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WO1999053919A1 - Treatment of generalized anxiety disorder with paroxetine - Google Patents

Treatment of generalized anxiety disorder with paroxetine Download PDF

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Publication number
WO1999053919A1
WO1999053919A1 PCT/US1999/008786 US9908786W WO9953919A1 WO 1999053919 A1 WO1999053919 A1 WO 1999053919A1 US 9908786 W US9908786 W US 9908786W WO 9953919 A1 WO9953919 A1 WO 9953919A1
Authority
WO
WIPO (PCT)
Prior art keywords
paroxetine
pharmaceutically acceptable
treatment
anxiety disorder
acceptable salt
Prior art date
Application number
PCT/US1999/008786
Other languages
French (fr)
Inventor
Rocco Zaninelli
Original Assignee
Smithkline Beecham Corporation
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 to AU38648/99A priority Critical patent/AU3864899A/en
Priority to BR9909791-5A priority patent/BR9909791A/en
Priority to CA002328896A priority patent/CA2328896A1/en
Priority to KR1020007011729A priority patent/KR20010034817A/en
Priority to EP99921431A priority patent/EP1073437A4/en
Priority to APAP/P/2000/001959A priority patent/AP2000001959A0/en
Priority to IL13916799A priority patent/IL139167A0/en
Priority to PL99343494A priority patent/PL343494A1/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP2000544323A priority patent/JP2002512189A/en
Priority to EA200001088A priority patent/EA200001088A1/en
Priority to SK1567-2000A priority patent/SK15672000A3/en
Publication of WO1999053919A1 publication Critical patent/WO1999053919A1/en
Priority to NO20005286A priority patent/NO20005286L/en
Priority to BG104939A priority patent/BG104939A/en

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
    • 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
    • A61K31/33—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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to a method for treatment of generalised anxiety disorder, and especially to the use of paroxetine in such treatment.
  • paroxetine the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4 -methylene- dioxyphenoxymethyl)-piperidine (see Example 2 of US-A-4007196).
  • the hydrochloride salt of paroxetine is approved for human use in therapy to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
  • paroxetine hydrochloride is supplied as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group).
  • Various crystalline anhydrate forms are also known (see WO96/24595 of SmithKline Beecham pic).
  • paroxetine has potential therapeutic utility as a medicament for treatment of generalised anxiety disorder.
  • the present invention provides a method treatment of generalised anxiety disorder, which method comprises administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate there of, to a human or non- human animal in need thereof.
  • the present invention also provides the use of paroxetine or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in treatment of generalised anxiety disorder.
  • a preferred pharmaceutically acceptable salt of paroxetine is crystalline hydrochloride.
  • Suitable procedures for preparing paroxetine hydrochloride include those mentioned in US Patents 4009196, 4721723, 4902801, 4861893 and 5039803 and PCT/GB93/00721.
  • Especially preferred is the hemi-hydrate, prepared as EP-A-0223403.
  • a medicament, for use in treatment of generalised anxiety disorder may be prepared by admixture of paroxetine or a pharmaceutically acceptable salt or solvate thereof with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • the medicament is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as a treatment of generalised anxiety disorder.
  • the suitable dosage range for paroxetine or a pharmaceutically acceptable salt or solvate depends on the severity of the generalised anxiety disorder and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • Paroxetine or a pharmaceutically acceptable salt or solvate thereof may be formulated for administration by any route, and examples are oral, sub-lingual, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may, if desired, be designed to give slow release of the paroxetine or a pharmaceutically acceptable salt or solvate thereof.
  • the medicaments may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • the medicaments 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 glycerine; tabletting lubricants, for example magnesium stearate; disintegrants. for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting 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 glycerine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrrolidon
  • Solid medicaments may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute paroxetine or a salt or solvate thereof throughout those medicaments employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the medicament may also be in the form of an ingestible capsule, for example of gelatin containing paroxetine or a salt thereof if desired with a carrier or other excipients.
  • Medicaments for oral administration as liquids 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 medicaments 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; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring
  • Paroxetine or a pharmaceutically acceptable salt or solvate thereof may also be administered by a non-oral route.
  • the medicaments may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the effective dose of the paroxetine or pharmaceutically acceptable salt or solvate depends on the severity of generalised anxiety disorder to be treated, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 2 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day, for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of paroxetine (calculated as free base) and be administered in multiples, if desired, to give the preceding daily dose.
  • compositions may be prepared in the manner as hereinbefore described.
  • Example 1 discloses a suitable pharmaceutical composition for use in the present invention.

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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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A method of treatment of generalised anxiety disorder, which method comprises administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof, to a human or non-human animal in need thereof.

Description

TREATMENT OF GENERALIZED ANXIETY DISORDER WITH
PAROXETINE
The present invention relates to a method for treatment of generalised anxiety disorder, and especially to the use of paroxetine in such treatment.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4 -methylene- dioxyphenoxymethyl)-piperidine (see Example 2 of US-A-4007196). The hydrochloride salt of paroxetine is approved for human use in therapy to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
In commercial use, paroxetine hydrochloride is supplied as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group). Various crystalline anhydrate forms are also known (see WO96/24595 of SmithKline Beecham pic).
It has now been surprisingly discovered that paroxetine has potential therapeutic utility as a medicament for treatment of generalised anxiety disorder.
Accordingly, the present invention provides a method treatment of generalised anxiety disorder, which method comprises administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate there of, to a human or non- human animal in need thereof.
The present invention also provides the use of paroxetine or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in treatment of generalised anxiety disorder.
A preferred pharmaceutically acceptable salt of paroxetine is crystalline hydrochloride. Suitable procedures for preparing paroxetine hydrochloride include those mentioned in US Patents 4009196, 4721723, 4902801, 4861893 and 5039803 and PCT/GB93/00721. Especially preferred is the hemi-hydrate, prepared as EP-A-0223403.
A medicament, for use in treatment of generalised anxiety disorder may be prepared by admixture of paroxetine or a pharmaceutically acceptable salt or solvate thereof with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
•1- Preferably, the medicament is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as a treatment of generalised anxiety disorder.
The suitable dosage range for paroxetine or a pharmaceutically acceptable salt or solvate depends on the severity of the generalised anxiety disorder and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
Paroxetine or a pharmaceutically acceptable salt or solvate thereof may be formulated for administration by any route, and examples are oral, sub-lingual, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may, if desired, be designed to give slow release of the paroxetine or a pharmaceutically acceptable salt or solvate thereof.
The medicaments may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The medicaments, for example those suitable for oral administration, 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 glycerine; tabletting lubricants, for example magnesium stearate; disintegrants. for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
Solid medicaments may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute paroxetine or a salt or solvate thereof throughout those medicaments employing large quantities of fillers. When the medicament is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The medicament may also be in the form of an ingestible capsule, for example of gelatin containing paroxetine or a salt thereof if desired with a carrier or other excipients. Medicaments for oral administration as liquids 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 medicaments 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; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
Paroxetine or a pharmaceutically acceptable salt or solvate thereof may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the medicaments may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
As mentioned hereinbefore, the effective dose of the paroxetine or pharmaceutically acceptable salt or solvate depends on the severity of generalised anxiety disorder to be treated, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 2 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day, for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Preferably the unit dose will contain from 2 to 20 mg of paroxetine (calculated as free base) and be administered in multiples, if desired, to give the preceding daily dose.
The present invention further provides a pharmaceutical composition for use in treatment of generalised anxiety disorder which comprises an effective amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof and a
-3- pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinbefore described.
The following Example discloses a suitable pharmaceutical composition for use in the present invention.
Example
The following are mixed together in a conventional manner and compressed into tablets of ca. 300 mg weight containing ca. 20 mg of paroxetine (calculated as the free base)
Paroxetine hydrochloride hemihydrate 228.8 g Dibasic calcium phosphate dihydrate 2441.2 g
Hydroxypropylmethyl cellulose 2910 150.0 g Sodium starch glycollate 150.0 g
Magnesium Stearate 30.0 g
Total tablet weight 3000.0 g
-4-

Claims

Claims
1. A method of treatment of generalised anxiety disorder, which method comprises administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate there of, to a human or non-human animal in need thereof.
2. Use of paroxetine or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in treatment of generalised anxiety disorder.
3. A pharmaceutical composition for use in treatment of generalised anxiety disorder which comprises an effective amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
4. A method according to claim 1, use according to claim 2, or a pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable salt of paroxetine is the hydrochloride.
-5-
PCT/US1999/008786 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine WO1999053919A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
IL13916799A IL139167A0 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine
CA002328896A CA2328896A1 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine
KR1020007011729A KR20010034817A (en) 1998-04-22 1999-04-22 Treatment of Generalized Anxiety Disorder With Paroxetine
EP99921431A EP1073437A4 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine
APAP/P/2000/001959A AP2000001959A0 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine.
AU38648/99A AU3864899A (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine
EA200001088A EA200001088A1 (en) 1998-04-22 1999-04-22 TREATMENT OF GENERAL ALARM CONDITION WITH PAROXETINE
PL99343494A PL343494A1 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine
JP2000544323A JP2002512189A (en) 1998-04-22 1999-04-22 Treatment of general anxiety with paroxetine
BR9909791-5A BR9909791A (en) 1998-04-22 1999-04-22 Treatment of anxiety disorders in general with partoxetine
SK1567-2000A SK15672000A3 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine
NO20005286A NO20005286L (en) 1998-04-22 2000-10-20 Treatment of general anxiety disorders with paroxetine
BG104939A BG104939A (en) 1998-04-22 2000-11-13 Treatment of generalized anxiety disorder with paroxetine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9808479.1A GB9808479D0 (en) 1998-04-22 1998-04-22 Method of treatment
GB9808479.1 1998-04-22

Publications (1)

Publication Number Publication Date
WO1999053919A1 true WO1999053919A1 (en) 1999-10-28

Family

ID=10830715

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/008786 WO1999053919A1 (en) 1998-04-22 1999-04-22 Treatment of generalized anxiety disorder with paroxetine

Country Status (20)

Country Link
EP (1) EP1073437A4 (en)
JP (1) JP2002512189A (en)
KR (1) KR20010034817A (en)
CN (1) CN1298301A (en)
AP (1) AP2000001959A0 (en)
AU (1) AU3864899A (en)
BG (1) BG104939A (en)
BR (1) BR9909791A (en)
CA (1) CA2328896A1 (en)
CZ (1) CZ20003885A3 (en)
EA (1) EA200001088A1 (en)
GB (1) GB9808479D0 (en)
HU (1) HUP0101350A3 (en)
ID (1) ID27546A (en)
IL (1) IL139167A0 (en)
NO (1) NO20005286L (en)
PL (1) PL343494A1 (en)
SK (1) SK15672000A3 (en)
TR (1) TR200003082T2 (en)
WO (1) WO1999053919A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2297550B (en) * 1995-02-06 1997-04-09 Smithkline Beecham Plc Paroxetine hydrochloride anhydrate substantially free of bound organic solvent
GB9514842D0 (en) * 1995-07-20 1995-09-20 Smithkline Beecham Plc Novel formulation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 1 January 1900, Columbus, Ohio, US; abstract no. 127:60554, XP002921638 *
See also references of EP1073437A4 *
XX; 1 January 1900 (1900-01-01), XP002921637, Database accession no. 98-01886 *

Also Published As

Publication number Publication date
AU3864899A (en) 1999-11-08
EP1073437A1 (en) 2001-02-07
KR20010034817A (en) 2001-04-25
AP2000001959A0 (en) 2000-12-31
SK15672000A3 (en) 2001-04-09
EA200001088A1 (en) 2001-04-23
IL139167A0 (en) 2001-11-25
NO20005286L (en) 2000-12-20
CN1298301A (en) 2001-06-06
PL343494A1 (en) 2001-08-27
EP1073437A4 (en) 2003-04-16
JP2002512189A (en) 2002-04-23
BG104939A (en) 2001-09-28
HUP0101350A3 (en) 2002-06-28
BR9909791A (en) 2000-12-26
NO20005286D0 (en) 2000-10-20
ID27546A (en) 2001-04-12
CZ20003885A3 (en) 2001-09-12
CA2328896A1 (en) 1999-10-28
HUP0101350A2 (en) 2002-05-29
TR200003082T2 (en) 2001-01-22
GB9808479D0 (en) 1998-06-17

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