Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-06
2002-07-30
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C514S457000
Reexamination Certificate
active
06426362
ABSTRACT:
TECHNICAL FIELD
This invention generally relates to non-naturally-occurring nutritional compositions for amelioration of disruption of energy metabolism secondary to stress comprising a tocopherol and/or a derivative thereof, and a synergist in effective amounts. The synergist can include a flavonoid, such as hesperetin, diosmin, combinations of such flavonoids or lactoferrin and/or derivatives thereof. Synergistic combinations of different forms of tocopherol, such as alpha- and gamma-tocopherol exemplified herein, also form a part of the present invention.
The invention also relates to non-naturally-occurring compositions comprising optimized formulations for amelioration of disruption of energy metabolism secondary to stress comprising a tocopherol and/or a derivative thereof, and an additional compound such as one or more flavonoids, exemplified by daidzein or biochanin A in effective amounts, empirically determined ratios of other flavonoids, other tocopherols, or lactoferrin, as exmplified herein. The invention also elates to methods of making such compositions.
BACKGROUND OF THE INVENTION
Metabolic pathways are of two types: anabolic, which are involved in synthetic work and require energy; and catabolic, which are degradative and energy-releasing. Catabolic and anabolic pathways can share a common partial sequence, which functions in one direction for synthesis and in the opposite direction for degradation. However, one route is never exactly the reverse of the other, since both need to be exergonic in their respective directions. For example, the pathways for glucose synthesis (gluconeogenesis) and glucose degradation (glycolysis) share many reactions in common, but each have several unique steps. These unique steps generally ensure thermodynamic irreversibility and can serve as regulatory sites. In the catabolic pathways, a substrate is sequentially degraded, releasing energy in the form of ATP (adenosine triphosphate). Catabolic pathways include both the anaerobic pathway, (i.e., fermentation) and the aerobic pathway (i.e., oxidative metabolism or respiration). For reviews, see Atkinson (1977)
Cellular Energy Metabolism and Its Regulation,
Academic Press, New York; Hochachka et al. (1993)
Surviving Hypoxia: Mechanisms of Control and Adaptation,
CRC Press, Inc., Fl.; and Alberts et al. (1994)
Molecular Biology of the Cell,
Garland Publ., New York. While metabolic pathways produce ATP, an essential energy carrier, by-products of these pathways include free radicals, which are potent cellular injurants.
Reactive oxygen species (ROS), also designated free radicals, include among other compounds singlet oxygen, the superoxide anion (O
2
.−), nitric oxide (NO.), and hydroxyl radicals. Mitochondria are particularly susceptible to damage induced by ROS, as these are generated continuously by the mitochondrial respiratory chain. See, for example, Boveris et al. (1973)
Biochem. J.
134:707-716; Turrens et al. (1997)
Biosc. Rep.
17:3-8; Tangeras et al. (1980)
Biochim. Biophys. Acta
589:162-175; Minotti et al. (1987)
Free Radic. Biol. Med.
3:379-387; Hermes-Lima et al. (1995)
Mol. Cell. Biochem.
145:53-60; Liu et al. (1997)
Biosc. Rep.
17:259-272; Kowaltowski et al. (1998)
FEBS Letters
425:213-216; Kowaltowski et al. (1995)
Am. J. Physiol.
269:C141-147; Kowaltowski et al. (1996)
J. Biol. Chem.
271:2929-2934. Free radicals attack membrane lipids and lipoproteins, generating carbon radicals. These in turn react with oxygen to produce a peroxyl radical, which may attack adjacent fatty acids to generate new carbon radicals. This process can lead to a chain reaction producing lipid peroxidation products. Halliwell (1994)
Lancet
344:721-724. Damage to the cell membrane can result in loss of cell permeability, increased intercellular ionic concentration, and/or decreased ability to excrete or detoxify waste products. The peroxynitrite anion (ONOO
−
), a reaction product of O
2
.
−
and nitric oxide (NO.) (Pryor et al. (1995)
Am J. Physiol.
268:699-722), appears to be responsible for many effects previously attributed to NO. Castro et al. (1994)
J. Biol. Chem.
269:29409-29415; Ischiropoulos et al. (1992)
Arch. Biochem. Biophys.
2:446-453; Halliwell et al. (1995)
Ann. Rheumat. Dis.
54:505-510; Salvemini et al. (1996a)
Br. J. Pharmacol.
118:829-838; Salvemini et al. (1996b),
Eur. J. Pharmacol.
303:217-220; Cuzzocrea et al. (1998)
Free Radic. Biol. Med.
24:450-459; Wizemann et al. (1994)
J. Leukoc. Biol.
56:759-768; Szabo et al. (1997)
J. Clin. Invest.
100:723-735. ROS can also contribute to damage to organs and organisms levels. These conditions include cell aging, as well as inflammation and cancer.
Free radicals are also problematic in organ transplantation, during which process cells and tissues experience hypoxia. After transplantation, the grafted tissue is reperfused with oxygenated blood. When reperfusion occurs and the flow of oxygen is restored, a burst of free radicals forms. The accumulation of free radicals contributes to post-transplantation injury in tissue giving rise to an increased number of damaged cells and an enhanced immune response by the recipient host. Zhao et al. (1996)
J. Neurosci. Res.
45:282-288; Unruh (1995)
Chest Surg. Clin. N. Am.
5:91-106. This immune response can lead to inflammation and reduced function in the transplanted tissue and/or rejection and failure of the graft.
Production of ROS also increases when cells experience a variety of stresses, including organ ischemia and reperfusion (as described above) and ultraviolet light exposure and other forms of radiation. Reiter et al. (1998)
Ann. N. Y. Acad. Sci.
854:410-424; Saini et al. (1998)
Res. Comm. Mol Pathol Pharmacol.
101:259-268; Gebicki et al. (1999)
Biochem. J.
338:629-636. ROS are also produced in response to cerebral ischemia, including that caused by stroke, traumatic head injury and spinal injury. In addition, when metabolism increases or a body is subjected to extreme exercise, the endogenous antioxidant systems are overwhelmed, and free radical damage can take place. Free radicals are reported to cause the tissue-damage associated with some toxins and unhealthful conditions, including toxin-induced liver injury. Obata (1997)
J. Pharm. Pharmacol.
49:724-730; Brent et al. (1992)
J. Toxicol. Clin. Toxicol.
31:173-196; Rizzo et al. (1994)
Zentralbl. Veterinarmed.
41:81-90; Lecanu et al. (1998)
Neuroreport
9:559-663. Exposure to hyperoxia also results in free-radical production, which can lead to lung damage if not counteracted by sufficient levels of antioxidants. Jenkinson (1989)
Clin. Chest Med.
10:37-47. Free radicals may also be responsible for freezing stress in plants. Tao et al. (1998)
Cryobiology
37:38-45.
In addition to stresses described above, cells are subject to other stresses, including hyper- and hypothermia, infection, osmotic, hyper- and hypo-gravity, starvation, growth in various reactors (such as bioreactors, fermentation, food preparation, etc.), toxicity (e.g., inhalation of toxic gases such as HCN, phosphates, thiophosphates), drug overdoses, and the like. Common to many of these stresses are injuries secondary to disruptions in energy metabolism. Treatment of these types of injuries includes administration of various individual or combinations of tocopherols which protect against disruptions of energy metabolism and the resulting cell injury during stress (“cytoprotectants”). For example, the time that mammalian cells can undergo stress induced energy dysfunction stress be extended by administration of purine derivatives, alone or in combination with electron acceptor compounds and/or amino acids. U.S. Pat. No. 5,801,159.
Because of the potentially damaging nature of free radicals, and because O
2
.
−
generation is continuous, the body has a number of antioxidant defense mechanisms including enzymes, such as vitamin E, vitamin C, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, NADP transhydrogenase, thiol peroxidase SP-22, copper and iron transport,
Brown Lesley A.
Miller Guy
Fay Zohreh
Galileo Laboratories, Inc.
Kwon Brian-Yong
Morrison & Foerster / LLP
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