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P1‐340: The efficacy of dextromethorphan HBr and quinidine sulfate (Neudexta) treatment on agitation in patients with Alzheimer's disease: The caregivers' voice and clinical experience
Author(s) -
ShuaHaim Joshua,
Smith Juanita
Publication year - 2012
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.2012.05.2026
Subject(s) - dextromethorphan , tolerability , quinidine , medicine , anesthesia , adverse effect , dosing
Background: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder affecting nearly 25 million patients. It is characterized by progressive cognitive decline and eventually a debilitating dementia. Currently available pharmacologic interventions only provide symptomatic relief without halting the progression of the disease. Thus, there is an enormous medical need for novel disease-modifying therapies that target the underlying neuropathological mechanisms involved in the development of AD. Strong genetic, physiological and biochemical evidence suggests that b -amyloid (Ab) plays a key role in AD. Preventing Ab aggregation is therapeutically attractive because this process is believed to be the main pathological event, and does not interfere with the physiological role of the amyloid precursor protein (APP). Methods:We have employed a set of rationally designed non-dye compounds. The aim was to inhibit Ab1-42 oligomerization and to disaggregate pre-formed Ab1-42 oligomers. Herein, we present in vitro data of our compounds obtained by thioflavin-T (ThT) assay and other biochemical assays. In addition, we present preclinical data of our compounds (metabolic stability, P-glycoprotein mediated drug efflux, brain penetration, etc.). Selected compounds were then administered to female hAPPL mice by gavage for the duration of 4 weeks. Results: The ThT-assay, used as first screening tool, was complemented by other biochemical assays and allowed the identification of compounds with suitable inhibition of Ab1-42 aggregation and toxicity Preclinical data allowed the selection of 6 compounds with suitable brain penetration for testing in female hAPPL mice. Although all 6 compounds displayed good inhibition of Ab1-42 aggregation and suitable brain penetration properties, not all of them improved spatial cognition of female hAPPL mice in the water-maze task. In addition, some compounds displayed a reduction of soluble and insoluble Ab in brain extracts. Conclusions: We have discovered a set of small molecules which prevented/reversed the pathological toxic effect of Ab and improved memory deficits of female hAPPL mice. Thus, these compounds could be promising candidates for the treatment of AD.