Modulation of Ab42 in vivo by y-secretase modulator in primates and XXXX .

@entity1 @entity5018 @entity5434 @entity23756 @entity195
INTRODUCTION: @entity5018 is one of the nonsteroidal anti-inflammatory drugs that have been shown to selectively lower pathogenic amyloid beta-peptide (Ab)42 without impairing overall y-secretase activity in vitro. This y-secretase modulator (GSM) activity has been hypothesized to contribute to the reduction in risk of developing @entity195 in chronic users of nonsteroidal anti-inflammatory drugs. However, it is unclear whether @entity5018 , within therapeutic dosing range, demonstrates GSM activity in @entity1 . In this study, we evaluated the effects of @entity5018 and a second-generation GSM, @entity23756 , on Ab levels in cerebrospinal fluid and plasma of young nonhuman primates and @entity1 . METHODS: Five to seven conscious @entity5434 ( @entity5434 ) were nontreated or treated with 30 mg/kg @entity23756 or 50 or 100 mg/kg @entity5018 and the plasma and cerebrospinal fluid were sampled at -8, 0 (baseline or right before treatment), 2, 4, 6, 8, 12, and 24 h postdosing. In addition, sixteen healthy @entity1 subjects were randomly assigned to receive either placebo or 800 mg @entity5018 given by intravenous administration and plasma were collected at 0 (before drug infusion), 0.5, 1, 2, 4, 6, 8, 10, and 24 h after dosing. RESULTS: A single dose of @entity23756 (30 mg/kg) decreased the ratio of Ab42 to Ab40 to 60% in plasma and the ratio of Ab42 to total Ab to 65% in cerebrospinal fluid from baseline to postdosing in monkeys. However, no significant changes were detected following @entity5018 treatment at 100 mg/kg. Consistent with the results from nonhuman primates, @entity5018 did not alter plasma Ab levels in @entity1 volunteers after a single 800 mg dose. CONCLUSIONS: @entity23756 exerted potent lowering of the ratio of Ab42 to Ab40 in nonhuman primates but the hypothesized GSM activity of @entity5018 could not be demonstrated in nonhuman primates and @entity1 after acute dosing.
