Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.

ABSTRACT:Semagacestat is a functional ␥-secretase inhibitor that has been shown to reduce the rate of formation of amyloid-␤ in vitro and in vivo. This study was conducted to characterize the disposition of semagacestat in humans. After a single 140-mg dose of [ 14 C]semagacestat administered as an oral solution to six healthy male subjects, semagacestat was rapidly absorbed (T max ϳ0.5 h) and eliminated from the systemic circulation (terminal t 1/2 ϳ2.4 h). The major circulating metabolites of semagacestat, M2 (hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (benzylic hydroxylation of the benzazepine ring), accounted for approximately 27 and 10% of total radioactivity exposure, respectively, as calculated from relative area under the plasma concentration versus time curve from 0 to 24 h derived from the plasma radiochro- Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by cognitive impairment. The prevalence rate is approximately 6% among those aged more than 65 years. Currently more than 4 million Americans suffer from AD, and this number is expected to quadruple by year 2050 as average lifespan increases (Rice et al., 2001;Joyce et al., 2007). AD has a substantial impact on patients, caregivers, and the healthcare system. Average total medical costs for AD patients are more than 5-fold higher than those for control populations. Development of pharmaceuticals for the treatment of AD would greatly benefit AD patients and society. The cause of AD is not yet clear. Pathological studies revealed the existence of neuritic plaques in the brains of AD patients (Desai and Grossberg, 2005;Blennow et al., 2006). The plaques are mainly composed of amyloid-␤ (A␤) peptides that are formed by the sequential cleavage of the amyloid precursor protein (APP). APP is first cleaved by the ␤-site APP-cleaving enzyme to form the N terminus of A␤, which is further cleaved by ␥-secretase at multiple sites to form A␤ isoforms ranging from 37 (A␤37) to 43 (A␤43) residues (Olson and Albright, 2008). Mutations in APP near cleavage sites resulting in the A␤ formation have been linked to AD in several families (Selkoe, 2001;Imbimbo, 2008). This observation suggests that a reduction in A␤ synthesis could slow the disease progression in patients with AD.Semagacestat, an azepine class ␥-secretase inhibitor, is one of a very few ␥-secretase inhibitors that have been advanced into clinical trials as potential disease-modifying agents for the treatment of AD (Olson and Albright, 2008). Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al., 2004;May et al., 2004;Lanz et al., 2006). A transgenic mouse model of AD was generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene encoding the APP V171F mutation (PDAPP mouse). These mice express high levels of human mutant APP and progressively develop many of the pathologArticle, publication date, and citation ...

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