Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-12
2002-04-02
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S556000
Reexamination Certificate
active
06365622
ABSTRACT:
This is A 371 of PCT/1T99/00268 filed Aug. 19, 1999.
The present invention relates to a composition for the prevention and/or treatment of tissular diseases brought about by the presence of free radicals due to environmental pollution; brain or myocardial damages induced by free radicals following cerebral or myocardial ischaemia and attendant riperfusion; of the toxic or diabetic neuropathies and of metabolic disorders in the glucose utilization.
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:
(a) acetyl L-carnitine or a pharmacologically acceptable salt thereof, optionally in combination with at least another “carnitine” where for “carnitine” is intended L-carnitine or an alkanoyl L-carnitine selected from the group comprising propionyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine or their pharmacologically acceptable salts; and
(1) &agr;-lipoic acid.
A systemic deficiency of alkanoyl L-carnitines (ubiquitous naturally-occurring compounds, the greatest concentrations of which are to be found above all in skeletal muscle and in the myocardium) is known to lead to muscular and functional deficits which can be restored to normal by the exogenous administration of these compounds.
The presence of acetyl L-carnitine has been ascertained both at cerebral level and in peripheral nervous tissue where its presence is necessary for normal nerve conduction.
The production of energy by carnitines occurs via intramitochondrial &bgr;-oxidation of fatty acids, as well as via the oxidation of branched-chain amino acids and regulation of insulin activity.
Important for the purposes of the characterization of the biological activity of carnitines are studies indicating their stabilising effects on cellular phospholipid membranes and on the integrity and deformability of erythrocytes.
Acetyl L-carnitine in particular protects cerebral tissue against peroxidative phenomena. While it has been ascertained that carnitine is necessary for normal growth, it is equally true that reduced carnitine levels compared to normal have been detected during ageing.
During the metabolic processes associated with ageing, an increase in oxidative processes is constantly detected together with a related increase in free radicals, which facilitates the onset of diabetic lesions.
Reduced mitochondrial activity leads to an increase in oxidants which the cell defences are no longer able to combat effectively.
The increase in peroxides, hydroxides and singlet oxygen produced by aerobic metabolism may lead to damage to macromolecules (DNA, proteins and lipids), which contributes to the onset of degenerative diseases, including diabetes, which usually arise during ageing. The reduced mitochondrial activity which comes about with ageing is also accompanied by a reduction in cardiolipin, a diphosphatyl-glycerol derivative which makes up part of the structure of the mitochondrial membrane and plays an important role in maintaining mitochondrial activity, particularly at the level of fatty acid &bgr;-oxidation processes. Mitochondrial activity, including the fatty acid &bgr;-oxidation processes, can be reactivated by the administration of acetyl L-carnitine, which is also capable of restoring normal cardiolipin concentrations in the mitochondria.
The positive effect of acetyl L-carnitine on mitochondrial activity is also proved by its ability to promote the utilization of the glycolytic pathway for ATP production. These effects are detected particularly at the neuronal level where acetyl L-carnitine has proved capable of preventing neuronal lesions or chronic neuronal degeneration.
In addition to a reduction in the carnitines present in the body during the processes of ageing, a reduction in growth factors (GF-I) is also detected and particularly a reduction in IGF-I (insulin-like growth factor).
IGF-I, IGF-II and relaxin are peptides belonging to the group of proinsulins also called somatomedins.
IGFs exert a homeostatic and trophic action, particularly at both central and peripheral nervous system level, and the clinical use of these peptides has yielded beneficial results in many degenerative nervous disorders including diabetic neuropathy.
The correlations existing between ageing and a reduction in carnitines and growth factors, including IGF-I, and the restoration of the levels of these factors by means of the exogenous administration of acetyl L-carnitine justify the interest in carnitines for the purposes of their use in the prevention and treatment of neurodegenerative diseases, including diabetic neuropathy.
It has been demonstrated that &agr;-lipoic acid also performs an important regulatory function on carbohydrate metabolism and insulin activity. &agr;-lipoic acid is widely distributed in nature in both the vegetable and animal worlds and can be taken with food. Recognised first as a growth factor for a number of micro-organisms, it was then isolated in ox liver as bound to many animal proteins. It acts as an important scavenger of free radicals, above all those deriving from environmental contamination. Recently, it has been shown that this compound is also useful in the regulation of glucose utilization and of insulin activity, so much so as to constitute an important factor in the prevention of diabetic neuropathies.
It has been demonstrated that lipid peroxidation, which is increased in diabetic neuropathy, can be controlled and reduced, both at cerebral level and at the level of the sciatic nerve or the ocular lens, by the administration of &agr;-lipoic acid or one of its enantiomers. Moreover, &agr;-lipoic acid inhibits the aldose reductase activated by hyperglycaemia, and therefore &agr;-lipoic acid may also play an important therapeutic role in diabetic complications.
&agr;-lipoic acid enhances the insulin-induced muscular utilisation of glucose and, in diabetic subjects, reduces resistance to the effects of insulin on glucose. Related to the antioxidant effect of &agr;-lipoic acid are also its neuro-protective capability against brain damage induced by ischaemia and its postulated therapeutic role in Parkinson's disease and AIDS.
The antioxidant effect of &agr;-lipoic acid may be either direct or indirect, via restoration of glutathione and ascorbic acid concentrations.
While the action of &agr;-lipoic acid on carbohydrate metabolism is due essentially to its ability to act as a coenzyme in the oxidative decarbohydroxylation of pyruvate and other &agr;-ketoacids and, through the acetates, in the activation of the tricarboxylic acid cycle leading to the formation of ATP, for the purposes of explaining the multiple favourable biological effects that this compound has in preventing diabetic damage, other pathways whereby &agr;-lipoic acid exerts its protective action should also be borne in mind.
Among these, one should bear in mind particularly the mechanism consisting in its ability, after reduction to dihydrolipoic acid, to inhibit the activation of the nuclear transcription factor (NF-kB) by reactive oxygen species (ROS), thus, in turn, inhibiting the associated cascade of neurotoxic and cytotoxic factors.
Since many of the complications associated with diabetes, such as neuropathies and ocular cataracts are mediated by ROS, inhibition of activation of the nuclear transcription factor may constitute a mechanism via which &agr;-lipoic acid may intervene in the prevention of diseases related to diabetes. Furthermore, one should also bear in mind that, in diabetic subjects, the concentrations of &agr;-lipoic acid are lower than normal values and that the administration of &agr;-lipoic acid may restore these levels to normal. It thus has an additive effect to that of insulin i
Henley III Raymond
Nixon & Vanderhye
Sigma-Tau HealthScience S.p.A.
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