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The use of non-selective γ-aminobutydc acid (GABA) enhancers, such as benzodiazepines in the treatment of anxiety disorders is still widespread but hampered by unfavourable side effects. Some of these may be associated with binding properties to certain subtypes of the GABAA receptor that are unnecessary for therapeutic effects. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the α1 subtype and significant efficacy at α2 and α3 subtypes of the GABAA receptor. This paper is a double-blind, four-way cross-over (n = 12) study to investigate the effects of MK-0343 (0.25 and 0.75 rag) in comparison to placebo and an anxiolytic dose (2 mg) of the non-selective agonist lorazepam. Effects were measured by eye movements, body sway, Visual Analogue Scales (VAS) and memory tests. Lorazepam impaired saccadic peak velocity (SPV), VAS alertness scores, postural stability and memory and increased saccadic latency and inaccuracy. MK-0343 0.75 mg was equipotent with lorazepam as indicated by SPV (-42.4 deg/s), saccadic latency (0.02 s) and VAS alertness scores (1.50 ln mm), while effects on memory and postural stability were smaller. MK-0343 0.25 mg only affected postural stability to a similar extent as MK-0343 0.75 mg. The effect profile of MK-0343 0.75 mg is different from the full agonist lorazepam, which could reflect the selective actions of this compound. Although less effect on VAS alertness was expected, diminished effects on memory and postural stability were present. Clinical studies in anxiety patients should show whether this dose of MK-0343 is therapeutically effective with a different side-effect profile. [ABSTRACT FROM AUTHOR]

TPA023, a GABAA α2,3 αsubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the α1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on postural stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectable effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak velocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABAA receptor subtypes. [ABSTRACT FROM AUTHOR]

Previous single-dose studies have shown clear blood pressure-lowering effects of a potential sustained release (SR) profile of rilmenidine, with concentration-dependent effects on the central nervous system. The aim of this study was to evaluate potential changes in concentration-effect-relationships for these central nervous system effects during a 4-week treatment period with an experimental SR formulation of rilmenidine 3 mg once daily in 15 mild-to-moderate hypertensive patients. The central nervous system effects of the treatment were evaluated using saccadic eye movements for sedative effects and visual analogue scales for subjective effects on alertness, mood and calmness. Measurements for pharmacokinetic and pharmacodynamic evaluations were performed on the first day of the treatment period and repeated after 1 week and 4 weeks of treatment. Drug concentrations increased during the study, whereas treatment related reductions in saccadic peak velocity (SPV) remained similar on all three study days. The slopes of the concentration-effect-curves for SPV remained unchanged throughout the study, while the intercepts tended to increase as a result of increased pre-dose values. Similar effects were observed for visual analogue scales for alertness: pre-dose values increased significantly during the study, while the size of the treatment responses (slopes) remained unaltered. The reasons for these adaptations cannot be determined but may include drug tolerance and habituations to study procedures. Blood pressure control remained stable and adequate throughout the study. [ABSTRACT FROM AUTHOR]