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Title:  Method of treating diseases caused by over-production of free-radicals

United States Patent:  6,835,401

Issued:  December 28, 2004

Inventors:  Soldati; Fabio (Savosa, CH)

Assignee:  Pharmaton SA (Bioggio, CH)

Appl. No.:  617838

Filed:  July 14, 2003

Abstract

The invention relates to a method for improving the cell protection which comprises the administration of a combination of the extracts of the plants Vitis vinifera and Lycopersicon esculentum with the vitamins C, E, beta-carotene and optionally selenium. Said combination can be used in the prevention of phatological conditions related in part to an overproduction of free radicals like aging, arteriosclerosis and cancer.

Description of the Invention

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is related to a novel method of improving the cell protection, which utilises the administration of the combination of the extracts of the plants Vitis vinifera and Lycopersicon esculentum with the vitamins C, E, beta-carotene and selenium, as well as the use of such combination for treating or preventing pathologies related to an overproduction of free radicals like aging, arteriosclerosis and cancer.

2. Background Art

Antioxidants act to protect components of the body against free radical damage (Harman D.; Holliday R. and M. Meydany--Editor, "Towards Prolongation of healthy life span", Annals of the New York Academy of Sciences, Vol. 854, 1998, New York; Stahlin H. B., "The Impact of Antioxidants on Chronic Disease in Aging and Old Age", Int. J. Vitamin. Nutr. Res. 69, 146-149, 1999).

Several epidemiological studies support the observation that an increase in antioxidant intake limits the clinical expression of coronary artery diseases and some tumours (Comstock G W; Alberg A J; Huang H Y, Wu K.; Burke A E; Hoffman S C; Norkus E P; Gross M.; Cutler R G; Morris J S; Spate V L; Helzlsouer K J, "The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity", Cancer Epidemiol Biomarkers Prev 6, 907-916, 1997). Individuals with high dietary intakes of antioxidants may have a greater life expectancy.

Individual conditions, environmental stress and oxidative stress induced by environmental and nutritional factors exert its influence on a wide variety of individuals with varying defense capacities.

In general terms, individuals with very well balanced defense mechanisms will remain free of chronic disease, but will eventually succumb to the overall aging processes. Much more likely, however, is the case where critical systems are insufficiently protected and become injured. The sequence of this process will be clinically diagnosed as chronic disease.

Antioxidants as important elements in the body's defense against oxidative stress thus have a general anti-aging property as well as a specific disease-protective function. Since the consequences of chronic disease are among the leading causes of disability in old age, primary prevention by adequate antioxidative defense has not only an "anti-aging" function, but more importantly, a specific chronic-disease-preventing function. However, it becomes clear that this is a life-long important protective mechanism: primary prevention of age-related chronic diseases has to start early in life and needs to be continued throughout the whole life span.

The relationship between antioxidants and chronic disease is probably best investigated in cardiovascular disease. A strong inverse relationship between plasma antioxidant concentration, morbidity, and mortality from coronary heart disease was demonstrated. The analyses of the data allowed to quantify the contribution of the different antioxidative vitamins. According to these results a sufficient intake of vitamin E is most important, followed by vitamin C and carotene intake.

In the analysis of a population with an overall very good vitamin E status, a strong effect of vitamin C and beta-carotene was observed. It is quite well known that other antioxidants without vitamin functions originating from food, such as flavonoids, polyphenols, or lycopene have very important antioxidative functions (Fuhrman B.; Ben-Yaish L.; Attias J.; Hayek T.; Avaram M., "Tomato lycopene and beta-carotene inhibit low-density lipoprotein oxidation and this effect depends on the lipoprotein vitamin E content", Nutr. Metab. Cardiovasc. Dis. 7, 433-443, 1997; Pastori M.; Pfander H.; Boscoboinik D.; Azzi A., "Lycopene in association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells", Biochem. Biophys. Res. Commun. 250 (3), 582-585, 1998; Boehm F.; Edge R.; McGarvey D J; Truscott T G, "Beta-carotene with vitamins E and C offers synergistic cell protection against Nox", FEBS Lett. 436, 387-389, 1998; Watkins T. R.--Editor, "Wine, Nutritional and Therapeutic Benefits", American Chemical Society Symposium Series 661, 1997, Washington D.C.).

In late adulthood and early old age, cancer is the leading cause of premature death. There is no question that a large majority of cancers are the result of environmental factors challenging the specific genetic endowment of tissue at high risk for proliferative disorders. Epidemiological evidence clearly demonstrates that a low intake of fruit and vegetables and low plasma concentrations of antioxidative vitamins correlated with a significantly elevated cancer morbidity and mortality. This holds true for gastrointestinal cancer and lung cancer, but also for prostate cancer and for breast cancer.

The neoplastic process is a highly complex sequence of events. Many potentially dangerous mutations occur continuously. Once these genetic changes have escaped the initial defense and repair mechanisms, these altered cells have to be eliminated by other defense mechanisms. One important mechanism is the apoptotic process. It may be that committed cells in the proliferative stage are protected by antioxidants against the body's own immune and apoptotic defense mechanisms. This might explain why antioxidants occur in higher concentration in breast cancer tissue. There is no doubt that a life-long high intake of a diet rich in fruit and vegetables and high in a variety of antioxidants substantially and significantly lowers the risk of malignant disorders in later life.

Primary degenerative brain disease and diseases related to cerebral vascular disturbances are the leading cause of disability in old age. Loss of autonomy, dependence and high social costs for individuals and society are the consequences of brain dysfunction. The impressive gain in individual life expectancy is overshadowed by the loss of mental function in old age. Hence, prevention and treatment of disorders leading to mental impairment have emerged as major challenge of the modern health care system. As in the previous examples, a combination of age-related functional changes superimposed by disorders of circulation or of certain neuronal systems leading to distinct chronic diseases are being observed.

Given the importance of antioxidants in the maintenance of cell integrity and cell function, antioxidants (vitamin E, carotenes, vitamin C) and other micronutrients from the food, e.g. polyphenols, flavonoids, lycopene, may decrease the risk of vascular disease, protect the neurons against oxidative stress and thus maintain neuronal function. Several epidemiological studies in elderly people have revealed a correlation between antioxidants and cognitive performance.

Other epidemiological data have shown that red wine may reduce the mortality rate from heart disease, the so called "French paradox". An analysis conducted on 34,014 men between 1978 and 1983 in Eastern France has shown that a moderate intake of wine (2-5 glasses of wine) was associated with a 24-31% reduction in all-cause mortality (Renaud S. C. et al., "Alcohol and Mortality in Middle-Aged Men from Eastern France", Epidemiology 9, 184-188, 1998).

Although many studies have been conducted with single antioxidant compounds, the pharmacological effects of the administration of the combination of antioxidant substances of natural origin as plant extracts of Vitis vinifera (Grape), of Lycopersicon esculentum (Tomato) with the vitamins C, E, beta-carotene and selenium have never been studied.

The Israeli Patent Application IL 121112 (Jun. 19, 1997) describes a synergistic mixture containing lycopene and vitamin E and its use in the prevention of LDL oxidation. The applicant also published the results in a scientific paper describing that the LDL protection by lycopene exceeded the protection by .beta.-carotene. However, this effect was selective only to LDL's with high vitamin E content and was potentiated when the carotenoids were present in combination with vitamin E (Fuhrman B.; Ben-Yaish L.; Attias J.; Hayek T.; Avaram M., loc. cit.).

The U.S. Pat. No. 5,648,377 (Jul. 15, 1997) relates to the combination of lycopene with an extract of Vitis vinifera showing that the combination exerts a synergistic antioxidant action.

BRIEF SUMMARY OF THE INVENTION

The object of this invention is the surprising discovery that the administration of the combination of the extracts of the plants Vitis vinifera and Lycopersicon esculentum combined with vitamin C, vitamin E, .beta.-carotene and optionally selenium significantly increases, in a synergistic manner, the cell protection. The results obtained from the described experimental tests show that the improvement of the cell protection with the combination of the mentioned substances are statistically greater than the combination of an extract of Vitis vinifera with lycopene (U.S. Pat. No. 5,648,377) or the combination of vitamin E with lycopene (IL Patent application 121112).

The invention therefore relates to a improved method of protecting the cell from a disease caused by an overproduction of free radicals, said method comprises administering a protective or therapeutically effective amount of a composition comprising synergistic amounts of a lipophilic antioxidant and a hydrophilic antioxidant and optionally an acceptable carrier, the improvement wherein is that said lipophilic antioxidant is a mixture consisting essentially of vitamin E, beta carotene and an extract of Lycopersicum esculentum, and said hydrophilic antioxidant is a mixture consisting essentially of vitamin C and an extract of Vitis vinifera.

In another aspect, the present invention provides a method of treating a subject suffering from a disease, which is caused by an overproduction of free radicals, comprising the administration of a therapeutically effective amount of a composition according to the present invention.

In a further aspect, the present invention provides a method of treating a subject suffering from an inflammation.

In another aspect, the method according to the present invention is applicable to the treatment of a subject suffering from atherosclerosis.

In yet another aspect, according to the invention there is provided a method for preventing the mutagenic activity induced by free radicals in a subject.

In still another aspect, the method of the present invention is useful for treating a subject suffering from a tumor.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment the method according to this invention includes the administration of vitamin E, beta carotene, an extract of Lycopersicum esculentum, vitamin C, an extract of Vitis vinifera and a selenium compound. Preferred selenium compounds are sodium selenite or selenium yeast.

The term "extract of Lycopersicum esculentum" as used hereinabove or hereinbelow includes a dilute composition of lycopene. Said lycopene may be obtained by extraction from plants, algae, fungi or genetically modified organisms or by synthesis. Preferably the extract from dried skin of tomatoes is directly utilized.

The term "extract of Vitis vinifera" as used hereinabove or hereinbelow includes a dilute composition procyandolic oligomers. Preferably the extract from the seeds of red vines is directly utilized.

In another preferred embodiment the method according to this invention includes the administration of:

(a) 5 to 20 parts, preferably 7.5 to 15 parts of vitamin E, in particular vitamin E acetate or vitamin E succinate;

(b) 1 to 15 parts, preferably 2 to 10 parts of beta-carotene;

(c) 1 to 4 parts, preferably 1.5 to 3 parts of lycopene in the form of an extract of Lycopersicum esculentum obtained from dried skin of tomatoes.

(d) 2 to 60 parts, preferably 5 to 50 parts of vitamin C, in particular the sodium salt thereof; and

(e) 1 to 30 parts, preferably 1.1 to 25 parts of Vitis vinifera extract in particular obtained from the seeds of red vines.

Preferably the lipophilic antioxidant and the hydrophilic antioxidant are administered in the presence of a pharmaceutically acceptable carrier. Suitable excipients are exemplified in: Remington: the science and practice of pharmacy. 19th ed. Easton: Mack Publ., 1995.

Most preferred carriers are selected from the group consisting of natural plant oils, fully or partially hydrogenated plant oils, in particular soybean oil, fully or partially hydrogenated soybean oil, rape oil, peanut oil, lecithins, in particular soylecithin or egglecithin, plant phosphatides, in particular soyphosphatide and natural waxes, in particular beeswax.

The compositions may be formulated as solids or solutions. Solid formulations maybe for preparation of a solution before injection. Preferably, the pharmaceutical compositions of the invention are administered in the form of soft or hard gelatin capsule, tablet, coated tablet, suppository or in the transdermal form. The dosage will be adjusted according to factors like body weight and health status of the patient, nature of the underlying disease, therapeutic window of the compound to be applied, solubility, and the like. It is within the knowledge of the expert to adjust dosage appropriately.

Accordingly, a further aspect of the present invention is the use of a composition of the invention in the preparation of a pharmaceutical composition for the treatment of a subject suffering from pathological conditions being caused at least in parts to an overproduction of free radicals like aging, inflammation, atherosclerosis or cancer. Furthermore, an aspect of the invention is a method of prevention and/or treatment of inflammation, atherosclerosis or cancer, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient.

The objective of this study was to evaluate first in rat erythrocytes the protective effect of the combination of the extracts of Vitis vinifera, Lycopersicon esculentum, vitamin C, vitamin E and beta-carotene against the UVB-induced damage and the existence of a cooperative interaction between its components, and then in keratinocytes cell lines the ability of selenium to increase the endogenous enzymatic antioxidant defenses.

Claim 1 of 10 Claims

What is claimed is:

1. A method of protecting a subject from a disease, or treating a subject suffering from a disease, wherein said disease is caused by an overproduction of free radicals, said method comprising administering to said subject a protective or therapeutically-effective amount of a composition consisting essentially of:

(a) 5 to 20 parts of vitamin E;

(b) 1 to 15 parts of beta carotene;

(c) 1 to 4 parts of lycopene obtained from the extraction of dried skin of tomatoes;

(d) 2 to 60 parts of vitamin C;

(e) 1 to 30 parts of an extract of vitis vinifera from red vine seeds; and a pharmaceutically acceptable carrier.


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