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O4-04-04: ABT-089 demonstrates efficacy in a human model of cognition and good tolerability in subjects with Alzheimer's disease taking acetylcholinesterase inhibitors

2009; Wiley; Volume: 5; Issue: 4S_Part_5 Linguagem: Inglês

10.1016/j.jalz.2009.05.543

1552-5279

Robert Lenz, Tushar Garimella, Sandeep Dutta, Charles Locke, Jeffrey D. Baker, Keith Wesnes, Paul Maruff, Walid Abi‐Saab, Mario Saltarelli,

Computational Drug Discovery Methods

ABT-089 is an α4β2 neuronal nicotinic receptor partial agonist discovered at Abbott (Abbott Park, IL, USA). ABT-089 has demonstrated preclinical efficacy in a variety of models of cognition, and has been found to be generally well tolerated with acceptable pharmacokinetics in healthy adults. Recent clinical studies examined the effects of ABT-089 in reversing scopolamine-induced cognitive deficits in healthy human subjects, and also evaluated the safety, tolerability and pharmacokinetics of ABT-089 in mild-to-moderate Alzheimer's disease (AD) patients receiving concomitant acetylcholinesterase inhibitors (AChEIs). A Phase 1, double-blind, multiple-dose, placebo-controlled, 4-period crossover study evaluated the ability of 3 doses of ABT-089 to produce procognitive effects in healthy adult male subjects (N = 16) in the presence and absence of scopolamine as assessed by two computerized batteries (Cognitive Drug Research (CDR) and CogState). A second Phase 1 double-blind, randomized, placebo-controlled multicenter study evaluated safety, tolerability and pharmacokinetics of multiple doses of ABT-089 in AD patients receiving AChEIs. Study drug was randomly assigned within each dose group such that five subjects received ABT-089 (10 mg, 20 mg or 30 mg BID) and two subjects received placebo BID for a total of 7 doses over 4 days. ABT-089 improved cognitive performance at steady state, and significantly reversed scopolamine-induced deficits on multiple measures of attention and cognition in healthy adults as measured by CDR and CogState. ABT-089 was safe and generally well tolerated by the AD patients. Two adverse events (paresthesia and headache, n = 2 each) occurred in greater than one subject receiving ABT-089. All adverse events were mild in severity except one syncopal vasovagal episode experienced by a subject during a phlebotomy procedure. No clinically significant findings were noted in vital signs or ECG parameters. ABT-089 exhibited a terminal half-life of 12 hours and approximately 50% greater serum concentrations in AD patients than observed in healthy, younger subjects. ABT-089 produced procognitive effects in healthy human subjects across several measures of attention. ABT-089 was generally well tolerated by patients with mild-to-moderate AD taking AChEIs with a tolerability profile similar to that observed in healthy younger subjects.