Use of basic amino acids and derivatives for lowering ceramide l

Details Use of basic amino acids and derivatives for lowering ceramide l Use of basic amino acids and derivatives for lowering ceramide l

1998-02-03

2000-09-05

Cook, Rebecca

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514561, 514171, A61K 3122

Patent

active

061143855

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to a novel therapeutic use of basic aminoacids, acylated basic aminoacids and their pharmacologically acceptable salts for the prophylaxis of diseases or the therapeutic treatment of cellular disorders accompanied by high levels of ceramide. In particular, the present invention relates to the use of L-carnitine, acyl L-carnitine derivatives and pharmacologically acceptable salts thereof for the prophylaxis of diseases or the therapeutic treatment of cellular disorders accompanied by high levels of ceramide.
2. Description of the Background
Ceramide is the basic molecule for the sphingolipids structure and metabolism thereof. All sphingolipids contain ceramide as main hydrophilic component and originate from ceramide through biosynthesis pathways which mainly modify the 1-hydroxy position thereof. In turn, sphingolipids play an important role in the transduction of the signal across the cellular membrane.
Ceramide plays an important role in the transduction of the signal across the cellular membrane. Molecules able to act upon the intracellular receptors (i.e. calcitriol) or the transmembrane receptors [i.e., gamma interferon (IFN-.gamma.), interleukin-1 (IL-1) and the nerve growth factor (NGF)] hydrolize sphingomyelin to ceramide. Ceramide activates phosphatases and protein kinases and, from a biological point of view, induces cellular apoptosis, growth and cell differentiation, modulates the expression of cydooxygenases and phospholipases and the activation of kB nuclear factors (NFkB) [Kuno, K. et al., J. Leukoc. Biol., 56(5): 542-7; Cifone, M. G. et al., J. Exp. Med., 180(4): 1547-52; Kolesnick R., Mol. Chem. Neuropathol., 21(2-3): 287-97; Jarvis, W. D. et al., Proc. Natl. Acad. Sci. U.S.A., 91(1): 73-7; Obeid, L. M. et al., Science, 259(5102): 1769-71].
It has now been found that variations in the concentration or in the metabolism of ceramide contribute to the pathogenesis of numerous illnesses or contribute to induce metabolic cellular disorders. Unfortunately, to date, there exist no methods to reduce ceramide levels in vivo.
Accordingly, one object of this invention is to provide a novel use of basic aminoacids, acylated basic aminoacids and their pharmacologically acceptable salt for reducing ceramide levels in vivo.
A second object of the present invention is to provide a novel use of basic aminoacids, acylated basic aminoacids and their pharmacologically acceptable salt for the prophylaxis of diseases or the therapeutic treatment of cellular disorders accompanied by high levels of ceramide.
It has in fact been found that administration of high doses of basic aminoacids, low molecular weight basic compounds or acyl derivatives thereof and pharmacologically acceptable salts thereof reduces ceramide levels and such compounds can thus be used for the treatment of diseases characterized by high levels of ceramide.
In particular, it has been found that basic aminoacids such as arginine, lysine, histidine, ornithine, and carnitine or acyl derivatives thereof and pharmacologically acceptable salts thereof can be used for the treatment of diseases characterized by high levels of ceramide.
In accordance with the invention, a novel use of basic aminoacids, basic aminoacid acyl derivatives and pharmacologically acceptable salts thereof is provided for lowering the levels of ceramide in vivo.
Suitable aminoacids include any amirnoacid with a basic charge such as argnine, lysine, histidine, ornithine and carnitine. These compounds are commercially available. Preferably, L-aminoacids are used. More preferably, carnitine is used. These compounds can be used as free aminoacids or as pharmaceutically acceptable salts.
Acyl derivatives of basic aminoacids can also be used in the present invention. C.sub.2-6 acyl aminoacids which are linear or branched can be used. These acids are well known to the pharmacologists and to the skilled of pharmaceutical technique. Particularly preferred acyl groups are acetyl, propionyl, butyryl, vale

REFERENCES:
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