Agents for use in the treatment of Alzheimer's disease

• US 6,323,218 B1
• Filed: 03/11/1998
• Issued: 11/27/2001
• Est. Priority Date: 03/11/1998
• Status: Expired due to Fees

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Huang, Xudong, Atwood, Craig S., Tanzi, Rudolph E., Bush, Ashley I.
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/038,154
• Time in Patent Office: 1,357 Days
• Field of Search: 514/311, 514/244, 514/420, 514/707
• US Class Current: 514/311
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to the identification of pharmacological agents to be used in the treatment of Alzheimer'"'"'s disease and related pathological conditions and compositions for treatment of conditions caused by amyloidosis, Aβ-mediated formation of ROS, or both, such as Alzheimer'"'"'s disease.

Claims

1. A method of treating amyloidosis in a subject, said method comprising administering to said subject a combination of (a) a metal chelator selected from the group consisting of:

bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof; and

(b) clioquinol, for a time and under conditions to bring about said treatment;

wherein said combination reduces, inhibits or otherwise interferes with Aβ

-mediated production of radical oxygen species.

2. The method of claim 1 wherein the metal chelator is bathocuproine.

3. The method of claim 1 further comprising administering a supplement selected from the group consisting of:

ammonium salt, calcium salt, magnesium salt, and sodium salt.

4. The method of claim 3 wherein the supplement is magnesium salt.

5. The method of claim 1 further comprising administering to the subject an effective amount of a compound selected from the group consisting of:

rifampicin disulfiram, indomethacin, and a pharmaceutically acceptable salt thereof.

6. A method of treating amyloidosis in a subject, said method comprising administering to said subject an effective amount of a combination of (a) a salt of a metal chelator, wherein said chelator is selected from the group consisting of:

bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof, and (b) clioquinol;

wherein said salt of the metal chelator is selected from the group consisting of;

ammonium, calcium, magnesium, and sodium; and

wherein said combination reduces, inhibits or otherwise interferes with Aβ

-mediated production of radical oxygen species.

7. The method of claim 6 wherein the metal chelator is bathocuproine.

8. The method of claim 6 wherein the salt of a metal chelator is a magnesium salt.

9. The method of claim 6 further comprising administering to said subject a compound selected from the group consisting of:

rifampicin, disulfiram, indomethacin, and a pharmaceutically acceptable salt thereof.

10. A method of treating amyloidosis in a subject, said method comprising administering to said subject a combination of (a) a metal chelator selected from the group consisting of:

bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof; and

(b) clioquinol, for a time and under conditions to bring about said treatment;

wherein said combination prevents formation of Aβ

amyloid, promotes, induces or otherwise facilitates resolubilization of Aβ

deposits, or both.

11. The method of claim 10 wherein the metal chelator is bathocuproine.

12. The method of claim 10 further comprising administering a supplement selected from the group consisting of:

ammonium salt, calcium salt, magnesium salt, and sodium salt.

13. The method of claim 12 wherein the supplement is magnesium salt.

14. The method of claim 10 further comprising administering to the subject an effective amount of a compound selected from the group consisting of:

rifampicin, disulfiram, indomethacin, and a pharmaceutically acceptable salt thereof.

34. The composition of claim 13 wherein the metal chelator is bathocuproine.

15. A method of treating amyloidosis in a subject, said method comprising administering to said subject an effective amount of a combination of (a) a salt of a metal chelator, wherein said chelator is selected from the group consisting of:

bathocuproine, bathophenianthroline, DTPTA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof, and (b) clioquinol;

wherein said salt of the metal chelator is selected from the group consisting of;

ammonium, calcium, magnesium, and sodium; and

wherein said combination prevents formation of Aβ

amyloid, promotes, induces or otherwise facilitates resolubilization of Aβ

deposits, or both.

16. The method of claim 15 wherein the metal chelator is bathocuproine.

17. The method of claim 15 wherein the salt of the metal chelator is a magnesium salt.

18. The method of claim 15 further comprising administering to said subject a compound selected from the group consisting of:

rifampicin, disulfiram, indomethacin, and a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition for treatment of conditions caused by amyloidosis, Aβ

-mediated ROS formation, or both, comprising;

(a) a metal chelator selected from the group consisting of;

bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof; and

(b) clioquinol, together with one or more pharmaceutically acceptable carriers or diluents.

20. The pharmaceutical composition of claim 19 wherein the metal chelator is bathocuproine.

21. The pharmaceutical composition of claim 19 further comprising a supplement selected from the group consisting of:

ammonium salt, calcium salt, magnesium salt, and sodium salt.

22. The pharmaceutical composition of claim 21 wherein the supplement is a magnesium salt.

23. The pharmaceutical composition of claim 19 further comprising a compound selected from the group consisting of:

rifampicin, disulfiram, and indomethacin.

24. A pharmaceutical composition for treatment of conditions caused by amyloidosis, Aβ

-mediated ROS formation, or both, comprising a combination of (a) a salt of a metal chelator selected from the group consisting of;

bathocuproine, bathophenanthrolinie, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof; and

(b) clioquinol;

wherein said salt of the metal chelator is selected from the group consisting of;

ammonium, calcium, magnesium, and sodium, together with one or more pharmaceutically acceptable carriers or diluents.

25. The pharmaceutical composition of claim 24 wherein the metal chelator is bathocuproine.

26. The pharmaceutical composition of claim 24 wherein the salt of the metal chelator is a magnesium salt.

27. The pharmaceutical composition of claim 24 further comprising a compound selected from the group consisting of:

rifampicin, disulfiram, and indomethacin.

28. A composition of matter comprising:

(a) a metal chelator selected from the group consisting of;

bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof; and

(b) clioquinol.

29. The composition of claim 28 wherein the metal chelator is bathocuproine.

30. The composition of claim 28 further comprising a supplement selected from the group consisting of:

ammonium salt, calcium salt, magnesium salt, and sodium salt.

31. The composition of claim 30 wherein the supplement is a magnesium salt.

32. The composition of claim 28 further comprising a compound selected from the group consisting of:

rifampicin, disulfiram, and indomethacin.

33. A composition of matter comprising a combination of (a) a salt of a metal chelator selected from the group consisting of:

bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, TPEN, and hydrophobic derivatives thereof; and

(b) clioquinol;

wherein said salt of the metal chelator is selected from the group consisting of;

ammonium, calcium, magnesium, and sodium.

35. The composition of claim 33 wherein the salt of the chelator is a magnesium salt.

36. The composition of claim 33 further comprising a compound selected from the group consisting of:

rifampicin, disulfiram, and indomethacin.