Muscarinic Agonist Therapy of Alzheimer's Disease

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Abstract
• Cholinergic projections to the cerebral cortex from certain basal forebrain nuclei degenerate in Alzheimer's disease. Nevertheless, attempts to alleviate this disorder through the administration of drugs that increase the availability of acetylcholine to postsynaptic receptor sites have generally yielded disappointing results. In an attempt to evaluate the therapeutic efficacy of cholinomimetics that act independently of the presynaptic cholinergic terminals, a double-blind, placebo-controlled trial of the muscarinic agonist RS-86 (2-ethyl-8 methyl-2,8 diazospiro [4.5]-decane-1,3-dione hydrobromide) was undertaken. Eight patients with Alzheimer's disease with mild to moderately advanced dementia received RS-86 orally at maximum individually tolerated dose levels for eight days. Although some verbal and visuospatial tests showed slight alterations, no consistent overall change in cognitive performance could be discerned. These results lend further support to the view that short-term administration of cholinomimetic monotherapies may fail in the symptomatic treatment of Alzheimer's dementia.