EP0999837A1 - Treatment of diabetes with rosiglitazone and insulin - Google Patents

Treatment of diabetes with rosiglitazone and insulin

Info

Publication number
EP0999837A1
EP0999837A1 EP98932169A EP98932169A EP0999837A1 EP 0999837 A1 EP0999837 A1 EP 0999837A1 EP 98932169 A EP98932169 A EP 98932169A EP 98932169 A EP98932169 A EP 98932169A EP 0999837 A1 EP0999837 A1 EP 0999837A1
Authority
EP
European Patent Office
Prior art keywords
compound
administration
insulin
pharmaceutically acceptable
diabetes
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Withdrawn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
EP98932169A
Other languages
German (de)
English (en)
French (fr)
Inventor
Stephen Alistair SmithKline Beecham Phar. SMITH
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0999837A1 publication Critical patent/EP0999837A1/en
Withdrawn legal-status Critical Current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
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or Type II diabetes and conditions associated with diabetes mellitus.
  • NIDDM non-insulin dependent diabetes
  • Insulin is a front line treatment agent for Type I diabetes (or Insulin Dependent Diabetes). It is also used as an antihyperglycaemic agent in the treatment ofNIDDM.
  • European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycaemic and hypolipidaemic activity.
  • One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter 'Compound (I)').
  • WO94/05659 discloses certain salts of Compound (I) including the maleate salt at example 1 thereof.
  • the invention provides a method for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus in a mammal such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of Compound (I) and insulin, to a mammal in need thereof.
  • the amount of Compound (I) administered is up to 12 mg, especially when administered per day.
  • the method comprises either co-administration of Compound (I) and insulin or the sequential administration thereof.
  • Co-administration includes administration of a formulation which includes both an insulin sensitiser, such as Compound (I), and insulin or, more suitably, the essentially simultaneous administration of separate formulations of each agent.
  • an insulin sensitiser such as Compound (I)
  • insulin or, more suitably, the essentially simultaneous administration of separate formulations of each agent.
  • the method comprises the administration of 2 to 12 mg of Compound (I), especially when admimstered per day.
  • the method comprises the administration of 2 to 4 , 4 to 8 or 8 to 12 mg of Compound (I) per day.
  • the method comprises the administration of 2 to 4mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 4 to 8mg, such as greater than 4 for example 4.1, to 8 mg, of Compound (I), especially when administered per day.
  • the method comprises the administration of 8 to 12 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 2 mg of Compound
  • the method comprises the administration of 4 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 8 mg of Compound (I), especially when administered per day.
  • Compound (I) and the insulin are each administered in a pharmaceutically acceptable form, including for Compound (I), pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts and solvates thereof.
  • Suitable pharmaceutically acceptable salted forms of Compound (I) include those described in EP 0306228 and WO94/05659.
  • a preferred pharmaceutically acceptable salt is a maleate.
  • Suitable pharmaceutically acceptable solvated forms of Compound (I) include those described in EP 0306228 and WO94/05659, in particular hydrates. Suitable pharmaceutically acceptable forms of insulin are referred to in standard reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).
  • Compound (I) or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be prepared using known methods, for example those disclosed in EP 0306228 and WO94/05659. The disclosures of EP 0306228 and WO94/05659 are incorporated herein by reference.
  • Compound (I) may exist in one of several tautomeric forms, all of which are encompassed by the term Compound (I) as individual tautomeric forms or as mixtures thereof.
  • Compound (I) contains a chiral carbon atom, and hence can exist in one or more stereoisomeric forms, the term Compound (I) encompasses all of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates.
  • Insulin is prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).
  • condition associated with diabetes includes conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.
  • 'Conditions associated with diabetes mellitus itself include hyperglycaemia, insulin resistance, including acquired insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include poly cystic ovarian syndrome and steroid induced insulin resistance and gestational diabetes. 'Complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy.
  • Renal diseases associated with Type II diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
  • nephropathy glomerulonephritis
  • glomerular sclerosis glomerular sclerosis
  • nephrotic syndrome hypertensive nephrosclerosis
  • end stage renal disease end stage renal disease.
  • the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
  • scalar amounts including mg amounts, of Compound (I) in a pharmaceutically acceptable form
  • the scalar amount referred to is made in respect of Compound (I) per se:
  • 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound (I).
  • Diabetes mellitus is preferably Type II diabetes.
  • the particularly beneficial effect on glycaemic control provided by the treatment of the invention is indicated to be a synergistic effect relative to the control expected for the sum of the effects of the individual active agents.
  • Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (Hb Ale). Such indices are determined using standard methodology, for example those described in: Tuescher A, Richterich, P., Sau. med. Wschr. 101 (1971), 345 and 390 and Frank P., 'Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988
  • the dosage level of each of the active agents when used in accordance with the treatment of the invention will be less than would have been required from a purely additive effect upon glycaemic control.
  • the active medicaments are preferably administered in pharmaceutical composition form.
  • such compositions can include both medicaments or one only of the medicaments.
  • compositions, formulations and methods of administration suitably refer to the compositions, formulations and administration of Compound (I).
  • compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycoUate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example star
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I)s suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
  • compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions are formulated according to conventional methods, such as those disclosed herein and in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).
  • the compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
  • Suitable dosages including unit dosages of the Compound of formula (I) comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I).
  • the two medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day.
  • Suitable dosages of insulin include those described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The * Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).
  • a range of 2 to 4mg includes a range of 2.1 to 4, 2.2 to 4, 2.3 to 4, 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2.8 to 4, 2.9 to 4 or 3 to 4mg.
  • a range of 4 to 8mg includes a range of 4.1 to 8, 4.2 to 8, 4.3 to 8, 4.4 to 8,
  • a range of 8 to 12 mg includes a range of 8.1 to 12, 8.2 to 12, 8.3 to 12, 8.4 to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12 or 11 to 12mg. No adverse toxicological effects have been established for the compositions or methods of the invention in the abovementioned dosage ranges.
  • lactose monohydrate is passed through a suitable screen and blended with the milled maleate salt of Compound (I).
  • Sodium starch glycoUate, hydoxypropyl methylcellulose, microcrystalline cellulose and the remaining lactose are passed through a suitable screen and added to the mixture. Blending is then continued.
  • the resulting mixture is then wet granulated with purified water.
  • the wet granules are then screened, dried on a fluid bed drier and the dried granules are passed through a further screen and finally homogenised.
  • the granules from above are placed into a tumble blender. Approximately two thirds of the lactose is screened and added to the blender. The microcrystalline cellulose, sodium starch glycoUate, magnesium stearate and remaining lactose are screened and added to the blender and the mixture blended together. The resulting mix is then compressed on a rotary tablet press to a target weight of 150mg for the 1, 2 and 4mg tablets and to a target weight of 300mg for the 8mg tablets. The tablet cores are then transferred to a tablet coating machine, pre-warmed with warm air (approximately 65°C) and film coated until the tablet weight has increased by 2.0% to 3.5%.
  • Aqueous film coating material 4.5 4.5 4.5 9.0

Landscapes

  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP98932169A 1997-06-18 1998-06-15 Treatment of diabetes with rosiglitazone and insulin Withdrawn EP0999837A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9712866.4A GB9712866D0 (en) 1997-06-18 1997-06-18 Novel method of treatment
GB9712866 1997-06-18
PCT/EP1998/003692 WO1998057636A1 (en) 1997-06-18 1998-06-15 Treatment of diabetes with rosiglitazone and insulin

Publications (1)

Publication Number Publication Date
EP0999837A1 true EP0999837A1 (en) 2000-05-17

Family

ID=10814527

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98932169A Withdrawn EP0999837A1 (en) 1997-06-18 1998-06-15 Treatment of diabetes with rosiglitazone and insulin

Country Status (30)

Country Link
EP (1) EP0999837A1 (enrdf_load_stackoverflow)
JP (1) JP2002504138A (enrdf_load_stackoverflow)
KR (1) KR20010013843A (enrdf_load_stackoverflow)
CN (1) CN1133431C (enrdf_load_stackoverflow)
AP (1) AP1287A (enrdf_load_stackoverflow)
AR (2) AR015894A1 (enrdf_load_stackoverflow)
AU (1) AU8216398A (enrdf_load_stackoverflow)
BG (1) BG104059A (enrdf_load_stackoverflow)
BR (1) BR9810444A (enrdf_load_stackoverflow)
CA (1) CA2294141A1 (enrdf_load_stackoverflow)
CO (1) CO4940454A1 (enrdf_load_stackoverflow)
DZ (1) DZ2521A1 (enrdf_load_stackoverflow)
EA (1) EA004800B1 (enrdf_load_stackoverflow)
GB (1) GB9712866D0 (enrdf_load_stackoverflow)
HU (1) HUP0003260A3 (enrdf_load_stackoverflow)
ID (1) ID23951A (enrdf_load_stackoverflow)
IL (1) IL133143A0 (enrdf_load_stackoverflow)
IN (1) IN189723B (enrdf_load_stackoverflow)
MA (1) MA26511A1 (enrdf_load_stackoverflow)
NO (1) NO996265D0 (enrdf_load_stackoverflow)
OA (1) OA11517A (enrdf_load_stackoverflow)
PE (1) PE104499A1 (enrdf_load_stackoverflow)
PL (1) PL343123A1 (enrdf_load_stackoverflow)
SK (1) SK179399A3 (enrdf_load_stackoverflow)
TR (1) TR199903095T2 (enrdf_load_stackoverflow)
TW (1) TW587937B (enrdf_load_stackoverflow)
UA (1) UA70299C2 (enrdf_load_stackoverflow)
UY (1) UY25050A1 (enrdf_load_stackoverflow)
WO (1) WO1998057636A1 (enrdf_load_stackoverflow)
ZA (1) ZA985237B (enrdf_load_stackoverflow)

Families Citing this family (15)

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Publication number Priority date Publication date Assignee Title
US6291495B1 (en) * 1997-02-24 2001-09-18 Robert B. Rieveley Method and composition for the treatment of diabetes
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
TWI249401B (en) 1999-04-14 2006-02-21 Takeda Chemical Industries Ltd Agent for improving ketosis
EP1284268B1 (en) 1999-04-23 2007-12-26 Smithkline Beecham Plc Preparation of a polymorphic form of a thiazolidinedione derivative
US6660716B1 (en) 1999-06-21 2003-12-09 Eli Lilly And Company Method for treating non-insulin dependent diabetes using thiazolidinediones with glucagon-like peptide-1 and agonists thereof
WO2001000223A2 (en) * 1999-06-25 2001-01-04 Minimed Inc. Multiple agent diabetes therapy
US6468507B1 (en) * 2000-05-01 2002-10-22 Aeropharm Technology, Inc. Non-aqueous aerosol formulation comprising rosiglitazone maleate, a non-aqueous carrier, and an amino acid stabilizer
GB0023970D0 (en) * 2000-09-29 2000-11-15 Smithkline Beecham Plc Novel pharmaceutical
WO2002067969A2 (en) 2001-02-21 2002-09-06 Medtronic Minimed, Inc. Stabilized insulin formulations
US6531461B1 (en) 2001-06-04 2003-03-11 Louis Obyo Obyo Nelson Medicament for the treatment of diabetes
US20020198203A1 (en) * 2001-06-07 2002-12-26 Wyeth Combination of a PTPase inhibitor and a thiazolidinedione agent
US6737401B2 (en) 2001-06-28 2004-05-18 Metronic Minimed, Inc. Methods of evaluating protein formulation stability and surfactant-stabilized insulin formulations derived therefrom
KR100699614B1 (ko) * 2002-11-08 2007-03-23 에프. 호프만-라 로슈 아게 퍼옥시좀 증식자 활성화된 수용체 작용제로서의 치환된4-알콕시옥사졸 유도체
US7264813B2 (en) 2003-09-24 2007-09-04 Nikken Sohonsha Corporation Therapeutic uses of Dunaliella powder
CN102389427A (zh) * 2011-10-10 2012-03-28 成都恒瑞制药有限公司 含有罗格列酮和盐酸西替利嗪的固体口服制剂

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RU2195282C2 (ru) * 1993-09-15 2002-12-27 Санкио Компани Лимитед Применение тиазолидиндионов для предотвращения или отдаления наступления инсулиннезависимого сахарного диабета (niddm)
EA199800177A1 (ru) * 1995-08-10 1998-10-29 Варнер-Ламберт Компани Способ снижения количества экзогенного инсулина, вводимого пациенту с инсулиннезависимым сахарным диабетом
EP0859608B1 (en) * 1995-09-18 2004-02-11 Ligand Pharmaceuticals, Inc. Treating niddm with rxr agonists

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Title
See references of WO9857636A1 *

Also Published As

Publication number Publication date
CA2294141A1 (en) 1998-12-23
BG104059A (en) 2000-10-31
AU8216398A (en) 1999-01-04
ID23951A (id) 2000-06-08
PL343123A1 (en) 2001-07-30
AP9901718A0 (en) 1999-12-31
AR015894A1 (es) 2001-05-30
EA200000042A1 (ru) 2000-08-28
DZ2521A1 (fr) 2003-02-08
HUP0003260A2 (hu) 2001-05-28
EA004800B1 (ru) 2004-08-26
CN1260715A (zh) 2000-07-19
PE104499A1 (es) 2000-01-13
GB9712866D0 (en) 1997-08-20
IN189723B (enrdf_load_stackoverflow) 2003-04-19
HUP0003260A3 (en) 2001-12-28
OA11517A (en) 2004-02-04
ZA985237B (en) 2000-02-17
UA70299C2 (en) 2004-10-15
AR012997A1 (es) 2000-11-22
MA26511A1 (fr) 2004-12-20
TR199903095T2 (xx) 2000-08-21
NO996265L (no) 1999-12-17
AP1287A (en) 2004-06-26
WO1998057636A1 (en) 1998-12-23
IL133143A0 (en) 2001-03-19
NO996265D0 (no) 1999-12-17
KR20010013843A (ko) 2001-02-26
SK179399A3 (en) 2000-11-07
CO4940454A1 (es) 2000-07-24
TW587937B (en) 2004-05-21
CN1133431C (zh) 2004-01-07
UY25050A1 (es) 2000-09-29
JP2002504138A (ja) 2002-02-05
BR9810444A (pt) 2000-09-05

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