Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-04-29
2004-07-27
Moran, Marjorie (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S118000
Reexamination Certificate
active
06767898
ABSTRACT:
TECHNICAL FIELD
The invention relates to specific saccharide compositions and methods for treating Alzheimer's disease and other amyloidoses; more particularly, it relates to compositions and methods for therapeutic intervention in Alzheimer's disease and other amyloidoses involving the use of substituted anionic groups in mono and poly saccharides or pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Alzheimer's disease is characterized by the accumulation of a 39-43 amino acid peptide termed the beta-amyloid protein or A&bgr;, in a fibrillar form, existing as extracellular amyloid plaques and as amyloid within the walls of cerebral blood vessels. Fibrillar A&bgr; amyloid deposition in Alzheimer's disease is believed to be detrimental to the patient and eventually leads to toxicity and neuronal cell death, characteristic hallmarks of Alzheimer's disease. Accumulating evidence implicates amyloid as a major causative factor of Alzheimer's disease pathogenesis.
A variety of other human diseases also demonstrate amyloid deposition and usually involve systemic organs (i.e. organs or tissues lying outside the central nervous system), with the amyloid accumulation leading to organ dysfunction or failure. In Alzheimer's disease and “systemic” amyloid diseases, there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
Much work in Alzheimer's disease has been accomplished, but little is conventually known about compounds or agents for therapeutic regimes to arrest amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses.
New compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses are therefore desperately needed.
DISCLOSURE OF THE INVENTION
A primary object of the present invention is to establish new methods and compositions which are useful for the treatment of the amyloid diseases. The amyloid diseases include, but are not limited to, the amyloid associated with Alzheimer's disease, Down's syndrome and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (wherein the specific amyloid is referred to as beta-amyloid protein or A&bgr;), the amyloid associated with chronic inflammation, various forms of malignancy and Familial Mediterranean Fever (wherein the specific amyloid is referred to as AA amyloid or inflammation-associated amyloidosis), the amyloid associated with multiple myeloma and other B-cell dyscrasias (wherein the specific amyloid is referred to as AL amyloid), the amyloid associated with type II diabetes (wherein the specific amyloid is referred to as amylin or islet amyloid), the amyloid associated with the prion diseases including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru and animal scrapie (wherein the specific amyloid is referred to as PrP amyloid), the amyloid associated with long-term hemodialysis and carpal tunnel syndrome (wherein the specific amyloid is referred to as beta
2
-microglobulin amyloid), the amyloid associated with senile cardiac amyloid and Familial Amyloidotic Polyneuropathy (wherein the specific amyloid is referred to as transthyretin or prealbumin), and the amyloid associated with endocrine tumors such as medullary carcinoma of the thyroid (wherein the specific amyloid is referred to as variants of procalcitonin).
The methods of the invention involve administering to a subject the therapeutic compound glucose pentasulfate, and pharmaceutically acceptable salts thereof, or derivatives thereof, which inhibit amyloid formation, deposition, accumulation and/or persistence, and/or which cause dissolution/disruption of pre-existing amyloid. Accordingly, the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs. The methods of the invention can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to amyloidosis. The methods of the invention result, at least in part, in directly inhibiting or causing a reduction in the beta-pleated sheet secondary structure of specific amyloid proteins, such as, but not limited to, the beta-amyloid protein (A&bgr;) of Alzheimer's disease and the islet amyloid polypeptide (i.e. amylin) of type II diabetes.
“Derivatives”, “related derivatives”, “derivatives thereof” or “closely related compounds” of glucose pentasulfate for the purposes of this application shall include but are not limited to, glucose monosulfate, glucose disulfate, glucose trisulfate, glucose tetrasulfate, and glucose pentasulfate existing as a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, hexasaccharide, nonasaccharide, decasaccharide or other polysaccharides of increasing length. In addition, “derivatives” of glucose pentasulfate, include but are not limited to, glucose pentasulfate, pharmaceutically acceptable salts thereof, and derivatives (referred to above) which have been substituted at sulfate-containing positions with other anionic group(s). Preferred substitutions include, but are not limited to, the replacement of sulfates with phosphates, phosphonates, carboxylates, sulphonates, and/or any ring compounds (i.e. alicyclic or heterocyclic groups) containing anionic groups. In addition, multiple anionic groups can be of the same structural group (i.e. all carboxylates) or, alternatively, a combination of different anionic groups can be used (i.e. carboxylates and phosphates).
An “anionic group” of a therapeutic compound of the invention is a negatively charged moiety. For purposes of the invention, the anionic group is negatively charged at physiological pH.
As used herein, the term “monosaccharide” are simple sugars usually of the formula C
6
H
12
O
6
that can be combined to form oligosaccharides or polysaccharides. Monosaccharide include enantiomers and both the D and L stereoisomers of monosaccharide. Carbohydrates, which include substituted and unsubstituted mono, oligo, and polysaccharides, can have multiple anionic groups attached to each monosaccharide moiety.
Another object of the present invention is to use the saccharide glucose pentasulfate and related derivatives for the treatment of amyloid formation, deposition, accumulation and/or persistence in Alzheimer's disease, type II diabetes and other amyloidoses. However, the glucose pentasulfate may exist as a monosaccharide, or as saccharides of increasing length (i.e. polysaccharides) such as, but not limited to, disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, hexasaccharides, heptasaccharides, octasaccharides, nonasaccharides, or decasaccharides.
Another object of the present invention is to use glucose pentasulfate and related derivatives for the treatment of amyloid formation, deposition, accumulation and/or persistence in Alzheimer's disease, type II diabetes and other amyloidoses.
Another object of the present invention is to use commercially available, or to make commercially available, pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sachets, cachets, vegicaps, liquid drops, elixers, suspensions, emulsions, solutions, syrups, tea bags, aerosols (as a solid or in a liquid medium), suppositories, sterile injectable solutions, and/or sterile packaged powders, which contain glucose pentasulfate or related derivatives to treat patients with Alzheimer's disease, type II diabetes and other amyloidoses.
Yet another object of the present invention is to use glucose pentasulfate or related derivatives as potent agents which inhibit amyloid formation, amyloid deposition, amyloid accumulation, amyloid persistence, amyloid-proteoglycan/glycosaminoglycan (PG/GAG) interactions, and/or cause a dissolution of pre-formed or pre-deposited amyloid fibrils in Alzheimer's disease, type II di
Castillo Gerardo M.
Snow Alan D.
Dwyer Patrick M.
Moran Marjorie
University of Washington
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