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.

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• 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)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Thiazole And Isothizaole Compounds (AREA)

Priority Applications (10)

Applications Claiming Priority (4)

Related Child Applications (1)

Publications (2)

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Family Applications (1)

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Cited By (6)

Citations (2)

• 1999
  • 1999-01-05 CA CA002317811A patent/CA2317811A1/en not_active Abandoned
  • 1999-01-05 AU AU17806/99A patent/AU1780699A/en not_active Abandoned
  • 1999-01-05 WO PCT/IL1999/000003 patent/WO1999034785A2/en not_active Application Discontinuation
  • 1999-01-05 JP JP2000527236A patent/JP2002500181A/ja active Pending
  • 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 PL PL99342098A patent/PL342098A1/xx unknown
  • 1999-01-05 EP EP99900116A patent/EP1043996A2/en not_active Withdrawn
  • 1999-01-05 KR KR1020007007567A patent/KR20010033978A/ko not_active Application Discontinuation
• 2000
  • 2000-07-07 NO NO20003529A patent/NO20003529L/no not_active Application Discontinuation

Patent Citations (2)

Non-Patent Citations (14)

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