22394
document
Safety , tolerability , and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers . Amyloid beta ( Abeta ) may play a central role in the pathogenesis of Alzheimer disease . A functional gamma-secretase inhibitor , LY450139 , was developed that inhibits Abeta formation in whole cell assays , transgenic mice , and beagle dogs . The authors wished to determine the safety and tolerability of this drug , and the reduction of Abeta in plasma and cerebrospinal fluid ( CSF ) after multiple doses . Volunteer subjects ( N = 37 ) were studied using doses from 5 to 50 mg/day given for 14 days . Plasma and CSF concentrations of LY450139 , Abeta ( 1-40 ) and Abeta ( 1-X ) ( " Abeta ( total ) " ) were determined , and safety and tolerability were assessed . The plasma half-life of LY450139 was approximately 2.5 hours . Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations , with a Cmax of 828 +/- 19.2 ng/mL after a 50-mg dose . Plasma Abeta concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration , with a maximum decrease of approximately 40 % relative to baseline . After returning to baseline , Abeta concentrations were transiently increased . CSF Abeta concentrations were unchanged . Adverse events reported by subjects taking 5-mg , 20-mg , or 40-mg doses were similar to those reported by subjects taking placebo . Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related . In this phase 1 volunteer study , reported adverse events after taking LY450139 were manageable . A dose-dependent reduction in plasma Abeta was demonstrated , and changes in plasma Abeta concentrations were temporally related to the pharmacokinetic characteristics of LY450139 .
22395
Intervention_Pharmacological
gamma-secretase inhibitor
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Intervention_Pharmacological
LY450139
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Intervention_Pharmacological
using doses from 5 to 50 mg/day given for 14 days . Plasma and CSF concentrations of LY450139 , Abeta ( 1-40 ) and Abeta ( 1-X ) ( " Abeta ( total ) " )
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Intervention_Pharmacological
LY450139
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Outcome_Other
Safety
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Outcome_Other
tolerability
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Outcome_Physical
changes in amyloid beta concentrations
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Outcome_Physical
Abeta in plasma and cerebrospinal fluid ( CSF )
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Outcome_Physical
Plasma and CSF concentrations of LY450139 , Abeta ( 1-40 )
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Outcome_Physical
Abeta ( 1-X ) ( " Abeta ( total ) " )
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Outcome_Physical
Plasma Abeta concentrations
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Outcome_Physical
Abeta concentrations
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Outcome_Physical
CSF Abeta concentrations
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Outcome_Adverse-effects
Adverse events
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Outcome_Physical
plasma Abeta
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Outcome_Physical
plasma Abeta
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Participant_Condition
subjects taking placebo .