Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-17
2001-01-23
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S255000, C540S465000
Reexamination Certificate
active
06177419
ABSTRACT:
BACKGROUND OF THE INVENTION
Molecular oxygen is an essential nutrient for nonfacultative aerobic organisms, including humans. Oxygen is used in many important ways, namely, as the terminal electronic acceptor in oxidative phosphorylation, in many dioxygenase reactions, including the synthesis of prostaglandins and of vitamin A from carotenoids, in a host of hydroxylase reactions, including the formation and modification of steroid hormones, and in both the activation and the inactivation of xenobiotics, including carcinogens. The extensive P-450 system uses molecular oxygen in a host of important cellular reactions. In a similar vein, nature employs free radicals in a large variety of enzymic reactions.
Excessive concentrations of various forms of oxygen and of free radicals can have serious adverse effects on living systems, including the peroxidation of membrane lipids, the hydroxylation of nucleic acid bases, and the oxidation of sulfhydryl groups and of other sensitive moieties in proteins. If uncontrolled, mutations and cellular death result.
Biological antioxidants include well-defined enzymes, such as superoxide dismutase, catalase, selenium glutathione peroxidase, and phospholipid hydroperoxide glutathione peroxidase. Nonenzymatic biological antioxidants include tocopherols and tocotrienols, carotenoids, quinones, bilirubin, ascorbic acid, uric acid, and metal-binding proteins. Various antioxidants, being both lipid and water soluble, are found in all parts of cells and tissues, although each specific antioxidant often shows a characteristic distribution pattern. The so-called ovothiols, which are mercaptohistidine derivatives, also decompose peroxides nonenzymatically.
Free radicals, particularly free radicals derived from molecular oxygen, are believed to play a fundamental role in a wide variety of biological phenomena. In fact, it has been suggested that much of what is considered critical illness may involve oxygen radical (“oxyradical”) pathophysiology (Zimmermen J J (1991)
Chest
100: 189S). Oxyradical injury has been implicated in the pathogenesis of pulmonary oxygen toxicity, adult respiratory distress syndrome (ARDS), bronchopulmonary dysplasia, sepsis syndrome, and a variety of ischemia-reperfuision syndromes, including myocardial infarction, stroke, cardiopulmonary bypass, organ transplantation, necrotizing enterocolitis, acute renal tubular necrosis, and other disease. Oxyradicals can react with proteins, nucleic acids, lipids, and other biological macromolecules producing damage to cells and tissues, particularly in the critically ill patient.
Free radicals are atoms, ions, or molecules that contain an unpaired electron (Pryor W A (1976)
Free Radicals in Biol
. 1: 1). Free radicals are usually unstable and exhibit short half-lives. Elemental oxygen is highly electronegative and readily accepts single electron transfers from cytochromes and other reduced cellular components; a portion of the O
2
consumed by cells engaged in aerobic respiration is univalently reduced to superoxide radical (•O
2
−
) (Cadenas E (1989)
Ann. Rev. Biochem
. 58: 79). Sequential univalent reduction of •O
2
−
produces hydrogen peroxide (H
2
O
2
), hydroxyl radical (•OH), and water.
Free radicals can originate from many sources, including aerobic respiration, cytochrome P-450-catalysed monooxygenation reactions of drugs and xenobiotics (e.g., trichloromethyl radicals, CCl
3
•, formed from oxidation of carbon tetrachloride), and ionizing radiation. For example, when tissues are exposed to gamma radiation, most of the energy deposited in the cells is absorbed by water and results in scission of the oxygen-hydrogen covalent bonds in water, leaving a single electron on hydrogen and one on oxygen creating two radicals H• and •OH. The hydroxyl radical, •OH, is the most reactive known in chemistry. It reacts with biomolecules and sets off chain reactions and can interact with the purine or pyrimidine bases of nucleic acids. Indeed, radiation-induced carcinogenesis may be initiated by free radical damage (Breimer L H (1988)
Brit. J. Cancer
57: 6). Also for example, the “oxidative burst” of activated neutrophils produces abundant superoxide radical, which is believed to be an essential factor in producing the cytotoxic effect of activated neutrophils. Reperfusion of ischemic tissues also produces large concentrations of oxyradicals, typically superoxide (Gutteridge J M C and Halliwell B (1990)
Arch. Biochem. Biophys
. 283: 223). Moreover, superoxide may be produced physiologically by endothelial cells for reaction with nitric oxide, a physiological regulator, forming peroxynitrite, ONOO
−
which may decay and give rise to hydroxyl radical, •OH (Marletta M A (1989)
Trends Biochem. Sci
. 14: 488; Moncada et al. (1989)
Biochem. Pharmacol
. 38: 1709; Saran et al. (1990)
Free Rad. Res. Commun
. 10: 221; Beckman et al. (1990)
Proc. Natl. Acad. Sci
. (
U.S.A
.) 87: 1620). Additional sources of oxyradicals are “leakage” of electrons from disrupted mitochondrial or endoplasmic reticular electron transport chains, prostaglandin synthesis, oxidation of catecholamines, and platelet activation.
Oxygen, though essential for aerobic metabolism, can be converted to poisonous metabolites, such as the superoxide anion and hydrogen peroxide, collectively known as reactive oxygen species (ROS). Increased ROS formation under pathological conditions is believed to cause cellular damage through the action of these highly reactive molecules on proteins, lipids, and DNA. During inflammation, ROS are generated by activated phagocytic leukocytes; for example, during the neutrophil “respiratory burst”, superoxide anion is generated by the membrane-bound NADPH oxidase. ROS are also believed to accumulate when tissues are subjected to ischemia followed by reperfusion.
Many free radical reactions are highly damaging to cellular components; they crosslink proteins, mutagenize DNA, and peroxidize lipids. Once formed, free radicals can interact to produce other free radicals and non-radical oxidants such as singlet oxygen (
1
O
2
) and peroxides. Degradation of some of the products of free radical reactions can also generate potentially damaging chemical species. For example, malondialdehyde is a reaction product of peroxidized lipids that reacts with virtually any amine-containing molecule. Oxygen free radicals also cause oxidative modification of proteins (Stadtman E R (1992)
Science
257: 1220).
•O
2
−
can also react, at a diffusion-limited rate, with NO; yielding peroxynitrite (Huie et al. (1993)
Free Rad. Res. Commun
. 18: 195).
It is also known that superoxide is involved in the breakdown of endothelium-derived vascular relaxing factor (EDRF), which has been identified as nitric oxide (NO), and that EDRF is protected from breakdown by superoxide dismutase. This suggests a central role for activated oxygen species derived from superoxide in the pathogenesis of vasospasm, thrombosis and atherosclerosis. See, for example Gryglewski R J et al., “Superoxide Anion is Involved in the Breakdown of Endothelium-derived Vascular Relaxing Factor”, (1986)
Nature
320: 454-456 and Palmer R M J et al., “Nitric Oxide Release Accounts for the Biological Activity of Endothelium Derived Relaxing Factor”, (1987)
Nature
327: 523-526.
Aerobic cells generally contain a number of defences against the deleterious effects of oxyradicals and their reaction products. Superoxide dismutases (SODs) catalyse the reaction:
2•O
2
−
+2H
+
→O
2
+H
2
O
2
which removes superoxide and forms hydrogen peroxide. H
2
O
2
is not a radical, but it is toxic to cells; it is removed by the enzymatic activities of catalase and glutathione peroxidase (GSH-Px). Catalase catalyses the reaction:
2H
2
O
2
→2H
2
O+O
2
and removes hydrogen peroxide and forms water and oxygen. GSH-Px removes hydrogen peroxide by using it to oxidise reduced glutathione (GSH) into oxidised glutathione (GSSG) according to the following reaction:
2GSH+H
2
O
2
&ra
Box Philip Charles
Campbell Ian Baxter
Giblin Gerard Martin Paul
Tranter George Edward
Walker Ann Louise
Eukarion, Inc.
Hamilton Brook Smith & Reynolds P.C.
Kight John
Robinson Binta
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