Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing
Reexamination Certificate
2000-06-09
2003-11-18
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
C424S400000, C424S450000, C424S684000, C424S724000, C424SDIG006, C514S052000, C514S706000, C514S730000, C514S731000, C514S732000, C514S734000, C514S736000, C514S836000, C514S970000, C514S973000
Reexamination Certificate
active
06649193
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention provides prophylactic, therapeutic and industrial antioxidant compositions that are enhanced with stabilized atomic hydrogen/free electrons. The invention also provides methods to prepare and use such antioxidant compositions.
2. Description of the Related Art
Molecular oxygen is an essential substance for all aerobic organisms, including humans. Oxygen is involved in many metabolic reactions ranging from energy production to the synthesis of vitamin A and prostaglandins and the deoxification and metabolism of drugs, chemicals and foods. Some forms of oxygen and oxygen-containing species are very reactive and can cause significant damage to the organism. Such moieties are termed reactive oxygen species (“ROS”).
ROS include hydrogen peroxide, hydroxyl radical, superoxide radical, singlet oxygen, etc. Hydrogen peroxide is relatively stable and remains until it is destroyed or reacts with molecules sensitive to oxidative damage. Other ROS, such as hydroxyl radicals, are very unstable and last no longer than a few picoseconds to seconds, depending on the environment. The hydroxyl radical is one example of another reactive group, referred to as free radical species. Free radicals are atoms, ions or molecules that contain an unpaired free electron. The presence of an unpaired free electron is one of the reasons for the high reactivity and short lifetime of most such species. Free radicals and ROS are normal products of metabolism and are actually involved in the regulation of cellular processes [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. However, the overproduction of ROS and free radicals is involved in the pathogenesis of a wide variety of human diseases [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. Such diseases include cancer, diabetes, AIDS, cardiovascular diseases, neurodegenerative diseases, skin diseases, autoimmune diseases and others.
ROS can damage biological macromolecules, cells, tissues and organs in many ways. Oxidation of sulfhydryl groups and other sensitive components of proteins can either increase or decrease the activity of enzymes. It was also recently discovered that oxidative modification of proteins is involved in the control and regulation of many cellular processes [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. Peroxidation of membrane lipids can result in crosslinking of unsaturated lipids and modification of the cellular permeability to different ions and molecules. Some ions such as calcium are also involved in the control and regulation of cellular processes. Hydroxylation of nucleic acid bases and the breakup of nucleic acids are also deleterious processes that result from the presence of excessive concentrations of ROS. Once formed, many free radicals are involved in “chain reactions” producing other free radicals and ROS. Even the scavenging and degradation of free radicals can produce highly reactive, damaging species. [E. R. Stadtman, Science, Vol. 257, 1220 (1992)].
Organisms, including humans, have evolved ways of handling dangerous ROS. Organisms posses a large number of defenses against the deleterious effects of ROS. [See, for instance, Oxidative Stress, Oxidants and Antioxidants, Academic Press, London, 1991]. Many enzymes and small molecules are used by aerobic cells to protect against the damage caused by ROS. Enzymes which are used to catalyze the removal or transformation of ROS include superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase etc. Small molecules used by aerobic cells to scavenge ROS include vitamins C, E and A, glutathione, ubiquinone, uric acid, carotenoids, etc. Superoxide dismutase is a very efficient catalyst for the removal of superoxide free radicals. Such removal results in the production of hydrogen peroxide. Catalase, in turn, is a very efficient catalyst for the removal of the hydrogen peroxide that is produced. Glutathione peroxidase and transferase enzymes are efficient in the removal of many ROS. Among small molecules, the most important molecule involved in the prevention of damage caused by ROS is a thiol-containing tripeptide, glutathione [see, for instance, Oxidative Stress, Oxidants and Antioxidants, Academic Press, London, 1991]. Glutathione (GSH) is present in all animal cells in millimolar concentrations and is directly involved in the reduction (and, thereby, detoxification) of ROS. Reduction of ROS by glutathione results in oxidation and dimerization of glutathione to the disulfide-linked dimer (GSSG). This oxidized form of glutathione is toxic and oxidizing in itself. Other small molecules such as ascorbate (vitamin C) or tocopherol (vitamin E) also can directly reduce ROS. The difference between enzymes such as superoxide dismutase and small molecules such as vitamin C is that the former can catalytically remove many molecules of ROS, while the latter reacts with oxidants stoichiometrically, usually in a 1:1 or 2:1 ratio.
However, ROS and free radicals are not always toxic. Recent evidence suggests that at moderately high concentrations, certain forms of ROS such as hydrogen peroxide, may act as signal transduction messengers involved in the control of cell proliferation, differentiation and death [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. Regulation of gene expression by different concentrations of many oxidants and antioxidants has recently been shown. It was shown that the activity of many proteins involved in signal transduction and gene transcription is modified by intracellular redox state [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. In fact, the regulation of gene expression by oxidants, antioxidants, and the cellular redox state has emerged as a novel subdiscipline in molecular biology that has promising therapeutic implications [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. Redox-regulated transcription factors such as AP-1 and NF&kgr;B have been shown to be implicated in the pathogenesis of many inflammatory diseases, cancer, AIDS, diabetes complications, atherosclerosis and neurodegenerative diseases. It was observed that critical steps in the signal transduction cascades are sensitive to oxidants and antioxidants. It was also shown that the interaction of some membrane proteins, protein phosphorylation and the binding and activation of transcription factors are sensitive to physiological oxidant-antioxidant homeostasis [C. K. Sen and L. Packer, FASEB J., Vol. 10, 227 (1996)]. Sen and Packer suggested those oxidants, antioxidants and other factors that influence intracellular redox status can be developed into novel potential prophylactic and therapeutic agents.
Scientists and other individuals involved in the development of pharmaceutical and dietetic products based on antioxidant action realized the potential usefulness of antioxidants long ago. Many products with potential therapeutic use are described in peer reviewed journals and patent literature. However, those products are currently not completely satisfactory. We will discuss such prior art literature below.
Small molecules are currently used as dietetic supplement antioxidants. Vitamins C and E are probably the most commonly used antioxidant supplements. However, both molecules can easily be oxidized and, when oxidized, become toxic themselves [M. Gabbay et al., Neuropharmacology, Vol. 35, 571 (1996)]. Novel synthetic molecules such as 21-aminosteroids, also termed lazaroids, showed some effect in the prevention of free radical damage to tissue after brain damage but did not show any beneficial effects in clinical trials with stroke patients [RANTTAS Investigators, Stroke, Vol. 27, 195 (1996)]. Lipoic acid and its derivatives have been proposed as therapeutic antioxidants, but those molecules rapidly leave cells and do not sufficiently protect affected tissues from oxidative damage [U.S. Pat. No. 5,728,735]. N-acetyl cysteine (NAC)
Cohen & Pontani, Lieberman & Pavane
Henceforth Hibernia Inc.
Pak John
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