Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-30
1998-11-03
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31425
Patent
active
058309071
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR93/01229, filed Dec. 10, 1993, which claims priority to FR92-15148 filed Dec. 16, 1992.
FIELD OF THE INVENTION
The present invention relates to a novel therapeutic application of riluzole or the pharmaceutically acceptable salts of this compound.
BACKGROUND OF THE INVENTION
Riluzole is known to be useful as an anticonvulsant, anxiolytic and hypnotic medicinal product (Patent EP 50,551), in the treatment of schizophrenia (EP 305,276), in the treatment of sleep disorders and depression (EP 305,277), in the treatment of cerebrovascular disorders and as an anesthetic (EP 282,971).
DESCRIPTION OF THE INVENTION
It has now been found, surprisingly, that this compound may also be used in the treatment of neurological lesions associated with trauma, and especially with spinal, cranial or craniospinal trauma.
The activity of this product has been demonstrated on lesions of the spinal cord in the model of cord lesion in rats by the technique of compression by means of a balloon at lumbar medullary level described by Zileli et al., Acta Neurochi, 108, 140-147 (1991) and Pointillart et al., J. of Neurotrauma, 10, 2, 201-213 (1993). Riluzole (4 mg/kg i.v./day) is injected 5 minutes after the trauma, and then every day for 7 days. In the untreated group (10 rats), 2 rats died on the third day, 7 rats did not recover from their lesion and 1 rat recovered from its lesion on the seventh day. In the group treated with riluzole (10 rats), 1 rat died on the fifth day, 1 rat did not recover from its lesion and 8 rats regained their motility and their somatosensory evoked potential (SEP) between the third and the seventh day.
The activity of this product with respect to lesions of the spinal cord has also been demonstrated either using the model of cord lesion in rats by the technique of ventral compression described by E.C. Benzel et al, Journal of Spinal Disorders, 3, 4, 334-338 (1990), or using the model of traumatic tetraplegia induced by compression of the spinal cord with an inflatable microballoon according to the technique described by D. Martin et al., Journal of Neuroscience Research, 32, 539-550 (1992).
In these tests, riluzole decreases the animals' neurological deficit (paraplegia) associated with lesion of the spinal cord as well as histopathological lesions (necrosis of the cord). This decrease is generally equal to or greater than 5%.
The activity of this product is also demonstrated in the model of medullary lesions on 15 "Fauve de Bourgogne" rabbits weighing 4 kg (.+-.200 g). The rabbits are divided into three groups and receive traumas of variable size, according to the following protocol: of valium.RTM. and 1/16 mg of atropine. 30 minutes later, an isotonic saline perfusion is instituted and the rabbits are anesthetized by slow intravenous injection of 40 mg/kg of Nesdonal.RTM.. A cardioscope is installed, since the animal may display a lasting apnoea with bradycardia, particularly on reinjection of Nesdonal.RTM.. specify the integrity of the sensory pathways of the cord. Stimulation is carried out on the internal popliteal sciatic (IPS) nerve. The intensity of stimulation is calculated so as to evoke a potential in the large-calibre sensory fibers, this being produced at the threshold level of motor stimulation (minimal movement of the foot). The signal is picked up by means of an electrode planted in the scalp in the contralateral parietal cortex. A reference electrode is placed on the median line of the scalp at frontal (Fz) level. An SEP is recorded before inserting the probe to serve as reference. Fogarty French 3 probe placed in the spinal canal in an extradural position. To this end, a lower lumbar laminectomy is carried out. Opening of the yellow ligament enables the probe to be inserted up to the level of the first lumbar vertebra, and the operating wound is closed up. A further SEP is recorded to check for the absence of functional lesion during insertion of the probe. The lesion is then produced by inflating the balloon with variable amounts of air (0.2,
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Doble Adam
Louvel Erik
Pratt Jeremy
Stutzmann Jean-Marie
MacMillan Keith D.
Rhone-Poulenc Rorer S.A.
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