WO1999034785A2 - Treatment of dyskinesias - Google Patents

Treatment of dyskinesias 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
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Prior art keywords
riluzole
dyskinesia
levodopa
pharmaceutical composition
patients
Prior art date
Application number
PCT/IL1999/000003
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French (fr)
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WO1999034785A3 (en
Inventor
Eldad Melamed
Ruth Djaldetti
Ilan Ziv
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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/en
Priority claimed from IL12710298A external-priority patent/IL127102A0/en
Priority to JP2000527236A priority Critical patent/JP2002500181A/en
Priority to CA002317811A priority patent/CA2317811A1/en
Priority to KR1020007007567A priority patent/KR20010033978A/en
Priority to IL13719099A priority patent/IL137190A0/en
Application filed by Mor-Research Applications Ltd. filed Critical Mor-Research Applications Ltd.
Priority to PL99342098A priority patent/PL342098A1/en
Priority to BR9906821-4A priority patent/BR9906821A/en
Priority to US09/582,989 priority patent/US6417210B1/en
Priority to EP99900116A priority patent/EP1043996A2/en
Priority to AU17806/99A priority patent/AU1780699A/en
Publication of WO1999034785A2 publication Critical patent/WO1999034785A2/en
Publication of WO1999034785A3 publication Critical patent/WO1999034785A3/en
Priority to NO20003529A priority patent/NO20003529L/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/425Thiazoles
    • A61K31/428Thiazoles condensed with carbocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/425Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs 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.

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  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (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

Levodopa-induced dyskinesia and tardative dyskinesia are ameliorated by administration of riluzole to needing subjects.

Description

TREATMENT OF DYSKINESIAS
FIELD OF THE INVENTION
The present invention concerns pharmaceutical compositions for the treatment of dyskinesias, particularly levodopa-induced dyskinesia and tardative dyskinesia.
BACKGROUND OF THE INVENTION
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. During the first years of treatment the patients enjoy a smooth and stable response to this treatment. However, after 2-5 years of chronic treatment with dopaminergic preparations, 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. Patients and families are often shameful by the unaesthetic and bizarre movements which can affect facial muscles, eyelids, mouth, cheeks, lips and tongue, upper and lower limbs and even trunk and respiratory muscles. This is one of the major reasons for social decline of afflicted patients.
At the beginning, when they first emerge, dyskinesias are mainly the peak-dose type, i.e., they are most prominent when levodopa plasma levels are high. When patients later develop response fluctuations after chronic levodopa treatment, dyskinesias may also appear at the beginning and again at the termination of an individual levodopa dose beneficial effect. When disease is more advanced, 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. When their illness progresses, the patients need increases in their daily levodopa dosage and the addition of other dopaminergic agents, e.g., dopamine agonists and MAO-B inhibitors. This is invariably associated with a rapid and intolerable increase of the frequency, distribution and severity of dyskinesias necessitating reduction of drugs. Dykinesias are probably and primarily caused by the action of excessive exogenous dopamine on denervation-supersensitive post-synaptic dopaminergic receptors. Normally, the dopamine formed from levodopa is stored in vesicles within the dopaminergic nerve-endings for regulated release into the synapse. As the disease progresses, more nigral dopaminergic neurons degenerate and there is more severe loss of their nerve-terminals in the basal ganglia (caudate and putamen nuclei).
It is believed that the decarboxylation of exogenous levodopa therefore shifts to non-dopaminergic striatal compartments. Since the generated dopamine molecules are not stored, they immediately interact and hyperactivate the postsynaptic dopaminergic receptors (mainly of the D2 subtype) resulting in the involuntary movements. There is no satisfactory treatment for dyskinesias. Discontinuation or reduction of levodopa and other dopaminergic drugs or addition of neuroleptic drugs that block dopaminergic receptors, can abolish the abnormal movements, but at the expense of severe aggravation of the Parkinsonian symptoms. The control-release levodopa preparations have been proven unhelpful. This despairing state of affairs suggested that it would be difficult if not impossible to dissociate the beneficial anti-Parkinsonian from the bad dyskinetic producing effects of levodopa. Behavioral and psychiatric disorders are usually treated by the administration of by various anti-psychotics, also termed: " neuroleptic drugs" the majority act by blockage of dopamine D2 receptor. Prolonged administration of anti-psychotic drugs often results in development of involuntary movements, termed: "tardative dyskinesia" . Riluzole (2-amino-6-trifluoromethoxy benzothiazole) has recently emerged as a pharmacological agent potentially useful to slow down the evolution of neurodegenerative diseases, such as amyotrophic lateral sclerosis. (Ben Simon et al., New Engl. J. Med., 330:585-91 (1994)). In addition, this molecule has been shown to display anticonvulsant, anti-ischemic, and neuroprotective properties under various experimental conditions. A clear understanding of the site and mechanism of action of this molecule is still lacking.
There has been recently a report (Palti et al. Exper. Neuro 1.146 13 J- 141 (1997)) that riluzole reduces various abnormal motor movement in baboons which were induced by 3-nitroproponic acid, serving as a model for progressive striatal degeneration, which is a model for Huntington's Disease.
SUMMARY OF THE INVENTION 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.
The term "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.
The term "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. The term "tardative dyskinesia" refers to dyskinesia brought about by the chronic administration of neuroleptic, anti-psychotic drugs of the Dopaminergic-receptor blocker type.
The term "riluzole" refers to 2-amino-6 trifluoromethoxy-benzothiazole. The term "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. Alternatively, it is possible to include in one dosage form, both the dyskinesia causing agent 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.
According to the method of the present invention, 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 invention will now be described with reference to some non-limiting examples.
DETAILED DESCRIPTION OF THE INVENTION I. Clinical Procedures
Twelve patients suffering from advanced Parkinson's Disease featuring dyskinesia, and twelve patients having appropriate criteria for tardative dyskinesia are participating in an open experiment for assessing the influence of riluzole on involuntary movement.
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
Movement Scale (AIMS).
Assessment of patients with tardative dyskinesia is carried out utilizing
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
25 mg. twice a day, and after a week, the dosage will be increased to 50 mg. twice a day. Patients are monitored once every two weeks in order to carry out a blood count and SMA (biochemical blood tests). In addition, a clinical assessment-involuntary-movement is carried out separately by two independent physicians. During the clinical trial, patients are asked to fill a detailed diary which will grade the severity of the dyskinesia and will assess daily function according to the following scale:
THE INTENSITY OF THE DYSKINESIA:
0-without dyskinesia 1-mild dyskinesia 2-medium dyskinesia, 3-severe dyskinesia
RATING OF DAILY FUNCTION:
1 - An improvement of daily function as compared to the basic condition
2 - No improvement in daily function
3 - Deterioration of daily function as compared to the basic condition At the end of the clinical trial, patients undergo blood tests, ECG 's, as well as neurological and psychological assessment.
In addition, patients are invited for routine check-ups two weeks from the end of the trial.
II. Clinical trials
Six patients suffering from advanced parkinson's disease with severe levodopa-induced dyskinesias participated in an open-label pilot study to assess safety, tolerability and efficacy of riluzole in attenuating the involuntary movements.
The patients were given optimal anti-Parkinsonian drug treatment during the three months prior to the clinical trial. Duration of study was six weeks. First two weeks served to accumulate baseline data. Patients filled up dyskinesias diaries in which they marked at every waking hour whether involuntary movements were present and their severity (mild/moderate and severe). Each patient was administered with half a tablet of riluzole (25 mg) once, in the morning, for four days. The dose was then increased to 25 mg, b.i.d. for additional four days (once in the morning and once in the early afternoon). The dose as then further increased to two 50 mg tablets (total of 100 mg. daily) which the patients took for three additional weeks. They continued to fill up their dyskinesias diaries throughout the trial period.
Results
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). There was no worsening of the Parkinsonian signs and symptoms when patients took riluzole. Likewise, there was no decrease in the efficacy of levodopa and other anti-Parkinsonian drugs and in the total daily time patients spent in "on " periods.
Riluzole was well-tolerated and there was no repart of adverse-effects. This preliminary open-label study indicates that administration of riluzole (50 mg. b.i.d) can attenuate levodopa-induced duskinesias in patients with Parkinson's disease without causing deterioration of the Parkinsonian signs and without suppression of levodopa efficacy.

Claims

CLAIMS:
1. A pharmaceutical composition for the amelioration of levodopa-induced dyskinesia and tardative dyskinesia, comprising as an active ingredient, a pharmaceutically effective amount of riluzole.
2. A pharmaceutical composition according to Claim 1 in a dosage form for the administration of about 25 to about 200 mg of riluzole per day.
3. A pharmaceutical composition acccording to Claim 2 in a dosage form for the administration of about 50 to about 100 mg of riluzole per day.
4. A method for ameliorating levodopa-induced dyskinesia or tardative dyskinesia comprising administering to a subject in need of such treatment, a therapeutically effective amount of riluzole.
5. A method according to Claim 4, wherein the riluzole is together with levodopa or with an anti-psychotic drug.
6. A method according to Claim 4, wherein the riluzole is administered in an amount of about 25 to about 200 mg per day.
7. A method according to Claim 6, wherein the ruluzole is administered in an amount of about 50 to about 100 mg per day.
8. Use of riluzole for the preparation of a pharmaceutical composition, for the amelioration of levodopa-induced dyskinesia and tardative dyskinesia.
9. Use according to Claim 8, wherein the prepared pharmaceutical composition is in a dosage form for administration of 25 to 200 mg of riluzole per day.
10. Use according to Claim 9, wherein the prepared pharmaceutical composition is in a dosage form for administration of 50 to 200 mg of riluzole per day.
11. Use according to Claim 10, wherein the prepared pharmaceutical composition is in a dosage form for administration of 50 to 100 mg of riluzole per day.
PCT/IL1999/000003 1998-01-09 1999-01-05 Treatment of dyskinesias WO1999034785A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU17806/99A AU1780699A (en) 1998-01-09 1999-01-05 Treatment of dyskinesias
EP99900116A EP1043996A2 (en) 1998-01-09 1999-01-05 Treatment of dyskinesias
CA002317811A CA2317811A1 (en) 1998-01-09 1999-01-05 Treatment of dyskinesias
KR1020007007567A KR20010033978A (en) 1998-01-09 1999-01-05 Treatment of Dyskinesias
IL13719099A IL137190A0 (en) 1998-01-09 1999-01-05 Pharmaceutical compositions for the treatment of dyskinesias
JP2000527236A JP2002500181A (en) 1998-01-09 1999-01-05 Dyskinesia treatment
PL99342098A PL342098A1 (en) 1998-01-09 1999-01-05 Pharmacological compositions for treating diskineses
BR9906821-4A BR9906821A (en) 1998-01-09 1999-01-05 Pharmaceutical composition and process to improve levodopa-induced dyskinesia and tardive dyskinesia, and use of riluzole for the preparation of a pharmaceutical composition
US09/582,989 US6417210B1 (en) 1998-01-09 1999-01-05 Treatment of dyskinesias and Parkinson's disease with riluzole and levodopa
NO20003529A NO20003529L (en) 1998-01-09 2000-07-07 Treatment of dyskinesia conditions

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 1998-01-09
IL12710298A IL127102A0 (en) 1998-11-17 1998-11-17 Pharmaceutical compositions for the treatment of dyskinesias
IL127102 1998-11-17

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

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WO1999034785A2 true WO1999034785A2 (en) 1999-07-15
WO1999034785A3 WO1999034785A3 (en) 1999-09-16

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CN (1) CN1290166A (en)
AU (1) AU1780699A (en)
BR (1) BR9906821A (en)
CA (1) CA2317811A1 (en)
NO (1) NO20003529L (en)
PL (1) PL342098A1 (en)
WO (1) WO1999034785A2 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2790670A1 (en) * 1999-03-12 2000-09-15 Aventis Pharma Sa Treatment or prevention of amyotrophic lateral sclerosis, using synergistic combination of riluzole and AMPA receptor antagonist, e.g. 5H,10H-imidazo (1,2-a) indeno (1,2-e) pyrazin-4-one derivative
WO2000054772A1 (en) * 1999-03-12 2000-09-21 Aventis Pharma S.A. Amyotropic lateral sclerosis treatment with a combination of riluzole and an ampa receptor antagonist
WO2001039776A1 (en) * 1999-12-01 2001-06-07 Aventis Pharma S.A. Combination of an ergoline and riluzole for preventing and treating motor neuron diseases
US6297254B1 (en) 1999-12-01 2001-10-02 Aventis Pharma S. A. Method for the prevention or treatment of a motoneuron disease
JP2003535113A (en) * 2000-06-05 2003-11-25 アベンテイス・フアルマ・ソシエテ・アノニム Use of riluzole or a salt thereof for preventing and treating adrenal leukodystrophy
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WO2000054772A1 (en) * 1999-03-12 2000-09-21 Aventis Pharma S.A. Amyotropic lateral sclerosis treatment with a combination of riluzole and an ampa receptor antagonist
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FR2801793A1 (en) * 1999-12-01 2001-06-08 Aventis Pharma Sa COMBINATION OF ERGOLIN AND RILUZOLE AND ITS USE AS A MEDICINAL PRODUCT
US6297254B1 (en) 1999-12-01 2001-10-02 Aventis Pharma S. A. Method for the prevention or treatment of a motoneuron disease
EP1464332A1 (en) * 1999-12-01 2004-10-06 Aventis Pharma S.A. Combination of nicergoline and riluzole for the prevention and treatment of motoneuronal disorders
JP2003535113A (en) * 2000-06-05 2003-11-25 アベンテイス・フアルマ・ソシエテ・アノニム Use of riluzole or a salt thereof for preventing and treating adrenal leukodystrophy
JP4848117B2 (en) * 2000-06-05 2011-12-28 アベンテイス・フアルマ・ソシエテ・アノニム Use of riluzole or its salts to prevent and treat adrenal white matter dystrophy
JP2004528359A (en) * 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 An improved transdermal therapeutic system for treating Parkinson's disease

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