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The central nervous system effects of the partial GABA-A?2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males.


ABSTRACT: AZD7325 is a novel ?2,3 -subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD7325 2?mg and 10?mg on the central nervous system (CNS) compared with placebo and lorazepam 2?mg.This double-blind, randomized, four way crossover study enrolled 16 healthy males and administered two validated CNS test batteries to measure drug effects on cognitive, neurophysiologic and psychomotor function and subjective feelings. The pharmacological selectivity of AZD7325 was compared with lorazepam by plotting saccadic peak velocity change from baseline (?SPV) against body sway (?Sway) and visual analogue scale for alertness(?VASalertness ). This analysis has previously been used to identify ?2,3 -subtype-selectivity.In contrast with the robust impairment caused by lorazepam (all P < 0.05 vs. placebo), neither dose of AZD7325 induced statistically significant effects on any pharmacodynamic measurements. Lorazepam-induced SPV-reduction was linearly related to changes in other neurophysiologic biomarkers. In contrast, the slopes of the regression lines were flatter for AZD7325, particularly for the ?log(Sway) -?SPV relation (estimate slope, AZD7325 10?mg vs. lorazepam, difference [95% confidence interval], P value -0.00036 vs. -0.00206, 0.001704 [0.000639, 0.002768], P = 0.0018) and the ?VASalertness -?SPV relationship (0.01855 vs. 0.08216, -0.06360 [-0.1046, -0.02257], P = 0.0024). AZD7325 10?mg and lorazepam induced different response patterns on VAS 'feeling high' and electro-encephalography.The characteristic ?SPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to ?2,3 -selective GABAA agonism. However, exploration of higher doses may be warranted. The paucity of effects on most CNS-PD parameters also indicates a mitigated side effect pattern, with potentially lower cognitive and neurophysiological side effect burden than non-selective benzodiazepines.

SUBMITTER: Chen X 

PROVIDER: S-EPMC4256620 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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The central nervous system effects of the partial GABA-Aα2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males.

Chen Xia X   Jacobs Gabriël G   de Kam Marieke M   Jaeger Judith J   Lappalainen Jaakko J   Maruff Paul P   Smith Mark A MA   Cross Alan J AJ   Cohen Adam A   van Gerven Joop J  

British journal of clinical pharmacology 20141201 6


<h4>Aims</h4>AZD7325 is a novel α2,3 -subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD7325 2 mg and 10 mg on the central nervous system (CNS) compared with placebo and lorazepam 2 mg.<h4>Methods</h4>This double-blind, randomized, four way crossover study enrolled 16 healthy males and administered two validated CNS test batteries to measure drug effects on cognitive, neurophysiologic and psychomotor function and subjecti  ...[more]

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