Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-29
2001-07-17
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S007600, C514S012200, C514S023000, C514S021800, C514S251000, C514S276000, C424S054000, C424S049000, C424S535000, C424S655000, C530S365000, C530S833000
Reexamination Certificate
active
06262019
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention provides a method of improving glutathione (GSH) concentrations, both intra and extra-cellularly, in mammals, thereby improving the cellular and humoral immune response. It comprises oral administration of a therapeutically effective amount of nutritional supplement which is composed of critical and synergistic quantities of amino acids, peptides, and bioflavanoids.
2. Brief Description of Related Art
Glutathione is a well-known tripeptide, which exists in two basic forms. The antioxidant form or “reduced glutathione” tripeptide is conventionally called “glutathione” and abbreviated as “GSH”. The oxidized form is a sulfur-sulfur linked compound known as glutathione disulfide (GSSG).
Glutathione in its biologically active, reduced form (GSH) has the formula:
and is appropriately named &ggr;-L-Glutamyl-L-cysteinylglycine. It is ubiquitous in animals, plants, and microorganisms and being water soluble is found mainly in the cell cytosol and other aqueous phases of the living system. Glutathione often attains millimolar levels inside living cells, which makes it one of the most highly concentrated intracellular antioxidants.
Glutathione is homeostatically controlled, both inside the animal cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it per the gamma-glutamyl cycle. (Meister A. Glutathione, Ascorbate and Cellular Protection Cancer Res (Suppl) 1994 (Apr 1); 54:1969S-1975S).
Glutathione is most concentrated in the mammal liver (10 mM), where the P450 Phase II″ enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of-SH/reducing power.
Briefly, glutathione synthesis occurs within animal cells in two closely linked enzymatically controlled reactions that utilize Adenosine Triphosphate (ATP) and draw on nonessential amino acids as substrates. First, cysteine and glutamate are combined (by the enzyme gamma-glutamyl cysteinyl synthetase, with availability of cysteine usually being the rate-limiting factor. Cysteine is generated from the essential amino acid methionine, from the degradation of dietary protein, or from turnover of endogenous proteins. The buildup of GSH acts to feedback-inhibit this enzyme, thereby helping to ensure homeostatic control over GSH synthesis.
The second GSH synthesis reaction combines gamma-glutamylcysteine with glycine to generate GSH (catalyzed by GSH synthetase).
With regard to the essentiality of GSH for the survival of the mammal, substantial information is available from studies on hereditary GSH depletion in the human, and from experimental depletion and repletion of GSH in animal models and cell cultures, see for example: Meister A. Larsson A. Glutathione Synthetase Deficiency and Other Disorders of the Gamma-Glutamyl Cycle; Scriver CR. et al eds. The Metabolic and Molecular Bases of Inherited Disease (Volume I). New York: McGraw-Hill: 1995:1461-1495 (Chapter 43); and Beutler E. Nutritional and Metabolic Aspects of Glutathione, Annu Rev Nutr 1989;9:287-302.
Reduced GSH levels in mammalian cells are associated with a wide variety of pathophysiologic states, including hepatic dysfunction, malignancies, HIV infection, pulmonary disease, Parkinson's disease, related immunologic illnesses and physiological conditions; see for example the descriptions in Kidd, Alternative Medicine Review, Vol. 2, No. 3, pages 156-176 (1997).
The consequences of sustained GSH depletion are fatal. As cellular GSH is depleted, first individual cells die in those areas most affected. Then zones of tissue damage begin to appear. Localized free-radical damage spreads across the tissue in an ever-widening, self-propagating wave.
An object of this invention is to promote gastrointestinal absorption and intracellular uptake of components which will maximize intracellular reduced glutathione production by a mammal including a human.
SUMMARY OF THE INVENTION
The invention comprises a composition of matter, which comprises in admixture:
N-acetylcysteine;
vitamin C; and
a pharmaceutically acceptable systemic carrier for oral administration.
In preferred embodiments, the invention further comprises one or more of the following:
alpha-lipoic acid;
sylmarin;
quercitin;
l-glutamine;
N-acetyl-d-glucosamine;
a probiotic.
The invention also comprises systemic administration of the composition of the invention to a mammal suffering from low glutathione levels, to stimulate the natural production of glutathione in the biological cells of the mammal.
The term “low glutathione levels” as used herein means a blood glutathione level below about 440 &mgr;g glutathione/10
10
erythrocytes, determined by the colorimetric method of Beutler et al., Improved Method for the Determination of Blood Glutathione, J. Lab. Clin. Med., 61;882-8(1963). Normal levels in humans ranges from about 440 to 654 &mgr;g/10
10
erythrocytes.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
Recently, there have been many scientific papers published discussing the direct relationship between decreased glutathione levels and the progression of many chronic diseases. Glutathione functions as an antioxidant, antitoxin and protector of red blood cells, and is extremely important to the immune system. It neutralizes free radicals minimizing the damage they cause and is profoundly important for cellular homeostasis.
As with other cell types, the proliferation, growth, and differentiation of immune cells is dependent on GSH. Both the T and the B lymphocytes require adequate levels of intracellular GSH to differentiate, and healthy humans with relatively low lymphocyte GSH were found to have significantly lower CD4 counts; Kinscherf R. Fischbach T. Mihm S. et al. Effect of glutathione depletion and oral N-acetylcysteine treatment on CD4+ and CD8+ cells. FASEB J 1994;8:448-451. Intracellular GSH is also required for the T-cell proliferative response to mitogenic stimulation, for the activation of cytotoxic T “killer” cells, and for many specific T-cell functions, including DNA synthesis for cell replication, as well as for the metabolism of interleukin-2 which is important for the mitogenic response; Wu D. Meydani S N, Sastre J. et al. In-vitro glutathione supplementation enhances interleukin-2 production and mitogenic response of peripheral blood mononuclear cells from young and old subjects; J Nutr 1994;124:655-663.
In summary, it has been demonstrated that decreased levels of glutathione may be a result of various types of prolonged stress, increased free radical formation and hyperactivity of the immune system. These factors in turn compromise the health of mammalian cells. Despite the apparent importance of adequate glutathione levels, little emphasis has heretofore been placed on replacing depleted stores. Some glutathione comes from the diet but the majority is made in the liver.
Studies have demonstrated that oral glutathione supplementation is not well absorbed by many of the mammal's cells and does not replenish losses inside cells where it is most needed; Witschi A. Reddy S. Stofer B. et al. The systemic availability of Oral Glutathione. Eur. J Clin. Pharmacol. 1992;43:667-669.
The sulfur-containing amino acid l-cysteine is the precursor that most limits the cellular biosynthesis of GSH. When substituted into the diet in place of the total protein allowance it was effective in raising GSH levels (see Witschi et al., supra.)
Glutathione esters, synthetic compounds prepared by linking the glycol end of GSH into ester bonds, have been the subject of much research by Meister, Anderson, supra., as potential oral GSH delivery compounds (see also U.S. Pat. No. 4,784,685). These esters do appear to be effective GSH delivery vehicles, but have the disadvantage that they yield alcohols in vivo when their ester bonds are broken, and their safety over the long term has yet to be satisfactor
Keller Robert H
Kirshenbaum David W
Carlson Karen Cochrane
Pitney Hardin Kipp & Szuch LLP
Tu Stephen
Vit-Immune, L. C.
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