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Title:  Combinations of riluzole and levodopa for the treatment of Parkinson's disease

United States Patent:  6,387,936

Inventors:  Blanchard-Bregeon; Veronique (Paris, FR); Imperato; Assunta (Paris, FR); Moussaoui; Saliha (Fontenay Sous Bois, FR); Obinu; Marie-Carmen (Paris, FR); Reibaud; Michel (Creteil, FR)

Assignee:  Aventis Pharma S.A. (Anthony, FR)

Appl. No.:  694860

Filed:  October 24, 2000

Foreign Application Priority Data:  Apr 24, 1998[FR] (98/05153)


Abstract

The invention concerns a combination of levodopa and riluzole or a pharmaceutically acceptable salt of said compound and the use of said combination for treating Parkinson Disease.

Description of the Invention

The present invention relates to a combination of L-DOPA and riluzole or a pharmaceutically acceptable salt of this compound and the use of this combination for the treatment of Parkinson's disease.

Parkinson's disease is connected with destruction of the locus niger (substantia nigra) which results in degeneration of the dopaminergic neurons of the nigrostriatial tract and therefore a massive decrease in the levels of dopamine in the striatum. To compensate the depletion of dopamine which is consequent to the degeneration of dopaminergic neurons of the nigrostriatial tract in parkinsonian patients, L-DOPA, (3-(3,4-dihydroxyphenyl)-L-alanine) or levodopa, which is converted into dopamine by dopa decarboxylase, is used as a symptomatic treatment of Parkinson's disease. After oral administration, the L-DOPA is massively decarboxylated at the peripheral level into dopamine, which does not cross the blood-brain barrier; this is why it is generally administered in combination with a decarboxylase inhibitor such as benserazide or carbidopa. These decarboxylase inhibitors actually allow the dose of L-DOPA to be reduced by approximately 5 (Rondot P. et al., Pharmacologie Clinique, bases de la therapeutique [Clinical Pharmacology, Therapeutic bases], published by J.-P. Giroud, G. Mathe and G. Meyniel, 2nd edition, Expansion Scientifique Frangaise, 1988, page 1127).

In patients suffering from Parkinson's disease, L-DOPA reduces the severity of symptoms such as bradykinesia (poverty of movements), muscular rigidity and trembling. However, chronic treatment with L-DOPA leads, in 30% to 80% of parkinsonian patients, to secondary effects and, in particular, to dyskinesias (J. G. Nutt, Neurology, 40, 340-345, 1990).

These dyskinesias are also reproduced by a chronic treatment with L-DOPA in marmosets rendered parkinsonian following an injection of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a toxin which destroys the dopaminergic neurons of the nigrostriatial path (R. K. B. Pearce et al., Movement Disorders, vol. 10, No. 6, 731-740, 1995; A. Ekesbo et al., Neuroreport, 8, 2567-2570, 1997).

Riluzole (2-amino-6-trifluoromethoxybenzo-thiazole) is marketed for the treatment of amyotrophic lateral sclerosis. It is also known for its neuroprotective effect in the treatment of Parkinson's disease (WO94/15601).

It has now been found that the combination of riluzole or one of its pharmaceutically acceptable salts and of L-DOPA improves the locomotory activity of parkinsonian marmosets and, in addition, prevents the dyskinesias induced by L-DOPA.

The activity of the riluzole and L-DOPA combination is determined according to the following protocol: 6 adult marmosets (Callithrix jacchus, Harlan UK) aged 25 months and weighing between 300 and 350 g are accommodated in stainless steel cages (50 cm in width.times.20 cm in depth.times.23 cm in height) with wire netting doors, these cages being connected to smaller cages (28.times.20.times.23 cm) in which the marmosets can sleep. The animals are accommodated in a controlled environment: temperature of 24+2oC., humidity of 55%, with a day-night cycle of 12 hours. The marmosets have free access to water and have available each day 35 g of food rich in carbohydrates, proteins and vitamins mixed with water, milk and sugar and also fresh fruit.

All the animals receive 3 injections of 2 mg/kg of MPTP by the subcutaneous route, on days 1, 7 and 32. On day 32, the animals are divided into 2 groups. Group 1 (control group) receives 2 oral administrations of 10% sucrose and group 2 (treated group) receives 2 oral administrations of riluzole (10 mg/kg) suspended in 0.5% methylcellulose, each day to day 104. On day 47, the two groups of animals receive an oral administration of L-DOPA (Modopar.RTM. 125 dispersible Roche (L-DOPA (25 mg)+benserazide (6.25 mg)). on day 48, they receive 2 oral administrations and from day 49 to day 104 they receive 3 oral administrations of L-DOPA each day.

LOCOMOTORY ACTIVITY

The locomotory activity is determined by placing the animals in test cages (50 cm.times.83 cm.times.77 cm) which are equipped with 3 perches onto which the animals can jump as well as a Plexiglas door in front of which is placed a camera. This camera is connected to an image analyser system (Vigie Primates, View PointR, which is capable of calculating the quantity of movements of 8 marmosets, simultaneously and independently for the duration of the test. The principle of this system is to quantify the movements of the animals in the cage in a determined time window (5s). The image is digitalized with a 800.times.600 definition with 256 levels of grey and the changes in pixels from one image to another are counted. This allows the locomotory activity to be classified into small, medium or large movements. Each class of movements is analysed every 10 minutes for a period of one hour. The locomotory activity of the animals is measured during the exploration phase, that is to say immediately after they are placed in the test cage.

DYSKINESIC SCORE

The dyskinesic score is determined according to a number of parameters and each with a different degree of intensity:

    PARA-                      DYSKINESIC SCORE
    METERS      0         1             2         3       4
    Perch test  normal    slight        moderate  marked  severe
    Climbing    normal    slight        moderate  marked  severe
    test
    Paws (front, normal    small         large
    rear)       amplitude amplitude     amplitude
                movement  movement      movement
    Posture     normal    moderate      marked
    (back)                curvature     curvature
    Jump        normal    uncoordinated
    Motility    normal    hyperactive
    Chorea      absent    present
    Dystonia    absent    present
    Expression  normal    repetitive
    Stereotyping absent    present
    Orolingual  absent    present
    movements
    Vocalization normal    for watching  for       absent
                                        communi-
                                        cating


This score is measured on days 57, 60, 67 and 104.

The evaluation is made 30 min or 2 h after the first daily injection of L-DOPA (4 h after the riluzole or sucrose solution).

Claim 1 of 20 Claims

What is claimed is:

1. A pharmaceutical composition comprising a combination of levodopa and riluzole or a pharmaceutically acceptable salt thereof.

 

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