DISSOLUTION OF AMYLOID FIBRILS BY FLAVONOIDS AND OTHER COMPOUNDS

• US 20100048510A1
• Filed: 12/14/2007
• Published: 02/25/2010
• Est. Priority Date: 12/15/2006
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Eisenberg, David S., Balbirnie, Melinda
• Granted Patent: US 9,463,195 B2
• Time in Patent Office: Days
• US Class Current: 514/82
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61M 1/30 Single needle dialysis ; Reciprocating systems, alternately withdrawing blood from and returning it to the patient, e.g. single-lumen-needle dialysis or single needle systems for hemofiltration or pheresis
• CPC Class Codes: A61M 1/3486 Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Methods for disrupting amyloid fibrils in a subject, comprising combining an effective amount of a β-2 microglobulin fibril disrupting compound with a medium associated with the subject, are disclosed. The invention also relates to combining the β-2 microglobulin fibril disrupting compound ex vivo with the blood during dialysis treatment of an animal. It also relates to methods for determining which compounds are effective at disrupting amyloid fibrils in a medium.

Claims

1. A method for disrupting amyloid fibrils in a subject, comprising combining an effective amount of one or more β

-2 microglobulin fibril disrupting compounds selected from the group consisting of benserazide hydrochloride, stictic acid, haemmatommic acid, meclocycline sulfosalicylate, dobutamine hydrochoride, apomorphine hydrochloride, primaquine diphosphate, pyrogallin, 7-deshydroxypyrogallin-4-carboxylic acid, methyl 7-deshydroxypyrogallin-4-carboxylate, purpurogallin, theaflavin, protoporphyrin IX, nalidixic acid, leoidin, dimenhydrinate, carminic acid, oxidopamine, dequalinium dichloride, econazole nitrate, everninic acid, methyleverninic acid, minocycline, chlorotetracycline, oxytetracycline, and pharmaceutically acceptable salts thereof, with a medium associated with the subject.

7. The method of claim 1, wherein the subject has amyloid fibrils comprising β

-2 microglobulin fibrils.

8. The method of claim 1, wherein the medium is blood, and the β

-2 microglobulin fibril disrupting compound is combined ex vivo with the blood during dialysis treatment of the subject.

9. The method of claim 8, wherein the β

-2 microglobulin fibril disrupting compound is combined ex vivo with the blood by introducing the β

-2 microglobulin fibril disrupting compound to the blood upstream of the dialysis membrane, to the blood downstream of the dialysis membrane, or to the dialysate solution upstream of the dialysis membrane.

10. The method of claim 1, wherein the β

-2 microglobulin fibril disrupting compound is administered to the subject such that it enters the medium.

12. The method of claim 10, wherein the β

-2 microglobulin fibril disrupting compound is administered at a dosage rate ranging from about 0.001 to about 100 milligrams per kilogram of subject body weight per day.

13. The method of claim 10, wherein the β

-2 microglobulin fibril disrupting compound is administered at a dosage rate ranging from about 0.01 to about 100 milligrams per kilogram of subject body weight per day.

14. The method of claim 10, wherein the β

-2 microglobulin fibril disrupting compound is administered at a dosage rate ranging from about 0.1 to about 10 milligrams per kilogram of subject body weight per day.

15. The method of claim 10, wherein the medium is blood and the β

-2 microglobulin fibril disrupting compound is administered to achieve a molar concentration in the blood in the range of from about 100 nM to about 10 mM.

16. The method of claim 10, wherein the medium is blood and the β

-2 microglobulin fibril disrupting compound is administered to achieve a molar concentration in the blood in the range of from about 1 μ

M to about 1 mM.

17. The method of claim 10, wherein the medium is blood and the β

-2 microglobulin fibril disrupting compound is administered to achieve a molar concentration in the blood in the range of from about 10 μ

M to about 100 μ

M.

18. The method of claim 10, wherein the β

-2 microglobulin fibril disrupting compound is administered to the subject orally;

nasally;

intraperitoneally;

parenterally;

by intravenous, intramuscular, topical, or subcutaneous injection;

or topically.

23. The method of claim 10, wherein the subject is a human.

25. The method of claim 1, wherein disrupting amyloid fibrils in the subject treats dialysis related amyloidosis in the subject.

37. The method of claim 1, wherein the β

-2 microglobulin fibril disrupting compound is selected from the group consisting of stictic acid, haematommic acid, benserazide hydrochloride, meclocycline sulfosalicylate, apomorphine hydrochloride, primaquine diphosphate, and combinations thereof.

2-6. -6. (canceled)

11. (canceled)

19-22. -22. (canceled)

24. A method comprising treating a subject having a disease or disorder selected from the group consisting of Alzheimer'"'"'s disease, type II diabetes, a systemic amyloidosis, dialysis related amyloidosis, and carpal tunnel syndrome, by administering an effective amount of a pharmaceutical composition comprising a β

-2 microglobulin fibril disrupting compound selected from the group consisting of benserazide hydrochloride, stictic acid, haemmatommic acid, meclocycline sulfosalicylate, dobutamine hydrochoride, apomorphine hydrochloride, primaquine diphosphate, pyrogallin, 7-deshydroxypyrogallin-4-carboxylic acid, methyl 7-deshydroxypyrogallin-4-carboxylate, purpurogallin, theaflavin, protoporphyrin IX, nalidixic acid, leoidin, dimenhydrinate, carminic acid, oxidopamine, dequalinium dichloride, econazole nitrate, eveminic acid, methyleveminic acid, minocycline, chlorotetracycline, oxytetracycline, and pharmaceutically acceptable salts thereof to the subject, and thereby treating the disease or disorder.

28. The method of claim 24, wherein the composition comprises a pharmaceutically effective carrier or diluent.

39. The method of claim 24, wherein the β

-2 microglobulin fibril disrupting compound is stictic acid or haemmatomic acid.

26-27. -27. (canceled)

29-32. -32. (canceled)

33. A dialysis system comprising an upstream blood side, an artificial kidney, and a downstream blood side, and a β

-2 microglobulin fibril disrupting compound.

34-36. -36. (canceled)

38. A method for treating dialysis-related amyloidosis in a subject comprising combining a β

-2 microglobulin fibril disrupting compound selected from the group consisting of one or more of epigallocatechin gallate, benserazide hydrochloride, stictic acid, haemmatommic acid, meclocycline sulfosalicylate, dobutamine hydrochoride, apomorphine hydrochloride, primaquine diphosphate, pyrogallin, 7-deshydroxypyrogallin-4-carboxylic acid, methyl 7-deshydroxypyrogallin-4-carboxylate, purpurogallin, theaflavin, protoporphyrin IX, nalidixic acid, leoidin, dimenhydrinate, carminic acid, oxidopamine, dequalinium dichloride, econazole nitrate, eveminic acid, methyleveminic acid, minocycline, chlorotetracycline, oxytetracycline, and pharmaceutically acceptable salts thereof with a medium associated with the subject, wherein the medium is blood and the β

-2 microglobulin fibril disrupting compound is combined ex vivo with the blood during dialysis treatment of the subject.