Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2000-01-03
2001-12-11
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C424S750000, C514S547000, C514S556000, C514S724000, C514S729000, C514S734000
Reexamination Certificate
active
06328998
ABSTRACT:
The present invention relates to a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal lipid metabolism or by an increase in platelet aggregation.
Within the context of the populations of the industrialised countries, a slow yet progressive increase in life expectancy is noted; this is not the case only in Italy, but also in other industrialised Western countries and in Japan. The main cause of death in Western countries is to be attributed primarily to diseases of the cardiovascular system, which, in addition to causing death, are also responsible for lengthy periods of hospitalisation and disablement, placing a substantial burden of cost on the national health system.
In Italy, cardiovascular diseases related to abnormal lipid metabolism account for more than 40% of the overall mortality. Our knowledge regarding the relationships between cholesterol and coronary heart disease stems from epidemiological studies conducted in recent years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis and coronary heart disease correlates closely with serum cholesterol levels. Peripheral neuropathies afflict a substantial number of people and, generally speaking, though not causing their deaths, are capable of worsening their quality of life. These pathologies constitute a heterogeneous group of diseases, inasmuch as their aetiology mar be secondary to viral (herpes zoster), ischaemic (atherosclerosis), metabolic (diabetes, kidney and liver failure), toxic (Adriamycin, isoniazide, nitrofurantoin), mechanical (compression, trapping, rupture), radiation and genetic factors as well as to factors related to diseases of the immune system. Moreover, whatever the actual aetiological cause of the disease form, abnormal membrane fluidity is always detectable as a result of an abnormality of cell lipids, cholesterol, gangliosides or platelet aggregation.
Data recently reported in the literature indicate, in fact, that the onset of diabetic peripheral neuropathy is facilitated by increased platelet aggregation.
In cases of hyperlipidaemia, correction of eating habits through an appropriate diet is always the first therapeutic measure. Satisfactory results are not always achieved, however, owing to widespread intolerance of strict alimentary discipline, to the severity of the hypercholesterolaemia, or to genetic-type resistance.
To achieve the desired results in these cases, i.e. normalisation of blood levels of triglycerides and cholesterol, pharmacological treatment has to be resorted to. There are many useful drugs on the market for the treatment of hypertriglyceridaemia and hypercholesterolaemia. The fibrates and statins are the best agents for this purpose, but are not devoid of side effects. The results of experiments in animals and man have suggested that, to reduce cholesterol levels, pharmacological treatment with these two classes of drugs should be given only to patients at high risk for coronary disease in the short term (
JAMA
1996; 275: 55-60). The polycosanols, which are a mixture of C
24
-C
32
long-chain aliphatic alcohols ranging from lignoceric acid (tetracosanol) to triacontanol. derived from the wax cuticle of sugar cane, from rice- or wheat-germ oil, or from the leaves of
Ginkgo biloba
or
Ephedra geradina
, are known to be used for the treatment of lipid metabolism disorders both experimentally induced and encountered in clinical practice. A similar favourable effect of polycosanols on platelet aggregation has been found both experimentally and clinically.
The serum triglyceride and serum cholesterol lowering effects of L-carnitine and of a number of alkanoyl L-carnitines are well known; U.S. Pat. No. 4,255,449 and U.S. Pat. No. 4,268,524 describe the use of L-carnitine and alkanoyl L-carnitines. respectively, for normalising abnormally high ratios of low-density lipoproteins (LDL) + very low-density lipoproteins (VLDL) to high-density lipoproteins (HDL), which constitute an aetiological factor in various cardiovascular diseases. Through beta-oxidation of fatty acids, L-carnitine is capable of preventing their accumulation and of supplying the cell energy requirement (Bremner Y,
TIBS
2, 207, 1977) via modulation of extra- and intra-mitochondrial CoA.
Equally well known is the use of acetyl L-carnitine in the therapeutic treatment of peripheral neuropathies; see, for example, U.S. Pat. No. 4,751,242. L-carnitine and particularly acetyl L-carnitine or propionyl L-carnitine can act by varying the lipid substrate from which the various vasoconstricting and aggregation-promoting factors derive as a result of the effects of cyclo-oxygenase and lipo-oxygenase, by reducing their formation and by promoting the synthesis of antiaggregant and vasodilating factors.
It has now been found unexpectedly that the co-ordinated use —a term which will be precisely defined here below—of L-carnitine or of an alkanoyl L-carnitine in which the linear or branched-chain alkanoyl has 2-6 carbon atoms, or of one of their pharmacologically acceptable salts, in combination with long-chain (C
24
-C
30
) aliphatic alcohols, particularly polycosanols or natural extracts containing polycosanols allows a potent synergistic effect to be achieved in terms of their cholesterolaemia- and triglyceridaemia-lowering and platelet-aggregation inhibiting action.
The well-known lack of toxic and side effects of L-carnitine or of the alkanoyl L-carnitines and polycosanols makes their co-ordinated use according to the invention particularly useful and safe both for the treatment of hypercholesterolaemic and/or hypertriglyceridaemic patients at high risk for cardiovascular disease in the short-, medium- or long term and for the prevention and treatment of diseases related to increased platelet aggregation and to a reduced oxygen concentration (ischaemia), such as, for example, peripheral neuropathies, and diabetic peripheral neuropathy in particular.
In the context of the invention described herein, what is meant by “co-ordinated use” of the afore-mentioned compounds is either their co-administration, i.e. the substantially simultaneous administration of L-carnitine or one of the alkanoyl L-carnitines, or one of their pharmacologically acceptable salts, and of at least one polycosanol, or, indifferently, the administration of a composition containing a combination or mixture of the aforesaid active ingredients, in addition to any excipients included.
The scope of the present invention therefore encompasses both the co-administration of L-carnitine or of an alkanoyl L-carnitine, or one of their pharmacologically acceptable salts, together with polycosanols, and pharmaceutical compositions, which can be administered orally or parenterally, containing a mixture of the two active ingredients.
The polycosanol should preferably be selected from the group comprising triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol and tetracontanol or natural products or extracts from natural products containing them, while the alkanoyl L-carnitine should be selected from the group comprising acetyl, propionyl, butyryl, valeryl and isovaleryl L-carnitine or one of their pharmacologically acceptable salts.
Even more preferably, the polycosanol should be hexacosanol and the alkanoyl L-carnitine propionyl L-carnitine or one of its pharmacologically acceptable salts.
What is meant by pharmacologically acceptable salt of an alkanoyl L-carnitine is any salt of the latter with an acid that does not give rise to unwanted toxic or side effects. These acids are well known to pharmacologists and to experts in pharmacy.
Examples of pharmacologically acceptable salts of alkanoyl L-carnitines, though not exclusively these, are chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, lactate, maleate and acid maleate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate.
One preferred composition, in unit dosage form, is a composition containing 1-100 mg of pol
Flood Michele C.
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
Tate Christopher R.
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