The current symptomatic treatment for cognitive dysfunction due to dementia (eg Alzheimer's disease) is moderately effective and causes dose limiting side effects. This thesis describes the phase 1... Show moreThe current symptomatic treatment for cognitive dysfunction due to dementia (eg Alzheimer's disease) is moderately effective and causes dose limiting side effects. This thesis describes the phase 1 development of new symptomatic treatments; Gln-1062 (pro-drug of galantamine) and HTL0009936 and HTL0018318 (both M1 muscarinic receptor partial agonists). Additionally, a new methodology was investigated, which can be applied when demonstrating pharmacological effects (biperiden challenge model), and a review of all biomarkers that were used to measure cholinergic effects is presented. Show less
This thesis describes several state-of-the-art challenge methods to study the cholinergic system in humans by measuring the effects of compounds that selectively act upon muscarinic or... Show moreThis thesis describes several state-of-the-art challenge methods to study the cholinergic system in humans by measuring the effects of compounds that selectively act upon muscarinic or nicotinic acetylcholine receptors. The thesis reveals part of the complexity of the cholinergic system, its changes related to aging, its relationship with cognitive function and performance, and its role in inflammation. Additionally, the methodology described in the thesis provides controlled circumstances using repeated measurement of drug concentrations and effects during a pharmacologic cholinergic challenge that can be used in drug development of new compounds with cholinergic activity. Show less
