Application of riluzole in the treatment of neurological lesions associated with trauma

Application of riluzole or its pharmaceutically acceptable salts in the treatment of neurological lesions related to traumatic injuries, especially spinal, cranial or cranial-spinal injuries.

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: 
a) preparation of animals: rabbits are injected intramuscularly with 5 mg 
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.. 
b) recording of somatosensory evoked potentials (SEP): these recordings 
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. 
c) production of trauma: trauma is produced by inflating the balloon of a 
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, 0.4 and 0.55 ml of air), and 
the probe is thereafter withdrawn. A further SEP measurement is carried 
out immediately after the trauma and is compared (amplitudes and 
latencies) with the reference SEP. 
d) The products are injected intraperitoneally once daily for 5 days, at 
doses of between 1 and 8 mg/kg. 
e) histology: a spine/cord block that includes the damaged level is removed 
and placed in 10% formalin. One week later, the cord is extracted from the 
block (this fixing time appears to be necessary in order to avoid a 
post-mortem lesion). A haemorrhagic area visible to the naked eye shows 
the level of the trauma. Serial histological sections specify the extent 
of the lesions. 
f) results: riluzole enables the neurological deficit associated with 
lesion of the spinal cord to be decreased, the sensory neurological 
pathways to be protected and the haemorrhagic necrotic area within the 
grey matter of the spinal cord to be decreased. These decreases are 
generally equal to or greater than 5%. 
The activity of this product in cranial trauma has also been demonstrated 
in rats according to the technique described by T. K. McIntosh et al., 
Central Nervous System Trauma, 4, 2, 119-134 (1987). 
In this test, riluzole improves the neurological score of animals which 
have undergone a cranial trauma and reduces the necrotic lesions. This 
decrease is generally equal to or greater than 5%. 
As pharmaceutically acceptable salts, the addition salts with inorganic 
acids, such as hydrochloride, sulphate, nitrate or phosphate, or organic 
acids, such as acetate, propionate, succinate, oxalate, benzoate, 
fumarate, maleate, methanesulphonate, isethionate, theophyllineacetate, 
salicylate, phenolphthalinate or methylenebis(.beta.-hydroxynaphthoate), 
or substitution derivatives of these derivatives, may be mentioned in 
particular. 
The medicinal products consist at least of riluzole, in free form or in the 
form of an addition salt with a pharmaceutically acceptable acid, in the 
pure state or in the form of a composition in which it is combined with 
any other pharmaceutically compatible product, which may be inert or 
physiologically active. The medicinal products according to the invention 
may be employed orally or parenterally. 
As solid compositions for oral administration, tablets, pills, powders 
(gelatin capsules, wafer capsules) or granules may be used. In these 
compositions, the active principle according to the invention is mixed 
with one or more inert diluents such as starch, cellulose, sucrose, 
lactose or silica, under a stream of argon. These compositions can also 
comprise substances other than diluents, for example one or more 
lubricants such as magnesium stearate or talc, a coloring, a coating 
(dragees) or a varnish. 
As liquid compositions for oral administration, pharmaceutically acceptable 
solutions, suspensions, emulsions, syrups and elixirs may be used, 
containing inert diluents such as water, ethanol, glycerol, vegetable oils 
or liquid paraffin. These compositions can comprise substances other than 
diluents, for example wetting, sweetening, thickening, flavoring or 
stabilizing products. 
The sterile compositions for parenteral administration can preferably be 
solutions, aqueous or non-aqueous, suspensions or emulsions. As a solvent 
or vehicle, water, propylene glycol, a polyethylene glycol, vegetable 
oils, especially olive oil, injectable organic esters, for example ethyl 
oleate, or other suitable organic solvents may be employed. These 
compositions can also contain adjuvants, especially wetting, tonicity, 
emulsifying, dispersing and stabilizing agents. The sterilization may be 
carried out in several ways, for example by aseptic filtration, by 
incorporation of sterilizing agents in the composition, by irradiation or 
by heating. They may also be prepared in the form of sterile solid 
compositions which can be dissolved at the time of use in sterile water or 
any other sterile injectable medium. 
The doses depend on the effect sought, the treatment period and the 
administration route used; they are generally between 50 and 800 mg per 
day via the oral route for an adult, with single doses ranging from 25 to 
200 mg of active substance, and between 25 and 600 mg per day via the 
intravenous route for an adult, with single doses ranging from 12.5 to 200 
mg of active substance. 
Generally speaking, the doctor will determine the appropriate dosage in 
accordance with the age, the weight and all other factors specific to the 
subject to be treated.

The examples which follow illustrate medicinal products according to the 
invention: 
EXAMPLE A 
Tablets containing a 50 mg dose of active product and having the following 
composition are prepared according to the usual technique: 
______________________________________ 
Riluzole 50 mg 
Mannitol 64 mg 
Microcrystalline cellulose 
50 mg 
Povidone excipient 12 mg 
Sodium carboxymethylstarch 
16 mg 
Talc 4 mg 
Magnesium stearate 2 mg 
Colloidal silica, anhydrous 
2 mg 
Mixture of methylhydroxypropyl- 
cellulose, polyethylene glycol 6000 
and titanium dioxide (72:3.5:24.5) 
q.s. 1 finished film-coated tablet 
weighing 245 mg 
______________________________________ 
EXAMPLE B 
Hard gelatin capsules containing a 50 mg dose of active product and having 
the following composition are prepared according to the usual technique: 
______________________________________ 
Riluzole 50 mg 
Cellulose 18 mg 
Lactose 55 mg 
Colloidal silica 1 mg 
Sodium carboxymethylstarch 
10 mg 
Talc 10 mg 
Magnesium stearate 1 mg 
______________________________________ 
EXAMPLE C 
An injection containing 10 mg of active product and having the following 
composition is prepared: 
______________________________________ 
Riluzole 10 mg 
Benzoic acid 80 mg 
Benzyl alcohol 0.06 cm.sup.3 
Sodium benzoate 80 mg 
Ethanol, 95% 0.4 cm.sup.3 
Sodium hydroxide 24 mg 
Propylene glycol 1.6 cm.sup.3 
Water q.s. 4 
cm.sup.3 
______________________________________ 
The invention also relates to the process for preparing medicinal products 
which can be used in the treatment of neurological lesions associated with 
trauma, and especially with spinal, cranial or craniospinal trauma, 
consisting in mixing riluzole or the pharmaceutically acceptable salts of 
this compound with one or more compatible and pharmaceutically acceptable 
diluents and/or adjuvants. 
The invention also relates to a method for treating a mammal, and in 
particular man, having neurological lesions associated with trauma, and 
especially with spinal, cranial or craniospinal trauma, comprising the 
administration of an effective amount of riluzole or the pharmaceutically 
acceptable salts of this compound. 
Although the invention has been described in conjunction with specific 
embodiments, it is evident that many alternatives and variations will be 
apparent to those skilled in the art in light of the foregoing 
description. Accordingly, the invention is intended to embrace all of the 
alternatives and variations that fall within the spirit and scope of the 
appended claims. The above references are hereby incorporated by 
reference.