Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1998-09-15
2000-03-14
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
A61K 31225
Patent
active
060373725
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel therapeutic use of an alkanoyl L-carnitine (as defined hereinbelow) or a pharmacologically acceptable salt thereof for the therapeutic treatment or prophylaxis of glutamate-mediated disturbances or diseases. More particularly, the present invention relates to the therapeutic treatment with an alkanoyl L-carnitine or a pharmacologically acceptable salt thereof of individuals in whom glutamate contributes towards the pathogenesis of a particular disease or gives rise to cytological disturbances, or alternatively to the prophylaxis of such diseases or disturbances.
Glutamate is a non-essential and glucogenic amino acid which is in equilibrium with .alpha.-ketoglutarate. It forms the amide, glutamine, by incorporating ammonia. By transamination, glutamine can give its amine group to various keto acids to form .alpha.-ketoglutaramate. The latter is then hydrolysed to .alpha.-ketoglutarate and ammonia by the action of a specific diaminase. The concentration of L-glutamate in peripheral blood ranges between 141 and 311 .mu.mol/L. Increased extracellular concentrations of glutamate can competitively inhibit the membrane transport of cystine into the cell, with consequent oxidative damage. High levels of glutamate are present in many morbid conditions, as already demonstrated by White in 1952 (White J. M. et al., J. Clin. Lab. Med. 40:703, 1952). It is, however, emphasized that high levels of glutamate were observed in individuals with tumours in the digestive apparatus, bronchial carcinomas, malignant lymphomas, Hodgkin's disease and breast and ovary tumours (Beaton J. R. et al., Can. Med. Ass. J. 65:219, 1951). Recently, high levels of glutamate have also been found in the plasma of individuals with HIV (human immunodeficiency virus) infections (Droge W. et al., J. Cancer. Res. Clin. Oncol. 114:124, 1988). In the central nervous system, it has been demonstrated that high concentrations of glutamate contribute towards neuronal damage by excitotoxic mechanisms, following binding of glutamate to the NMDA (N-methyl-D-aspartate) receptors, and on account of oxidative stress, following competition for the uptake of cystine by neurons (Dewhurst S. et al., Molecular Medicine Today 1:16, 1996).
From that which has been outlined above, it is evident that variations in the concentration or in the metabolism of glutamate can contribute towards the pathogenesis of many diseases or give rise to cytological disturbances. Examples of diseases or disturbances characterized by altered levels of glutamate include cancer, infection with HIV, immunodeficiencies, drug dependencies, headaches, chronic fatigue syndrome, schizophrenic disorders, epilepsy, amyotrophic lateral sclerosis and other motor neuron diseases and peripheral neuropathies, senile and presenile dementias, apoplexy and sequences thereof, cerebrovascular ischaemic diseases, decreased cerebral flow and altered cerebral metabolism, neurodegenerative diseases, Huntington's disease, Parkinson's disease, prion protein diseases, meningoencephalitis, and Chinese restaurant syndrome.
The use of certain substances can also give rise to high levels of glutamate. Examples of such substances are cocaine and sulpiride.
According to the present invention, the administration of an alkanoyl L-carnitine wherein the alkanoyl group has 2-6 carbon atoms or a pharmacologically acceptable salt thereof can alleviate glutamate-mediated cytological disturbances.
Preferably, the alkanoyl L-carnitine is selected from the group comprising acetyl-, propionyl-, butyryl-, valeryl- and isovaleryl-L-carnitine.
In the description which follows, the expression pharmacologically acceptable salt of an alkanoyl L-carnitine is understood to refer to any salt of the latter with an acid which does not give rise to undesired toxic effects or side effects. These acids are well known to pharmacologists and to persons skilled in the pharmaceutical field.
Non-limiting examples of such salts are: chloride; bromide; iodide; aspartate, particularly hydrogen aspartate; citrate,
REFERENCES:
patent: 4194006 (1980-03-01), Cavazza
Henley III Raymond
Mendes s.r.l.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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