Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-06
1997-08-12
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514917, A61K 31425
Patent
active
056566476
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel therapeutic application of riluzole (6-trifluoro-methoxy-2-aminobenzothiazole) or the pharmaceutically acceptable salts of this compound.
BACKGROUND OF THE INVENTION
Riluzole is 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 anaesthetic (EP 282,971).
DESCRIPTION OF THE INVENTION
It has now been found, surprisingly, that this compound may also be used to promote restoration following radiation.
Restoration following radiation is useful in X-ray therapy, in particular in the treatment of cancers, and against other sources of harmful radiation such as those encountered by persons in areas in the vicinity of nuclear explosions.
EXAMPLES
The activity of the product has been demonstrated on the rhinencephalon of young rats subjected to an overall gamma irradiation.
Irradiation is performed by means of a gamma ray source, cobalt-60.
The animals used are 15-day-old male Sprague-Dawley strain rats weighing 28 to 33 g, which are placed in an aerated Plexiglass restraining box undergoing a rotation of 180.degree. in order to carry out homogeneous overall irradiations in a single dose of 1.5 and 2.5 Gy, the dose rate of which is 0.2 Gy per minute. The survival time between irradiation and sacrifice is 6 hours. All the animals are fixed by intra-aortic perfusion of a fixative fluid composed of 1% of paraformaldehyde, 1% of glutaraldehyde and 0.05% of calcium chloride in 0.4M phosphate buffer, pH 7.3. To prevent coagulation, 0.04 ml of heparin is injected into the ventricle, and 0.3 ml of 1% sodium nitrite to clear the vessels of red cells.
The animals are anaesthetized by intraperitoneal injection of 3% pentobarbitone sodium. The animals are then laid on their back and fixed to the operating table. The thoracic cage is opened and held open by means of 2 clamps. The heart is thus exposed, the tip of the left ventricle is incised and the perfusion cannula is introduced up to the beginning of the arch of the aorta and clamped. The right atrium is incised and perfusion is performed. Inflow of the perfusion fluid is effected under gravity. After perfusion, the animal's head is cut off and the brain is removed, immersed in fixative fluid and stored overnight at 4.degree. C.
On the day following perfusion, frontal sections of the gyrus dentatus are cut under a binocular magnifier. The fragments collected are immersed in the washing fluid for 5 minutes. They are then dehydrated in alcohol baths of increasing concentration and thereafter included in Araldite. 1-micrometer semi-thin sections are prepared using a Reichert ultramicrotome with glass knives. They are stained in the heated state with a filtered 1% solution of toluidine blue prepared in 1% borate buffer, and then observed using an Orthoplan microscope.
The comparative study consists in counting on 3 non-serial sections (separated by 10 micrometers each) for each rat and on an aggregate of 1000 cells (granular and subgranular) in total. The number of pyknotic cells is counted, and then the number of surviving cells observed in this area. This enables the percentage of surviving cells relative to the number of cells in the area to be calculated (percentage survival=100.times.living cells/living cells+pyknotic cells).
The product under study is administered intraperitoneally at doses of 1, 2, 4 and 8 mg/kg, 20 minutes after irradiation (at the beginning of pyknosis).
The results obtained are recorded in the following tables, and show that, after treatment with the test product, neuronal degeneration is less than in irradiated controls not receiving a product.
TEST 1 ______________________________________
IR- CONTROLS RILUZOLE (2 mg/kg)
RADIATION
CELLULAR SURVIVAL
CELLULAR SURVIVAL
______________________________________
1.5 Gy 88.8% 91.2%
2.5 Gy 87.1% 92.2%
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REFERENCES:
patent: 4370338 (1983-01-01), Mizoule
patent: 4826860 (1989-05-01), Johnson et al.
patent: 4918090 (1990-04-01), Johnson et al.
patent: 5236940 (1993-08-01), Audiau et al.
patent: 5240948 (1993-08-01), Gueremy et al.
J. Neurosci., vol. 9, No. 11, 1989, pp. 3720-3727, C. Malgouris et al., "Riluzole, a Novel Antiglutamate, Prevents Memory Loss . . . ".
Database WPI, Week 8511, Derwent Publications Ltd., London, GB.
Pratt Jeremy
Stutzmann Jean-Marie
Reamer James H.
Rhone-Poulenc Rorer S.A.
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