Pharmaceutical compositions for the therapy of involutive cerebr

Details Pharmaceutical compositions for the therapy of involutive cerebr Pharmaceutical compositions for the therapy of involutive cerebr

1987-10-08

1990-08-21

Howard, Jacqueline V.

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus esters

514 77, C07F 910, A61K 31685

Patent

active

049507761

DESCRIPTION:

BRIEF SUMMARY
This invention relates to pharmaceutical compositions suitable for the therapy of involutive cerebral syndromes, containing as the active principle glycerophosphoryl-O-serine (herinafter indicated also as GPS) or its salts with alkali or alkali earth metals.
Pharmaceutical compositions containing as the active principle phosphatidylserine (PS), suitable for the therapy of psycho-organic syndromes due to an involutive origin, or to cerebrovascular deficiency, are known and used.
Phosphatidylserine (PS) is generally extracted from mammals brain in admixture with phosphatidylethanolamine ("cephalinic fraction") and subsequently purified. From a chemical point of view, PS is the double-acylated product with fatty, mainly unsaturated acids at the hydroxy groups of the glycerine residue of glycerophosphonyl-O-serine; but due to the presence of the unsaturated fatty acid, PS turns out to be unstable since it easily undergoes peroxydation. For example, standard .alpha.-phosphatidyl-L-serine decomposes in fact at room temperature, in an amount of 0.5% per day (Sigma Catalogue--1986 Ed., p. 971).
As a result of this fact complex stabilization techniques are used in order to minimize instability in the extractive phase, during the purification and the finished product.
From a biochemical point of view, phosphatidylserine is known to stimulate ACh release from the cerebral cortex in the anaesthetized rat. The stimulation may be inhibited by dopaminergic antagonists and by lesions in the septum (J. Neurochem. 32, 529, 533).
These data suggest that PS indirectly acts stimulating a dopaminergic system which, in its turn, increases ACh output from the cholinergic nervous terminations, which cholinergic fibers stimulated by PS derive from or go through the septum (Cholinergic Mechanism: Phylogenetic Aspects, Central and Peripheral Synapses, Clinical Significance--Ed. by E. Pepen Plenum Publishing Co., N.Y. 1981, 685).
It has also been shown that PS prevents scopolamine induced disruption of spontaneous alternations in newborn rats (in: Aging of the brain and dementia--Ed. by Amaducci--Raven Press N.Y. 1980, 271).
By evaluating the inhibition of the scopolamine electrocorticographic effects in the rat or in rabbit by PS, a further confirmation of the influence of the same on the cholinergic cortical mechanisms, is achieved (phospholipids in the Nervous System Vol. 1--Ed. by L. Horrocks--Raven Press N.Y. 1982, 165).
Haloperidol antagonizes ACh increase in the striatum induced by PS; the PS in its turn decreases the ACh spontaneous output from striatum slices. These data, as a whole, prove that PS is able to activate dopaminergic receptors in the caudatum (Phospholipids in Nervous System Vol. 1, Ed. by L. Horrocks, Raven Press N.Y. 1982, 165).
This gives value to the hypotheses that stimulation of ACh output from the cerebral cortex may be mediated by the activation of subcortical dopaminergic mechanisms.
It has been moreover shown that low doses of PS increase noradrenaline turnover, activate thyrosine-hydroxylase and accumulate c-AMP mainly in the hypothalamus (Life SCI. 23, 1093, 1978).
A direct cerebral effect of PS is supported by experiments in which, by injecting PS both intracerebroventricularly and intravenously, there are produced the same stimulating effects as evidenced on decreased learning ability in old rats (J. Lipid Res. 21, 1053, 1980).
However, this is not sufficient to confirm whether PS is active per se, or after metabolic conversion.
On the other hand, the metabolic fate of the exogenous PS administered orally and by i.v. involves the conversion thereof by monodeacylation into lyso-PS (Acta Physiol. Scand. 34, 147, 1954; Phospholipids in Nervous System vol. 1, Metabolism Ed. by L. Horrocks, Raven Press N.Y. 1981, 173).
By evaluating the kinetics by means of [U.sup.14 --C] PS, it is evidenced that the amount of lyso-PS gradually increases in the blood and decreases in the liver and brain (J. Neurochem. 33, 1061, 1979). This reflects the reacylation rate of lyso-PS occurring in the liver and brain. On the

REFERENCES:
patent: 4595680 (1986-06-01), della Valle et al.
patent: 4624852 (1986-11-01), Wurlman
patent: 4624946 (1986-11-01), Scolastics et al.
patent: 4775758 (1988-10-01), Nojima et al.

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