhibitor may be present with a single of distinct container means.
  • the present invention also provides a composition of matter for use in breast cancer therapy in humans, comprising (a) an antineoplastic agent in a pharmaceutically acceptable carrier and/or diluent, and (b) an aromatase inhibitor in a pharmaceutically acceptable carrier and/or diluent, in amounts effective to produce a superadditive antitumor effect.
  • a further aspect of the present invention is a breast cancer therapy method for use in humans, in need thereof, the method comprising administering to said human (a) an antineoplastic agent and (b) an aromatase inhibitor, in amounts effective to produce a superadditive antitumor effect.
  • the invention also provides a method for lowering the side effects caused by breast cancer therapy with an antineoplastic agent in humans, in need thereof, the method comprising administering to said mammal a combination preparation of (a) an antineoplastic agent and (b) an aromatase inhibitor, in a quantity to produce a superadditive antitumor effect. Accordingly, said combination preparation can be used for lowering the side-effects caused by breast cancer antineoplastic therapy in mammals, including humans, while controlling the growth of neoplasm formation.
  • the superadditive antitumor effect results in an anti breast cancer therapy having increased effectiveness in controlling, i.e. slowing, interrupting, arresting, stopping or reversing, the neoplasm formation.
  • controlling the growth of the neoplasm refers to slowing, interrupting, arresting or stopping its growth and it does not necessarily indicate a total elimination of the neoplasm.
  • anti-plastic agent is meant to comprise both a single antineoplastic cytotoxic drug and "cocktails", i.e. mixtures of such drugs, according to the clinical practice.
  • the term "humans” is meant to comprise both female and male human beings.
  • the antineoplastic agent may comprise 1 to 4, preferably 1, 2 or 3, antineoplastic drugs, in particular a single antineoplastic drug.
  • antineoplastic drug in particular a single antineoplastic drug.
  • aromatase inhibitor is meant to comprise both a single aromatase inhibitor agent and cocktails of such inhibitors.
  • the aromatase inhibitor preferably comprises 1 or a mixture of 2 aromatase inhibitor agents, in particular a single aromatase inhibitor agent.
  • the combination preparation according to the invention can also include combination packs or compositions in which the constituents are placed side by side and can therefore be administered simultaneously, separately or sequentially to one and the same human being.
  • An antineoplastic agent is preferably selected from the group comprising: an antineoplastic topoisomerase ⁇ inhibitor, an antineoplastic antimicrotubule agent, an antineoplastic alkylating agent, an antineoplastic an ti metabolite and an antineoplastic topoisomerase I inhibitor.
  • An antineoplastic topoisomerase II inhibitor is preferably: a) an anthracycline compound e.g. doxorubicin (including liposomal formulations), epirubicin (including liposomal formulation), idarubicin and nemorubicin; and b) an anthraquinone compound e.g.
  • An antimicrotubule agent is preferably: a) a taxane compound e.g. paclitaxel (including liposomal formulations) and docetaxel; and b) a vinca alkaloid e.g. vinblastine and vinorelbine.
  • a taxane compound e.g. paclitaxel (including liposomal formulations) and docetaxel
  • a vinca alkaloid e.g. vinblastine and vinorelbine.
  • An alkylating agent is preferably cyclophosphamide, ifosfamide, melphalan and PNU 159548.
  • An antineoplastic antimetabolite agent is e.g. 5-fluorouracil, capecitabine, gemcitabine, methotrexate and edatrexate.
  • An antineoplastic topoisomerase I inhibitor is e.g. topotecan, irinotecan, 9- nitrocamptothecin and PNU 166148.
  • An antineoplastic agent is preferably epirubicin, doxorubicin, liposome-encapsulated doxorubicin, docetaxel, paclitaxel and liposome-encapsulated paclitaxel.
  • An aromatase inhibitor according to the present invention may be a steroidal compound, in particular a steroidal compound selected from exemestane and formestane, or a non-steroidal compound selected from aminoglutethimide, fadrozole, vorozole, letrozole, anastrozole and YM 511.
  • an aromatase inhibitor is a compound selected from exemestane, formestane, anastrozole, fadrozole or letrozole, in particular exemestane.
  • compositions and methods of treating are those comprising a) 1, 2 or 3 antineoplastic agents selected from epirubicin, doxorubicin, idarubicin, paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide and vinorelbine, and b) one or two, in particular one, steroidal aromatase inhibitor selected from exemestane, formestane, anastrozole, letrozole and fadrozole.
  • antineoplastic agents selected from epirubicin, doxorubicin, idarubicin, paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide and vinorelbine
  • b) one or two, in particular one, steroidal aromatase inhibitor selected from exemestane, formestane, anastrozole, letrozole and fadrozole selected from exemestane, formestane, anastrozole
  • the present inventor has discovered that using a combination of an aromatase inhibitor and a cytotoxic agent it is possible to obtain a better control of the growth of breast tumor growth and a longer duration of tumor response.
  • the effect of the combination of the present invention is shown for instance by the following in vivo experiments which are intended to illustrate but not to limit the present invention.
  • DMBA dimethylbenzanthracene
  • Tumor growth of control and treated groups were expressed as ratio of initial tumor weight, measured the first day of treatment.
  • tumor response to the drug was designed as CR (complete remission, disappearance of the tumor), PR (partial remission, >50% reduction in tumor weight); NC (no change, ⁇ 50% increase or decrease) or P (progression, >50% increase).
  • the appearance of new tumors during the 4-week treatment regimen was evaluated.
  • Exemestane dissolved in benzylic alcohol (3% of final volume) and diluted in sesame oil, was administered s.c, 6 days a week for 4 weeks.
  • Epirubicin dissolved in sterile 0.9% NaCl solution, was administered i.v., once a week for 4 weeks.
  • Docetaxel dissolved in 13% ethanol and diluted in 5% glucose solution, was administered i.v., once a week for 4 weeks.
  • Figure 1 shows the effect of exemestane and epirubicin given alone or in combination on the growth of DMBA-induced tumors in rats, in which:
  • Figure 1 illustrates tumor growth (expressed as ratio of initial tumor weight) during the 4-week treatment period of control and treated groups.
  • the single treatment with exemestane or epirubicin 3 mg/kg/wk caused a reduction of tumor growth, however a higher antitumor effect was observed when the two drugs were combined.
  • Interestingly combined treatments resulted in a longer duration of tumor response: in fact 4 weeks after the end of the treatment (week 8) tumor regrowth was completed in the groups treated with single agents while in the group treated with the combination of exemestane and epirubicin 3 mg/kg/wk tumor weight was still inhibited.
  • Table 2 shows the results obtained combining exemestane and docetaxel.
  • Docetaxel at 1.5 mg/kg/wk was effective inducing 41% tumor response (CR+PR), an effect similar to that observed after exemestane treatment (44% tumor response).
  • CR+PR tumor response
  • When the two drugs were combined a super additive effect was observed, and almost all tumor regressed (92%). Also the appearance of new tumors was completely suppressed (0 tumor per rat) only with the combination. It is of note that no obvious increased general toxicity was ever observed with the combinations, as evaluated for instance in terms of body weight loss.
  • Figure 2 shows the time-course effect of 4-week treatment with exemestane alone or combined with docetaxel on DMBA-induced mammary tumors in rats, in which:
  • an antineoplastic agent in therapy in combination with an aromatase inhibitor antitumor agent.
  • effective antineoplastic amount refers to an amount which is effective, upon single or multiple dose administration to the patient, in controlling the growth of the neoplasm or in prolonging the survivability of the patient beyond that expected in the absence of such treatment.
  • controlling the growth of the neoplasm refers to slowing, interrupting, arresting or stopping its growth and it does not necessarily indicates a total elimination of the neoplasm.
  • An effective amount of an aromatase inhibitor antitumor agent may vary from about 0.5 to about 500 mg pro dose 1-2 times a day.
  • Exemestane for example, may be administered orally in a dosage range varying from about 5 to about 200 mg, and particularly, from about 10 to about 25 mg, or parenterally from about 50 to about 500 mg, in particular from about 100 to about 250 mg.
  • Fadrozole may be administered orally in a dosage range varying from about 0.5 to about 10 mg, and particularly, from about 1 to about 2 mg.
  • Letrozole for example, may be administered orally in a dosage range varying from about 0.5 to about 10 mg, and particularly, from about 1 to about 2.5 mg.
  • Formestane for example, may be administered parenterally in a dosage range varying from about 250 to about 500 mg, and particularly, from about 250 to about 300 mg.
  • Anastrozole for example, may be administered orally in a dosage range varying from about 0.5 to about 10 mg, and particularly, from about 1 to about 2 mg.
  • the effective antineoplastic amounts of the various antineoplastic agents are well known and appreciated in the art.
  • an effective antineoplastic amount of vinblastine may vary from about 3 mg/m 2 to about 10 mg/m 2 .
  • An effective antineoplastic amount of doxorubicin may vary from about 20 mg/m to about 100 mg/m 2 .
  • An effective antineoplastic amount of epirubicin may vary from about 20 mg/m to about 200 mg/m 2 .
  • An effective antineoplastic amount of idarubicin may vary from about 1 mg/m 2 to about 50 mg/m 2 .
  • An effective antineoplastic amount of mitoxantrone may vary from about lOmg/m to about 20 mg/m 2 .
  • An effective antineoplastic amount of paclitaxel may vary from about 100 mg/m 2 to about 300 mg/m 2 .
  • An effective antineoplastic amount of docetaxel may vary from about 50 mg/m 2 to about 100 mg/m 2 .
  • An effective antineoplastic amount of vinorelbine may vary from about 15 mg/m to about 30 mg/m 2 .
  • An effective antineoplastic amount of cyclophosphamide may vary from about 100 mg/m 2 to about 1500 mg/m 2 .
  • An effective antineoplastic amount of melphalan may vary from about 1 mg/m 2 to about 10 mg/m 2 .
  • An effective antineoplastic amount of 5-fluorouracil may vary from about 100 mg/m to about 1000 mg/m 2 .
  • An effective antineoplastic amount of capecitabine may vary from about 10 mg/m 2 to about 1000 mg/m 2 .
  • An effective antineoplastic amount of methotrexate may vary from about 10 mg/m to about 1000 mg/m 2 .
  • An effective antineoplastic amount of topotecan may vary from about 1 mg/m to about 5 mg/m 2 .
  • an effective antineoplastic amount of irinotecan may vary from about 50 mg/m to about 350 mg/m 2 .
  • an aromatase inhibitor can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
  • it can be administered orally, subcutaneously, intraperitoneally, intramuscularly, intravenously, transdermally, and the like.
  • Oral or intramuscular administration is generally preferred.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular circumstances, including the disease state to be treated, the stage of the disease, the form of administration of the selected cytotoxic agent and the manner of co-administration selected.
  • GB-2, 177,700 discloses the preparation of pharmaceutical compositions comprising exemestane and a suitable carrier or excipient.
  • the selected antineoplastic agent can be administered by the appropriate route and dosing schedule as is well known and accepted for the particular agent.
  • epirubicin, doxorubicin, idarubicin, paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide and vinblastine can be administered intravenously.
  • Idarubicin and cyclophosphamide can also be given orally.

Abstract

L'invention concerne une composition qui s'utilise dans un traitement contre le cancer du sein chez l'humain. Cette composition contient, en quantités effectives pouvant déclencher une action antitumorale superadditive, a) un agent antinéoplastique dans un transporteur pharmaceutiquement acceptable et/ou un diluant; et b) un inhibiteur d'aromatase dans un transporteur pharmaceutiquement acceptable et/ou un diluant.
EP00917084A 1999-05-18 2000-04-14 Methode de traitement combinee mettant en oeuvre un inhibiteur d'aromatase et un autre compose biologiquement actif Withdrawn EP1178831A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9911582.6A GB9911582D0 (en) 1999-05-18 1999-05-18 Combined method of treatment comprising an aromatase inhibitor and a further biologically active compound
GB9911582 1999-05-18
PCT/EP2000/003407 WO2000069467A1 (fr) 1999-05-18 2000-04-14 Methode de traitement combinee mettant en oeuvre un inhibiteur d'aromatase et un autre compose biologiquement actif

Publications (1)

Publication Number Publication Date
EP1178831A1 true EP1178831A1 (fr) 2002-02-13

Family

ID=10853700

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00917084A Withdrawn EP1178831A1 (fr) 1999-05-18 2000-04-14 Methode de traitement combinee mettant en oeuvre un inhibiteur d'aromatase et un autre compose biologiquement actif

Country Status (6)

Country Link
EP (1) EP1178831A1 (fr)
JP (1) JP2003512301A (fr)
AR (1) AR029451A1 (fr)
AU (1) AU3820700A (fr)
GB (1) GB9911582D0 (fr)
WO (1) WO2000069467A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ524104A (en) * 2000-09-08 2004-12-24 Pharmacia Italia S Exemestane as chemopreventing agent
WO2002039995A2 (fr) * 2000-11-16 2002-05-23 Pharmacia & Upjohn Company Traitement combine de maladies dependantes des oestrogenes
PL414997A1 (pl) * 2001-02-19 2016-02-29 Novartis Ag Zastosowanie 40-O-(2-hydroksyetylo)-rapamycyny do leczenia guzów litych nerki
DE60219617T2 (de) * 2001-05-16 2008-01-03 Novartis Ag Kombination von n- 5- 4-(4-methyl-piperazino-methyl)-benzoylamido -2-methylphenyl -4-(3-pyridil)-2pyrimidine-amin mit einem biphosphonat
JP5449775B2 (ja) * 2005-10-19 2014-03-19 チャバフ ピーティーワイ エルティーディー 乳癌の治療に使用されるアロマターゼ阻害薬による副作用の低減
TR201816243T4 (tr) 2011-01-31 2018-11-21 Lucolas M D Ltd Aromataz inhibitörlerinin ve antioksidanların kombinasyonları.
AU2015336929B2 (en) 2014-10-22 2021-03-18 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
AU2016343297A1 (en) 2015-10-22 2018-05-10 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
EP3976048A4 (fr) 2019-06-03 2023-07-12 Havah Therapeutics Pty Ltd Formulations pharmaceutiques et systèmes pour l'administration d'un agent androgène et d'un inhibiteur de l'aromatase, et procédés d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO0069467A1 *

Also Published As

Publication number Publication date
JP2003512301A (ja) 2003-04-02
WO2000069467A1 (fr) 2000-11-23
GB9911582D0 (en) 1999-07-21
AU3820700A (en) 2000-12-05
AR029451A1 (es) 2003-07-02

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