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P1‐446: Memantine and prevention of worsening across multiple domains: Post hoc analysis of a randomized, placebo‐controlled trial in patients with moderate Alzheimer's disease
Author(s) -
Miller Michael L.,
Tocco Michael,
Hendrix Suzanne,
Hofbauer Robert K.,
Graham Stephen M.,
Perhach James L.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1001
Subject(s) - memantine , placebo , asha , medicine , post hoc analysis , randomized controlled trial , disease , psychology , clinical psychology , physical therapy , dementia , alternative medicine , pathology , linguistics , philosophy
Background: Preclinical research as well as preliminary human studies suggest that blocking of 5 hydroxytrypamine [5 HT6] receptors has an effect on cognitive function by stimulating the release of the two neurotransmitters acetylcholine and glutamate. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized, in part, by a number of deficits in the the function of these neurotransmitters. To date, direct modification of these systems alone leads to only small improvements in the symptoms associated with the disease. Efforts are now underway to evaluate 5 HT6 antagonism as a mechanism for modulating multiple neurotransmitter systems in order to mediate events associated with synpatic plasticity and impact cognition. Methods: Ascending single oral doses of SAM-760 will be administered to healthy young adult and elderly subjects in a placebo controlled, inpatient, 8-12 sequential dose group fashion with 8 subjects per group (6 receiving SAM-760 and 2 receiving matching placebo). Additional cohorts will include a food effect (high fat meal) and drug-drug interaction (ketoconazole, N 1⁄4 12-16) evaluation. Full safety evaluations will be administered at baseline (pretreatment), ongoing during the treatment period and posttreatment to assure appropriate study entry, continuous safety monitoring and final follow up (for any continuing events). Results: Safety and tolerability will be evaluated and presented from adverse events, summaries of physical examinations, supine and orthostatic vital sign measurements, cardiac rhythm monitoring, 12-lead digital ECGs, neurological evaluations, clinical laboratory test results. Preliminary SAM-760 and metabolite (in a limited cohort) pharmacokinetics will also be presented. Conclusions: An initial phase 1 study was designed to assess the safety, tolerability, preliminary pharmacokinetic and CNS effects of SAM-760, a 5 HT6 receptor antagonist, as a potential symptomatic treatment for reducing the cognitive deficits in patients with mild to moderate AD. A drug of similar mechanism of action to that of SAM 760 (i.e., SAM531) is currently in phase 2 development and shows potential as such a treatment: the current compound has been proposed as a promising backup for the this lead compound.