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A randomized phase 1 single-dose polysomnography study of ASP8062, a GABA B receptor positive allosteric modulator
Psychopharmacology ( IF 3.4 ) Pub Date : 2021-01-12 , DOI: 10.1007/s00213-020-05738-y
Mark Walzer , Ruishan Wu , Maha Ahmad , Jon Freeman , Gary Zammit , Gerard J. Marek

Rationale

Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear.

Objectives

This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg).

Methods

Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability.

Results

In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity.

Conclusions

Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.



中文翻译:

GABA B受体阳性变构调节剂ASP8062的随机1期单剂量多导睡眠图研究

基本原理

先前的研究表明,睡眠多导睡眠图和脑电图终点可用于评估GABA能活动。但是,尚不清楚GABA B受体阳性的变构调节剂对睡眠终点的影响。

目标

这项1期研究比较了单剂量ASP8062(35 mg或70 mg),一种GABA B受体阳性变构调节剂与安慰剂和帕罗西汀(40 mg)。

方法

健康的成年志愿者被随机分为四种治疗方法(35 mg ASP8062、70 mg ASP8062,帕罗西汀40 mg或匹配的安慰剂),每种治疗间隔14天。通过多导睡眠监测仪得出的主要终点是N3或SWS阶段的时间以及快速眼动(REM)睡眠的时间。次要终点包括对睡眠阶段和脑电图参数,药代动力学,夜间生长激素(GH)和安全性/耐受性的影响。

结果

在20名随机志愿者中,ASP8062导致整个晚上的SWS明显增加,并且似乎是剂量依赖性的;这种增加主要发生在晚上的前三分之一。ASP8062不会影响REM睡眠的时间。帕罗西汀对SWS无影响,但显着减少了REM睡眠时间。用ASP8062还观察到GH释放增加的剂量依赖性趋势。头痛和恶心是ASP8062最常报告的治疗紧急不良事件(TEAE)。大多数TEAE的病情轻重。

结论

单剂量ASP8062(35和70毫克)似乎导致中枢神经系统的渗透和增强的GABA能活性,这通过慢波睡眠和生长激素释放的增加来衡量。

更新日期:2021-01-12
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