A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator

Abstract 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.

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Safety and pharmacokinetics of the muscarinic positive allosteric modulator VU319: A phase 1 single dose study

Alzheimer s & Dementia ◽

10.1002/alz.045359 ◽

2020 ◽

Vol 16 (S9) ◽

Author(s):

Paul A. Newhouse ◽

Alexander C. Conley ◽

Alexandra P. Key ◽

Jennifer U. Blackford ◽

Jerri M. Rook ◽

...

Keyword(s):

Single Dose ◽

Phase 1 ◽

Allosteric Modulator ◽

Positive Allosteric Modulator ◽

Single Dose Study ◽

Dose Study

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0079 A Phase 1 Single-dose Polysomnography Study Of ASP8062, A GABAB Receptor Positive Allosteric Modulator

SLEEP ◽

10.1093/sleep/zsy061.078 ◽

2018 ◽

Vol 41 (suppl_1) ◽

pp. A32-A32 ◽

Cited By ~ 1

Author(s):

M Walzer ◽

R Wu ◽

M Ahmad ◽

J Freeman ◽

G Zammit ◽

...

Keyword(s):

Single Dose ◽

Gabab Receptor ◽

Phase 1 ◽

Allosteric Modulator ◽

Positive Allosteric Modulator

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A synthetic peptide-based erythropoiesis stimulating agent (ESA) (Hematide) demonstrates dose dependent activity and is well tolerated in a phase 1 single dose, dose escalating study in normal healthy volunteers (NHV)

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.8180 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 8180-8180 ◽

Cited By ~ 4

Author(s):

R. B. Stead ◽

J. Lambert ◽

D. Wessels ◽

J. Iwashita ◽

K. Leuther ◽

...

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Synthetic Peptide ◽

Phase 1 ◽

Dependent Activity ◽

Dose Dependent ◽

Dose Escalating

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In vitro impact of pegvisomant on growth hormone-secreting pituitary adenoma cells

Endocrine Related Cancer ◽

10.1530/erc-16-0140 ◽

2016 ◽

Vol 23 (7) ◽

pp. 509-519 ◽

Cited By ~ 2

Author(s):

Thomas Cuny ◽

Caroline Zeiller ◽

Martin Bidlingmaier ◽

Céline Défilles ◽

Catherine Roche ◽

...

Keyword(s):

Growth Hormone ◽

Cell Line ◽

Primary Cultures ◽

Somatostatin Analogs ◽

Primary Tumors ◽

Dependent Inhibition ◽

Dose Dependent Inhibition ◽

The Impact ◽

Dose Dependent

Pegvisomant (PEG), an antagonist of growth hormone (GH)-receptor (GHR), normalizes insulin-like growth factor 1 (IGF1) oversecretion in most acromegalic patients unresponsive to somatostatin analogs (SSAs) and/or uncontrolled by transsphenoidal surgery. The residual GH-secreting tumor is therefore exposed to the action of circulating PEG. However, the biological effect of PEG at the pituitary level remains unknown. To assess the impact of PEG in vitro on the hormonal secretion (GH and prolactin (PRL)), proliferation and cellular viability of eight human GH-secreting tumors in primary cultures and of the rat somatolactotroph cell line GH4C1. We found that the mRNA expression levels of GHR were characterized in 31 human GH-secreting adenomas (0.086 copy/copy β-Gus) and the GHR was identified by immunocytochemistry staining. In 5/8 adenomas, a dose-dependent inhibition of GH secretion was observed under PEG with a maximum of 38.2±17% at 1μg/mL (P<0.0001 vs control). A dose-dependent inhibition of PRL secretion occurred in three mixed GH/PRL adenomas under PEG with a maximum of 52.8±11.5% at 10μg/mL (P<0.0001 vs control). No impact on proliferation of either human primary tumors or GH4C1 cell line was observed. We conclude that PEG inhibits the secretion of GH and PRL in primary cultures of human GH(/PRL)-secreting pituitary adenomas without effect on cell viability or cell proliferation.

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Neurochemical changes underlying cognitive impairment in olfactory bulbectomized rats and the impact of the mGlu5-positive allosteric modulator CDPPB

Brain Research ◽

10.1016/j.brainres.2021.147577 ◽

2021 ◽

pp. 147577

Author(s):

Agata Płoska ◽

Paulina Cieślik ◽

Anna Siekierzycka ◽

Leszek Kalinowski ◽

Joanna M Wierońska

Keyword(s):

Cognitive Impairment ◽

Allosteric Modulator ◽

Positive Allosteric Modulator ◽

Neurochemical Changes ◽

The Impact

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Abstract P204: Stroke Topography Impacts Sleep Architecture in Post-Acute Stroke

Stroke ◽

10.1161/str.52.suppl_1.p204 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Stefanie N Howell ◽

Stephanie E Robinson ◽

Grace S Griesbach

Keyword(s):

Ischemic Stroke ◽

Rem Sleep ◽

Sleep Efficiency ◽

Sleep Architecture ◽

Sleep Stages ◽

Apnea Hypopnea Index ◽

Close Monitoring ◽

Stroke Patients ◽

Significant Difference ◽

The Impact

Introduction/Objective: Sleep-wake disturbances (SWDs) are common amongst stroke patients; however, little work has been done on the effect of stroke location on sleep architecture. The aim of this study was to investigate the impact of stroke topography on prevalence and severity of SWDs in the post-acute phase of ischemic stroke recovery. Methods: Ischemic stroke patients (n=55) were assessed for SWDs via overnight attended polysomnography in a post-acute rehabilitation setting. The mean age was 55 ± 1.4 years and mean latency from injury was 106 ± 11 days. Sleep measures included total sleep time (TST), sleep and REM latency, sleep efficiency, percent time in sleep stages, apnea/hypopnea index (AHI), wake after sleep onset (WASO), and arousal index. Patients who did not have at least four hours of TST were excluded. Stroke patients were identified as having supratentorial or infratentorial injuries. Results: Results showed a significant difference between supratentorial and infratentorial stroke in regards to sleep efficiency, REM sleep, and sleep apnea. Patients with infratentorial stroke (n=15) displayed significantly poorer sleep efficiency (F(1,53)=12.386, p<.001), decreased REM sleep (F(1,53)=5.944), p<.05) and higher AHI (F(1,53)=4.698, p<.05). In addition to displaying a decreased amount of REM, infratentorial stroke patients displayed significantly shorter bouts of REM (F(1,52)=7.482, p<.01). Neither age nor AHI were significantly correlated with the amount or duration of REM (p>.05). Conclusion: Infratentorial ischemic stroke patients display significant disruptions in sleep and may require close monitoring for sleep-wake disturbances in the post-acute period. REM sleep is particularly effected when compared to supratentorial ischemic stroke.

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