Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2000-12-21
2003-05-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S400000, C424S441000, C424S451000, C424S464000, C424S484000, C424S489000
Reexamination Certificate
active
06565876
ABSTRACT:
This application is a 371 of PCT/IT00/00158 filed Apr. 19, 2000.
The present invention relates to a composition for the prevention and/or treatment of cardiovascular and neurocerebral disorders, various tissue anoxic forms, energetic muscular deficits, inflammatory type-abnormalities, blood alterations of coagulation such as thrombosis, and tissue proliferation forms.
Accordingly, the composition may take the form and exert the action of a dietary supplement or of an actual medicine, depending upon the support or preventive action, or the strictly therapeutic action, which the composition is intended to exert in relation to the particular individuals it is to be used in.
More particularly the present invention relates to an orally, parenterally, rectally or transdermally administrable composition which comprises in combination as characterizing ingredients:
(a) propionyl L-carnitine or a pharmacologically acceptable salt thereof, optionally in combination with another “carnitine”, where for “carnitine” is intended L-carnitine or an alkanoyl L-carnitine selected from the group comprising acetyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or their pharmacologically acceptable salts; and
(b) an inositol phosphate selected from the group comprising inositol monophosphate, inositol tetraphosphate, inositol pentaphosphate, particularly inositol hexaphosphate (IP6).
Both the carnitines and inositol hexaphosphate are well known for their important metabolic and pharmacological effects which have led to numerous favourable pharmacological and clinical findings.
As regards the carnitines, the role they play in the processes of &bgr;-oxidation of fatty acids and ATP synthesis is well known.
They are also endowed with important antioxidant activity, as demonstrated by their protective effect against the lipoperoxidation of the phospholipid cell membranes and against oxidative stress induced at myocardial and endothelial cell level. These biochemical effects of the carnitines are reflected in the favourable results obtained in clinical practice when they are used in the treatment of various forms of atherosclerosis, myocardial ischaemia, peripheral vasculopathy or diabetes.
Also as regards inositol hexaphosphate (IP6), numerous research studies of both biochemical and clinical nature have been published, which pinpoint its activities and use in the prevention and treatment of various pathological changes. Although the interest in this compound dates back many years, when the ability of certain plant seeds containing high percentages of IP6 to maintain their germinative capacity intact for very long periods of time was attributed to the antioxidant action of IP6, it was only recently that researchers began to detect its antithrombotic and antiatherosclerotic properties and its cardioprotective ability against damage caused by infarction as well as its ability to afford protection against the onset of tumour processes. These properties may be related in part to its high antioxidant capability and, on the other, to its ability to interfere with the release of cytokines and other products induced by the activation of receptors regulating cell transduction systems.
It is well known, in fact, that inositol hexaphosphate, IP6 or phytin, is present in high percentages in all tissues and cells. IP6 constitutes 1-5% by weight of many cereals and legumes, such as, for example, rice, wheat and soya, in which it constitutes approximately 50% of the phosphorus reserve. In clinical practice, the main areas in which IP6 has been successfully used relate above all to the treatment of hypercholesterolaemia and atherosclerosis, as well as hypercalcaemia and the resolution of kidney stones. Equally promising results have been achieved experimentally with its use in inhibiting ADP-induced platelet aggregation or the reperfusion damage of organs such as the heart.
Its incorporation in erythrocytes, moreover, leads to a greater availability of utilisable oxygen in those situations where the oxygen utilisation capability seems to be reduced, as in organ ischaemia, haemolytic anaemia, pulmonary insufficiency and erythrocytosis.
It should be recalled that the main factor underlying this activity of IP6 is its potent antioxidant action related above all to its iron-chelating ability.
As regards the vasculoprotective, neuroprotective and anti-anoxic effects of IP6, its incorporation in erythrocytes increases their stability to iron ions which can be released within the erythrocytes themselves and, moreover, by increasing their affinity for oxygen, make greater amounts of oxygen available at the level of tissues which have become anoxic.
Though the antioxidant effect of IP6 may account for its favourable activity at the metabolic and cardiovascular level, other mechanisms highlighted in recent studies have to be taken into consideration with regard to its anti-inflammatory, immunostimulant and anticancer properties.
IP6 and inositol pentaphosphate, IP5, are among the main inositol phosphates present in cells. In addition to modifying haemoglobin affinity for oxygen and acting as neurotransmitters, they perform an important function in the transduction of signals from the surface of the cell to its interior, in gene activation and in the formation of cytokines and factors regulating cell growth.
In the case of IP6's anticancer activity, the dephosphorylation of IP6 to IP5 and IP3 and a lowering of the pool of inositol phosphates characterised by lower phosphorylation, the prevalence of which regulates or inhibits cell growth, are postulated. IP6, moreover, is capable of blocking the activity of phosphatidylinositol-3-kinase (PI-3-kinase) and thus of blocking the Epidermal Growth Factor and the transduction of extracellular signals regulated by activation of protein kinase.
Another factor with a bearing on the anticancer activity of IP6 is that its dephosphorylation to IP3 is regarded as being related to the opening of the related calcium channels, an increase in which is not only a critical element in cell proliferation, but also an important factor in the induction of cell apoptosis. It has been found, moreover, that IP6 competes with the insulin Growth Factor receptors (IGF-II), and as a result it has been demonstrated that its gene overexpression gives rise to different tumour lines. IGF receptors, in any event, have been found to be important in initiating cellular hyperplasia.
In the anti-inflammatory, immunostimulant and anticancer action of IP6, then, two different mechanisms can be considered. One is peculiar to antioxidant agents which, like salicylic acid, inhibit the activation of gene transmission via the NK-kb-IkB system, and the other which, via the inositol phosphate pool, regulates growth factors. From the practical point of view, in the anticancer field, the use of IP6 has proved effective in inhibiting colon cancers induced in animals by azoxymethane with a dose-dependent activity.
Its use has also appeared to be equally effective in carcinoma of the breast induced by 7,12-dimethylbenzanthracene (DMBA) or by methyl-nitrosourea. Favourable results have also been obtained with the use of IP6 in cancers of the lung, prostate and liver. Tests conducted in human subjects, mainly on adenocarcinoma and leukaemia cells, have verified the anticancer efficacy of IP6.
It has now surprisingly been found that a combination composition containing as its characterising components:
(a) propionyl L-carnitine or one of its pharmacologically acceptable salts; and
(b) an inositol phosphate, selected from the group consisting of inositol monophosphate, inositol tetraphosphate, inositol pentaphosphate and, particularly, inositol hexaphosphate (IP6) is extremely effective in the prevention and/or treatment of cardiovascular and neurocerebral disorders and of the various forms of tissue anoxia, inflammatory-type abnormalities, muscular energy deficits and tissue proliferation forms, as a result of the potent, unexpected synergistic effect exerted by its components.
It has also been
Evans Charesse
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
Sigma-Tau HealthScience S.p.A.
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