AU1780699A - Treatment of dyskinesias - Google Patents
Treatment of dyskinesias Download PDFInfo
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- AU1780699A AU1780699A AU17806/99A AU1780699A AU1780699A AU 1780699 A AU1780699 A AU 1780699A AU 17806/99 A AU17806/99 A AU 17806/99A AU 1780699 A AU1780699 A AU 1780699A AU 1780699 A AU1780699 A AU 1780699A
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- AU
- Australia
- Prior art keywords
- riluzole
- levodopa
- dyskinesia
- patients
- per day
- 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.)
- Abandoned
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- 208000012661 Dyskinesia Diseases 0.000 title claims description 61
- 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 description 32
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 32
- 229960004502 levodopa Drugs 0.000 claims description 32
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims description 30
- 229960004181 riluzole Drugs 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 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
- 239000000203 mixture Substances 0.000 claims 1
- 239000003196 psychodysleptic agent Substances 0.000 claims 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 12
- 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 6
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 5
- 208000015592 Involuntary movements Diseases 0.000 description 4
- 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
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- 230000000750 progressive effect Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 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
- 208000024453 abnormal involuntary movement Diseases 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
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 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
- 230000002159 abnormal effect Effects 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
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- 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
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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)
Description
WO 99/34785 PCT/IL99/00003 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. 5 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 10 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 15 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 20 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 WO 99/34785 PCT/IL99/00003 2 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 5 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 10 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 15 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. 20 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 25 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 WO 99/34785 PCT/IL99/00003 3 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 5 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 10 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. 15 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 D 2 receptor. Prolonged administration of anti-psychotic drugs often results in development of involuntary movements, termed: "tardative dyskinesia" . 20 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 25 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 13J-141 (1997)) that riluzole reduces various abnormal motor movement in baboons WO 99/34785 PCT/IL99/00003 4 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 5 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 10 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 15 (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. 20 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 25 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 WO 99/34785 PCT/IL99/00003 5 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. 5 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 10 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 15 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. 20 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 25 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 WO 99/34785 PCT/IL99/00003 6 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 5 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 10 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 15 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: 20 THE INTENSITY OF THE DYSKINESIA: 0-without dyskinesia 1-mild dyskinesia 2-medium dyskinesia, 3-severe dyskinesia 25 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 WO 99/34785 PCT/IL99/00003 7 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. 5 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 10 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 15 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 20 100 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 25 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).
WO 99/34785 PCT/IL99/00003 8 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. 5 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 (11)
1. A pharmaceutical composition for the amelioration of levodopa-induced dyskinesia and tardative dyskinesia, comprising as an active ingredient, a 5 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. 10
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. 15
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 20 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 25 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.
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 |
IL122883 | 1998-11-17 | ||
IL12710298A IL127102A0 (en) | 1998-11-17 | 1998-11-17 | Pharmaceutical compositions for the treatment of dyskinesias |
IL127102 | 1998-11-17 | ||
PCT/IL1999/000003 WO1999034785A2 (en) | 1998-01-09 | 1999-01-05 | Treatment of dyskinesias |
Publications (1)
Publication Number | Publication Date |
---|---|
AU1780699A true AU1780699A (en) | 1999-07-26 |
Family
ID=26323572
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU17806/99A Abandoned AU1780699A (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 |
ATE246919T1 (en) * | 2001-05-08 | 2003-08-15 | Sanol Arznei Schwarz Gmbh | IMPROVED TRANSDERMAL THERAPEUTIC SYSTEM FOR THE TREATMENT OF PARKINSON'S DISEASE |
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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 WO PCT/IL1999/000003 patent/WO1999034785A2/en not_active Application Discontinuation
- 1999-01-05 CN CN99802790A patent/CN1290166A/en active Pending
- 1999-01-05 CA CA002317811A patent/CA2317811A1/en not_active Abandoned
- 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 KR KR1020007007567A patent/KR20010033978A/en not_active Application Discontinuation
- 1999-01-05 PL PL99342098A patent/PL342098A1/en unknown
- 1999-01-05 JP JP2000527236A patent/JP2002500181A/en active Pending
- 1999-01-05 AU AU17806/99A patent/AU1780699A/en not_active Abandoned
-
2000
- 2000-07-07 NO NO20003529A patent/NO20003529L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CA2317811A1 (en) | 1999-07-15 |
WO1999034785A2 (en) | 1999-07-15 |
KR20010033978A (en) | 2001-04-25 |
PL342098A1 (en) | 2001-05-21 |
CN1290166A (en) | 2001-04-04 |
NO20003529D0 (en) | 2000-07-07 |
EP1043996A2 (en) | 2000-10-18 |
BR9906821A (en) | 2000-10-17 |
WO1999034785A3 (en) | 1999-09-16 |
NO20003529L (en) | 2000-09-08 |
JP2002500181A (en) | 2002-01-08 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |