Treatment of Alzheimer's Disease Using Compounds that Reduce the Activity of Non Selective Ca Activated ATP- Sensitive Cation Channels Regulated by SUR1 Receptors

Abstract

NSC antagonists are disclosed as useful in the treatment of dementia, in delaying the onset of dementia, and in the prevention of dementia. Dementia so treated may be, for example, Alzheimer's Disease (AD). NSC antagonists for treating dementia such as AD may be administered alone, a) in combination with other drugs used for treating dementia, b) in combination with drugs that stabilize or increase blood plasma glucose levels, or with both a) and b). Pharmaceutical compositions, dosage forms, and methods for using the same are disclosed, which include NSC antagonists, NSC antagonists combined with dementia drugs, NSC antagonists combined with glucose-level stabilizing or enhancing drugs, or combinations of these. Dosage forms may be designed to provide stable plasma levels for extended periods of time. Exemplary pharmaceutical compositions include compositions including glibenclamide and memantine; glibenclamide and donepezil; tolbutamide and memantine; tolbutamide and donepezil; and these compositions further including glucagon and/or glucose.

1 - 41 . (canceled) 
     
     
         42 . A method of treating dementia, comprising administering an NSC antagonist to a patient in need of such treatment, wherein said NSC antagonist comprises an antagonist of activity of the NC Ca-ATP  channel, the TRPM4 channel, or the TRPM5 channel. 
     
     
         43 . The method of  claim 42 , wherein said dementia is Alzheimer's Disease (AD). 
     
     
         44 . The method of  claim 42 , wherein said NSC antagonist is selected from glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof. 
     
     
         45 . The method of  claim 42 , further comprising administration of an other compound, wherein said other compound is a compound used in the treatment of dementia. 
     
     
         46 . The method of  claim 45 , wherein said dementia is Alzheimer's Disease (AD). 
     
     
         47 . The method of  claim 45 , wherein said NSC antagonist is selected from glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof. 
     
     
         48 . The method of  claim 45 , wherein said other compound used in the treatment of dementia is selected from memantine, donepezil, galantamine, rivastigmine, tacrine, and combinations thereof. 
     
     
         49 . A pharmaceutical composition comprising a NSC antagonist; a compound used in the treatment of dementia; and a pharmaceutically acceptable carrier. 
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein said NSC antagonist is selected from glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof. 
     
     
         51 . The pharmaceutical composition of  claim 49 , wherein said compound used in the treatment of dementia is selected from memantine, donepezil, galantamine, rivastigmine, tacrine, and combinations thereof. 
     
     
         52 . The pharmaceutical composition of  claim 49  comprising glibenclamide; a compound selected from memantine, donepezil, galantamine, rivastigmine, tacrine, and combinations thereof; and a pharmaceutically acceptable carrier. 
     
     
         53 . The pharmaceutical composition of  claim 49  comprising tolbutamide; a compound selected from memantine, donepezil, galantamine, rivastigmine, tacrine, and combinations thereof; and a pharmaceutically acceptable carrier. 
     
     
         54 . The pharmaceutical composition of  claim 49  comprising chlorpropamide; a compound selected from memantine, donepezil, galantamine, rivastigmine, tacrine, and combinations thereof; and a pharmaceutically acceptable carrier. 
     
     
         55 . The pharmaceutical composition of  claim 49 , further comprising a compound effective to increase blood plasma glucose levels. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein said compound effective to increase blood plasma glucose levels is selected from glucose and glucagon. 
     
     
         57 . The method of  claim 42 , wherein treating dementia comprises preventing or delaying the onset of AD. 
     
     
         58 . The method of  claim 45 , wherein treating dementia comprises preventing or delaying the onset of AD. 
     
     
         59 . The method of  claim 57 , wherein said NSC antagonist is selected from glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non-steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof. 
     
     
         60 . The method of  claim 58 , wherein said other compound used in the treatment of dementia is selected from memantine, donepezil, galantamine, rivastigmine, tacrine, and combinations thereof. 
     
     
         61 . The method of  claim 57 , further comprising administration of a compound effective to increase blood plasma glucose levels.