Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-02-22
2002-04-30
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S400000, C424S489000, C514S228800
Reexamination Certificate
active
06380252
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel therapeutic use of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine or pharmacologically acceptable salts thereof for increasing the levels of IGF-1 (insulin-like growth factor 1) for the therapeutic treatment or prophylaxis of cytological disorders or diseases related to IGF-1. More particularly, the present invention relates to the use of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine or pharmacologically acceptable salts thereof for the therapeutic treatment or prophylaxis of individuals in whom IGF-1 contributes towards the pathogenesis of a particular disease or provokes cytological disorders. The present invention also relates to the use of any of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine or pharmacologically acceptable salts thereof in combination with any of L-carnitine, coenzyme Q10, vitamin E and/or Se-L-methionine and pharmaceutically acceptable salts and derivatives thereof in the treatment of hepatitis-C virus and/or for increasing the levels of IGF-1.
Like other growth factors, IGF-1 promotes cell growth and differentiation. The administration of IGF-1 obtained as a protein purified by molecular biology methods has made it possible to confirm the effects observed in vitro with cells, on animal models and in man. Essentially, the action of IGF-1 is similar to that of insulin, that is to say an increase in the uptake of glucose, a reduction in ketones and fatty acids in the serum and an increase in protein synthesis. In accordance with these and other metabolic effects, clinical studies have been undertaken in order to evaluate the efficacy of IGF-1 in a range of diseases. IGF-1 has been administered to patients with type-II diabetes, to cachectic patients, to patients with ischemic damage at the neuronal, myocardial or renal level, and has been proposed for repairing and regenerating tissues (W. L. Lowe, Insulin-like growth factors, Scientific American Science and Medicine p. 62, March 1996).
From the above, it is clear that the administration of IGF-1 may be therapeutically useful in various morbid conditions. Examples of diseases or disorders which may be prevented, cured or improved by the administration of IGF-1 include neuropathies of the optic nerve and of the olfactory nerve, neuralgia of the trigeminal nerve, Bell's paralysis, amyotrophic lateral sclerosis and other motor neuron diseases, degeneration of the retina, osteoporosis, arthropathy, arthritis, cervical spondylosis and hernia of the intervertebral discs, clinical syndromes of reduced height, cachexia, acute or chronic hepatic necrosis, Turner's syndrome, sarcopoenia, growth hormone insensitivity syndromes, diabetes, obesity, asthenia in general and in particular myasthenia and heart asthenia, immunodeficiencies and reperfusion injuries. IGF-1 moreover appears to be useful for the cicatrization of wounds, the healing of ulcers, the treatment of burns, tissue regeneration in general and in particular that of cutaneous, intestinal and hepatic tissue, and the formation of dentine.
Unfortunately, the administration of IGF-1 in man brings about undesirable effects such as oedema, pain in the temporomandibular joint and arthralgia. These symptoms are such as to prevent the administration of IGF-1 from being recommended or are responsible for interrupting the treatment. It is therefore necessary to find novel substances which are capable of inducing the production of IGF-1.
In addition, hepatitis C virus (HCV) is the most common cause of viral hepatitis in the developed world. In some populations of the Middle East the incidence of antibodies against HCV peaks up to 6%. Despite many advances in the knowledge of HCV, the pathogenesis of this infection is still not characterized in all its aspects. In particular, it is not presently known how HCV causes hepatic cell injury; the histological findings of the livers of HCV-infected patients revealing a variety of complex interactions between host and viral factors. The most striking observation at the ultrastructural level is the severe alteration in the mitochondria of hepatocytes from patients who are HCV-infected. The dysfunction of the mitochondria leads to the promotion of both immune- and non-immune-mediated death of the hepatocyte. In chronic HCV infection, this sequence of events leads to chronic hepatic necrosis and finally even to cirrhosis in advanced disease.
Even though the “standard” treatment of HCV-infected patients is based on the use of interferons—mainly alpha-IFN (&agr;-IFN), eventually in association with other antivirals (i.e. ribavirin), the inventors surprisingly found that compositions that contain any of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine or pharmacologically acceptable salts thereof in combination with any of L-carnitine, coenzyme Q10, Vitamin E and/or Se-L-Methionine and pharmaceutically acceptable salts and derivatives thereof can lead to new therapeutic strategies for HCV treatment as well as other conditions where IGF-1 levels are deficient and which lead to increased and/or prolonged cell death (i.e. HIV-infection, retinal damage, and also those noted above). This formulation can be given as dietary supplement or as a drug.
According to one embodiment of the present invention, the administration of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine or pharmacologically acceptable salts thereof is capable of inducing the production of IGF-1 without the undesirable effects produced by the administration of exogenous IGF-1.
According to another embodiment of the present invention, the administration of any of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine or pharmacologically acceptable salts thereof in combination with any of L-carnitine, coenzyme Q10, vitamin E and/or Se-L-methionine and pharmaceutically acceptable salts and derivatives thereof can lead to new therapeutic strategies for HCV treatment as well as other conditions where IGF-1 levels are deficient.
In the description which follows, the expression pharmacologically acceptable salt of L-acetylcarnitine, of L-isovalerylcarnitine or of L-propionylcarnitine is understood to refer to any salt of the above with an acid which does not give rise to undesirable toxicity or side-effects. Such acids are well known to pharmacologists and to experts in the pharmaceutical field.
Non-limiting examples of such salts are; chloride; bromide; iodide; aspartate, in particular hydrogen aspartate; citrate, in particular hydrogen citrate; tartrate; phosphate, in particular hydrogen phosphate; fumarate, in particular hydrogen fumarate; glycerophosphate, glucose phosphate; lactate; maleate, in particular hydrogen maleate; orotate; oxalate, in particular hydrogen oxalate; sulphate, in particular hydrogen sulphate; trichloroacetate, trifluoroacetate and methanesulphonate.
In the description which follows, for the purposes of brevity and for ease of explanation, reference will be made only to L-acetylcarnitine, it being understood that the description given applies also to the above-mentioned L-isovalerylcarnitine and L-propionylcarnitine and to pharmacologically acceptable salts thereof.
Therapeutic uses of L-acetylcarnitine, L-isovalerylcarnitine and L-propionylcarnitine for the therapeutic treatment of myocardial arrhythmia and ischemia, peripheral functional vasculopathy of the arteries, senile dementia, peripheral neuropathies and myopathies are already previously known. For instance, EP 0 516 594 A1, the entire contents of which are hereby incorporated by reference, discloses the use of propionyl- and isovaleryl L-carnitine for treating myopathies, neuronal degeneration and for inhibiting proteolysis. Cardiov. Res. 1986, 20:536-541, the entire contents of which are hereby incorporated by reference, deals with the protection of the ischaemic myocardium by propionyl L-carnitine. Docum. Ophtal. 1988, 70:89-96, the entire contents of which are hereby incorporated by reference, hints at t
Evans Charesse L.
Page Thurman K.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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