Visual motor co‐ordination and dynamic visual acuity.

AIMSAZD7325 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. METHODSThis 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 (ΔSPV) against body sway (ΔSway) and visual analogue scale for alertness(ΔVASalertness). This analysis has previously been used to identify α2,3-subtype-selectivity. RESULTSIn 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 Δlog(Sway) −ΔSPV relation (estimate slope, AZD7325 10 mg CONCLUSIONThe characteristic ΔSPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to α2,3-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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• AZD7325 is a novel partial α2,3 subtype-selective GABA receptor modulator with minimal in vitro efficacy at the α1 and α5 receptor subtypes. Since preclinical studies have associated the GABA α1,α2/α3, and α5 subtypes with sedation, anxiolysis and cognition, respectively, the compound is expected to produce anxiolytic effects in humans with reduced depression on the central nervous system. • Using positron emission tomography (PET), in vivo occupancy of CNS GABA receptors suggested that AZD7325 could achieve clinically effective doses. WHAT THIS STUDY ADDS• This study provided a comprehensive map regarding the pharmacodynamic effects of AZD7325 on a variety of CNS domains. The novel compound was associated with a specific electro-encephalogram (EEG) signature.• Compared with lorazepam, the concept of pharmacological selectivity was demonstrated by the relatively dominant effects on saccadic eye movements compared with those on postural stability, subjective alertness and cognition.• The CNS effects were modest, suggesting that the pharmacodynamically/clinically effective concentrations of AZD7325 might be higher than those predicted by GABA-receptor occupancy.

Section: Methodsmentioning

confidence: 99%

The central nervous system effects of the partial GABA‐Aα_2,3‐selective receptor modulator AZD7325 in comparison with lorazepam in healthy males

Chen

Jacobs

Kam

et al. 2014

“…Effects of triprolidine confirm previous findings (Nicholson, 1979;Nicholson & Stone, 1983;Nicholson etal., 1982). Change in dynamic visual acuity and visuomotor coordination suggest that altered neuromuscular mechanisms are likely to be the common denominator (Borland & Nicholson, 1984). Indeed, morphine-like compounds modulate saccadic and smooth pursuit eye movements (Griffiths et al, 1984;Rothenberg et al, 1980a,b), and such effects would displace the target image from the fovea with loss of visual acuity.…”

Section: Discussionmentioning

confidence: 99%

Effects of a mu‐opioid receptor agonist (codeine phosphate) on visuo‐ motor coordination and dynamic visual acuity in man.

Bradley¹,

Nicholson²

1986

Self Cite

1 Effects of codeine (30, 60 and 90 mg) on visuo-motor coordination and dynamic visual acuity, together with critical flicker fusion, digit symbol substitution, complex reaction time and subjective assessments of mood, were studied from 0.75-2.0 h after ingestion by six healthy female adults. The study was double-blind and placebo controlled, and triprolidine (10 mg) was used as the active control. 2 The effect on visuo-motor coordination was limited and was dose related and linear, and performance was altered on visuo-motor coordination with 60 and 90 mg codeine, and on dynamic visual acuity with 90 mg codeine (P < 0.05). No other effect of codeine was detected.3 Modulated neuromuscular function is likely to be the common denominator of the changes in performance with codeine, though nausea, but not sedation, may be a contributory factor. It is possible that altered performance with codeine may involve interactions with different receptors than those which lead to sedation.

“…The adaptive tracking test, as originally described by Borland & Nicholson [41], was performed as previously explained [42].The average performance and the standard deviation of scores over a 3.5-min period were used for analysis.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects

Liem-Moolenaar

Boer²,

Timmers³

et al. 2011

Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK-PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK-PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems.