Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-01
1997-05-13
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3153
Patent
active
056293127
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel therapeutic application of lamotrigine or the pharmaceutically acceptable salts of this compound.
Lamotrigine or the pharmaceutically acceptable salts of this compound are described as anticonvulsants and antiepileptics, in particular in Patent EP 247,892.
It has now been found, surprisingly, that this compound may also be used in the treatment of neuro-AIDS.
The term neuro-AIDS includes disorders involving dementia, cognitive disorders, neuropathies, myopathies, ocular disorders and all neurological symptoms associated with the HIV-1 virus.
The activity of lamotrigine in neuro-AIDS was demonstrated in the test of neuronal death induced by the GP-120 protein, an envelope protein of the HIV-1 virus, according to the following protocol:
Cortical cell cultures are prepared according to the method described by SINDOU et al., Brain Res., 572, 242-246 (1992). After 8 to 10 days of culture, neurons which have acquired a correct neuritic shape are used for the tests. The cells are kept at 37.degree. C. in a CO.sub.2 incubator for the whole of the experiment.
Neuronal survival is assessed before application and after 24 hours of application of the test product by a colorimetric technique using Tuspan Blue, counting predetermined fields (semi-quantitative method). A minimum of 4 culture dishes per concentration (100 neurons per dish) were analysed.
In a first series, neuronal survival of the culture medium was determined without any product. Neuronal survival is then approximately 87%.
In a second series, the toxicity of the GP120 in culture was demonstrated. The GP120 was applied alone to the culture medium for 24 hours at a concentration of 20 pmol, and brings about a neuronal death which is of the order of 43%.
In the third series, the test product dissolved in dimethyl sulphoxide (10.sup.-3 M) is applied 5 minutes before the application of GP120 and thereafter incubated for 24 hours at concentrations from 10.sup.-7 to 10.sup.-8 mol. Neuronal survival is greater than 80%.
As pharmaceutically acceptable salts, there may be mentioned, in particular, 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, methylenebis(.beta.-hydroxynaphthoate) or substitution derivatives of these derivatives.
The medicinal products consist at least of lamotrigine, 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 such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (drag ees) or a varnish.
As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs, containing inert diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin, may be used. These compositions can comprise substances other than diluents, for example wetting, sweetening, thickening, flavouring or stabilizing products.
The sterile compositions for parenteral administration can preferably be suspensions, emulsions or aqueous or non-aqueous solutions. As a solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate,
REFERENCES:
Sussman et al., "Dramatic Response to Lamotrigine in Two Patients With Neurologic Deficits Secondary to Frequent Intractable Seizures", Epilepsia, 30(5):662 (1989).
Nakamura-Craig et al., "Analgesic Effects of Lamotrigine in an Experimental Model of Neuropathic Pain in Rats", British Journal of Pharmacology, 107, p. 336P (1992).
Koppel et al., "Antiepileptic Drug Treatment in Patients With Aids", Epilepsia, 33(3):69 (1992).
Meldrum et al., "Excitatory Amino Acid Receptors And Disease", Current Opinion in Neurology and Neurosurgery, 5(4):508-513 (1992).
Kieburtz et al., "Excitotoxcity And Dopaminergic Dysfunction in The Acquired Immunideficiency Syndrome Dementia Complex", Arch. Neurol. 48(12):1281-1284 (1991).
Bousseau Anne
Doble Adam
Louvel Erik
Henley III Raymond
Rhone-Poulenc Rorer S.A.
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