Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-06
1997-08-19
MacMillan, Keith
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 924
Patent
active
056589000
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel therapeutic application of anticonvulsants chosen from carbamazepine and oxcarbazepine or the pharmaceutically acceptable salts of these compounds.
BACKGROUND OF THE INVENTION
Carbamazepine and oxcarbazepine are described as anticonvulsants and antiepileptics, in particular in Patent EP 50,589.
DESCRIPTION OF THE INVENTION
It has now been found, surprisingly, that these compounds may also be used in the treatment of Parkinson's disease and parkinsonian syndromes.
The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is known to induce a syndrome similar to Parkinson's disease. This syndrome results from a degeneration of the dopaminergic nigrostriatal neurons in primates (R. S. Burns et al., Proc. Natl. Acad. Sci., 80, 4546-4550 (1983)), in man (J. W. Langston et al., Science, 219, 979-980 (1983)) and in mice (R. E. Heikkila et al., Science, 224, 1451-1453 (1984)).
EXAMPLES
The activity of the products was hence demonstrated in mice by measuring MPTP-induced decreases in the levels of striatal dopamine, of 3,4-dihydroxyphenylacetic acid and of homovanillic acid in comparison with those of control animals.
Mice (C57BL/6) weighing 20-25 g are injected intraperitoneally 3 times at 2-hour intervals with 15 mg/kg of MPTP. Thirty minutes before the first injection of MPTP, and then 2 hours 30 minutes, 5 hours 30 minutes and 7 hours 30 minutes after the first injection of MPTP, from 1 to 40 mg/kg of the product under study, depending on the product, are administered. Over the next 3 days, from 1 to 40 mg/kg of the product under study, depending on the product, are administered twice daily. The mice are sacrificed 8 days after injection of MPTP. The striatum is dissected and stored at -70.degree. C. until the time of its analysis. Dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels are measured by high pressure liquid chromatography with electrochemical detection. Statistical analyses are performed using ANOVA followed by Scheffe's test.
The results obtained with doses of 20 mg/kg of carbamazepine are recorded in the following table:
______________________________________ 3,4-dihydroxy-
phenylacetic
homovanillic
acid level
acid level dopamine level
pmol/mg in the
pmol/mg in the
pmol/mg in the
striatum striatum striatum
(% relative to
(% relative to
(% relative to
controls) controls) controls)
______________________________________
controls 54 .+-. 3 95 .+-. 3 856 .+-. 27
animals 22 .+-. 4 62 .+-. 3 415 .+-. 22
receiving only
(-59%) (-35%) (-52%)
MPTP
animals 48 .+-. 4 90 .+-. 6 765 .+-. 30
treated with
(-12%) (-5%) (-11%)
carbamazepine
______________________________________
These results demonstrate clearly that these products are capable of preventing MPTP-induced decreases in the dopemine, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the stiatum.
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 of at least one anticonvulsant chosen from carbamazepine and oxcarbazepine, 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 su
REFERENCES:
patent: 2948718 (1960-08-01), Schindler et al.
patent: 3642775 (1972-02-01), Schindler et al.
patent: 4431641 (1984-02-01), Mondadori
Neuroreport, vol. 1, No. 1, 1990 pp. 26-28, H. Lampe et al., "Carbamazepine Blocks NMDA-Activated Currents in Cultured Spinal . . . ".
Experientia, vol. 48, No. 8, 1992, pp. 751-753, J.M. Lancaster et al., "Carbamazepine Inhibits NMDA-Induced Depolarizations in Cortical . . . ".
Soc. Neurosci. Abstr., vol. 18, No. 1-2, 1992, pp. 381, T. Dalkara et al., "Carbamazepine and Phenytoin Inhibit NMDA Receptor-Mediated . . . ".
Trends in Neurosciences, vol. 12, No. 8, 1989, pp. 285-286, Klockgether "Excitatory Amino Acids and the Basal Ganglia: Implications for . . . ".
Neurology, vol. 37, No. SUPL, 1987, p.339, E. Melamed et al., "Effect of Anticonvulsants on the Neurotoxicity of MPTP . . . ".
J.E.F. Reynolds, "Martindale, The Extra Pharmacopoeia", 1989, The Pharmaceutical Press, London pp. 400-402.
Embase Abstract # 92250451, Cai et al, Eur. J. Pharmacol. (1992) 219/1 (53-57). Abstract only.
Life Sciences, vol. 54, No. 4, 1994, pp. 245-252, Stacey et al., "The Novel Anticonvulsant Lamotrigine Prevents Dopamine Depletion . . . ".
Chemical Abstracts, vol. 115, No. 15, Oct. 1991, Ohio, abstract No. 150162.
Boireau Alain
Bordier Fran.cedilla.oise
Doble Adam
Dubedat Pierre
Louvel Erik
MacMillan Keith
Rhone-Poulenc Rorer S.A.
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