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- Withdrawn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
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)
- 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)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (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
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL12288398A IL122883A0 (en) | 1998-01-09 | 1998-01-09 | Pharmaceutical compositions for the treatment of dyskinesias |
IL12288398 | 1998-01-09 | ||
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 (en) |
JP (1) | JP2002500181A (en) |
KR (1) | KR20010033978A (en) |
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) |
Families Citing this family (6)
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 |
AU3295900A (en) * | 1999-03-12 | 2000-10-04 | Aventis Pharma S.A. | Amyotropic lateral sclerosis treatment with a combination of riluzole and an ampa receptor antagonist |
FR2801793B1 (en) * | 1999-12-01 | 2003-07-04 | 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 |
FR2809620B1 (en) * | 2000-06-05 | 2002-08-02 | Aventis Pharma Sa | USE OF RILUZOLE OR ITS SALTS FOR THE PREVENTION AND TREATMENT OF ADRENOLEUCODYSTROPHY |
ES2203563T3 (en) * | 2001-05-08 | 2004-04-16 | Schwarz Pharma Ag | IMPROVED TRANSDERMAL THERAPEUTIC SYSTEM FOR THE TREATMENT OF PARKINSON'S DISEASE. |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2688138B1 (en) * | 1992-03-06 | 1995-05-05 | Rhone Poulenc Rorer Sa | APPLICATION OF AMINO-2 TRIFLUOROMETHOXY-6 BENZOTHIAZOLE TO OBTAIN A MEDICINE FOR THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS. |
FR2700117B1 (en) * | 1993-01-07 | 1995-02-03 | Rhone Poulenc Rorer Sa | Application of anti-convulsants in the treatment of Parkinson's disease and parkinsonian syndromes. |
-
1999
- 1999-01-05 CA CA002317811A patent/CA2317811A1/en not_active Abandoned
- 1999-01-05 KR KR1020007007567A patent/KR20010033978A/en not_active Application Discontinuation
- 1999-01-05 CN CN99802790A patent/CN1290166A/en active Pending
- 1999-01-05 EP EP99900116A patent/EP1043996A2/en not_active Withdrawn
- 1999-01-05 BR BR9906821-4A patent/BR9906821A/en not_active IP Right Cessation
- 1999-01-05 AU AU17806/99A patent/AU1780699A/en not_active Abandoned
- 1999-01-05 PL PL99342098A patent/PL342098A1/en unknown
- 1999-01-05 WO PCT/IL1999/000003 patent/WO1999034785A2/en not_active Application Discontinuation
- 1999-01-05 JP JP2000527236A patent/JP2002500181A/en active Pending
-
2000
- 2000-07-07 NO NO20003529A patent/NO20003529L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9934785A2 * |
Also Published As
Publication number | Publication date |
---|---|
AU1780699A (en) | 1999-07-26 |
NO20003529L (en) | 2000-09-08 |
KR20010033978A (en) | 2001-04-25 |
CA2317811A1 (en) | 1999-07-15 |
PL342098A1 (en) | 2001-05-21 |
NO20003529D0 (en) | 2000-07-07 |
BR9906821A (en) | 2000-10-17 |
CN1290166A (en) | 2001-04-04 |
WO1999034785A3 (en) | 1999-09-16 |
JP2002500181A (en) | 2002-01-08 |
WO1999034785A2 (en) | 1999-07-15 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
Effective date: 20000720 |
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AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
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AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20000720;LT PAYMENT 20000720;LV PAYMENT 20000720;MK PAYMENT 20000720;RO PAYMENT 20000720;SI PAYMENT 20000720 |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: MELAMED, ELDAD Owner name: DJALDETTI, RUTH Owner name: NST NEUROSURVIVAL TECHNOLOGIES LTD. Owner name: MOR-RESEARCH APPLICATIONS LTD. |
|
17Q | First examination report despatched |
Effective date: 20031201 |
|
18D | Application deemed to be withdrawn |
Effective date: 20050802 |
|
D18D | Application deemed to be withdrawn (deleted) | ||
17Q | First examination report despatched |
Effective date: 20031201 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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R18D | Application deemed to be withdrawn (corrected) |
Effective date: 20070920 |