OA11631A - Treatment of diabetes with thiazolidinedione and alpha-glucosidase inhibitor. - Google Patents

Treatment of diabetes with thiazolidinedione and alpha-glucosidase inhibitor. Download PDF

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Publication number
OA11631A
OA11631A OA9900295A OA9900295A OA11631A OA 11631 A OA11631 A OA 11631A OA 9900295 A OA9900295 A OA 9900295A OA 9900295 A OA9900295 A OA 9900295A OA 11631 A OA11631 A OA 11631A
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OA
OAPI
Prior art keywords
compound
glucosidase inhibitor
insulin
composition according
pharmaceutically acceptable
Prior art date
Application number
OA9900295A
Inventor
Stephen Alistair Smith
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9712865.6A external-priority patent/GB9712865D0/en
Priority claimed from GBGB9806708.5A external-priority patent/GB9806708D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of OA11631A publication Critical patent/OA11631A/en

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    • 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
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Fodder In General (AREA)

Abstract

A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser and an alpha-glucosidase inhibitor antihyperglycaemic agent, to a mammal in need thereof.

Description

1 NOVEL METHOD OF TREATMENT ' '
This invention relates to a method of treatment, in particular to a method for treatmentand/or prophylaxis of diabètes mellitus, especially non-insulin dépendent diabètes(NIDDM), conditions associated with diabètes mellitus and certain complicationsthereof.
Alpha glucosidase inhibitor antihyperglycaemic agents, such as Acarbose,Emiglitate and Miglitol, are commonly used in the treatment of NIDDM (or Type IIdiabètes).
European Patent Application, Publication Number 0,306,228 relates to certainthiazolidinedione dérivatives disclosed as having antihyperglycaemic andhypolipidaemic 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 sait.
It is now surprisingly indicated that Compound (I) in combination with analpha glucosidase inhibitor antihyperglycaemic agent provides a particularlybénéficiai effect on glycaemic control, such combination is therefore particularlyuseful for the treatment and/or prophylaxis of diabètes mellitus, conditions associatedwith diabètes mellitus and certain complications thereof.
Accordingly, the invention provides a method for the treatment and/orprophylaxis of diabètes mellitus, conditions associated with diabètes mellitus andcertain complications thereof, in a mammal such as a human, which methodcomprises administering an effective non-toxic and pharmaceutically acceptableamount of Compound (I) and an alpha glucosidase inhibitor antihyperglycaemicagent, to a mammal in need thereof.
The method comprises either co-administration of Compound (I) and analpha glucosidase inhibitor antihyperglycaemic agent or the sequential administrationthereof.
Co-administration includes administration of a formulation which includesboth Compound (I) and an alpha glucosidase inhibitor antihyperglycaemic agent. A suitable alpha glucosidase inhibitor antihyperglycaemic agent is Acarbose.
Other suitable alpha glucosidase inhibitor antihyperglycaemic agents areEmiglitate and Miglitol.
In one particular aspect, the method comprises the administration of 2 to 12mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to 4,4 to 8 or 8 to12 mg of Compound (I) per day. 2 011631
Particularly, the method comprises the administration of 2 to 4mg ofCompound (I), especially when administered per day.
Particularly, the method comprises the administration of 4 to 8mg, such asgreater than 4 for example 4.1, to 8 mg, of Compound (I), especially whenadministered per day.
Particularly, the method comprises the administration of 8 to 12 mg ofCompound (I), especially when administered per day.
Preferably, the method comprises the administration of 2 mg of Compound(I), especially when administered per day.
Preferably, the method comprises the administration of 4 mg of Compound(I), especially when administered per day.
Preferably, the method comprises the administration of 8 mg of Compound(I), especially when administered per day.
It will be understood that Compound (I) and the alpha glucosidase inhibitorantihyperglycaemic agent are each administered in a pharmaceutically acceptableform, including pharmaceutically acceptable dérivatives such as pharmaceuticallyacceptable salts, esters and solvatés thereof, as appropriate.
Suitable pharmaceutically acceptable salted forms of Compound (I) includethose described in EP 0306228 and WO94/05659. A preferred pharmaceuticallyacceptable sait 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 the alpha glucosidase inhibitorantihyperglycaemic agent dépend upon the particular agent used but includes knownpharmaceutically acceptable forms of the particular compound chosen. Suchdérivatives are found or are referred to in standard reference texts such as the Britishand US Pharmacopoeias, Remingtoris Pharmaceutical Sciences (Mack PublishingCo.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press).
Compound (I) or, a pharmaceutically acceptable sait thereof, or apharmaceutically acceptable solvaté thereof, may be prepared using known methods,for example those disclosed in EP 0306228 and WO94/05659. The disclosures of EP0306228 and WO94/05659 are incorporated hereinby reference.
Compound (I) may exist in one of several tautomeric forms, ail 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 up to two stereoisomeric forms, the term Compound (I) encompasses ail of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates. 3 011631
The alpha glucosidase inhibitor antihyperglycaemic agent of choice isprepared according to known methods, such methods are found or are referred to instandard reference texts, such as the British and US Pharmacopoeias, Remington'sPharmaceutical Sciences (Mack Publishing Co.) and Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press).
When used herein the terni 'prophylaxis of conditions associated with diabètesmellitus' includes the treatment of conditions such as insulin résistance, impairedglucose tolérance, hyperinsulinaemia and gestational diabètes.
Conditions associated with diabètes include hyperglycaemia and insulinrésistance, especially acquired insulin résistance and obesity. Further conditionsassociated with diabètes include hypertension, cardiovascular disease, especiallyatherosclerosis certain eating disorders, in particular the régulation of appetite andfood intake in subjects suffering from disorders associated with under-eating ,such asanorexia nervosa, and disorders associated with over-eating, such as obesity andanorexia bulimia. Additional conditions associated with diabètes include polycysticovarian syndrome and steroid induced insulin résistance.
The complications of conditions associated with diabètes mellitusencompassed herein includes rénal disease, especially rénal disease associated withthe development of Type II diabètes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage rénal disease. As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for examplethe term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
In the method of the invention, the active médicaments are preferablyadministered in pharmaceutical composition form. As indicated above, suchcompositions can include both médicaments or one only of the médicaments.
Accordingly, in one aspect of the invention provides a pharmaceuticalcomposition comprising Compound (I), especially 2 to 12 mg thereof, an alphaglucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptablecarrier therefor.
Such compositions may be prepared by admixing Compound (I), especially 2to 12 mg thereof, the alpha glucosidase inhibitor antihyperglycaemic agent and apharmaceutically acceptable carrier therefor.
Usually the compositions are adapted for oral administration. However, theymay be adapted for other modes of administration, for example parentéraladministration, sublingual or transdermal administration. 011631
The compositions may be in the form of tablets, capsules, powders, granules,lozenges, suppositories, reconstitutable powders, or liquid préparations, such as oralor stérile parentéral solutions or suspensions.
In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.
Unit dose présentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; Allers, forexample lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;tabletting lubricants, for example magnésium stéarate; disintegrants, for examplestarch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose;or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amountappropriate 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).
In the treatments the médicaments may be administered from 1 to 6 times aday, but most preferably 1 or 2 times per day.
Suitable dosages including unit dosages of the alpha glucosidase inhibitorantihyperglycaemic agent, include the known dosages and unit doses for thesecompounds as described or referred to in reference texts such as the British and USPharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.),
Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press)
The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may be used to distributethe active agent throughout those compositions employing large quantities of Allers.
Such operations are of course conventional in the art. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice, in particularwith an enteric coating.
Oral liquid préparations may be in the form of, for example, émulsions,syrups, or élixirs, or may be presented as a dry product for reconstitution with wateror other suitable vehicle before use. Such liquid préparations may containconventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stéarategel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitanmonooleate, or acacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such as esters of glycérine,propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl 5 011631 p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
For parentéral administration, fluid unit dosage forms are prepared utilizingthe compound and a stérile vehicle, and, depending on the concentration used, can beeither suspended or dissolved in the vehicle. In preparing solutions the compound canbe dissolved in water for injection and filter sterilized before fîlling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, apreservative and buffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after fîlling into the vial and the waterremoved under vacuum. Parentéral suspensions are prepared in substantially the samemanner, except that the Compound (I)s suspended in the vehicle instead of beingdissolved, and sterilization cannot be accomplished by filtration. The compound canbe sterilized by exposure to ethylene oxide before suspending in the stérile vehicle.Advantageously, a surfactant or wetting agent is included in the composition tofacilitate uniform distribution of the compound.
Compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending upon the method ofadministration.
Compositions may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.
The compositions are formulated according to conventional methods, such asthose disclosed in standard reference texts, for example the British and USPharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) andMartindale The Extra Pharmacopoeia (London The Pharmaceutical Press) andHarry's Cosmeticology (Leonard Hill Books).
In a further aspect, the présent invention also provides a pharmaceuticalcomposition comprising Compound (I), especially 2 to 12 mg thereof, an alphaglucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptablecarrier therefor, for use as an active therapeutic substance.
In particular, the présent invention provides a pharmaceutical compositioncomprising Compound (I), especially 2 to 12 mg thereof, an alpha glucosidaseinhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor,for use in the treatment and/or prophylaxis of diabètes mellitus, conditions associatedwith diabètes mellitus and certain complications thereof.
No adverse toxicological effects hâve been established for the compositions ormethods of the invention in the abovementioned dosage ranges.
The following example illustrâtes the invention but does not limit it in any way.
ο (Λ Ο Ν> Μ sg* >§ *< Λ g Ο* ο ο CZ5 Ο ο
CL Ω
I ο Μ L/i Ui 3 £- Η-* Ο Ο Ο tu Ο Ο Ο ?Γ ρ k> <"+· Ο œ £ £- R a 0 crq
"I Λ Ο. β*· « 0 Ό 0 0 0 5 *β •Ί (ΐ Ό 0 *< 0
(-F Ο 0 ο «5 η ο 0 ο Λ 0 (Β- *1 0 Π> Η cr CD* 011631 Β (g Ο Ο g
I 3 ο 3 >1 >3 g Ο eu
0μ»—· ·0CTO &amp; π> 35 I—*>—4 Ο >-*· (g 3 S. <d 0. fa. 7 011631
The concentrate was then formulated into tablets using the following:

Claims (8)

  1. 8 - 011631
    1. A pharmaceutical composition comprising an insulin sensi-tiser, an alpha glucosidase inhibitor antihyperglycaemic agentand a pharmaceutically acceptable carrier therefor.
  2. 2. A composition according to claim 1 wherein the alphaglucosidase inhibitor antihyperglycaemic agent is acarbose, emi-glitate or miglitol.
  3. 3. A composition according to claim 1 or claim 2 whereinthe alpha glucosidase inhibitor antihyperglycaemic agent is acar-bose.
  4. 4. A composition according to any one of daims 1 to 3 whe- rein the insulin sensitiser is Compound (I)
  5. 5. A composition according to any one of daims 1 to 4 which comprises 2 to 12 mg of Compound (I).
  6. 6. A pharmaceutical composition comprising an insulin sensiti-ser an alpha glucosidase inhibitor antihyperglycaemic agent anda pharmaceutically acceptable carrier therefor, for use as anactive therapeutic substance.
  7. 7. A pharmaceutical composition comprising an insulin sensiti-ser, an alpha glucosidase inhibitor antihyperglycaemic agent anda pharmaceutically acceptable carrier therefor, for use in thetreatment of diabètes raellitus and conditions associated withdiabètes mellitus.
  8. 8. A composition according to any one of daims 1, 7 or 8 wherein the insulin sensitiser is ( + )-5-[[4-[{3,4-dihydro-6-hydroxy-2,5,7,8-tetramethy1-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(1-methy1 -cyclohexyl)methoxy]benzy1]thiazolidine-2,4-dione (or ciglitazone) 5-[4-[2-(ethylpyridin-2-yl)ethoxyjbenzy 1 ] thiazolidine-2,4-dione(or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylme-thy1)thiazolidine-2,4-dione (or englitazone); or a pharmaceuti-cally acceptable form thereof.
OA9900295A 1997-06-18 1999-12-17 Treatment of diabetes with thiazolidinedione and alpha-glucosidase inhibitor. OA11631A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9712865.6A GB9712865D0 (en) 1997-06-18 1997-06-18 Novel method of treatment
GBGB9806708.5A GB9806708D0 (en) 1998-03-27 1998-03-27 Novel method

Publications (1)

Publication Number Publication Date
OA11631A true OA11631A (en) 2004-11-22

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OA9900295A OA11631A (en) 1997-06-18 1999-12-17 Treatment of diabetes with thiazolidinedione and alpha-glucosidase inhibitor.

Country Status (24)

Country Link
EP (1) EP0975343A1 (en)
JP (1) JP2001523271A (en)
KR (1) KR20010013845A (en)
CN (1) CN1274282A (en)
AP (1) AP9901720A0 (en)
AR (2) AR014881A1 (en)
AU (1) AU8799998A (en)
BG (1) BG103966A (en)
BR (1) BR9810186A (en)
CA (1) CA2294134A1 (en)
CO (1) CO4940453A1 (en)
DZ (1) DZ2519A1 (en)
EA (1) EA200000040A1 (en)
IL (1) IL133138A0 (en)
MA (1) MA26510A1 (en)
NO (1) NO996270D0 (en)
NZ (1) NZ501345A (en)
OA (1) OA11631A (en)
PE (1) PE89199A1 (en)
PL (1) PL337577A1 (en)
SK (1) SK179499A3 (en)
TR (1) TR199903072T2 (en)
UY (1) UY25051A1 (en)
WO (1) WO1998057635A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
DE60004658T2 (en) 1999-04-23 2004-06-24 Smithkline Beecham Plc, Brentford THIAZOLIDINDEDE DERIVATIVE AND ITS USE AS ANTIDIBLE
WO2002080936A1 (en) 2001-04-04 2002-10-17 Ortho Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and ppar modulators
JP4590158B2 (en) 2001-04-04 2010-12-01 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド Combination therapy comprising a glucose reabsorption inhibitor and a retinoid-X receptor modulator
FR2832930A1 (en) * 2001-12-03 2003-06-06 Lipha PHARMACEUTICAL COMPOSITION COMPRISING AN ALPHA-GLUCOSIDASE INHIBITOR AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR THE PREPARATION OF MEDICINES FOR TREATING DIABETES
JP2004067575A (en) * 2002-08-06 2004-03-04 Yaizu Suisankagaku Industry Co Ltd Diabetes treatment effect enhancer
CN101121004B (en) * 2006-08-08 2010-07-21 鲁南制药集团股份有限公司 Medicine composition containing insulin intensifier and miglitol
CN101584688B (en) * 2008-05-24 2010-11-10 鲁南制药集团股份有限公司 Medicament composition for treating diabetes and complications of diabetes
CN101584705B (en) * 2008-05-24 2010-10-27 鲁南制药集团股份有限公司 A kind of pharmaceutical composition for treating diabetes and its complications

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900435A (en) * 1991-08-26 1999-05-04 Pharmacia & Upjohn Company Composition, food product and uses of 3-guanidinopropionic acid
US5917052A (en) * 1994-09-28 1999-06-29 Shaman Pharmaceuticals, Inc. Hypoglycemic agent from cryptolepis
TWI238064B (en) * 1995-06-20 2005-08-21 Takeda Chemical Industries Ltd A pharmaceutical composition for prophylaxis and treatment of diabetes

Also Published As

Publication number Publication date
AR014881A1 (en) 2001-04-11
AU8799998A (en) 1999-01-04
EP0975343A1 (en) 2000-02-02
NO996270L (en) 1999-12-17
SK179499A3 (en) 2000-11-07
PL337577A1 (en) 2000-08-28
NO996270D0 (en) 1999-12-17
BR9810186A (en) 2000-08-08
AP9901720A0 (en) 1999-12-31
DZ2519A1 (en) 2003-02-01
CN1274282A (en) 2000-11-22
UY25051A1 (en) 2000-09-29
AR013352A1 (en) 2000-12-27
JP2001523271A (en) 2001-11-20
EA200000040A1 (en) 2000-08-28
CO4940453A1 (en) 2000-07-24
MA26510A1 (en) 2004-12-20
IL133138A0 (en) 2001-03-19
CA2294134A1 (en) 1998-12-23
TR199903072T2 (en) 2000-07-21
NZ501345A (en) 2001-10-26
PE89199A1 (en) 1999-10-23
KR20010013845A (en) 2001-02-26
BG103966A (en) 2000-07-31
WO1998057635A1 (en) 1998-12-23

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