TREATMENT OF DISCINESIAS DESCRIPTION OF THE INVENTION • The present invention concerns pharmaceutical compositions for the treatment of dyskinesias, particularly levodopa-induced dyskinesia and tardive dyskinesia. Parkinson's disease is a disorder related to age, progressively neurodegenerative. The frequency ratio is approximately 0.5% in the
• 10 mature population of 50-59, 1% in ages of 60-69, 2% in the group in ages of 70-79 and it rises above 3% in those who have 80 and more. The proportions of frequency are similar in Europe. Parkinson's disease is characterized by a
relatively selective generation of dopaminergic neurons in the sub tantia nigra pars compacta with loss of dopamine from the striatum. The pathology shows depigmentation of
• substantia nigra and intracellular inclusions (Lewy bodies). The cardinal features of the disease
include numbness, stiffness, bradykinesia, and postural instability. The current treatment of the motor signs of Parkinson's disease is based on the replacement of dopamine. This involves the administration of levodopa, usually combined with an inhibitor of
decarboxylase. Exogenous levodopa becomes the
^^ i striatum in dopamine and fill the reduced dopaminergic concentrations in the vassal ganglia. As well
• Dopamine agonists may be useful. During the first years of treatment, patients enjoy a mild 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 are dyskinesias
induced by levodopa (involuntary movements is coreifor). They occur in the majority (80-100%) of patients' as their disease progresses. Dyskinesias may be initially mild but may become more and more progressive, complex, generalized, violent, and
can severely interfere with motor function, speech, coordination and stability of posture. Patients and families are often embarrassed by the movements without esthetic and bizarre which can affect the facial muscles, eyelids, mouth, cheeks,
lips and tongue, upper and lower limbs and even trunk and respiratory muscles. This is one of the main reasons for the social decline of the afflicted patients .. At the beginning, when they emerge at the beginning, the
dyskinesias are mainly of the peak dose type, ie they are more prominent when the plasma levels of levodopa are high. When patients develop more
* late fluctuations in response after chronic treatment with levodopa, dyskinesias may also appear at the beginning 5 and again at the end of an individual benefit-so effect of levodopa dose. When the disease is more advanced, the discourses predominate in the form of "all or none", that is to say they are present throughout the duration of a period of "functioning", induced by a
successful oral simple dose of levodopa. Such dyskinesias induced by levodopa also represent a major limiting factor in the pharmacological treatment of Parkinson's disease. When your disease progresses, patients
need an increase in their daily dose of levodopa and the addition of other dopammérgicos agents, for example dopamine agonists. and MAO-B inhibitors. This is invariably associated with a rapid and intolerable increase in the frequency, distribution and severity of the dyskinesias that
needs drug reduction. The dyskinesias are probably and mainly caused by the action of excessive exogenous dopamine on post-smápticos dopaminergic receptors supersensitive to denervation. Normally, the dopamma formed of levodopa is stored in vesicles within the
dopammergic nerve terminals for regulated release within the sj apsis. As the disease progresses, more dopaminergic neurons of the nigra degenerate and there is a more severe loss of their nerve terminals in the vasal ganglia (caudate nucleus and putamen). Accordingly, it is believed that the decarboxylation of exogenous levodopa changes to compartments of the non-dopaminergic stompate. Since the generated dopamine molecules are not stored, it interacts immediately and overactivates the post-synaptic dopamine receptors (mainly the
• 10 subtype D2) which results in involuntary movements. There is no satisfactory treatment for dyskinesias. The discontinuation or reduction of levodopa and other dopaminergic drugs or the addition of neuroleptic drugs that block dopamine receptors can abolish
abnormal movements, but at the expense of severe worsening of Parkinson's symptoms. Controlled release levodopa preparations have proven to be useless. This desperate state of events suggests that it would be difficult if not impossible to dissociate the beneficial antiparkinson effects
of the bad dyskinetics that levodopa produces. Behavioral and psychiatric disorders are usually treated with the administration of various antipsychotics, also called: "neuroleptic drugs" most act by blocking the dopamine D2 receptor. The
prolonged administration of antipsychotic drugs
s -'- e - ^ 'í' * '' - .. * frequently results in the development of involuntary movements, called: "tardive dyskinesia". Recently, riluzole (2-amino-6-trifluoromethoxy benzothiazole) has emerged as a potentially useful pharmacological agent to slow the progression of neurodegenerative diseases, such as amyotrophic lateral sclerosis. (Ben Simón et al., New Engl. J. Med., 330: 585-91 (1994)). In addition, this molecule has been shown to exhibit anticonvulsant, antihischemic and neuroprotective properties under various experimental conditions. A clear understanding of the site and mechanism of action of this molecule is still lacking. Recently there has been a report (Palti et al., Exper. Neuro 1.146 13J-141 (1997)) that riluzole reduces various abnormal motor movements in mandrels, which were induced by 3-n-troproponic acid, following as a model for the progressive degeneration of the striatum, which is a model for Huntington's disease. The present invention provides, in one of its aspects, a pharmaceutical composition for the improvement of levodopa-induced dyskinesia and tardive dysmesia, which comprises as an active ingredient, a pharmaceutically effective amount of riluzole. The present invention provides for another of its aspects, the use of riluzole for the preparation of a pharmaceutical composition for the improvement of dyskinesia
• induced by levodopa and late discsia. The term "improvement" refers to a decrease 5 in the abnormal involuntary movements that characterizes these two types of disciplesia, as can be determined for example, using the Abnormal Involuntary Movement Scale (AIMS) as will be specified below. The term "levodopa-induced dyskinesia" is
• 10 refers to dyskinesia, that is to say involuntary choreiform movements, caused by the chronic administration of levodopa, for example in patients suffering from Parkinson's Disease. The term "tardive dyskinesia" refers to the dyskinesia effected by the chronic administration of neuroleptic drugs, antipsychotics of the Dopaminergic receptor blocker type. The term "reluzole" refers to 2-amino-6-t-fluoro-methoxy-benzothiazole. 20 The term "effective amount" refers to an amount that causes a reduction in patients' AIMS-without causing severe side effects. The dosage of the active ingredient must be empirically tested for each specific indication, and
depends on various factors, such as the weight of the
patient, the duration of administration of levodopa or the neuroleptic pharmaceutical composition, age,
• etc. Generally speaking, the dosage should be from about 25 to about 200 mg per day, preferably from about 50 to about 200 mg per day, more preferably from about 50 to about 100 mg per day. The pharmaceutical composition of the invention may comprise only riluzole and a pharmaceutically carrier
• 10 acceptable. Alternatively, it is possible to include in a dosage form, the agent causing dyskinesia such as the neuroleptic drug (in the case of tardive dyskinesia), or levodopa (in the case of levodopa-induced dyskinesia) together with the
riluzole . The present invention also concerns a method for improving the dyskinesia induced by levodopa or the
^^ tardive 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, riluzole can be administered separately, ie not simultaneously with the agent that causes dyskinesia (such as the neuroleptic drug or levodopa), or it can be administered
alternatively together with the agents that cause dyskinesia either by the administration of the two drugs simultaneously or by the formation of both drugs in
• the form of a single dose. The invention will now be described with reference to some non-limiting examples. I. Clinical Procedures Twelve patients suffering from the disease
Advanced Parkinson's show dyskinesia, and twelve patients who have appropriate criteria for tardive dyskinesia are
• 10 participants in an open experiment to assess the influence of riluzole on involuntary movement. Parkinson's patients are balanced by optimal dopaminergic treatment in the three months prior to the clinical trial. Patients with tardive dyskinesia, who are already balanced by neuroleptic treatment, do not reduce the dose of neuroleptic drug, and do not stop other treatments, which they receive. Clinical assessment of the Parkinson's patient is carried out using the Disease Rating Scale
Unified Parkinson's (UPDRS) and the assessment of the involuntary movement will be carried out by the Movement Scale
Abnormal Involuntary (AIMS). The assessment of patients with late discsia is carried out using AIMS. The test is carried out
out for six weeks. Before the start of the test, patients undergo blood and urine tests, chest X-rays, an ECG, as well as general and neurological physical assessments. During the clinical trial, the patient is treated with riluzole having an initial dose of 25 mg twice a day, and after one week, the dose will be increased to 50 mg twice a day. Patients are monitored once every two weeks to perform hematimetry and SMA (biochemical blood tests). In addition, a clinical assessment of involuntary movement is carried out in
• 10 separated by two independent doctors. During the clinical trial, patients are asked to fill in a detailed diary which will graduate the severity of the dyskinesia and assess the daily function according to the following scale: The intensity of the dyskinesia: 15 0 - without discines to 1 - dyskinesia mild 2 - medium dyskinesia • 3 - severe dyskinesia. Classification of the daily function: 20 1 - an improvement of the daily function compared to the basic condition 2 - without improvement in the daily function 3- deterioration of the daily function compared with the basic condition. 25 At the end of the chemical test, patients undergo ECG blood tests, as well as neurological and psychological assessment. In addition, patients are invited to routine check-ups starting two weeks after the end of the test. 5 II Clinical trials Six patients suffering from advanced Parkinson's disease with severe levodopa-induced dyskinesias participate in an open-label pilot study to assess the safety, tolerance and efficacy of riluzole
• 10 to attenuate involuntary movements. The patients were given optimal antiparkinson drug treatment during the three months prior to the chemical test. The duration of the study was six weeks. The first two weeks served to accumulate data from the
baseline. The patients filled a diary of diaries in which they marked every waking hour if the involuntary movements were present and their severity
• (light / moderate and severe). Each patient was administered 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 four additional days (once in the morning and once in the afternoon). The dose was then further increased to two tablets of 50 mg (a total of 100 mg daily) which patients took during
three additional weeks. They continued filling their diaries with
-lÉállfiiJSHsS? feÉ i-j £? Éi »aft &-1 dyskinesias during the trial period. Results It was found that riluzole treatment is effective in attenuating discolourations. The average daily 5 hours of wakefulness spent with dysplasia decreased by approximately 24% from 6.9213.67 hours before treatment to 5.2614.23 hours during treatment (P <0.01, paired t test). The average daily wake hours spent in severe dyskinesia were reduced by approximately 30% from
• 10 2.76 ± 1.77 hours before treatment up to 1.94 + 2.40 hours during treatment with riluzole (0.01 <p <0.05, paired t test). There was no worsening of Parkinson's signs and symptoms when patients took riluzole. In the same way, there was no decrease in the efficiency of the
drugs of levodopa and other antiparkinsonians in the total daily time that patients spent in the periods of "treatment". • Riluzole was well tolerated and there were no reports of adverse effects. These studies marked open
preliminary reports indicate that the administration of riluzole (50 mg b.i.d) may attenuate levodopa-induced dyskinesias in patients with Parkinson's disease without causing deterioration of Parkinson's signs and without suppression of levodopa efficiency.