Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2001-01-19
2002-02-26
Clardy, S. Mark (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C424S401000, C424S064000, C424S070100
Reexamination Certificate
active
06350785
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions and methods for treating cell damage caused by reactive oxygen species in relation to a variety of skin or mucosal membrane disorders. More specifically, the present invention relates to the treatment of skin and mucosal membrane disorders through the topical delivery of compounds that inhibit the production or release of reactive oxygen metabolites.
Reactive oxygen metabolites are often produced by the incomplete reduction of oxygen. The complete reduction of one molecule of O
2
to water is a four-electron process. Oxidative metabolism continually generates partially reduced species of oxygen, which are far more reactive, and hence more toxic than O
2
itself. A one-electron reduction of O
2
yields superoxide ion (O
2
−
); reduction by an additional electron yields hydrogen peroxide (H
2
O
2
), and reduction by a third electron yields a hydroxyl radical (OH•), and a hydroxide ion. Nitrous oxide (NO), is another interesting reactive oxygen metabolite, produced through an alternative pathway. Hydroxyl radicals in particular are extremely reactive and represent the most active mutagen derived from ionizing radiation. All of these species are generated and must be converted to less reactive species if the organism is to survive.
Particular cells of the immune system have harnessed the toxic effects of ROMs as an effector mechanism. Professional phagocytes, polymorphonuclear leukocytes (neutrophils, PMN), monocytes, macrophages, and eosinophils function to protect the host in which they reside from infection by seeking out and destroying invading microbes. These phagocytic cells possess a membrane-bound enzyme system that can be activated to produce toxic oxygen radicals in response to a wide variety of stimuli.
The “increased respiration of phagocytosis” (the respiratory burst) was reported and thought to be a result of increased mitochondrial activity providing additional energy for the processes of phagocytosis. It was later shown that a non-mitochondrial enzymatic system produced the increased levels of oxygen metabolites since the respiratory burst continued even in the presence of mitochondrial inhibitors such as cyanide and antimycin A. In 1968, Paul and Sbarra showed clearly that stimulated phagocytes produced hydrogen peroxide and in 1973 Babior and co-workers established that superoxide was a major product of the oxidase. (Paul and Sbarra,
Biochim Biophys Acta
156(1): 168-78 (1968); Babior, et al.,
J Clin Invest
52
(3): 741-4 (1973). It is now generally accepted that the enzyme is membrane bound, exhibits a preference for NADPH (K
m=
45 &mgr;M) over NADH (K
m=
450 &mgr;M), and converts oxygen to its one electron-reduced product, superoxide.
NADPH+H+H
++
2O
2
→NADP
++
2H
++
2O
2
−
The hydrogen peroxide arises from subsequent dismutation of the superoxide.
2O
2
−+2H
+
→H
2
O
2
+O
2
−
The enzyme activity is almost undetectable in resting (unstimulated phagocytes, but increases dramatically upon stimulation. Patients with the rare genetic disorder chronic granulomatous disease (CGD), have a severe predisposition to chronic recurrent infection. The neutrophils from these patients phagocytose normally but the respiratory burst is absent and NADPH oxidase activity (and radical production) is undetectable, indicating that the oxidase and its product, the reactive oxygen metabolites, (ROMS) have an important bactericidal function.
Neutrophils and macrophages produce oxidizing agents to break through the protective coats or other factors that protect phagocytosed bacteria. The large quantities of superoxide, hydrogen peroxide, and hydroxyl ions are all lethal to most bacteria, even when found in very small quantities.
While there are beneficial effects of these oxygen metabolites, it is clear that inappropriate production of oxygen metabolites can result in severely deleterious effects. A number of these deleterious effects manifest themselves in the dermal tissues and mucosal membranes of the host. For example, a variety of skin disorders including herpes simplex infections, and chemical and heat induced skin lesions can be exacerbated by unwanted concentrations of reactive oxygen metabolites. Effective compositions and methods to reduce and minimize the production and release of ROMs in patients suffering from a variety of disparate disorders would be a great boon to medicine and serve to reduce and eliminate a substantial amount of human suffering.
Topically administered salves, balms and other such medicaments are well known in the art. The application of mud or plant extracts such as aloe vera are just two examples of such medicaments. For a discussion of aloe vera, see U.S. Pat. No. 4,857,328, which is hereby incorporated by reference. The use of two different histamine derivatives as topically administered skin medicaments has also been discussed previously. The first may be found in a series of U.S. Patents to Jack et al., which disclose the use of a pharmaceutical composition of water, water soluble vinyl polymer gel, an amine alcohol dispersant and 1H-imidazole-4-ethanamine phosphate to treat certain skin disorders. See U.S. Pat. Nos. 5,294,440; 5,679,337; and 5,716,610. The second is found in U.S. Pat. No. 5,792,784, which discloses a pseudo-dipeptide product obtained by coupling histamine or a methyl-substituted histamine and an amino acid.
SUMMARY OF THE INVENTION
The present invention is directed to methods and compositions for reducing enzymatically produced ROM-mediated damage to a subject's skin or mucosal membranes by the topical application of ROM production and release inhibiting compositions. One embodiment of the present invention is a method for inhibiting and reducing enzymatically produced ROM-mediated oxidative damage to a subject's skin or mucosal membranes comprising the step of topically delivering an effective dose of a ROM production and release inhibitory compound in a pharmaceutically acceptable carrier to a subject suffering from ROM-mediated oxidative damage to said subject's skin or mucosal membranes.
In one aspect of this embodiment, the ROM-mediated oxidative damage to said subject's skin or mucosal membranes is a viral disease selected from the group consisting of herpes labialis, herpes genitalis, herpes zoster, and varicella zoster. In another aspect, the ROM-mediated oxidative damage to said subject's skin or mucosal membranes results from an injury selected from the group consisting of photodermatitis, thermal burns, lacerations, and cosmetic surgery.
In another embodiment of the present invention the ROM production and release inhibitory compound is selected from the group consisting of histamine, histamine dihydrochloride, histamine diphosphate, other histamine salts, esters, prodrugs, H
2
receptor agonists, serotonin, and 5HT agonists. In another embodiment, the ROM production and release inhibitory compound is a compound that promotes the release of endogenous histamine stores. In an aspect of this embodiment, compounds that promote the release of endogenous histamine stores are selected from the group consisting of IL-3, retinoic acid, 9-cis-retinoic acid, all-trans-retinoic acid, and allergens.
Another embodiment of the present invention contemplates a composition comprising an effective dose of a compound that inhibits the production or release of enzymatically produced ROMs in a pharmaceutically acceptable carrier adapted for topical delivery. In one aspect of this embodiment, the compound is selected from the group consisting of histamine, histamine dihydrochloride, histamine diphosphate, other histamine salts, esters, prodrugs, H
2
receptor agonists, serotonin, and 5HT agonists. In another aspect, the compound is a compound that promotes the release of endogenous histamine stores. In still another aspect, the compound that promotes the release of endogenous histamine stores is selected from the group consisting of
Knobbe Martens Olson & Bear LLP
Maxim Pharmaceuticals, Inc.
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