Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-01
2002-11-12
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S009100
Reexamination Certificate
active
06479533
ABSTRACT:
BACKGROUND OF THE INVENTION
Mitochondria are subcellular organelles present: in all oxygen-utilizing eukaryotic organisms in which energy in the form of adenosine triphosphate (ATP) is generated, and oxygen is reduced to water. Ninety percent of the oxygen taken in is consumed in mitochondria. A substantial byproduct of this ATP generation is the formation of potentially toxic oxygen radicals. For example, it is estimated that 1-2% of all reduced oxygen yields superoxide (O
2
—) and hydrogen peroxide (H
2
O
2
). Other reactive oxygen species (ROS) that form are singlet oxygen (
1
O
2
) and hydroxyl radical (OH•). Under stress conditions in the cell this can rise to 10% of all consumed oxygen. Mitochondrial membranes are sensitive to lipid peroxidation and depolarization resulting from these ROS. Mitochondrial damage is also a result of exposure to sunlight, which forms ROS as indicated above. Because damage to mitochondria is believed to be the cause or an important factor in some diseases, such as cancer, diabetes, cataract, neurodegenerative disease, porphyrias, cardiovascular disease, and also a contributor to the complications of aging, a method of protecting mitochondria from such damage, repairing such damage, is desired. Furthermore, exposure to adverse environmental factors, including industrial air pollutants and petroleum and tobacco combustion products, may contribute to oxidative damage to pulmonary and other tissues of the body. In addition, various therapeutic regimens such as chemo-therapeutic drugs and radiation therapy for the treatment of dysproliferative diseases induce significant oxidant stress-related side effects, such as cardiotoxicity. The present invention relates to applied agents which protect the mitochondria from such damage.
Eukaryotic (e.g. plant and animal) cells differ from prokaryotic cells (e.g. bacteria, viruses and the like) in that they contain mitochondria. To the extent that damage to mitochondria is debilitating to eukaryotic cells, they are hypersensitive to this damage relative to prokaryotic cells. Treatments designed to inactivate such bacteria and viruses by ROS, such as photodynamic therapy (PDT, treatment of cells with pro-dyes or dyes followed by exposure to light) have the unwanted side effects of damaging the mitochondria of the host non-diseased cells. The present invention relates to reducing the toxicity of ROS to mitochondria, and thus improving the therapeutic index of therapies utilizing ROS to inactivate prokaryotic organisms.
In some cases one portion of tissue is the target for inactivation by ROS while the surrounding tissue should be spared. For example, the hair and hair follicle are targets for PDT and so-called photothermolysis therapy while the surrounding skin should be preserved. The present invention relates to protection of the mitochondria in the surrounding tissue and thus enhancing the relative efficacy of the cosmetic or therapeutic treatment in inactivating target tissue.
L-ergothioneine is a sulphur-containing amino acid that is found in many mammalian tissues but is not endogenously synthesized and must be consumed in the diet. By L-ergothioneine I include ergothioneine and all its derivatives and congeners that in aqueous solution are 2-thio-imidazoles and are predominantly in the thione rather than the thiol form. L-ergothioneine exists in some tissues in millimolar quantities, its exact role is uncertain (see: Melville, 1959, Vitamins and Hormones 7:155-204). It is generally regarded as an antioxidant, although results are conflicting. Some regard it as a scavenger of hydrogen peroxide (see: Hartman, 1990, Methods in Enzymology 186:310-318) while others contend that it does not readily react with hydrogen peroxide but does scavenge hydroxyl radical (see: Akamnu et al. 1991, Arch. Biochem. Biophys. 298:10-16, 1991). Although previous in vitro studies have demonstrated its ability to protect DNA and proteins against phototoxic drug binding induced by UV radiation. (e.g., van den Brooke et al., 1993, J. Photochem. Photobiol. B 17:279-286), and to protect bacteriophage against gamma-irradiation (Hartman et al., 1988, Radiation Research 114:319-330), in vivo results have not been as promising. Although L-ergothioneine has been claimed as useful in topical formulations for scavenging radicals and UV light protectants for hair a skin damage (e.g., WO 9404129), Van den Broeke et al. (1993, mnt. J. Radiat. Biol. 63:493-500) did not find topically applied L-ergothioneine effective in an animal model of UV-induced phototoxic drug binding to epidermal biomolecules. Other proposed in vivo uses have included lowering of circulating lipoprotein (a) levels (U. S. Pat. No. 5,272,166), and inhibiting skin pigmentation, for example, to remove dark spots and freckles (JP 63008335 and JP 61155302).
As described above, numerous disease processes are attributed to the body's adverse reaction to the presence of elevated levels of reactive oxygen species (ROS) described above. In the eye, cataract, macular degeneration and degenerative retinal damage are attributed to ROS. Other organs and their ROS-related diseases include: lung cancer induced by tobacco combustion products and asbestos; accelerated aging and its manifestations, including skin damage; atherosclerosis; diseases of the nervous system such as Parkinson's disease, Alzheimer's disease, muscular dystrophy, multiple sclerosis; other lung diseases including emphysema and bronchopulmonary dysphasia; iron overload diseases such as hemochromatosis and thalassemia; pancreatitis; diabetes; renal diseases including autoimmune nephrotic syndrome and heavy metal-induced nephrotoxicity; and radiation injuries. Certain anti-neoplastic drugs such as adriamycin and bleomycin induce severe oxidative damage, especially to the heart, limiting the patient's exposure to the drugs. Redox-active metals such as iron induce oxidative damage to tissues; industrial chemicals and ethanol, by exposure and consumption, induce an array of oxidative damage-related injuries, such as cardiomyopathy and liver damage. Airborne industrial and petrochemical-based pollutants, such as ozone, nitric oxide, and halogenated hydrocarbons, induce oxidative damage to the lungs, gastrointestinal tract, and other organs. Protecting mitochondria from these many etiologic agents is desirable.
Photodynamic therapy (PDT) is the use of light, especially laser light, to activate a chromophore to produce ROS, which can be either endogenous (melanin, hemoglobin) or exogenous (applied dye or pro-dye metabolized or converted to a dye) for the purpose of destroying a target with ROS. PDT is used to kill diseased cells such as tumor cells, but it is also used to destroy non-eukaryotic cellular targets such as viruses and hair. An unwanted side-effect of PDT to destroy non-eukaryotic cellular targets is the destruction of living eukaryotic cells by destruction of their mitochondria, such as red blood cells or epidermal cells. This unwanted cell killing is the limiting factor in the usefulness of these PDT therapies in applications such as blood sterilization and laser hair removal. In general Type I oxidation reactions lead to lipid peroxidation that damage mitochondria while singlet oxygen (Type II reactions) destroy non-cellular targets (see I. Rosenthal and E. Ben-Hur, Int. J. Radiat. Biol., 1995, 67:85, and S. Rywkin, L. Lenny, J. Goldstein, N. Geacintov, H. Margolis-Nunno and B. Horowitz, Photochem. Photobiol. 1992, 56:463). The invention conceives of the use of L-ergothioneine to selectively quench Type I oxidation reactions while not interfering with singlet oxygen (Type II reactions).
Inactivation of viruses, such as HIV, by PDT involves the generation of singlet oxygen that is toxic to the virus. However, if the viral inactivation occurs in the presence of living cells, such as blood cells, the cellular components (red and white blood cells) can be damaged by Type I reactions. Another example is light activated hair removal, the so-called selective photothermolysis. In this process l
Applied Genetics Incorporated Dermatics
Klee Maurice M.
Reamer James H.
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