Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-07-11
1997-11-11
Spivack, Phyllis G.
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
056864752
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR95/00023 Jan. 9, 1995.
The present invention relates to a novel therapeutic application of riluzole or the pharmaceutically acceptable salts of this compound.
Riluzole, or 2-amino-6-trifluoromethoxybenzothiazole, is useful as an anticonvulsant, anxiolytic and hypnotic medicinal product (EP Patent 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).
It has now been found, surprisingly, that this compound may also be used in the treatment of mitochondrial diseases.
Mitochondrial diseases are degenerative diseases which are linked to different mechanisms such as, for example, anomalies of mitochondrial DNA (deletions, point mutations, depletions, duplications), anomalies of cellular DNA coding for mitichondrial enzymes or complex macromolecular mitochondrial elements, acquired conditions caused by toxic substances (for example MPTP or CO) or by medicinal products (for example chloramphenicol, AZT or acetylsalicylic acid). Mitochondrial diseases which may be mentioned are Kearns-Sayre syndrome, MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres), MELAS syndrome (Mitochondrial Encephalopathy, Myopathy, Lactic Acidosis and Stroke-like episodes) and Leber's disease (I. Nonaka, Current Opinion in Neurology and Neurosurgery, 5 (1992) 622).
The action of riluzole in the treatment of mitochondrial diseases is demonstrated by its protective effect in the cyanide test. It is known in fact that potassium cyanide exerts a toxic effect by inhibition of cytochrome oxidase aa3, the terminal enzyme in the electron transport sequence at the mitochondrial level. Thus in mice potassium cyanide (3 mg/kg i.v.) induces abdominal contractions and tonic attacks followed by death within 20 seconds.
Male adult mice weighing 22-25 g (CD1 COBS, Charles River), housed under controlled temperature and lighting conditions, receive food and drinking water ad libitum. The vehicle or the product to be studied is given to groups of 6 animals, either intraperitoneally 30 minutes before the intravenous bolus administration of a lethal dose (3 mg/kg) of potassium cyanide, or orally 1 hour before the administration of potassium cyanide. In the control group, all of the mice die within 20 seconds, whereas the ED50 for riluzole i.p. is 4.5 mg/kg and the ED50 for riluzole p.o. is 7.8 mg/kg.
The action of riluzole in the treatment of mitochondrial diseases is also demonstrated by its effect on the mitochondrial metabolism of the rat liver.
The metabolic activity of the mitochondrion is monitored by the consumption of oxygen by polarography, using a Clark electrode (marketed by Bioblock). The experimental setup consists of a glass chamber thermostated at 27.degree. C. by a hot water system. A magnetic bar placed within the chamber permits continuous stirring of the reaction medium and facilitates the establishment of equilibrium between the dissolved oxygen and the gas diffusing through the membrane of the electrode. The mitochondria, the substrate (succinate) and ADP (adenosine diphosphate) are introduced into the reaction chamber through a small aperture situated in the upper part of the apparatus. A Clark electrode is immersed in the reaction medium via an opening which is hermetically sealed by a screw stopper. The consumption of oxygen is plotted by a recorder which is connected to a YSI model 5300 Biological Oxygen Monitor (marketed by Bioblock).
Mitochondria from the liver of the male SD rat are isolated at +4.degree. C. by differential centrifugation according to the method described by Appelmans et al., Biochem. J., 59 (1955) 438-445. The mitochondrial pellet is taken up in from 1 to 3 ml of 0.25M sucrose buffer and homogenized using a pipette.
The oxygen consumption of the mitochondria (1.2 mg of proteins per ml) is measured in 5 ml of Chance buffer, consisting of 12 mM of NaF, 26 mM of NaCl, 58 mM of KCl and 3 mM of succinate substrate, so as to bring
REFERENCES:
patent: 5236940 (1993-08-01), Audiau et al.
Meldrum, B.S., "Anti-excitatory amino acid approach in the treatmetn of neurodengenerative disorders," Eur. Neuropsychopharmacol. (Netherlands), vol. 3, No. 3, (1993), pp. 184-185.
Martin, D., et al., "The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1," Eur. J. Pharmacol., vol. 250, No. 3, (1993), pp. 473-476.
Nonaka, I., "Mitochondrial diseases," Current Opinion in Neurology and Neurosurgery, vol. 5, No. 5, (1992), pp. 622-632.
Matthews, P.M., "Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies," Neurology, vol. 43, No. 12, (1993), pp. 2484-2490.
Delumeau Jean-Christophe
Martinet Michel
Reibaud Michel
Stutzmann Jean-Marie
Rhone-Poulenc Rorer S.A.
Spivack Phyllis G.
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