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Title:  Method for increasing the concentration of ascorbic acid in brain tissues of a subject

United States Patent:  6,221,904

Inventors:  Agus; David B. (Brooklyn, NY); Vera; Juan C. (New York, NY); Golde; David W. (New York, NY)

Assignee:  Sloan-Kettering Institute for Cancer Research (New York, NY)

Appl. No.:  443785

Filed:  November 19, 1999

Abstract

This invention provides a method for increasing the ascorbic acid concentration in brain tissues of a subject which comprises administering to the subject an amount of dehydroascorbic acid effective to increase the concentration of ascorbic acid in brain tissues. This invention also provides that the dehydroascorbic acid enters the tissues through the facilitative glucose transporter.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a method for increasing the ascorbic acid concentration in brain tissues of a subject which comprises administering to the subject an amount of dehydroascorbic acid effective to increase the concentration of ascorbic acid in brain tissues. This invention also provides the above-described method wherein the dehydroascorbic acid enters the tissues through the facilitative glucose transporter.

This invention also provides a method for increasing the ascorbic acid concentration in brain tissues of a subject which comprises administering to the subject an amount of dehydroascorbic acid effective to increase the antioxidant potential of the brain tissues.

In an embodiment of this invention, the subject is a human. In a separate embodiment, the human subject has a neurodegenerative disease. Such neurodegenerative disease includes but is not limited to Alzheimer's Disease, Parkinson's Disease or other forms of presenile dementia.

In another embodiment, the subject has neurovascular disease. This invention is useful for treating or preventing stroke or neurovascular diseases.

The subject may carry genetic diseases with central nervous system manifestations. In an embodiment, the genetic disease is the Huntington's disease.

For a separate embodiment, the subject has schizophrenia. In a still another embodiment, the human subject has a behavioral disorder. Such behavioral disorder includes, but is not limited to dysthymia, involution depression, aggressiveness via dominance, hyperactivity, deprivation syndrome, separation anxiety, intermittent anxiety, instrumental sociopathy, stereotypies, phobia or socialization disorders.

As it will be easily appreciated by persons of skills in the art, this invention is applicable to both human and animal diseases which could be treated by antioxidants. This invention is intended to be used in husbandry and veterinary medicine.

In this invention, the dehydroascorbic acid may be administered orally, intravenously, subcutaneously, intramuscularly or by other routes or circumstances of administration by which the dehydroascorbic acid will not be hydrolyzed. Dehydroascorbic acid hydrolyses easily in aqueous solution. It is the intention of this invention to administer the dehydroascorbic acid in a stabilized form. It is known that dehydroascorbic acid is stable under low pH conditions. Accordingly, dehydroascorbic acid may be stored in low pH and then administered directly to a large vein of a subject. Alternatively, dehydroascorbic acid may be stored in powdered form and hydrated before administering to a subject.

Moreover, dehydroascorbic acid may be encapsulated in liposomes at low pH. The encapsulated dehydroascorbic acid will then be administered to a subject. In a preferred embodiment, the encapsulated dehydroascorbic acid is administered orally.

U.S. Pat. No. 4,822,816 describes uses of aldono-lactones and salts of L-threonic, L-xylonic and L-lyxonic to stabilize the dehydroascorbic acid. The content of U.S. Pat. No. 4,822,816 is hereby incorporated into this application by reference. Accordingly, this method provides another means for stabilization of the dehydroascorbic acid.

Finally, appropriate amounts of ascorbic acid and ascorbate oxidase may be administered together to a subject to produce an amount of dehydroascorbic acid effective to increase the concentration of ascorbic acid in the brain tissues of the subject. Ascorbate oxidase catalyzes oxidation of L-ascorbic acid, and it is commercially available. U.S. Pat. No. 5,612,208 describes a new ascorbate oxidase and its gene, the content of which is hereby incorporated into this application by reference. Accordingly, ascorbate oxidase may be produced by the recombinant DNA technology.

Using this invention, the brain tissues of a subject may be loaded with the maximum amount of ascorbic acid.

Dehydroascorbic acids may exist in various salt forms. It is the intention of this invention to encompass these forms. The salts upon hydration will generate dehydroascorbic acid.

This invention provides a method for treating or preventing dementia of a subject comprising administering to the subject an amount of dehydroascorbic acid effective to increase the concentration of ascorbic acid in brain tissues.

This invention also provides a method for treating or preventing neurodegenerative disease of a subject comprising administering to the subject an amount of dehydroascorbic acid effective to increase the antioxidant potential of the brain tissues.

This invention also provides a combination therapy wherein an effective amount of dehydroascorbic acid is administered with therapeutic agents for the neurodegenerative disease. The administration may be performed concomitantly or at different time points. When treating the Alzheimer's disease, the therapeutic agents include, but are not limited to, Estrogen, Vitamin E (alpha-tocopherol), Tacrine (Tetrahydroacridinamine), Selegiline (Deprenyl), and Aracept (Donepezil). With respect to the Parkinson's disease, the therapeutic agents include, but are not limited to, the anticholinergic class of drugs, clozapine, levodopa with carbidopa or benserazide, Selegiline (Deprenyl), and dopamine agonist class of drugs.

This invention provides a method for treating or preventing stroke or neurovascular disease or other diseases which can be caused by lipid perioxidation of a subject comprising administering to the subject an amount of dehydroascorbic acid effective to increase the concentration of ascorbic acid in brain tissues.

This invention also provides a method for treating or preventing stroke or neurovascular disease or other diseases which can be caused by lipid perioxidation of a subject comprising administering to the subject an amount of dehydroascorbic acid effective to increase the antioxidant potential of the brain tissues.

These diseases include, but are not limited to stroke, atherosclerosis and neurodegenerative disorders.

Moreover, this invention provide a method for treating or preventing central nervous system manifestations of genetic diseases. The conditions of the disease will be improved by increasing the antioxidant potential of the brain. Prevention of such central nervous system manifestations of genetic disease may even be prevented if the antioxidant potential of the brain maintain to be a high level. This genetic disease includes, but not limited to, Huntington's disease.

This invention provides a method for preventing or treating behavioral disorders of a subject comprising administering to the subject an amount of dehydroascorbic acid effective to increase the concentration of ascorbic acid in brain tissues. This invention finally provides a method for preventing or treating behavioral disorders of a subject comprising administering to the subject an amount of dehydroascorbic acid effective to increase the antioxidant potential of the brain tissues. Such behavioral disorder includes, but is not limited to dysthymia, involution depression, aggressiveness via dominance, hyperactivity, deprivation syndrome, separation anxiety, intermittent anxiety, instrumental sociopathy, stereotypies, phobia or socialization disorders.

When treating or preventing the behavioral disorders, dehydroascorbic acid may be used in combination with other drugs. They may be administered concomitantly or at different time points.

In another embodiment, the behavioral disorder is schizophrenia.

Claim 1 of 9 Claims

What is claimed is:

1. A method of treating or preventing a disease or order in a subject which comprises administering to the subject an amount of dehydroascorbic acid or a salt thereof effective to increase the concentration of ascorbic acid in the subject's brain tissue, wherein the disease or order is selected from the group consisting of a neurodegenerative disease, a neurovascular disease, a disease which involves the oxidative modification of lowdensity lipoprotein or lipid perioxidation, a behavior disorder, dementia, Huntington's Disease and schizophrenia, so as to thereby treat or prevent a disease or order in the subject.

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