Agents for use in the treatment of alzheimer's disease

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, are disclosed.

What is claimed is:  
     
         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, and TPEN, or 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, and indomethacin, or 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, and TPEN, or 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, and indomethacin, or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A method of treating amyloidosis in a subject, said method comprising administering to said subject an effective amount of a combination of (a) a chelator specific for copper, and (b) clioquinol; wherein said combination reduces, inhibits or otherwise interferes with Aβ-mediated production of radical oxygen species.  
     
     
         11 . The method of  claim 10  wherein the chelator specific for copper is specific for the reduced form of copper.  
     
     
         12 . The method of  claim 11  wherein the chelator is bathocuproine or a hydrophobic derivative thereof.  
     
     
         13 . A method of treating amyloidosis in a subject, said method comprising administering to said subject an effective amount of a combination of (a) an alkalinizing agent and (b) clioquinol; wherein said combination reduces, inhibits or otherwise interferes with Aβ-mediated production of radical oxygen species.  
     
     
         14 . The method of  claim 13  wherein the alkalinizing agent is magnesium citrate.  
     
     
         15 . The method of  claim 13  wherein the alkalinizing agent is calcium citrate.  
     
     
         16 . 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, and TPEN, or 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.  
     
     
         17 . The method of  claim 16  wherein the metal chelator is bathocuproine.  
     
     
         18 . The method of  claim 16  further comprising administering a supplement selected from the group consisting of: ammonium salt, calcium salt, magnesium salt, and sodium salt.  
     
     
         19 . The method of  claim 18  wherein the supplement is magnesium salt.  
     
     
         20 . The method of  claim 16  further comprising administering to the subject an effective amount of a compound selected from the group consisting of: rifampicin, disulfiram, and indomethacin, or a pharmaceutically acceptable salt thereof.  
     
     
         21 . 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, and TPEN, or 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.  
     
     
         22 . The method of  claim 21  wherein the metal chelator is bathocuproine.  
     
     
         23 . The method of  claim 21  wherein the salt of the metal chelator is a magnesium salt.  
     
     
         24 . The method of  claim 21  further comprising administering to said subject a compound selected from the group consisting of: rifampicin, disulfiram, and indomethacin, or a pharmaceutically acceptable salt thereof.  
     
     
         25 . A method of treating amyloidosis in a subject, said method comprising administering to said subject an effective amount of a combination of (a) a chelator specific for copper, and (b) clioquinol; wherein said combination prevents formation of Aβ amyloid, promotes, induces or otherwise facilitates resolubilization of Aβ deposits, or both.  
     
     
         26 . The method of  claim 25  wherein the chelator specific for copper is specific for the reduced form of copper.  
     
     
         27 . The method of  claim 26  wherein the chelator is bathocuproine or a hydrophobic derivative thereof.  
     
     
         28 . A method of treating amyloidosis in a subject, said method comprising administering to said subject an effective amount of a combination of (a) an alkalinizing agent and (b) clioquinol; wherein said combination prevents formation of Aβ amyloid, promotes, induces or otherwise facilitates resolubilization of Aβ deposits, or both.  
     
     
         29 . The method of  claim 28  wherein the alkalinizing agent is magnesium citrate.  
     
     
         30 . The method of  claim 28  wherein the alkalinizing agent is calcium citrate.  
     
     
         31 . 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, and TPEN, or hydrophobic derivatives thereof; and (b) clioquinol, together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         32 . The pharmaceutical composition of  claim 31  wherein the metal chelator is bathocuproine.  
     
     
         33 . The pharmaceutical composition of  claim 31  further comprising a supplement selected from the group consisting of: ammonium salt, calcium salt, magnesium salt, and sodium salt.  
     
     
         34 . The pharmaceutical composition of  claim 33  wherein the supplement is a magnesium salt.  
     
     
         35 . The pharmaceutical composition of  claim 31  further comprising a compound selected from the group consisting of: rifampicin, disulfiram, and indomethacin.  
     
     
         36 . 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, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, and TPEN, or 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.  
     
     
         37 . The pharmaceutical composition of  claim 36  wherein the metal chelator is bathocuproine.  
     
     
         38 . The pharmaceutical composition of  claim 36  wherein the salt of the metal chelator is a magnesium salt.  
     
     
         39 . The pharmaceutical composition of  claim 36  further comprising a compound selected from the group consisting of: rifampicin, disulfiram, and indomethacin.  
     
     
         40 . A pharmaceutical composition for treatment of conditions caused by amyloidosis, Aβ-mediated ROS formation, or both, comprising a chelator specific for copper, with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         41 . The pharmaceutical composition of  claim 40  wherein the chelator is specific for the reduced form of copper.  
     
     
         42 . The pharmaceutical composition of  claim 41  wherein the chelator specific for the reduced form of copper is bathocuproine or a hydrophobic derivative thereof.  
     
     
         43 . A pharmaceutical composition for treatment of conditions caused by amyloidosis, Aβ-mediated ROS formation, or both, comprising a combination of (a) an alkalinizing agent and (b) clioquinol; together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         44 . The pharmaceutical composition of  claim 43  wherein the alkalinizing agent is magnesium citrate.  
     
     
         45 . The pharmaceutical composition of  claim 43  wherein the alkalinizing agent is calcium citrate.  
     
     
         46 . A composition of matter comprising: (a) a metal chelator selected from the group consisting of: bathocuproine, bathophenanthroline, DTPA, EDTA, EGTA, penicillamine, TETA, and TPEN, or hydrophobic derivatives thereof; and (b) clioquinol.  
     
     
         47 . The composition of  claim 46  wherein the metal chelator is bathocuproine.  
     
     
         48 . The composition of  claim 46  further comprising a supplement selected from the group consisting of: ammonium salt, calcium salt, magnesium salt, and sodium salt.  
     
     
         49 . The composition of  claim 48  wherein the supplement is a magnesium salt.  
     
     
         50 . The composition of  claim 46  further comprising a compound selected from the group consisting of: rifampicin, disulfiram, and indomethacin.  
     
     
         51 . 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, and TPEN, or 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.  
     
     
         52 . The composition of  claim 51  wherein the metal chelator is bathocuproine.  
     
     
         53 . The composition of  claim 51  wherein the salt of the chelator is a magnesium salt.  
     
     
         54 . The composition of  claim 51  further comprising a compound selected from the group consisting of: rifampicin, disulfiram, and indomethacin.  
     
     
         55 . A composition of matter comprising a combination of (a) an alkalinizing agent and (b) clioquinol.  
     
     
         56 . The composition of  claim 55  wherein the alkalinizing agent is magnesium citrate.  
     
     
         57 . The composition of  claim 55  wherein the alkalinizing agent is calcium citrate.