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WO1999034785A2 - Traitement de la dyskinesie - Google Patents

Traitement de la dyskinesie Download PDF

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Publication number
WO1999034785A2
WO1999034785A2 PCT/IL1999/000003 IL9900003W WO9934785A2 WO 1999034785 A2 WO1999034785 A2 WO 1999034785A2 IL 9900003 W IL9900003 W IL 9900003W WO 9934785 A2 WO9934785 A2 WO 9934785A2
Authority
WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/IL1999/000003
Other languages
English (en)
Other versions
WO1999034785A3 (fr
Inventor
Eldad Melamed
Ruth Djaldetti
Ilan Ziv
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.)
Mor Research Applications Ltd
Original Assignee
Mor Research Applications 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
Priority claimed from IL12288398A external-priority patent/IL122883A0/xx
Priority claimed from IL12710298A external-priority patent/IL127102A0/xx
Priority to US09/582,989 priority Critical patent/US6417210B1/en
Priority to IL13719099A priority patent/IL137190A0/xx
Priority to BR9906821-4A priority patent/BR9906821A/pt
Priority to CA002317811A priority patent/CA2317811A1/fr
Priority to EP99900116A priority patent/EP1043996A2/fr
Priority to AU17806/99A priority patent/AU1780699A/en
Application filed by Mor Research Applications Ltd filed Critical Mor Research Applications Ltd
Priority to JP2000527236A priority patent/JP2002500181A/ja
Priority to PL99342098A priority patent/PL342098A1/xx
Priority to KR1020007007567A priority patent/KR20010033978A/ko
Publication of WO1999034785A2 publication Critical patent/WO1999034785A2/fr
Publication of WO1999034785A3 publication Critical patent/WO1999034785A3/fr
Priority to NO20003529A priority patent/NO20003529L/no
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/41—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)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

On a constaté une amélioration de la dyskinésie induite par la lévodopa et de la dyskinésie tardive en administrant à certains sujets du riluzole.
PCT/IL1999/000003 1998-01-09 1999-01-05 Traitement de la dyskinesie Ceased WO1999034785A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
PL99342098A PL342098A1 (en) 1998-01-09 1999-01-05 Pharmacological compositions for treating diskineses
KR1020007007567A KR20010033978A (ko) 1998-01-09 1999-01-05 운동이상증의 치료법
JP2000527236A JP2002500181A (ja) 1998-01-09 1999-01-05 ジスキネジーの処置
BR9906821-4A BR9906821A (pt) 1998-01-09 1999-01-05 Composição farmacêutica e processo para melhorar a discinesia induzida por levodopa e discinesia tardia, e, uso de riluzol para a preparação de uma composição farmacêutica
CA002317811A CA2317811A1 (fr) 1998-01-09 1999-01-05 Traitement de la dyskinesie
EP99900116A EP1043996A2 (fr) 1998-01-09 1999-01-05 Traitement de la dyskinesie
AU17806/99A AU1780699A (en) 1998-01-09 1999-01-05 Treatment of dyskinesias
US09/582,989 US6417210B1 (en) 1998-01-09 1999-01-05 Treatment of dyskinesias and Parkinson's disease with riluzole and levodopa
IL13719099A IL137190A0 (en) 1998-01-09 1999-01-05 Pharmaceutical compositions for the treatment of dyskinesias
NO20003529A NO20003529L (no) 1998-01-09 2000-07-07 Behandling av dyskinesi-tilstander

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IL12288398A IL122883A0 (en) 1998-01-09 1998-01-09 Pharmaceutical compositions for the treatment of dyskinesias
IL122883 1998-11-17
IL12710298A IL127102A0 (en) 1998-11-17 1998-11-17 Pharmaceutical compositions for the treatment of dyskinesias
IL127102 1998-11-17

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/899,639 Continuation US6669122B2 (en) 1999-01-11 2001-07-05 Method and apparatus for shaping particles by ultrasonic cavitation

Publications (2)

Publication Number Publication Date
WO1999034785A2 true WO1999034785A2 (fr) 1999-07-15
WO1999034785A3 WO1999034785A3 (fr) 1999-09-16

Family

ID=26323572

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL1999/000003 Ceased WO1999034785A2 (fr) 1998-01-09 1999-01-05 Traitement de la dyskinesie

Country Status (10)

Country Link
EP (1) EP1043996A2 (fr)
JP (1) JP2002500181A (fr)
KR (1) KR20010033978A (fr)
CN (1) CN1290166A (fr)
AU (1) AU1780699A (fr)
BR (1) BR9906821A (fr)
CA (1) CA2317811A1 (fr)
NO (1) NO20003529L (fr)
PL (1) PL342098A1 (fr)
WO (1) WO1999034785A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
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
WO2000054772A1 (fr) * 1999-03-12 2000-09-21 Aventis Pharma S.A. Traitement de la sclerose laterale amyotrophique avec une association de riluzole et d'un antagoniste des recepteurs ampa
WO2001039776A1 (fr) * 1999-12-01 2001-06-07 Aventis Pharma S.A. Association d'une ergoline et du riluzole pour la prevention et le traitement des maladies motoneuronales
US6297254B1 (en) 1999-12-01 2001-10-02 Aventis Pharma S. A. Method for the prevention or treatment of a motoneuron disease
JP2003535113A (ja) * 2000-06-05 2003-11-25 アベンテイス・フアルマ・ソシエテ・アノニム 副腎脳白質ジストロフィーを予防および治療するためのリルゾールもしくはその塩の使用
JP2004528359A (ja) * 2001-05-08 2004-09-16 シュバルツ　ファルマ　アクチェンゲゼルシャフト パーキンソン氏病を治療するための改善された経皮吸収治療システム

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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.

Cited By (9)

* Cited by examiner, † Cited by third party
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
WO2000054772A1 (fr) * 1999-03-12 2000-09-21 Aventis Pharma S.A. Traitement de la sclerose laterale amyotrophique avec une association de riluzole et d'un antagoniste des recepteurs ampa
WO2001039776A1 (fr) * 1999-12-01 2001-06-07 Aventis Pharma S.A. Association d'une ergoline et du riluzole pour la prevention et le traitement des maladies motoneuronales
FR2801793A1 (fr) * 1999-12-01 2001-06-08 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
EP1464332A1 (fr) * 1999-12-01 2004-10-06 Aventis Pharma S.A. Association de la nicergoline et du riluzole pour la prévention et le traitement des maladies motoneuronales
JP2003535113A (ja) * 2000-06-05 2003-11-25 アベンテイス・フアルマ・ソシエテ・アノニム 副腎脳白質ジストロフィーを予防および治療するためのリルゾールもしくはその塩の使用
JP4848117B2 (ja) * 2000-06-05 2011-12-28 アベンテイス・フアルマ・ソシエテ・アノニム 副腎脳白質ジストロフィーを予防および治療するためのリルゾールもしくはその塩の使用
JP2004528359A (ja) * 2001-05-08 2004-09-16 シュバルツ　ファルマ　アクチェンゲゼルシャフト パーキンソン氏病を治療するための改善された経皮吸収治療システム

Also Published As

Publication number Publication date
AU1780699A (en) 1999-07-26
KR20010033978A (ko) 2001-04-25
PL342098A1 (en) 2001-05-21
EP1043996A2 (fr) 2000-10-18
BR9906821A (pt) 2000-10-17
CA2317811A1 (fr) 1999-07-15
CN1290166A (zh) 2001-04-04
NO20003529D0 (no) 2000-07-07
JP2002500181A (ja) 2002-01-08
WO1999034785A3 (fr) 1999-09-16
NO20003529L (no) 2000-09-08

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