Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-02-12
2000-11-28
Jarvis, William R. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514401, 514397, A61K 31415
Patent
active
061536385
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of Efaroxan, which is the compound of the following formula: ##STR1## as well as its therapeutically acceptable salts, its racemic form or its optically active isomers, for the preparation of a medicinal product for the treatment of Huntington's disease.
The subject of the present invention is the use of Efaroxan to obtain a neuroprotective medicinal product for the treatment of Huntington's disease and its progression.
Huntington's disease is considered as a pathological consequence of lesions of the GABA-ergic and cholinergic systems in the striatum which are caused by excitotoxic substances on the complex: ion channels-NMDA receptor.
The clinical manifestations of Huntington's disease are motor disorders, in particular abnormal choreiform movements which gradually worsen and are subsequently accompanied by bradykinesia and muscular rigidity, as well as by neuropsychiatric problems such as depression, suicidal tendencies and personality and cognitive disorders. These disorders are very soon manifested by a loss of visuospatial acuity which can precede the choreiform movements by a few years, with cognitive loss as is observed in patients whose frontal lobe is affected.
One particular aspect of the disease is memory loss, in particular the recall function. In neuropathological terms, one characteristic of the disease is a marked atrophy of the corpus striatum, in which the efferent systems and interneurones are affected, along with pronounced gliosis. To a lesser extent, the same phenomenon is observed in the globus pallidus, the thalamus, the substantia nigra, the locus coeruleus and the cortex.
No treatment is currently available to care for or delay the development of Huntington's disease.
It is known that Efaroxan: 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline, has antagonistic properties on the .alpha..sub.2 -adrenergic receptors. This compound is described in patent application GB 2,102,422, as is its therapeutic application as an antidepressant and antimigraine medicinal product. This compound is also described in patent application WO 92/05171, which reveals the action of the levo-rotatory enantiomer to treat diabetes, as an agent for blocking the potassium channels.
Our patents WO 94/00715 and WO 94/00841 also relate to the use of Efaroxan in the treatment of Parkinson's disease and in Alzheimer's disease.
The present invention relates to the use of Efaroxan for the preparation of a medicinal product for the treatment of Huntington's disease.
The term Efaroxan refers to the compound of formula: ##STR2## its therapeutically acceptable salts, its racemic mixture or its optically active isomers.
Pharmacological Study
Quinolinic acid, an endogenous metabolic of tryptophan, acts as a powerful agonist on the NMDA receptor (Eur. J. Pharm (1981), 72, 411). When injected into the striatum in rats and monkeys, it causes neurochemical and morphological changes similar to those observed in Huntington's disease (Life Sci. (1984), 35, 19) and are reflected by a deficiency in spatial acuity, cognitive abilities and recall. This attack of the striatum thus accounts for Huntington's disease (Behav. Brain Res. (1987), 24, 125).
In brains affected by the disease, the level of enzyme for the synthesis of quinolinic acid, 3-hydroxy-anthranilate oxygenase (3-HAO), is high. Furthermore, the level of kynurenic acid (another tryptophan metabolite and a quinolinic acid antagonist) is lowered, thus implying a poor balance between these two acids--quinolinic acid and kynurenic acid--in brains affected by Huntington's disease (Pharmacol. Rev. 1993, 45, 309).
Thus, a pharmacological intervention capable of restoring the functions of the striatum in this model can be useful in the treatment of the motor and cognitive manifestations of Huntington's disease in man (J. Neuroscience (1988), 8, 3901 and Pharmacol. Rev. (1993), 45, 309).
The parameters measured are: is a marker of the cholinergic neurones in this part of the brain. A reduction in the activity of ChAT, following an
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Colpaert Francis
Imbert Thierry
Marien Marc
Martel Jean-Claude
Jarvis William R. A.
Kim Vickie
Pierre Fabre Medicament
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