EP1003521A1 - Procedes de potentialisation de l'estramustine phosphate intraveineux - Google Patents

Procedes de potentialisation de l'estramustine phosphate intraveineux

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Publication number
EP1003521A1
EP1003521A1 EP99914884A EP99914884A EP1003521A1 EP 1003521 A1 EP1003521 A1 EP 1003521A1 EP 99914884 A EP99914884 A EP 99914884A EP 99914884 A EP99914884 A EP 99914884A EP 1003521 A1 EP1003521 A1 EP 1003521A1
Authority
EP
European Patent Office
Prior art keywords
estramustine
cancer
estramustine phosphate
administered
phosphate
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Withdrawn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
EP99914884A
Other languages
German (de)
English (en)
Other versions
EP1003521A4 (fr
Inventor
Michael S. Kopreski
Beryl Asp
Bo Fredholm
Per-Olv Gunnarsson
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.)
Pharmacia and Upjohn Co LLC
Original Assignee
Pharmacia and Upjohn Co
Upjohn 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
Application filed by Pharmacia and Upjohn Co, Upjohn Co filed Critical Pharmacia and Upjohn Co
Publication of EP1003521A1 publication Critical patent/EP1003521A1/fr
Publication of EP1003521A4 publication Critical patent/EP1003521A4/fr
Withdrawn legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of estramustine phosphate, a non- nitrogen mustard carbamate derivative of estradiol-17b-phosphate. as a high dose infusion.
  • the present invention further relates to methods to potentiate intravenously administered estramustine phosphate and to methods for treating cancer by intravenously administering estramustine phosphate. Discussion of the Background: Cytotoxic effects have been shown to be due to the intact estramustine molecule (Hartley-Asp, 1982). Tissue culture studies have shown that estramustine (EM) is an anti-mitotic agent, causing a dose-dependent blocking of tumor cell division in the metaphase (Hartley-Asp, 1984).
  • Metaphase arrest is known to be caused by an interference of drugs with the microtubule structure that forms the mitotic spindle. It has been shown, with the help of immunohistochemistry. that dose-dependent disturbances of interphase microtubules occur in cultured human prostatic cells (Mareel 1988. Dahllof 1993). Treatment with EM in vitro inhibited the assembly of microtubules composed of only tubulin demonstrating a direct interaction with tubulin (Dahllof 1993). In addition, an interaction with microtubule associated proteins (MAPs) has been demonstrated (Stearns 1988). MAPs are highmolecular weight proteins that are believed to be important in stabilizing microtubules. That EM exhibits the mechanism of action of an anti-mitotic agent has been confirmed in vivo (Ekl ⁇ v. 1992).
  • Estramustine phosphate is thus an anti-mitotic agent currently used in the treatment of advanced adenocarcinoma of the prostate.
  • its activity in hormone-refractory prostate cancer is comparable to that of several other cytotoxic agents that have been studied in a series of multi-institutional, randomized trials by the National Prostatic Cancer Project (Murphy, 1983).
  • the drug is usually administered orally at a dose of 10-15 mg/ kg/day. it is approved for intravenous administration in several countries.
  • estramustine phosphate when administered intravenously has been used at dosages and according to a schedule paralleling the oral administration for the drug, i.e. at recommended dosages of 300- 600 mg daily given intravenously and usually repetitively over for several consecutive days. This is then followed by orally administered drug.
  • estramustine phosphate Phase II trials (Seidman, 1992, Hudes, 1992. Pienta. 1994.
  • estramustine phosphate oral was combined with Etoposide. Fifty two patients were evaluable: including 20 patients with soft tissue disease, in
  • estramustine phosphate appears to be dependent on the presence of the estramustine binding protein (EMBP) (Eklov. 1996). This is found under normal conditions only in the prostate (Forsgren. 1979, Flucher. 1989). However, a similar protein has also been identified in many cancerous tissues, as well as prostate tumors, such as lung, breast glioma. colon, pancreas (Bj ⁇ rk.1991. Bergh 1988. Eklov 1996. Edgren 1996. Von Schoultz. 1994. Bergenheim. 1993).
  • EMBP estramustine binding protein
  • This protein binds estra- and estro-mustine (EaM and EoM) with very high affinity and is thought to be responsible for the selective retention of EoM in the prostate tumor, where a ratio of 1 :6 to 1 : 1 1 plasma/tumor has been found in prostate cancer patients treated with estramustine phosphate oral and intravenously, respectively (Norlen 1988. Walz 1988).
  • EMBP estra- and estro-mustine
  • the present invention describes methods of potentiating the therapeutic use and efficacy of intravenously administered estramustine phosphate It provides for the intravenous administration of estramustine phosphate in dosages exceeding 1300 mg It also provides for intravenous administration of estramustine phosphate at dosages exceeding 950 mg/nr (milligrams per square meter of body surface area) It further provides for administration of high dose intravenous estramustine phosphate as a single dose, which may further be administered on a weekly or longer schedule.
  • the present invention enables optimization of pharmacokinetics as to maximize therapeutic advantage, and further enables use of intravenous estramustine phosphate in combination with other therapies, including other chemotherapies, providing further improved therapeutic benefit
  • the present invention enables use of intravenous estramustine phosphate as therapy for multiple tumor types, including prostate, breast, lung, ovarian, colorectal. melanoma, pancreatic, and brain cancers Thus, one application of the present ⁇ n ⁇
  • Another application is to provide a schedule of intravenous administration, whereby that schedule enables optimization of pharmacokinetics of estramustine phosphate and its metabolites at minimal toxicity. and further wherebv said optimization permits convenient and efficacious combination regimens of therapy
  • an application of the present invention permits the use of intravenous estramustine phosphate in combination with other therapeutic regimens, including cytotoxic chemotherapy
  • Another application of the present inv ention is to provide a method which increases binding saturation and prolongs binding duration of estramustine phosphate or its metabolites to estramustine binding protein or estramustine binding protein-like protein (EMBP).
  • EMBP estramustine binding protein-like protein
  • the present invention provides application to treatment of cancers having EMBP, including but not limited to prostate, breast, lung, ovarian, colorectal. melanoma, pancreatic, and brain cancers, by intravenous administration.
  • cancers having EMBP including but not limited to prostate, breast, lung, ovarian, colorectal. melanoma, pancreatic, and brain cancers, by intravenous administration.
  • Another application of the present invention is to provide a method of rapidly relieving symptoms secondary to cancer, inclusive of but not limited to cancer- induced pain and urinary obstruction. Further, the present invention enables these applications for use of intravenous estramustine phosphate independent of the formulation. Thereby, the present invention provides for the infusion of estramustine phosphate as free drug, as protein- bound drug, or as drug within liposomes.
  • the present invention describes a formulation of estramustine phosphate wherein the estramustine phosphate is administered intravenously in conjunction with liposomes.
  • the method of the present invention in which doses above 900 mg/nr (generally greater than 1300 mg per dose) can be administered safely and within an effective schedule is extremely unexpected.
  • the present invention teaches the advantage of intravenous estramustine in combination with other chemotherapy agents.
  • the present invention further teaches the advantage of high dose intravenous estramustine in combination with other chemotherapeutic agents.
  • intravenous estramustine phosphate may be used to treat tumors having elevated EMBP-like protein (herein referred to simply as EMBP).
  • EMBP EMBP-like protein
  • novel and non-obvious applications of the present invention can be recognized from a comparison of the pharmacokinetic data following oral administration estramustine phosphate with that following high-dose intravenous administration of estramustine phosphate.
  • the pharmacokinetic and toxicity data can be recognized from a comparison of the pharmacokinetic data following oral administration estramustine phosphate with that following high-dose intravenous administration of estramustine phosphate.
  • estromustine EoM
  • estrone analogue of EM are the major metabolic steps after administration of oral estramustine phosphate in man.
  • EoM is the predominant metabolite found in plasma when estramustine phosphate is
  • estromustine is approximately 44%(Gunnarsson. 1984). After intravenous
  • estramustine phosphate is initially found in plasma but is rapidly hydrolyzed to the same metabolites as are found after oral administration, the major
  • estromustine metabolite being estromustine. Both estramustine and estromustine are further
  • estromustine had a half lives of 10-20 hours.
  • the present invention teaches the ability to administer estramustine phosphate at doses above 950 mg/m 1 ( I e , greater than 1300 mg)
  • estramustine phosphate is administered at a single infusion dosage exceeding 950 mg/m 1
  • Intravenous administration is performed either through a central or peripheral intravenous route
  • the contents of packaged estramustine phosphate intended for intravenous usage are dissolved, wherein the packaged contents may consist of but are not limited to a lyophi zed powder of the meglumine salts in vials of estramustine phosphate, oi similar freeze- d ⁇ ed estramustine phosphate which are first dissolved in sterile water such as 5 ml sterile water per 300 mg estramustine phosphate, or in 5% dextrose in water for intravenous administration In the preferred method.
  • estramustine phosphate When estramustine phosphate is administered through a peripheral intravenous route, it is preferred that a longer duration of infusion and greater total infusional volume be utilized to minimize vascular irritation.
  • the estramustine phosphate solution can be mixed with various amounts but preferably 3-5% human albumin or other plasma proteins including synthetic plasma proteins to achieve protein binding of the estramustine phosphate and therefore minimize any potential vascular damage.
  • estramustine phosphate may be further realized using other preparations or formulations of estramustine phosphate.
  • One particularly advantageous preparation of the chemotherapeutic agent estramustine phosphate which enables infusion of estramustine phosphate through either a peripheral or central vein, both at high doses and also doses less than 1300 mg. involves the infusion of estramustine phosphate in conjunction with liposomes (herein referred to as liposome encapsulated estramustine phosphate or liposomal estramustine).
  • liposome encapsulated estramustine phosphate or liposomal estramustine liposomal estramustine.
  • estramustine phosphate solution is first prepared in the manner described above and then injected into a vial containing empty liposomes available as a Ivophilized powder. Following adequate hvdration of the liposomes. the vials are vortexed and sonicated, followed by infusion into the patient.
  • estramustine phosphate When estramustine phosphate is administered through a central venous route, said administration may be performed through either a temporary or permanent venous access device, including but not limited to a triple lumen catheter. Hickman
  • estramustine phosphate in the present invention is greater than 1300 mg, it is preferred that the patient be treated at a dose exceeding 950 mg/nr Thereby, one preferred method is to administer a single intravenous dosage of 1000 mg/m 2 Another preferred method is to administer a single intravenous dosage of 1500 mg/nr Furthermore, a dosage of 2000 mg/nr mav be administered However. the invention is inclusive of other dosages above 950 mg/m 2 and the preferred dosages are not to imply limitation
  • estramustine phosphate administration in the invention is a single infusion given once weekly to a maximal dose of 4000 mg or 3500 mg/m 2
  • Another preferred schedule is administration of a single drug infusion once every two weeks
  • Another preferred schedule is administration of a single drug infusion once ev ery three weeks
  • Another preferred schedule is administration of a single drug infusion once every four weeks
  • One schedule may be preferred over another in consideration of schedules with other concomitant therapy These schedules may repeat in a serial or repetitive fashion.
  • the invention described herein enables methods to prolong blood and/or tissue levels at high elevations tor estramustine phosphate metabolites, including estromustine. estramustine. estrone and estradiol Thereb . enhanced synergistic interactions ith other therapies is enabled, wherein such other therapies include but are not limited to chemotherap . radiotherapy, monoclonal antibodies, and biologic
  • the present invention provides maximization of therapeutic benefit by prolongation of elevated blood and tissue levels of estramustine phosphate and its
  • estramustine phosphate is administered intravenously at dosages exceeding 950 mg/m 2 . which are administered in combination with other cancer therapies, inclusive
  • radiotherapy but not limited to radiotherapy, chemotherapy, monoclonal antibodies, and biologic
  • therapeutic benefit is potentiated by administering intravenous estramustine phosphate at single dosages exceeding 950 mg/nr, with
  • chemotherapeutic agents preferably on the day of, or the day prior to administration
  • the other chemotherapeutic agents consist of anti-mitotic agents or anti-
  • microtubule agents inclusive of but not limited to taxanes. including taxol and
  • taxotere and agents including vinblastine. vincristine, etoposide. navelbine.
  • doxorubicin doxorubicin, irinotecan (CPT-1 1 ). and liposome encapsulated chemotherapeutic
  • liposome encapsulated taxanes such as liposome encapsulated
  • paclitaxel It may be further beneficial if a combination with a monoclonal therapy is utilized, that the monoclonal agent include a radionucleotide or an anti-growth factor agent.
  • Plasma or serum levels of estromustine are further sustained when
  • estramustine phosphate is administered intravenously as a single infusion at a dosage
  • the infusion may optionally be repeated in a serial or repetitive manner to maintain elevated blood levels of the estromustine phosphate metabolites. Sustained levels of estramustine phosphate and its metabolites thereby enable sustained therapeutic benefit.
  • the present invention thereby provides a method to increase the binding saturation of estramustine or its metabolites to estramustine binding protein or like- protein by administering estramustine phosphate intravenously at a single infusion dose exceeding 950 mg/m 2 .
  • the binding duration of estramustine phosphate or its metabolites to estramustine binding protein or estramustine binding protein-like protein (EMBP) is increased in the invention by administering the drug at intravenous dosages exceeding 950 mg/nr.
  • EMBP estramustine binding protein-like protein
  • estramustine phosphate be administered intravenously wherein the single dosage exceeds 950 mg/m 2 when treating cancers having either estramustine binding protein or estramustine binding protein like- protein, inclusive of but not limited to the group of cancers including prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, and cancers of the brain.
  • Said cancers may further be treated using liposomal estramustine. either as a single agent or in combination with other chemotherapies.
  • Said administrations are preferably repeated in serial or repetitive fashion at schedules of the invention, with or without combination of other therapies.
  • said schedules may include combinational treatment of intravenous estramustine phosphate with other chemotherapeutic therapies given on a once weekly, a once e ⁇ ery two week, a once every three week, or a once every four week schedule, and variations therein
  • intravenously administered estramustine phosphate be administered in combination with other chemotherapeutic cytotoxic agents when used in the treatment of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ova ⁇ an.
  • estramustine phosphate be administered in combination with radiation when used in the treatment of prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and cancers of the brain
  • estramustine phosphate be administered at intravenous dosages exceeding 950 mg/m 2 when used in combination with other cancer therapies
  • the present invention enables both objective and subjective therapeutic benefit Benefit achiev ed may relate to reduction of tumor size, improved quality of life, reduction of tumor obstruction, such as urinary obstruction, reduction of cancer- induced pain, improved survival, reduction in time to cancer recurrence, or other evidence of improvement
  • rapid objectiv e oi subjective therapeutic benefit is achieved bv administering estramustine phosphate intravenously at a dosage exceeding 950 mg/m ⁇ either as a single agent or preferably in combination with other cancer therapies
  • the invention enables rapid relief of cancer-induced urinary obstruction, and rapid relief of cancer-induced pain
  • Example 1 Two patients with advanced metastatic prostate cancer were treated with estramustine phosphate intravenously given through a central line. The
  • phosphate was administered as a single infusion on a weekly schedule in a repetitive
  • PSA prostate specific antigen
  • Example 2 Three patients with advanced metastatic prostate cancer were
  • Estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion. Each infusional dose was
  • Example 3 Three patients with advanced metastatic prostate cancer were treated with estramustine phosphate administered intravenously through a central line at a dosage of 1500 mg/m 2 . Estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion. The infusional dose was administered either over 30 minutes or over 1 hour. The infusions were well tolerated with one patient demonstrating a response in bulky tumor adenopathy.
  • Example 4 Three patients with advanced metastatic prostate cancer were treated with estramustine phosphate intravenously given through a central line. The patients received an estramustine phosphate dosage of 2000 mg/m 2 . Estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion. Each infusional dose was administered over a 60 minute infusion. An anti- thrombotic agent was additionally administered for venous thrombosis prophylaxis.
  • estramustine phosphate infusions were well tolerated without serious toxicity, and with evidence of PSA response.
  • Ekl ⁇ v S. Mahdy E, Wester K et al. Estramustine-binding protein (EMBP) content in four different cell lines and its correlation to estramustine induced metaphase arrest.
  • Fl ⁇ chter S. Nelde HJ. Bj ⁇ rk P et al. Effect of treatment on the expression of estramustine-binding protein (EMBP) in prostatic cancer patients: An immunohistochemical study. The Prostate 14:27-43, 1989
  • Mareel MM Storme GA. Dragonetti CH. De Bruyne GK. Hartley-Asp B, Segers JL. Rabaey ML. Antiinvasive activity of estramustine on malignant MO,
  • Nagel R, K ⁇ lln C-P Treatment of advanced carcinoma of the prostate with
  • Petrylak DP Shelton GB. Mac Arthur RB et al.: Phase I trial of Docetaxel -
  • Tew KD Estramustine binds MAP-2 to inhibit microtubule

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'estramustine phosphate est un médicament chimiothérapeutique antimitotique à efficacité prouvée contre le cancer. L'invention concerne des méthodes permettant de potentialiser les avantages thérapeutiques de l'estramustine phosphate intraveineux. L'invention consiste à administrer l'estramustine phosphate intraveineux à haute dose, une seule dose dépassant 1300 mg. On améliore ainsi efficacement la pharmacocinétique de l'estramustine phosphate. L'invention consiste également à administrer l'estramustine phosphate par voie intraveineuse afin de l'utiliser dans des posologies combinées avec d'autres agents chimiothérapeutiques. On peut appliquer les avantages thérapeutiques de la formulation d'estramustine phosphate intraveineux au traitement de divers cancers, notamment le cancer de la prostate, le cancer du sein, le cancer du poumon, le cancer colorectal, le cancer pancréatique, le cancer ovarien, le mélanome, ainsi que d'autres cancers.
EP99914884A 1998-03-27 1999-03-26 Procedes de potentialisation de l'estramustine phosphate intraveineux Withdrawn EP1003521A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7954298P 1998-03-27 1998-03-27
US79542P 1998-03-27
PCT/US1999/004275 WO1999049869A1 (fr) 1998-03-27 1999-03-26 Procedes de potentialisation de l'estramustine phosphate intraveineux

Publications (2)

Publication Number Publication Date
EP1003521A1 true EP1003521A1 (fr) 2000-05-31
EP1003521A4 EP1003521A4 (fr) 2003-07-23

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Application Number Title Priority Date Filing Date
EP99914884A Withdrawn EP1003521A4 (fr) 1998-03-27 1999-03-26 Procedes de potentialisation de l'estramustine phosphate intraveineux

Country Status (16)

Country Link
EP (1) EP1003521A4 (fr)
JP (1) JP2001508810A (fr)
KR (1) KR20010021656A (fr)
CN (2) CN1636598A (fr)
AU (1) AU750010B2 (fr)
BR (1) BR9906425A (fr)
CA (1) CA2295049A1 (fr)
EA (1) EA004647B1 (fr)
HU (1) HUP0200547A3 (fr)
ID (1) ID24504A (fr)
IL (1) IL133612A0 (fr)
NO (1) NO20002343L (fr)
NZ (1) NZ501987A (fr)
PL (1) PL342969A1 (fr)
WO (1) WO1999049869A1 (fr)
ZA (1) ZA997821B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0003201D0 (en) * 2000-02-11 2000-04-05 Pharmacia & Upjohn Spa Method to potentiate the therapeutic efficacy of taxane and derivatives thereof
US6436913B1 (en) * 2000-07-25 2002-08-20 Pharmacia & Upjohn Company Use of estramustine phosphate in the treatment of bone metastasis
RU2471511C1 (ru) * 2011-05-04 2013-01-10 Федеральное государственное бюджетное учреждение "Ростовский научно-исследовательский онкологический институт" Министерства здравоохранения и социального развития Российской Федерации (ФГБУ "РНИОИ" Минздравсоцразвития России) Способ лечения метастазов в печень рака толстой кишки

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS617292A (ja) * 1984-06-20 1986-01-13 Japan Atom Energy Res Inst 制癌剤を結合させたエストラサイト系化合物を製造する方法
US5077056A (en) * 1984-08-08 1991-12-31 The Liposome Company, Inc. Encapsulation of antineoplastic agents in liposomes
MX9203808A (es) * 1987-03-05 1992-07-01 Liposome Co Inc Formulaciones de alto contenido de medicamento: lipido, de agentes liposomicos-antineoplasticos.
ATE194767T1 (de) * 1992-03-23 2000-08-15 Univ Georgetown In liposomen verkapseltes taxol und verwendungsverfahren
FR2697752B1 (fr) * 1992-11-10 1995-04-14 Rhone Poulenc Rorer Sa Compositions antitumorales contenant des dérivés du taxane.

Also Published As

Publication number Publication date
CN1273530A (zh) 2000-11-15
JP2001508810A (ja) 2001-07-03
HUP0200547A3 (en) 2003-07-28
WO1999049869A1 (fr) 1999-10-07
AU750010B2 (en) 2002-07-11
PL342969A1 (en) 2001-07-16
IL133612A0 (en) 2001-04-30
CA2295049A1 (fr) 1999-10-07
EA199901081A1 (ru) 2000-12-25
ID24504A (id) 2000-07-20
ZA997821B (en) 2000-08-01
AU3353399A (en) 1999-10-18
EA004647B1 (ru) 2004-06-24
CN1636598A (zh) 2005-07-13
NZ501987A (en) 2002-10-25
NO20002343D0 (no) 2000-05-04
NO20002343L (no) 2000-05-04
KR20010021656A (ko) 2001-03-15
HUP0200547A2 (hu) 2002-07-29
EP1003521A4 (fr) 2003-07-23
BR9906425A (pt) 2000-07-11

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