SUR1 Antagonists Block NCCa-ATP Channels to Halt Neuronal Death
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Solution Overview
Problem
Current treatments for dementia, particularly Alzheimer's Disease, are inadequate in effectively addressing neuronal cell death and progression of the disease, with unclear associations between Type 2 Diabetes and AD, and limited therapeutic options for dementia.
Innovation Solution
The use of sulfonylurea receptor antagonists and blockers of non-selective channels, such as the NCCa-ATP, TRPM4, and TRPM5 channels, to treat dementia by antagonizing SUR1 receptors, including compounds like glibenclamide and other sulfonylurea mimetics, to reduce neuronal cell death and slow disease progression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for dementia are used, then existing therapeutic options are maintained, but they are inadequate in effectively addressing neuronal cell death and progression of the disease
Solution Approach 1:
The patent introduces SUR1 receptor antagonists as intermediary compounds that block the harmful NCCa-ATP channel activity. These antagonists serve as mediators between the harmful channel activity and neuronal cell death, preventing the detrimental effects while providing a new therapeutic mechanism for dementia treatment
Solution Approach 2:
The patent changes the therapeutic parameter by targeting a specific receptor (SUR1) and channel (NCCa-ATP) that is dysregulated in dementia. By altering the molecular target from conventional approaches to this specific channel-receptor system, the treatment achieves better effectiveness in addressing neuronal cell death
2Reliability
If sulfonylurea drugs are used to block NCCa-ATP channels, then neuronal cell death is reduced, but the association between Type 2 Diabetes and AD remains unclear
Solution Approach 1:
The patent segments the complex diabetes-AD relationship by focusing specifically on the SUR1 channel mechanism. By isolating and targeting this particular molecular pathway, the treatment provides neuronal protection while the broader diabetes-AD association can be studied separately through this defined mechanism
3Reliability
If non-selective channel blockers are used, then dementia symptoms are ameliorated, but selectivity for specific channels must be achieved
Solution Approach 1:
The patent applies local quality by designing antagonists with specific affinity for the SUR1 receptor associated with the NCCa-ATP channel. This localized targeting ensures that the drug acts selectively on the harmful channel in the brain while minimizing effects on other channels, achieving both efficacy and selectivity
Data Source
AI summary
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.