CZ300489B6 - Farmaceutický prostredek obsahující konjugát žlucové kyseliny nebo soli žlucové kyseliny s mastnou kyselinou pro lécbu syndromu ztucnelých jater - Google Patents

Farmaceutický prostredek obsahující konjugát žlucové kyseliny nebo soli žlucové kyseliny s mastnou kyselinou pro lécbu syndromu ztucnelých jater Download PDF

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Publication number
CZ300489B6
CZ300489B6 CZ20032710A CZ20032710A CZ300489B6 CZ 300489 B6 CZ300489 B6 CZ 300489B6 CZ 20032710 A CZ20032710 A CZ 20032710A CZ 20032710 A CZ20032710 A CZ 20032710A CZ 300489 B6 CZ300489 B6 CZ 300489B6
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CZ
Czechia
Prior art keywords
acid
bile
fatty
salt
animals
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CZ20032710A
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Czech (cs)
English (en)
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CZ20032710A3 (cs
Inventor
Gilat@Tuvia
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Galmed International Limited
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Application filed by Galmed International Limited filed Critical Galmed International Limited
Publication of CZ20032710A3 publication Critical patent/CZ20032710A3/cs
Publication of CZ300489B6 publication Critical patent/CZ300489B6/cs

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542Carboxylic acids, e.g. a fatty acid or an amino acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Botany (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
CZ20032710A 2001-04-17 2002-04-15 Farmaceutický prostredek obsahující konjugát žlucové kyseliny nebo soli žlucové kyseliny s mastnou kyselinou pro lécbu syndromu ztucnelých jater CZ300489B6 (cs)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IL142650A IL142650A (en) 1998-04-08 2001-04-17 Use of bile acid conjugates or bile salts and fatty acids or fatty acids in the preparation of pharmaceuticals for lowering cholesterol, for the treatment of fatty liver and for the treatment of hyperglycemia and diabetes

Publications (2)

Publication Number Publication Date
CZ20032710A3 CZ20032710A3 (cs) 2004-04-14
CZ300489B6 true CZ300489B6 (cs) 2009-06-03

Family

ID=11075322

Family Applications (2)

Application Number Title Priority Date Filing Date
CZ2008296A CZ309042B6 (cs) 2001-04-17 2002-04-15 Použití konjugátu žlučové kyseliny nebo soli žlučové kyseliny s mastnou kyselinou nebo farmaceutického prostředku jej obsahujícího pro snížení cholesterolu a léčbu hyperglykémie a diabetu
CZ20032710A CZ300489B6 (cs) 2001-04-17 2002-04-15 Farmaceutický prostredek obsahující konjugát žlucové kyseliny nebo soli žlucové kyseliny s mastnou kyselinou pro lécbu syndromu ztucnelých jater

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CZ2008296A CZ309042B6 (cs) 2001-04-17 2002-04-15 Použití konjugátu žlučové kyseliny nebo soli žlučové kyseliny s mastnou kyselinou nebo farmaceutického prostředku jej obsahujícího pro snížení cholesterolu a léčbu hyperglykémie a diabetu

Country Status (24)

Country Link
US (2) US7501403B2 (enExample)
EP (2) EP1379254B1 (enExample)
JP (1) JP4324706B2 (enExample)
KR (1) KR100883080B1 (enExample)
CN (1) CN1259918C (enExample)
AT (2) ATE432705T1 (enExample)
AU (2) AU2002307771B2 (enExample)
BR (1) BR0208924A (enExample)
CA (2) CA2444266C (enExample)
CY (1) CY1106853T1 (enExample)
CZ (2) CZ309042B6 (enExample)
DE (2) DE60232559D1 (enExample)
DK (2) DK1379254T3 (enExample)
EA (1) EA007565B1 (enExample)
ES (2) ES2289137T3 (enExample)
HU (1) HU230548B1 (enExample)
IL (1) IL142650A (enExample)
MX (1) MXPA03009553A (enExample)
NO (2) NO333910B1 (enExample)
NZ (1) NZ528868A (enExample)
PL (2) PL211438B1 (enExample)
PT (2) PT1379254E (enExample)
UA (1) UA78699C2 (enExample)
WO (1) WO2002083147A1 (enExample)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL142650A (en) 1998-04-08 2007-06-03 Galmed Int Ltd Use of bile acid conjugates or bile salts and fatty acids or fatty acids in the preparation of pharmaceuticals for lowering cholesterol, for the treatment of fatty liver and for the treatment of hyperglycemia and diabetes
US8975246B2 (en) 2001-04-17 2015-03-10 Galmed Research And Development Ltd. Bile acid or bile salt fatty acid conjugates
PT2182954T (pt) * 2007-07-25 2019-02-06 Univ Graz Medizinische Utilização de ácidos nor-biliares no tratamento de arteriosclerose
US9314444B2 (en) 2009-01-12 2016-04-19 Biokier, Inc. Composition and method for treatment of NASH
KR20170138573A (ko) 2009-01-12 2017-12-15 바이오키어 인코포레이티드 당뇨병 치료 조성물 및 치료방법
US9006288B2 (en) 2009-01-12 2015-04-14 Biokier, Inc. Composition and method for treatment of diabetes
EP2391370B1 (en) 2009-02-02 2015-06-03 Galmed Research and Development Ltd. Methods and compositions for treating alzheimer's disease
US20120202890A1 (en) 2011-02-08 2012-08-09 Nian Wu Polymer-carbohydrate-lipid conjugates
AU2013256362A1 (en) * 2012-05-01 2014-11-13 Catabasis Pharmaceuticals, Inc. Fatty acid conjugates of statin and FXR agonists: compositions and methods of use
CN103571617A (zh) * 2012-07-26 2014-02-12 丰益(上海)生物技术研发中心有限公司 改进的动物油脂加工工艺
ES2701077T3 (es) 2012-11-29 2019-02-20 St Pharm Co Ltd Conjugado de oligómero de ácido biliar para un nuevo transporte vesicular y uso del mismo
IL227890A0 (en) * 2013-08-08 2014-01-30 Galderm Therapeutics Ltd Antiaging compounds containing bile acid and fatty acid conjugates
US11571431B2 (en) 2013-12-04 2023-02-07 Galmed Research And Development Ltd Aramchol salts
ES2732845T3 (es) * 2013-12-04 2019-11-26 Galmed Res & Development Ltd Sales de Aramchol
CN106413719A (zh) * 2014-06-01 2017-02-15 盖尔梅德研究与发展有限公司 用于治疗脂肪营养不良的脂肪酸胆汁酸缀合物
US10849911B2 (en) 2015-06-10 2020-12-01 Galmed Research And Development Ltd. Low dose compositions of Aramachol salts
IL243707A0 (en) 2016-01-20 2016-05-01 Galmed Res And Dev Ltd Treatment to regulate the microbiota in the intestine
US11197870B2 (en) 2016-11-10 2021-12-14 Galmed Research And Development Ltd Treatment for hepatic fibrosis
CN116687850A (zh) 2022-02-24 2023-09-05 甘莱制药有限公司 包含环状膦酸酯化合物的药物组合物及其制备方法与用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856953A (en) * 1973-05-15 1974-12-24 Intellectual Property Dev Corp Method of treating fatty liver
WO1999052932A1 (en) * 1998-04-08 1999-10-21 Galmed International Ltd. Fatty acid derivatives of bile acids and bile acid derivatives

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3859437A (en) * 1972-06-02 1975-01-07 Intellectual Property Dev Corp Reducing cholesterol levels
IT1167479B (it) * 1981-07-24 1987-05-13 Carlo Scolastico Derivati dell'acido chenodesossicolico
IT1167478B (it) * 1981-07-24 1987-05-13 Carlo Scolastico Derivati dell'acido ursodesossicolico
JPS6164701A (ja) * 1984-09-06 1986-04-03 Meito Sangyo Kk カチオン化デキストラン誘導体とポリウロン酸の高分子電解質錯体及びその利用
DE3930696A1 (de) * 1989-09-14 1991-03-28 Hoechst Ag Gallensaeurederivate, verfahren zu ihrer herstellung, verwendung als arzneimittel
US5278320A (en) * 1992-09-11 1994-01-11 Merck & Co., Inc. Cholesterol lowering compounds produced by directed biosynthesis
DE4432708A1 (de) * 1994-09-14 1996-03-21 Hoechst Ag Modifizierte Gallensäuren, Verfahren zu ihrer Herstellung und ihre Verwendung
US6576660B1 (en) * 1997-10-31 2003-06-10 Arch Development Corporation Methods and compositions for regulation of 5-α-reductase activity
US20030153541A1 (en) * 1997-10-31 2003-08-14 Robert Dudley Novel anticholesterol compositions and method for using same
IL142650A (en) 1998-04-08 2007-06-03 Galmed Int Ltd Use of bile acid conjugates or bile salts and fatty acids or fatty acids in the preparation of pharmaceuticals for lowering cholesterol, for the treatment of fatty liver and for the treatment of hyperglycemia and diabetes
US6620821B2 (en) * 2000-06-15 2003-09-16 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
JP2006306800A (ja) * 2005-04-28 2006-11-09 Kirin Brewery Co Ltd ファルネソイドx受容体活性化剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856953A (en) * 1973-05-15 1974-12-24 Intellectual Property Dev Corp Method of treating fatty liver
WO1999052932A1 (en) * 1998-04-08 1999-10-21 Galmed International Ltd. Fatty acid derivatives of bile acids and bile acid derivatives

Also Published As

Publication number Publication date
CA2703688C (en) 2012-07-31
EP1379254B1 (en) 2007-06-20
ES2328966T3 (es) 2009-11-19
KR100883080B1 (ko) 2009-02-10
HU230548B1 (hu) 2016-11-28
AU2007200191B2 (en) 2008-09-04
PT1379254E (pt) 2007-07-10
CA2444266A1 (en) 2002-10-24
US7501403B2 (en) 2009-03-10
HUP0400801A2 (hu) 2004-08-30
DK1379254T3 (da) 2007-10-15
US20090149537A1 (en) 2009-06-11
HUP0400801A3 (en) 2012-09-28
MXPA03009553A (es) 2004-05-24
US8110564B2 (en) 2012-02-07
DK1790346T3 (da) 2009-10-12
DE60220775T2 (de) 2008-03-06
PL211438B1 (pl) 2012-05-31
EP1790346A3 (en) 2007-08-22
CA2444266C (en) 2010-07-27
CY1106853T1 (el) 2012-05-23
CN1529603A (zh) 2004-09-15
NO20131219L (no) 2003-11-28
DE60220775D1 (de) 2007-08-02
IL142650A (en) 2007-06-03
EA007565B1 (ru) 2006-12-29
US20040121993A1 (en) 2004-06-24
PL205057B1 (pl) 2010-03-31
CA2703688A1 (en) 2002-10-24
UA78699C2 (en) 2007-04-25
ES2289137T3 (es) 2008-02-01
WO2002083147A1 (en) 2002-10-24
PT1790346E (pt) 2009-09-04
NO20034609D0 (no) 2003-10-15
BR0208924A (pt) 2004-04-20
EA200301017A1 (ru) 2005-04-28
CZ20032710A3 (cs) 2004-04-14
AU2002307771B2 (en) 2006-10-19
NO333910B1 (no) 2013-10-14
IL142650A0 (en) 2002-03-10
NZ528868A (en) 2005-09-30
CZ309042B6 (cs) 2021-12-22
EP1790346A2 (en) 2007-05-30
CZ2008296A3 (enExample) 2004-04-14
JP4324706B2 (ja) 2009-09-02
DE60232559D1 (de) 2009-07-16
NO20034609L (no) 2003-11-28
CN1259918C (zh) 2006-06-21
KR20030092063A (ko) 2003-12-03
AU2007200191A1 (en) 2007-02-08
EP1790346B1 (en) 2009-06-03
JP2004525962A (ja) 2004-08-26
NO335087B1 (no) 2014-09-08
PL366585A1 (en) 2005-02-07
EP1379254A1 (en) 2004-01-14
ATE432705T1 (de) 2009-06-15
ATE365044T1 (de) 2007-07-15

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