EP1043996A2 - Treatment of dyskinesias - Google Patents
Treatment of dyskinesiasInfo
- Publication number
- EP1043996A2 EP1043996A2 EP99900116A EP99900116A EP1043996A2 EP 1043996 A2 EP1043996 A2 EP 1043996A2 EP 99900116 A EP99900116 A EP 99900116A EP 99900116 A EP99900116 A EP 99900116A EP 1043996 A2 EP1043996 A2 EP 1043996A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- riluzole
- dyskinesia
- levodopa
- pharmaceutical composition
- patients
- 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- Withdrawn
Links
- 208000012661 Dyskinesia Diseases 0.000 title claims abstract description 64
- 238000011282 treatment Methods 0.000 title claims description 20
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 33
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960004502 levodopa Drugs 0.000 claims abstract description 33
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960004181 riluzole Drugs 0.000 claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000002552 dosage form Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000000561 anti-psychotic effect Effects 0.000 claims description 2
- 239000003196 psychodysleptic agent Substances 0.000 claims 1
- 230000001668 ameliorated effect Effects 0.000 abstract 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 14
- 208000018737 Parkinson disease Diseases 0.000 description 9
- 230000003291 dopaminomimetic effect Effects 0.000 description 8
- 239000003176 neuroleptic agent Substances 0.000 description 8
- 229960003638 dopamine Drugs 0.000 description 7
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 7
- 208000015592 Involuntary movements Diseases 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000164 antipsychotic agent Substances 0.000 description 3
- 238000009534 blood test Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000701 neuroleptic effect Effects 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002618 waking effect Effects 0.000 description 3
- 206010008748 Chorea Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229940035678 anti-parkinson drug Drugs 0.000 description 2
- 210000004227 basal ganglia Anatomy 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 229940052760 dopamine agonists Drugs 0.000 description 2
- 210000005064 dopaminergic neuron Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 238000007427 paired t-test Methods 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 230000001144 postural effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 210000003523 substantia nigra Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 206010008752 Choreiform movements Diseases 0.000 description 1
- 241001573498 Compacta Species 0.000 description 1
- 229940123736 Decarboxylase inhibitor Drugs 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 206010071390 Resting tremor Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 208000024453 abnormal involuntary movement Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 210000003467 cheek Anatomy 0.000 description 1
- 238000011976 chest X-ray Methods 0.000 description 1
- 238000009535 clinical urine test Methods 0.000 description 1
- 239000003954 decarboxylase inhibitor Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000035614 depigmentation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000142 dyskinetic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 210000001097 facial muscle Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004558 lewy body Anatomy 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229940052740 other dopaminergic agent in atc Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 210000002637 putamen Anatomy 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000003019 respiratory muscle Anatomy 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention concerns pharmaceutical compositions for the treatment of dyskinesias, particularly levodopa-induced dyskinesia and tardative dyskinesia.
- Parkinson's disease is an age related, progressive neurodegenerative disorder.
- the prevalence rate is approximately 0.5% in the population aged 50-59, 1% in ages 60-69, 2% in the 70-79 age group and rises to over 3% in those who are 80 and older. Prevalence rates are similar in Europe.
- Parkinson's disease is characterized by a relatively selective degeneration of dopaminergic neurons in the substantia nigra pars compacta with loss of striatal dopamine.
- the pathology shows depigmentation of the substantia nigra and intracellular inclusions (Lewy bodies).
- the cardinal features of the disease include resting tremor, rigidity, bradykinesia and postural instability.
- Current treatment of the motor signs of Parkinson's disease is based on dopamine replacement. This involves the administration of levodopa, usually combined with a decarboxylase inhibitor. Exogenous levodopa is converted in the striatum to dopamine and replenishes the reduced dopaminergic concentrations in the basal ganglia.
- Dopamine agonists may be helpful as well.
- the patients enjoy a smooth and stable response to this treatment.
- 75% of patients develop disabling and incapacitating motor complications.
- One of the most common side effects is the levodopa-induced dyskinesias (choreiform involuntary movements). They occur in the majority (80-100%) of the patients as their illness progresses.
- Dyskinesias may be initially mild but they can become more and more progressive, complex, generalized, violent, and may severely interfere with motor function, speech, coordination and postural stability.
- dyskinesias are mainly the peak-dose type, i.e., they are most prominent when levodopa plasma levels are high.
- dyskinesias may also appear at the beginning and again at the termination of an individual levodopa dose beneficial effect.
- dyskinesias predominate in an "all or none” fashion, i.e., they are present throughout the duration of an "on" period, induced by a successful single oral dose of levodopa.
- Such levodopa-induced dyskinesias also represent a major limiting factor in the pharmacological treatment of Parkinson's disease.
- Dykinesias are probably and primarily caused by the action of excessive exogenous dopamine on denervation-supersensitive post-synaptic dopaminergic receptors.
- the dopamine formed from levodopa is stored in vesicles within the dopaminergic nerve-endings for regulated release into the synapse.
- more nigral dopaminergic neurons degenerate and there is more severe loss of their nerve-terminals in the basal ganglia (caudate and putamen nuclei).
- the present invention provides, by one of its aspects, a pharmaceutical composition for the amelioration of levodopa-induced dyskinesia and tardative dyskinesia, comprising as an active ingredient, a pharmaceutically effective amount of riluzole.
- the present invention provides, by another of its aspects, use of riluzole for the preparation of a pharmaceutical composition for the amelioration of levodopa-induced dyskinesia and tardative dyskinesia.
- amelioration refers to a decrease in the abnormal involuntary movements characterizing these two types of dyskinesia, as can be determined for example, by using the Abnormal Involuntary Movement Scale (AIMS) as will be specified hereinbelow.
- AIMS Abnormal Involuntary Movement Scale
- levodopa-induced dyskinesia refers to dyskinesia, i.e. involuntary choreiform movements, brought about by the chronic administration of levodopa, for example in patients suffering from Parkinson's Disease.
- disorderative dyskinesia refers to dyskinesia brought about by the chronic administration of neuroleptic, anti-psychotic drugs of the Dopaminergic-receptor blocker type.
- riluzole refers to 2-amino-6 trifluoromethoxy-benzothiazole.
- effective amount refers to an amount that brings about to a reduction in the AIMS of the patients without causing severe side effects.
- the dosage of the active ingredient should be tested empirically for each specific indication, and depends on various factors, such as the patient's weight, the length of time of administration of the levodopa or the neuroleptic pharmaceutical composition, age, etc. Generally speaking, the dosage should be of about 25 to about 200 mg per day, preferably of about 50 to about 200 mg per day, most preferably of about 50 to about 100 mg per day.
- the pharmaceutical composition of the invention may comprise solely riluzole and a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier such as the neuroleptic drug (in the case of tardative dyskinesia), or levodopa (in the case of levodopa-induced dyskinesia) together with the riluzole.
- the present invention further concerns a method for ameliorating levodopa-induced dyskinesia or tardative dyskinesia by administering to a subject in need of such treatment, a therapeutically effective amount of riluzole.
- the riluzole may be administrated separately, i.e. not simultaneously with the dyskinesia-causing agent (such as the neuroleptic drug or the levodopa), or alternatively may be administered together with the dyskinesia-causing agents either by administration of the two medicaments simultaneously or by forming both medicaments in a single dosage form.
- the dyskinesia-causing agent such as the neuroleptic drug or the levodopa
- the Parkinson patients are balanced by optimal dopaminergic treatment in the three months prior to the clinical trial.
- the patients with tardative dyskinesia which are already balanced by neuroleptic treatment, do not reduce the dosage of the neuroleptic drug, and do not cease other treatments, which they receive.
- the clinical assessment of the Parkinson patient is carried out by using the Unified Parkinson's Disease Rating Scale (UPDRS) and the assessment of involuntary movement will be carried out by the Abnormal Involuntary
- AIMS Movement Scale
- AIMS AIMS.
- the trial is carried out for six weeks. Prior to the beginning of the trial, patients undergo blood and urine tests, a chest X-ray, an ECG, as well as general physical and neurological evaluations. During the clinical trial, the patients are treated with riluzole having an initial dosage of
- dyskinesia 1-mild dyskinesia 2-medium dyskinesia, 3-severe dyskinesia
- Treatment with riluzole was found to be effective in attenuating the dyskinesias.
- Mean daily waking hours spent with dyskinesias decreased by about 24% from 6.92 ⁇ 3.67 hours before treatment to 5.26 ⁇ 4.23 hours during treatment (P ⁇ 0.01; paired t-test).
- Mean daily waking hours spent in severe dyskinesias reduced by about 30% from 2.76 ⁇ 1.77 hours before treatment to 1.94 ⁇ 2.40 hours during treatment with riluzole (0.01 ⁇ p ⁇ 0.05; paired t-test).
- Parkinsonian signs and symptoms when patients took riluzole.
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL12288398 | 1998-01-09 | ||
| IL12288398A IL122883A0 (en) | 1998-01-09 | 1998-01-09 | Pharmaceutical compositions for the treatment of dyskinesias |
| IL12710298 | 1998-11-17 | ||
| IL12710298A IL127102A0 (en) | 1998-11-17 | 1998-11-17 | Pharmaceutical compositions for the treatment of dyskinesias |
| PCT/IL1999/000003 WO1999034785A2 (en) | 1998-01-09 | 1999-01-05 | Treatment of dyskinesias |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1043996A2 true EP1043996A2 (en) | 2000-10-18 |
Family
ID=26323572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP99900116A Withdrawn EP1043996A2 (en) | 1998-01-09 | 1999-01-05 | Treatment of dyskinesias |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1043996A2 (enExample) |
| JP (1) | JP2002500181A (enExample) |
| KR (1) | KR20010033978A (enExample) |
| CN (1) | CN1290166A (enExample) |
| AU (1) | AU1780699A (enExample) |
| BR (1) | BR9906821A (enExample) |
| CA (1) | CA2317811A1 (enExample) |
| NO (1) | NO20003529L (enExample) |
| PL (1) | PL342098A1 (enExample) |
| WO (1) | WO1999034785A2 (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2790670A1 (fr) * | 1999-03-12 | 2000-09-15 | Aventis Pharma Sa | Association riluzole et antagoniste des recepteurs ampa |
| JP2002539162A (ja) * | 1999-03-12 | 2002-11-19 | アベンテイス・フアルマ・ソシエテ・アノニム | リルゾールおよびａｍｐａ受容体アンタゴニストの組み合わせ剤を用いる筋萎縮性側索硬化症の治療 |
| FR2801793B1 (fr) * | 1999-12-01 | 2003-07-04 | Aventis Pharma Sa | Association d'une ergoline et de riluzole et son utilisation comme medicament |
| US6297254B1 (en) | 1999-12-01 | 2001-10-02 | Aventis Pharma S. A. | Method for the prevention or treatment of a motoneuron disease |
| FR2809620B1 (fr) * | 2000-06-05 | 2002-08-02 | Aventis Pharma Sa | Utilisation du riluzole ou ses sels pour la prevention et le traitement de l'adrenoleucodystrophie |
| ATE246919T1 (de) * | 2001-05-08 | 2003-08-15 | Sanol Arznei Schwarz Gmbh | Verbessertes transdermales therapeutisches system zur behandlung von morbus parkinson |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2688138B1 (fr) * | 1992-03-06 | 1995-05-05 | Rhone Poulenc Rorer Sa | Application de l'amino-2 trifluoromethoxy-6 benzothiazole pour obtenir un medicament destine au traitement de la sclerose laterale amyotrophique. |
| FR2700117B1 (fr) * | 1993-01-07 | 1995-02-03 | Rhone Poulenc Rorer Sa | Application d'anticonvulsivants dans le traitement de la maladie de Parkinson et des syndromes parkinsoniens. |
-
1999
- 1999-01-05 WO PCT/IL1999/000003 patent/WO1999034785A2/en not_active Ceased
- 1999-01-05 PL PL99342098A patent/PL342098A1/xx unknown
- 1999-01-05 KR KR1020007007567A patent/KR20010033978A/ko not_active Withdrawn
- 1999-01-05 JP JP2000527236A patent/JP2002500181A/ja active Pending
- 1999-01-05 EP EP99900116A patent/EP1043996A2/en not_active Withdrawn
- 1999-01-05 CN CN99802790A patent/CN1290166A/zh active Pending
- 1999-01-05 BR BR9906821-4A patent/BR9906821A/pt not_active IP Right Cessation
- 1999-01-05 AU AU17806/99A patent/AU1780699A/en not_active Abandoned
- 1999-01-05 CA CA002317811A patent/CA2317811A1/en not_active Abandoned
-
2000
- 2000-07-07 NO NO20003529A patent/NO20003529L/no not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9934785A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9906821A (pt) | 2000-10-17 |
| WO1999034785A2 (en) | 1999-07-15 |
| JP2002500181A (ja) | 2002-01-08 |
| NO20003529L (no) | 2000-09-08 |
| CN1290166A (zh) | 2001-04-04 |
| NO20003529D0 (no) | 2000-07-07 |
| AU1780699A (en) | 1999-07-26 |
| WO1999034785A3 (en) | 1999-09-16 |
| CA2317811A1 (en) | 1999-07-15 |
| KR20010033978A (ko) | 2001-04-25 |
| PL342098A1 (en) | 2001-05-21 |
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