Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-30
2001-10-02
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000
Reexamination Certificate
active
06297254
ABSTRACT:
The present invention relates to the combination of an ergoline, chosen from nicergoline and lumilysergol, and of riluzole or one of its pharmaceutically acceptable salts, the pharmaceutical compositions containing it and their use in the prevention and/or treatment of motoneuron diseases.
Riluzole is marketed for the treatment of amyotrophic lateral sclerosis. This compound is also useful as an anticonvulsant, an anxiolytic and a hypnotic (EP 50551), in the treatment of schizophrenia (EP 305276), in the treatment of sleep disorders and of depression (EP 305277), in the treatment of cerebrovascular disorders and as an anesthetic (EP 282971), in the treatment of spinal, cranial or craniospinal traumas (WO 94/13288), as a radiorestorative (WO 94/15600), in the treatment of Parkinson's disease (WO 94/15601), in the treatment of neuro-AIDS (WO 94/20103), in the treatment of mitochondrial diseases (WO 95/19170).
Nicergoline or (8&bgr;)-10-methoxy-1,6-dimethylergoline-8-methanol-5-bromonicotinate (Sermion®) exhibits in particular &agr;-blocking properties, &agr;2-adrenolytic properties (CARPENE C. et al., J. Pharmacol., 14, 57-66 (1983)), antiischemic properties (CAHN R. et al., Chem. Abstracts, 107, 228784x (1987); UEDAT et al., Chem. Abstracts, 118, 225224f (1993)), anticalcium properties (TAKAHASHI K. et al., Br. J. Pharmacol., 100, 705-710 (1990)), antioxidant properties (TANAKA M. et al., Neurosci. Let., 248, 67-72 (1998)), antithrombotic properties (Chem. Abstracts 105, 54314k (1986)). It enhances learning and memory capacity (Chem. Abstracts, 113, 52358u (1990); Chem. Abstracts, 111, 108396h, 1989; Chem. Abstracts, 109, 86208c, 1988; Chem. Abstracts, 106, 12788e, 1987; Chem. Abstracts, 115, 198237s, 1991).
Lumilysergol or 1,6-dimethyl-8&bgr;-hydroxymethyl-10&agr;-methoxyergoline or 1-methyl-10&agr;-methoxy-9,10-dihydrolysergol is one of the metabolites of nicergoline (F. ARCAMONE et al., Biochem. Pharmacol., 21 (16), 2205-2013 (1972)). This compound exhibits, like nicergoline but to a lesser degree, &agr;1-adrenergic and 5HT1a serotoninergic properties. It is also useful as an intermediate for the preparation of nicergoline (patent FR 2,616,788). The combination of riluzole and nicergoline for the treatment of spacticity is described in WO 00/30642.
It is known that, in vitro, motoneurons cultured with no trophic factor die within 48 to 72 hours (AG. ESTEVEZ et al., J. Neurosci., 18 (3), 923-931 (1998) and 18 (10), 3708-3714 (1998)).
Moreover, neuronal death induced by trophic factor deprivation can be partially prevented when the motoneurons are cultured on monolayers of astrocytes or in the presence of a conditioned medium obtained from astrocytes. In addition, the production, by the astrocytes, of trophic activity for the motoneurons is stimulated by riluzole (H. PELUFFO et al., Neuroscience letters, 228, 207-211 (1997)).
It has now been found that the combination of riluzole or one of its pharmaceutically acceptable salts and of an ergoline chosen from nicergoline and lumilysergol acts synergistically and greatly increases the trophic activity secreted by the astrocytes. This association can thus be used in the prevention and/or treatment of motoneurone diseases.
Motoneuron diseases include in particular amyotrophic lateral sclerosis, progressive spinomuscular atrophy, infantile muscular atrophy, primary lateral sclerosis.
The general protocol used is described by H. PELUFFO et al., Neuroscience letters, 228, 207-211 (1997).
REFERENCES:
patent: 5780489 (1998-07-01), Brooks
patent: 4240798 (1993-06-01), None
patent: WO 99/34785 (1999-07-01), None
patent: WO 00/30642 (2000-06-01), None
Sanderink et al., Involvement of human CYPIA isoenzmes in the metabolism and drug interactions of riluzole in vitro., J. Pharma. and Exper. Ther., 282(3):1465-1472 (1997).
Martinet et al., Pharmacokinetics and metabolism of riluzole., Drugs of Today, 33(8):587-594 (1997).
Louvel et al., Therapeutic advances in amyotrophic lateral sclerosis., Trends in Pharma. Sci. 18(6):196-203 (1997).
Dib Michel
Stutzmann Jean-Marie
Aventis Pharma S. A.
Henley III Raymond
Newman Irving
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