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S Deacon - One of the best experts on this subject based on the ideXlab platform.
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enhanced slow wave sleep and improved sleep maintenance after Gaboxadol administration during seven nights of exposure to a traffic noise model of transient insomnia
Journal of Psychopharmacology, 2012Co-Authors: Derkjan Dijk, Jonas Lundahl, N Stanley, John A Groeger, A Legters, A Trap K Huusom, S DeaconAbstract:Slow wave sleep (SWS) has been reported to correlate with sleep maintenance, but whether pharmacological enhancement of SWS also leads to improved sleep maintenance is not known. Here we evaluate the time-course of the effects of Gaboxadol, an extra-synaptic gamma-aminobutyric acid (GABA) agonist, on SWS, sleep maintenance, and other sleep measures in a traffic noise model of transient insomnia. After a placebo run-in, 101 healthy subjects (20-78 y) were randomized to Gaboxadol (n = 50; 15 mg in subjects <65 y and 10 mg in subjects ≥65 y) or placebo (n = 51) for 7 nights (N1-N7). The model caused some disruption of sleep initiation and maintenance, with greatest effects on N1. Compared with placebo, Gaboxadol increased SWS and slow wave activity throughout N1 to N7 (p < 0.05). Gaboxadol reduced latency to persistent sleep overall (N1-N7) by 4.5 min and on N1 by 11 min (both p < 0.05). Gaboxadol increased total sleep time (TST) overall by 16 min (p < 0.001) and on N1 by 38 min (p < 0.0001). Under Gaboxadol, wakefulness after sleep onset was reduced by 11 min overall (p < 0.01) and by 29 min on N1 (p < 0.0001), and poly-somnographic awakenings were reduced on N1 (p < 0.05). Gaboxadol reduced self-reported sleep onset latency overall and on N1 (both p < 0.05) and increased self-reported TST overall (p < 0.05) and on N1 (p < 0.01). Subjective sleep quality improved overall (p < 0.01) and on N1 (p < 0.0001). Increases in SWS correlated with objective and subjective measures of sleep maintenance and subjective sleep quality under placebo and Gaboxadol (p < 0.05). Gaboxadol enhanced SWS and reduced the disruptive effects of noise on sleep initiation and maintenance.
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eeg power spectra response to a 4 h phase advance and Gaboxadol treatment in 822 men and women
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2011Co-Authors: Derkjan Dijk, Vladimir Svetnik, James K Walsh, Yevgen Tymofyeyev, Shubhankar Ray, S DeaconAbstract:Study Objective:To explore the effect of Gaboxadol on NREM EEG in transient insomnia using power spectral analysis and evaluate the response between men and women.Methods:This was a randomized, dou...
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alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by Gaboxadol and zolpidem
Sleep, 2010Co-Authors: Vladimir Svetnik, Ellen Snyder, Bjarke Ebert, James K Walsh, Shubhankar Ray, Raffaele Ferri, S DeaconAbstract:CYCLIC ALTERNATING PATTERN (CAP) IS A SPONTANEOUS RHYTHM DETECTABLE DURING NREM SLEEP CHARACTERIZED BY EEG OSCILLATIONS BELIEVED to correspond to periods of cyclic activation and unstable sleep depth. Each oscillation is composed of an EEG transient (phase A of the cycle) separated by intervals of background activity (phase B of the cycle). Three main CAP phase A EEG patterns have been described: Subtype A1 is based on the type and frequency of EEG synchronized slow waves; subtype A3 on the EEG fast rhythms; and subtype A2 on a combination of both.1 The hierarchical activation from slower EEG patterns (moderate autonomic activation without sleep disruption)2–4 to faster EEG patterns (robust activation associated with visible sleep fragmentation) can have different meanings. A1 subtypes are associated with SWS and sleep continuity; A2 and A3 are associated with initiation of REM and relative arousability.5 Sequences of CAP are present in NREM sleep, and the ratio of CAP time to NREM sleep time, i.e., CAP rate, has been described as a physiological marker of sleep instability.5–7 It has been reported that CAP rate increases8 in patients with insomnia while the amount of standard EEG arousals does not necessarily increase9,10 indicating that CAP is a sensitive marker of unstable sleep.11,12 It has also been found13–17 that CAP was significantly correlated with self-reported measures of sleep quality, and more strongly than traditional PSG measures. Such findings suggest that CAP can be used not only as a marker of sleep disruption but also for evaluating insomnia treatments with regards to their effects on sleep stability and to predict self-reported sleep quality. The present work applies CAP analysis to PSG data from a large clinical study evaluating sleep restoring effects of GBX in a human model of transient insomnia.18 This current analysis is a post hoc evaluation of this study data with the focus on CAP. Since ZOL was used as an active reference drug, the study provides a unique opportunity to evaluate effects on CAP of two sleep agents with different mechanisms of actions. Although GBX is no longer in clinical development for insomnia, it represents a useful pharmacological probe to evaluate the effects of enhancing SWS/SWA through direct GABAA receptor mechanisms. GBX has functional selectivity for the d-containing receptor GABAA subtype that is insensitive to benzodiazepines. By comparison, ZOL allosterically modulates GABAA receptors. Therefore, a comparison of the 2 drugs with respect to CAP may help to further understand the differences in sleep state stability between these 2 mechanisms of action. The phase advance sleep model of transient insomnia used in the study by Walsh et al.18 involves moving bedtime earlier by 2-5 h and produces reliable sleep disruption in otherwise good sleepers. The first hours of the advanced sleep period occur during the “forbidden zone” for sleep, when the circadian arousal system promotes alertness, reducing the likelihood of sleep.19 A key advantage of the acute phase advance model is to produce the transient insomnia known to result from time zone shifts, which typically prevents people from obtaining adequate sleep after travelling to a new time zone. Drug treatment effects have been demonstrated in prior studies using a phase advance procedure.20,21 Walsh et al.18 presented results on the effects of GBX on conventional polysomnographic (PSG) and spectral measures of NREM sleep in this model. This paper extends the prior findings of Walsh et al.18 using post hoc analysis of the same data to test for CAP effects. Firstly, it evaluates the effects of transient insomnia on CAP parameters. Secondly, it compares effects of transient insomnia on CAP parameters and its effects on spectral and traditional PSG measures. Thirdly, it compares the differential effects of the 2 drugs, ZOL and GBX, on CAP parameters and assesses if the changes are in the direction of a more stable, “normal” sleep when subjects in this study are allowed to sleep during their habitual bedtime. Finally, taking advantage of having a multitude of objective and subjective sleep measures, this paper compares them with respect to their correlations with self-reported sleep quality. Presented results may also serve to define new valuable endpoints in future insomnia research and potentially other diseases where an altered sleep pattern is considered a core component of the disease.
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sex differences and the effect of Gaboxadol and zolpidem on eeg power spectra in nrem and rem sleep
Journal of Psychopharmacology, 2010Co-Authors: Derkjan Dijk, James K Walsh, Lynette M James, Stuart Peters, S DeaconAbstract:Hypnotics that interact with the GABA(A) receptor have marked effects on the electroencephalogram (EEG) during sleep. It is not known whether the effects of hypnotics on EEG power spectra differ between the sexes. The effects of 5, 10 and 15 mg of Gaboxadol (GBX) and 10 mg of zolpidem (ZOL) on EEG power spectra were assessed in a randomized, double-blind, placebo-controlled, 5-way cross-over design study using a phase-advance model of transient insomnia. Sleep stage specific EEG power spectra were computed in 36 men and 45 women. GBX enhanced power density in delta and theta activity in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and suppressed sleep spindle activity in NREM sleep. The increase of delta and theta activity in NREM and REM sleep was significantly larger for women than for men but the suppression of spindle activity did not differ between the sexes. After ZOL administration, no sex differences were observed in the reduction of delta and theta activity in NREM sleep, but the increase in sleep spindle activity in NREM sleep was greater in women than in men. These sex dependent and differential effects of GBX and ZOL may be related to their differential affinity for GABA(A) receptor subtypes and their modulation by neurosteroids.
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Effect of Gaboxadol on Sleep in Adult and Elderly Patients with Primary Insomnia: Results From Two Randomized, Placebo-Controlled, 30-Night Polysomnography Studies
Sleep, 2008Co-Authors: D. Alan Lankford, Christopher Lines, Bruce C. Corser, Yan-ping Zheng, Duane B. Snavely, S DeaconAbstract:Gaboxadol IS A NOVEL HYPNOTIC WITH A DISTINCT MECHANISM OF ACTION COMPARED WITH CURRENT HYPNOTICS.1,2 TRADITIONAL BENZODIAZEPINE (e.g., triazolam) and non-benzodiazepine (e.g., zolpidem) hypnotics, collectively referred to as benzodiazepine receptor agonists (BzRAs), share a similar mode of action as allosteric modulators of γ-aminobutyric acid type A (GABA-A) receptors. By contrast, Gaboxadol is an agonist that acts directly on the GABA binding site of the GABA-A receptor and has no affinity for the benzodiazepine binding site. It has highest functional activity for δ-containing GABA-A receptors where it behaves as a super-agonist (i.e., more efficacious than GABA in a functional assay). δ-Containing GABA-A receptors are insensitive to BzRAs, probably exist mainly extrasynaptically, and are localized predominantly in the thalamus, dentate gyrus, cerebellum, and cortex. These characteristics have led to Gaboxadol being classified as a selective extrasynaptic GABA-A agonist (SEGA).3 The functional consequences of these anatomical and pharmacological differences are yet to be understood. Both BzRAs and Gaboxadol appear to have sleep maintenance properties and beneficial effects on sleep onset, although less consistently with regard to sleep onset for Gaboxadol. Two previous exploratory PSG studies demonstrated that short term treatment with Gaboxadol 10, 15, and 20 mg increased sleep continuity over an initial 2 nights of treatment in patients with primary insomnia.4,5 Effects on measures of sleep onset were only observed in one study with Gaboxadol 15 mg.4 Effects on sleep onset, as well as maintenance, have also been observed for Gaboxadol in larger studies using a model of transient insomnia.6,7 From a sleep architecture perspective, clear differences are observed between BzRAs and Gaboxadol. Numerous studies have shown that classical benzodiazepines promote stage 2 NREM sleep and reduce both slow wave sleep (SWS) and REM sleep, while non-benzodiazepines may increase stage 2 sleep but have no effect on other visually scored sleep stages.8–13 Gaboxadol has shown consistent increases in SWS with no significant effect on stage 2 or REM sleep in healthy adult/elderly subjects and early phase studies in patients with primary insomnia.4–6,14–17 Clear differences in NREM EEG spectral profiles are also observed between zolpidem and Gaboxadol, with the latter selectively enhancing lower frequency slow wave activity (SWA), underlining a neurochemical difference in the mechanism of action between zolpidem and Gaboxadol.6 Other putative sleep agents, including the 5-HT2A/2C receptor antagonists ritanserin and seganserin and the GABA reuptake inhibitor tiagabine, as well as α2δ calcium channel modulators, also increase SWS/SWA.18–21 In terms of the functional significance of sleep there has been much interest in SWS and the development of SWS-enhancing compounds for treating insomnia. There are marked age-related changes in sleep maintenance and continuity measures, but perhaps the most striking observation is that SWS is reduced with age.22–24 SWS is a marker of homeostatic sleep drive, and it is an intriguing question whether increased sleep problems seen with age are in fact the result of changes in SWS, and whether enhancement of SWS might result in more restorative, less fragmented sleep in the elderly. The objectives of the present studies were to confirm the efficacy and SWS-enhancing properties of Gaboxadol in 2 large phase 3 PSG studies, one in adult and one in elderly adult patients with primary insomnia, and to determine whether the short term efficacy (1–3 nights) on objective measures of sleep seen to date could be maintained over 30 nights. Based on previous findings suggesting greater drug exposure in elderly patients (Cmax and AUC0-inf of Gaboxadol 20 mg increased by approximately 40%, t½ increased from 1.5 to 2 h),25 the maximum Gaboxadol dose investigated was 10 mg in the elderly patients versus 15 mg in adult patients. To our knowledge, the elderly study constitutes the largest PSG dataset yet available in this population and is the first to evaluate the PSG effects of a SWS-enhancer in elderly patients over an extended period. Since SWS declines with age, there is interest in the potential differential effects of a SWS-enhancer in the elderly compared to adult insomniac patients. The adult study is therefore presented here in the same paper to allow an illustrative comparison of elderly and adult primary insomnia patients before and after treatment with Gaboxadol in large 4-week treatment studies with identical designs and specifically identical PSG entry criteria.
Bjarke Ebert - One of the best experts on this subject based on the ideXlab platform.
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synergistic antidepressant like action of Gaboxadol and escitalopram
European Neuropsychopharmacology, 2012Co-Authors: Trine Christensen, Bjarke Ebert, Cecile Betry, Ouissame Mniefilali, Adeline Etievant, Nasser Haddjeri, Ove WiborgAbstract:According to current theories on the etiopathogenesis and pathophysiology of depression, both GABAergic and monoaminergic transmitter systems are perturbed. Consequently, the present study addressed the putative antidepressant action of the sedative-hypnotic GABAA receptor agonist, Gaboxadol, separately and in combination with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The rat chronic mild stress model was used to test the chronic antidepressant properties of Gaboxadol in this depression model. Sucrose intake used as a read-out on anhedonic-like behavior indicated that the drug response rate for Gaboxadol (5 mg/kg/day, i.p.) was similar to that measured for escitalopram (5 mg/kg/day, i.p.), however, the rate increased when the two drugs were co-administered, suggesting a synergistic action. Using in vivo electrophysiological recordings in dorsal raphe nucleus (DRN) of anesthetised rats, the present results showed that one week treatment with Gaboxadol (5 mg/kg/day, i.p.) or with escitalopram (5 mg/kg/day, i.p.), followed by a 24 h washout period, did not affect DRN 5-HT neuronal firing per se, but in rats treated with both drugs for one week, the firing rate of DRN 5-HT neurons was significantly increased. Immunohistochemical estimations of cell proliferation in the hippocampal dentate gyrus did not reveal any effect of Gaboxadol on chronic mild stressed rats, indicating that neurogenesis per se is not systematically associated with recovery from anhedonic-like behavior. Taken together, our data reveal for the first time an antidepressant action of Gaboxadol and indicate a synergistic mechanism, regarding rapid onset of action and efficacy, when co-administered with escitalopram.
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combining escitalopram with Gaboxadol provides no additional benefit in the treatment of patients with severe major depressive disorder
The International Journal of Neuropsychopharmacology, 2012Co-Authors: Siegfried Kasper, Bjarke Ebert, Klaus Larsen, Brigitte TonnoirAbstract:The aim of this proof-of-concept study was to compare the efficacy of escitalopram (20 mg/d) in combination with fixed doses of Gaboxadol to escitalopram (20 mg) in the treatment of patients with severe major depressive disorder (MDD). Adult patients were randomized to 8 wk of double-blind treatment with fixed doses of placebo (n=71), escitalopram (20 mg, n=140), escitalopram (20 mg)+Gaboxadol (5 mg) (n=139), or escitalopram (20 mg)+Gaboxadol (10 mg) (n=140). The pre-defined primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 8) in Montgomery-Asberg Depression Rating Scale (MADRS) total score using last observation carried forward (LOCF). There was no statistically significant difference in the mean change from baseline in MADRS total score between the 20 mg escitalopram+10 mg Gaboxadol group and the 20 mg escitalopram group [difference=-0.45 MADRS points (95% CI -2.5 to 1.6, p=0.6619, full analysis set (FAS), LOCF, ANCOVA)] at week 8. The mean treatment differences to placebo at week 8 were -5.6 (95% CI -8.0 to -3.1, p<0.0001) (20 mg escitalopram), -5.1 (95% CI -7.5 to -2.7, p<0.0001) (20 mg escitalopram+5 mg Gaboxadol), and -6.0 (95% CI -8.4 to -3.6, p<0.0001) (20 mg escitalopram+10 mg Gaboxadol). The most common adverse events reported in the active treatment groups for which the incidence was higher than that in the placebo group, comprised nausea, anxiety and insomnia. There were no clinically relevant efficacy differences between a combination of escitalopram and Gaboxadol compared to escitalopram alone in the treatment of severe MDD. All active treatment groups were superior in efficacy to placebo and were well tolerated.
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gaba site agonist Gaboxadol induces addiction predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons
The Journal of Neuroscience, 2012Co-Authors: Elena Vashchinkina, Bjarke Ebert, Anne Panhelainen, Olga Y Vekovischeva, Teemu Aittaaho, Nancy A Ator, Esa R KorpiAbstract:Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABA A receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism. Here, we have tested a non-benzodiazepine direct GABA site agonist 4,5,6,7-tetrahydroisoxazolol[4,5- c ]pyridine-3-ol (THIP) (also known as Gaboxadol) that acts preferentially via high-affinity extrasynaptic GABA A receptors. A single sedative dose of THIP (6 mg/kg) to mice induced glutamate receptor plasticity for at least 6 d after administration. Increased AMPA/NMDA receptor current ratio and increased frequency, amplitude, and rectification of AMPA receptor responses suggested persistent targeting of GluA2-lacking AMPA receptors in excitatory synapses of VTA dopamine neurons ex vivo after THIP administration. This effect was abolished in GABA A receptor δ −/− mice, which have a loss of extrasynaptic GABA A receptors. In behavioral experiments, we found neither acute reinforcement in intravenous self-administration sessions with THIP at relevant doses using a yoked control paradigm in mice nor in baboons using a standard paradigm for assessing drug abuse liability; nor was any place preference found after conditioning sessions with various doses of THIP but rather a persistent aversion in 6 mg/kg THIP-conditioned mice. In summary, we found that activation of extrasynaptic δ-subunit-containing GABA A receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion.
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p 2 d 012 combining escitalopram with Gaboxadol provides no additional benefit in the treatment of patients with severe major depressive disorder
European Neuropsychopharmacology, 2011Co-Authors: Siegfried Kasper, Bjarke Ebert, Klaus Larsen, Brigitte TonnoirAbstract:The aim of this proof-of-concept study was to compare the efficacy of escitalopram (20 mg/d) in combination with fixed doses of Gaboxadol to escitalopram (20 mg) in the treatment of patients with severe major depressive disorder (MDD). Adult patients were randomized to 8 wk of double-blind treatment with fixed doses of placebo (n=71), escitalopram (20 mg, n=140), escitalopram (20 mg)+Gaboxadol (5 mg) (n=139), or escitalopram (20 mg)+Gaboxadol (10 mg) (n=140). The pre-defined primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 8) in
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selective gaba transporter inhibitors tiagabine and ef1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic gabaa receptor agonist Gaboxadol
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Karsten K Madsen, Povl Krogsgaardlarsen, Bjarke Ebert, Rasmus P Clausen, Arne Schousboe, Steve H WhiteAbstract:Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive on GABAA receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1, and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of Gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1–5 mg/kg) selectively activates extrasynaptic α4-containing GABAA receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, when administered in combination with Gaboxadol, resulted in reduced anticonvulsant efficacy and Rotarod impairment associated with Gaboxadol. In contrast, tiagabine, when administered in combination with Gaboxadol, did not modify the anticonvulsant action of Gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABAA receptors.
Jonas Lundahl - One of the best experts on this subject based on the ideXlab platform.
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eeg spectral power density profiles during nrem sleep for Gaboxadol and zolpidem in patients with primary insomnia
Journal of Psychopharmacology, 2012Co-Authors: Jonas Lundahl, Stephen Deacon, Damien Maurice, Luc StanerAbstract:There is significant interest in the functional significance and the therapeutic value of slow-wave sleep (SWS)-enhancing drugs. A prerequisite for studies of the functional differences is characterization of the electroencephalography (EEG) spectra following treatment in relevant patients. We evaluate for the first time Gaboxadol and zolpidem treatments in insomniac patients using power spectra analysis. We carried out two randomized, double-blind, crossover studies. Study 1, 38 patients received Gaboxadol 10 mg and 20 mg and zolpidem 10 mg; study 2, 23 patients received Gaboxadol 5 mg and 15 mg. Treatments were administered during two nights and compared with placebo. Gaboxadol 10, 15 and 20 mg enhanced slow-wave activity (SWA) and theta power. In 1 Hz bins Gaboxadol 10 and 20 mg enhanced power up to 9 Hz. In study 2, 15 mg Gaboxadol showed a similar effect pattern. Zolpidem suppressed theta and alpha power, and increased sigma power, with no effect on SWA. In the 1 Hz bins zolpidem suppressed power between 5-10 Hz. Gaboxadol dose-dependently increased SWA and theta power in insomniac patients. In contrast, zolpidem did not affect SWA, reduced theta and alpha activity and enhanced sigma power. EEG spectral power differences may be consequences of the different mechanisms of action for zolpidem and the SWS-enhancing agent, Gaboxadol.
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enhanced slow wave sleep and improved sleep maintenance after Gaboxadol administration during seven nights of exposure to a traffic noise model of transient insomnia
Journal of Psychopharmacology, 2012Co-Authors: Derkjan Dijk, Jonas Lundahl, N Stanley, John A Groeger, A Legters, A Trap K Huusom, S DeaconAbstract:Slow wave sleep (SWS) has been reported to correlate with sleep maintenance, but whether pharmacological enhancement of SWS also leads to improved sleep maintenance is not known. Here we evaluate the time-course of the effects of Gaboxadol, an extra-synaptic gamma-aminobutyric acid (GABA) agonist, on SWS, sleep maintenance, and other sleep measures in a traffic noise model of transient insomnia. After a placebo run-in, 101 healthy subjects (20-78 y) were randomized to Gaboxadol (n = 50; 15 mg in subjects <65 y and 10 mg in subjects ≥65 y) or placebo (n = 51) for 7 nights (N1-N7). The model caused some disruption of sleep initiation and maintenance, with greatest effects on N1. Compared with placebo, Gaboxadol increased SWS and slow wave activity throughout N1 to N7 (p < 0.05). Gaboxadol reduced latency to persistent sleep overall (N1-N7) by 4.5 min and on N1 by 11 min (both p < 0.05). Gaboxadol increased total sleep time (TST) overall by 16 min (p < 0.001) and on N1 by 38 min (p < 0.0001). Under Gaboxadol, wakefulness after sleep onset was reduced by 11 min overall (p < 0.01) and by 29 min on N1 (p < 0.0001), and poly-somnographic awakenings were reduced on N1 (p < 0.05). Gaboxadol reduced self-reported sleep onset latency overall and on N1 (both p < 0.05) and increased self-reported TST overall (p < 0.05) and on N1 (p < 0.01). Subjective sleep quality improved overall (p < 0.01) and on N1 (p < 0.0001). Increases in SWS correlated with objective and subjective measures of sleep maintenance and subjective sleep quality under placebo and Gaboxadol (p < 0.05). Gaboxadol enhanced SWS and reduced the disruptive effects of noise on sleep initiation and maintenance.
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a 2 week efficacy and safety study of Gaboxadol and zolpidem using electronic diaries in primary insomnia outpatients
Sleep Medicine, 2009Co-Authors: Goran Hajak, Henrik Loft, Jan Hedner, Mirjam Eglin, Signe I Storustovu, Simone Lutolf, Jonas LundahlAbstract:Abstract Objectives To evaluate the efficacy and safety profile of Gaboxadol, a selective extrasynaptic GABA A agonist (SEGA) previously in development for the treatment of insomnia. Methods This was a randomised, double-blind, placebo-controlled, parallel-group, 2-week, Phase III study of Gaboxadol 5, 10 and 15mg in outpatients meeting the DSM-IV criteria of primary insomnia ( N =742). Zolpidem 10mg was used as active reference. Results At weeks 1 and 2, significant improvement in total sleep time (sTST) compared to placebo was seen for all doses of Gaboxadol (all p p p p Conclusions Gaboxadol 15mg treatment for 2 weeks significantly improved sleep onset and maintenance variables as well as sleep quality and daytime function, as did zolpidem. Gaboxadol 5 and 10mg also showed benefits on most efficacy variables. Gaboxadol was generally safe and well tolerated, with no evidence of withdrawal symptoms or rebound insomnia after discontinuation of short-term treatment. For zolpidem, transient rebound insomnia was observed.
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short term treatment with Gaboxadol improves sleep maintenance and enhances slow wave sleep in adult patients with primary insomnia
Psychopharmacology, 2007Co-Authors: Jonas Lundahl, Luc Staner, Corinne Staner, Henrik Loft, S DeaconAbstract:Rationale Gaboxadol is a selective extrasynaptic GABAA agonist, previously in development for the treatment of insomniac patients.
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the selective extrasynaptic gabaa agonist Gaboxadol improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia
Sleep, 2007Co-Authors: James K Walsh, Stephen Deacon, Derkjan Dijk, Jonas LundahlAbstract:Results: Wakefulness after sleep onset (WASO) decreased (P <0.05) and total sleep time (TST) increased (P <0.001) in all treatments versus PBO. Latency to persistent sleep was shorter (P <0.05) than PBO for all treatments except GBX5. GBX10 and GBX15 increased slow wave activity (SWA; 0.75-4.5 Hz, P <0.001) and theta activity (4.75-7.75Hz; P <0.001) and reduced sigma activity (12.25-15.0 Hz; significant for GBX15 only, P <0.001) compared to PBO in NREM sleep EEG, in a dose-response manner. Zolpidem suppressed power density over a broad low frequency range including delta and theta frequencies (2.25-8.0 Hz, P <0.05) and also enhanced sigma activity (P <0.001). Self-reported sWASO and sTST improved for all treatments versus PBO (P <0.05). Self-reported sleep latency was reduced following GBX10 (P <0.05) and ZOL10 (P <0.001). Neither drug treatment was associated with residual effects the morning after treatment. Conclusions: Gaboxadol and zolpidem improved objective and subjective efficacy measures in this model of transient insomnia. The Gaboxadol-induced enhancement of SWA and theta activity and the reduction of sigma activity contrasts with zolpidem’s effects on the spectral EEG. These differences may reflect the different mechanisms of action of the
James K Walsh - One of the best experts on this subject based on the ideXlab platform.
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eeg power spectra response to a 4 h phase advance and Gaboxadol treatment in 822 men and women
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2011Co-Authors: Derkjan Dijk, Vladimir Svetnik, James K Walsh, Yevgen Tymofyeyev, Shubhankar Ray, S DeaconAbstract:Study Objective:To explore the effect of Gaboxadol on NREM EEG in transient insomnia using power spectral analysis and evaluate the response between men and women.Methods:This was a randomized, dou...
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alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by Gaboxadol and zolpidem
Sleep, 2010Co-Authors: Vladimir Svetnik, Ellen Snyder, Bjarke Ebert, James K Walsh, Shubhankar Ray, Raffaele Ferri, S DeaconAbstract:CYCLIC ALTERNATING PATTERN (CAP) IS A SPONTANEOUS RHYTHM DETECTABLE DURING NREM SLEEP CHARACTERIZED BY EEG OSCILLATIONS BELIEVED to correspond to periods of cyclic activation and unstable sleep depth. Each oscillation is composed of an EEG transient (phase A of the cycle) separated by intervals of background activity (phase B of the cycle). Three main CAP phase A EEG patterns have been described: Subtype A1 is based on the type and frequency of EEG synchronized slow waves; subtype A3 on the EEG fast rhythms; and subtype A2 on a combination of both.1 The hierarchical activation from slower EEG patterns (moderate autonomic activation without sleep disruption)2–4 to faster EEG patterns (robust activation associated with visible sleep fragmentation) can have different meanings. A1 subtypes are associated with SWS and sleep continuity; A2 and A3 are associated with initiation of REM and relative arousability.5 Sequences of CAP are present in NREM sleep, and the ratio of CAP time to NREM sleep time, i.e., CAP rate, has been described as a physiological marker of sleep instability.5–7 It has been reported that CAP rate increases8 in patients with insomnia while the amount of standard EEG arousals does not necessarily increase9,10 indicating that CAP is a sensitive marker of unstable sleep.11,12 It has also been found13–17 that CAP was significantly correlated with self-reported measures of sleep quality, and more strongly than traditional PSG measures. Such findings suggest that CAP can be used not only as a marker of sleep disruption but also for evaluating insomnia treatments with regards to their effects on sleep stability and to predict self-reported sleep quality. The present work applies CAP analysis to PSG data from a large clinical study evaluating sleep restoring effects of GBX in a human model of transient insomnia.18 This current analysis is a post hoc evaluation of this study data with the focus on CAP. Since ZOL was used as an active reference drug, the study provides a unique opportunity to evaluate effects on CAP of two sleep agents with different mechanisms of actions. Although GBX is no longer in clinical development for insomnia, it represents a useful pharmacological probe to evaluate the effects of enhancing SWS/SWA through direct GABAA receptor mechanisms. GBX has functional selectivity for the d-containing receptor GABAA subtype that is insensitive to benzodiazepines. By comparison, ZOL allosterically modulates GABAA receptors. Therefore, a comparison of the 2 drugs with respect to CAP may help to further understand the differences in sleep state stability between these 2 mechanisms of action. The phase advance sleep model of transient insomnia used in the study by Walsh et al.18 involves moving bedtime earlier by 2-5 h and produces reliable sleep disruption in otherwise good sleepers. The first hours of the advanced sleep period occur during the “forbidden zone” for sleep, when the circadian arousal system promotes alertness, reducing the likelihood of sleep.19 A key advantage of the acute phase advance model is to produce the transient insomnia known to result from time zone shifts, which typically prevents people from obtaining adequate sleep after travelling to a new time zone. Drug treatment effects have been demonstrated in prior studies using a phase advance procedure.20,21 Walsh et al.18 presented results on the effects of GBX on conventional polysomnographic (PSG) and spectral measures of NREM sleep in this model. This paper extends the prior findings of Walsh et al.18 using post hoc analysis of the same data to test for CAP effects. Firstly, it evaluates the effects of transient insomnia on CAP parameters. Secondly, it compares effects of transient insomnia on CAP parameters and its effects on spectral and traditional PSG measures. Thirdly, it compares the differential effects of the 2 drugs, ZOL and GBX, on CAP parameters and assesses if the changes are in the direction of a more stable, “normal” sleep when subjects in this study are allowed to sleep during their habitual bedtime. Finally, taking advantage of having a multitude of objective and subjective sleep measures, this paper compares them with respect to their correlations with self-reported sleep quality. Presented results may also serve to define new valuable endpoints in future insomnia research and potentially other diseases where an altered sleep pattern is considered a core component of the disease.
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sex differences and the effect of Gaboxadol and zolpidem on eeg power spectra in nrem and rem sleep
Journal of Psychopharmacology, 2010Co-Authors: Derkjan Dijk, James K Walsh, Lynette M James, Stuart Peters, S DeaconAbstract:Hypnotics that interact with the GABA(A) receptor have marked effects on the electroencephalogram (EEG) during sleep. It is not known whether the effects of hypnotics on EEG power spectra differ between the sexes. The effects of 5, 10 and 15 mg of Gaboxadol (GBX) and 10 mg of zolpidem (ZOL) on EEG power spectra were assessed in a randomized, double-blind, placebo-controlled, 5-way cross-over design study using a phase-advance model of transient insomnia. Sleep stage specific EEG power spectra were computed in 36 men and 45 women. GBX enhanced power density in delta and theta activity in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and suppressed sleep spindle activity in NREM sleep. The increase of delta and theta activity in NREM and REM sleep was significantly larger for women than for men but the suppression of spindle activity did not differ between the sexes. After ZOL administration, no sex differences were observed in the reduction of delta and theta activity in NREM sleep, but the increase in sleep spindle activity in NREM sleep was greater in women than in men. These sex dependent and differential effects of GBX and ZOL may be related to their differential affinity for GABA(A) receptor subtypes and their modulation by neurosteroids.
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enhancing slow wave sleep with sodium oxybate reduces the behavioral and physiological impact of sleep loss
Sleep, 2010Co-Authors: James K Walsh, Janine M Hallporter, Kara S Griffin, Ehren Dodson, Elizabeth H Forst, Denise Troy Curry, Rhody D Eisenstein, Paula K SchweitzerAbstract:SLOW WAVE SLEEP (SWS) HAS BEEN HYPOTHESIZED TO BE A STATE OF RELATIVELY HIGH NEURAL RECUPERATION FROM WAKEFULNESS.1,2 THIS HYPOTHESIS has been prompted by a number of observations, including: (a) enhanced SWS following sleep deprivation in proportion to the duration of prior wakefulness3; (b) reduced amounts of SWS during nocturnal sleep following afternoon/evening naps4; (c) a decline in SWS across a night of sleep5; and (d) increased SWS following nights of fragmented sleep.6 Within the two-process model of sleep regulation, heightened SWS has been viewed as reflecting Process S, the homeostatic component.7 Many authors have proposed that increased SWS represents ongoing cortical recovery from prior wakefulness activities and is a time of relatively heightened neurophysiologic restoration or recuperation.1,2,8 In a prior study involving selective SWS deprivation, there was a suggestion from post hoc analyses that SWS may play a role in preventing adverse effects of sleep loss.9 Additionally, we recently published the results of two investigations of pharmacologically enhanced SWS (with tiagabine or Gaboxadol) during sleep restriction, which demonstrated evidence of preserved alertness or neurobehavioral performance despite sleep restriction.10,11 In the current study, we examined whether pharmacological enhancement of SWS with sodium oxybate reduces the impact of sleep deprivation upon sleepiness, attention, cognition, mood, and recovery sleep. Sodium oxybate has been demonstrated to increase SWS and/or slow wave activity (SWA) in a dose-related fashion in normal subjects12,13 and in patients with narcolepsy14,15 and fibromyalgia.16 Sodium oxybate is the sodium salt of γ-hydroxybutyrate, an endogenous fatty acid synthesized in the brain, which appears to exert most of its effects through GABAB receptors, although it binds to both GHB and GABAB receptors.17 Time to peak plasma concentration is 0.5-1.25 hours and the elimination half-life ranges from about 30 to 50 minutes.18
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efficacy of the selective extrasynaptic gabaa agonist Gaboxadol in a model of transient insomnia a randomized controlled clinical trial
Sleep Medicine, 2008Co-Authors: James K Walsh, David Mayleben, Christine Guicopabia, Kristel Vandormael, Rebecca Martinez, S DeaconAbstract:Abstract Objective The hypnotic efficacy of Gaboxadol, a selective extrasynaptic GABAA agonist (SEGA), was evaluated in a phase-advance model of transient insomnia. Methods Healthy subjects (18–64 years) completed a randomized, double-blind, parallel group study in which the sleep period was advanced 4 h from habitual sleep time. Polysomnographic (PSG) and self-reported sleep measures were used to compare Gaboxadol 10 mg (N = 271) and 15 mg (N = 274) versus placebo (N = 277). Results In the placebo group, the phase-advance procedure disrupted sleep maintenance as measured by PSG wakefulness after sleep onset (WASO) and self-reported WASO (sWASO), and also, to a lesser extent, disrupted sleep onset as measured by PSG latency to persistent sleep (LPS) and self-reported time to sleep onset (sTSO). Both doses of Gaboxadol decreased WASO and sWASO versus placebo (p ⩽ 0.05). Gaboxadol 15 mg also reduced LPS versus placebo (p ⩽ 0.01) and both doses reduced sTSO versus placebo (p ⩽ 0.01). PSG and self-reported total sleep time as well as ratings of sleep quality were improved with both Gaboxadol doses relative to placebo (all p ⩽ 0.01 or better). The amount of slow wave sleep (SWS) was greater with both doses of Gaboxadol than with placebo (p ⩽ 0.001). No group differences in the amount of rapid eye movement sleep were found. Most PSG and self-report measures indicated a mild dose response. The percentage of subjects with adverse events was low ( Conclusions Gaboxadol 10 and 15 mg were efficacious in significantly reducing the sleep maintenance and sleep onset disruption produced by this model of transient insomnia, with effects generally being most pronounced for the 15 mg dose. Gaboxadol also enhanced SWS.
Carsten Uhd Nielsen - One of the best experts on this subject based on the ideXlab platform.
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carrier mediated γ aminobutyric acid transport across the basolateral membrane of human intestinal caco 2 cell monolayers
European Journal of Pharmaceutics and Biopharmaceutics, 2012Co-Authors: Carsten Uhd Nielsen, Mette Carstensen, Birger BrodinAbstract:Abstract The aim of the present study was to investigate the transport of γ-aminobutyric acid (GABA) across the basolateral membrane of intestinal cells. The proton-coupled amino acid transporter, hPAT1, mediates the influx of GABA and GABA mimetic drug substances such as vigabatrin and Gaboxadol and the anticancer prodrug δ-aminolevulinic acid across the apical membrane of small intestinal enterocytes. Little is however known about the basolateral transport of these substances. We investigated basolateral transport of GABA in mature Caco-2 cell monolayers using isotope studies. Here we report that, at least two transporters seem to be involved in the basolateral transport of GABA. The basolateral uptake consisted of a high-affinity system with a K m of 290 μM and V max of 75 pmol cm −2 min −1 and a low affinity system with a K m of approximately 64 mM and V max of 1.6 nmol cm −2 min −1 . The high-affinity transporter is Na + and Cl − dependent. The substrate specificity of the high-affinity transporter was further studied and Gly-Sar, Leucine, Gaboxadol, sarcosine, lysine, betaine, 5-hydroxythryptophan, proline and glycine reduced the GABA uptake to approximately 44–70% of the GABA uptake in the absence of inhibitor. Other substances such as β-alanine, GABA, 5-aminovaleric acid, taurine and δ-aminolevulinic acid reduced the basolateral GABA uptake to 6–25% of the uptake in the absence of inhibitor. Our results indicate that the distance between the charged amino- and acid-groups is particular important for inhibition of basolateral GABA uptake. Thus, there seems to be a partial substrate overlap between the basolateral GABA transporter and hPAT1, which may prove important for understanding drug interactions at the level of intestinal transport.
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Gaboxadol has affinity for the proton coupled amino acid transporter 1 slc36a1 hpat1 a modelling approach to determine ic50 values of the three ionic species of Gaboxadol
European Journal of Pharmaceutical Sciences, 2011Co-Authors: Sidsel Balsgaard Frolund, Nicolas Rapin, Carsten Uhd NielsenAbstract:Abstract The human proton-coupled amino acid transporter, SLC36A1 (hPAT1), is situated in the apical membrane of small intestinal epithelium. It is involved in cellular uptake of amino acids and orally administered drug substances such as δ-aminolevulinic acid, vigabatrin and Gaboxadol. Gaboxadol (Gbx) is a selective extrasynaptic GABA A receptor agonist with high oral bioavailability in rat, dog and human. It is a zwitterionic compound with p K a values of 4.3 and 8.1. Dependent on the pH of the solution Gbx will be present as three individual ionic species, i.e. cationic (Gbx + ), zwitterionic (Gbx +/− ) and anionic (Gbx − ). The aim of the present study was to elucidate the individual affinities of Gbx + , Gbx +/− and Gbx − for SLC36A1. The ability of Gbx to concentration-dependently inhibit a SLC36A1 mediated l -[ 3 H]proline uptake was investigated in Caco-2 cell monolayers at apical pH 5.0–6.8. The IC 50 values were computed using an in silico model relying on a genetic algorithm. The IC 50 values of Gbx + , Gbx +/− and Gbx − were estimated to 2.6 mM, 16 mM and >1000 mM. This indicates that the positive charge is essential for Gbx binding to SLC36A1. The negative charge is tolerated in the zwitterionic form, whereas no affinity is observed for the anionic form.
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5 hydroxy l tryptophan alters Gaboxadol pharmacokinetics in rats involvement of pat1 and roat1 in Gaboxadol absorption and elimination
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Mie Larsen, Rene Holm, Klaus Gjervig Jensen, Christina Sveigaard, Birger Brodin, Carsten Uhd NielsenAbstract:Abstract The aim was to investigate the effect of 5-hydroxy- l -tryptophan (5-HTP) on Gaboxadol pharmacokinetics in rats. As both 5-HTP and Gaboxadol bind to the human proton-coupled amino acid transporter, hPAT1, a drug–drug interaction at the level of intestinal absorption might occur. The in vitro transport of Gaboxadol was measured across the hPAT1-expressing cell line Caco-2, and via the rat organic anion transporter, rOat1, in Xenopus oocytes pre-injected with rOat1 cRNA. The in vivo pharmacokinetic profile of Gaboxadol after oral administration to rats was investigated in the absence and presence of a pre-dose of 5-HTP. In Caco-2 cell monolayers >80% of the absorptive Gaboxadol transport was suggested to be hPAT1-mediated. In rats, the initial absorption rate of Gaboxadol was decreased in the presence of 5-HTP. The AUC of Gaboxadol was increased by a factor of 3.6–5.5 when rats were pre-dosed with 5-HTP. Gaboxadol was a substrate for the renal transporter rOat1 with a Km-value of 151 μM. 5-HTP did not interact with rOat1. In conclusion, Gaboxadol acts as a substrate for hPAT1 and is a substrate of rOat1. In rats, 5-HTP decreased the initial absorption rate and increased AUC of Gaboxadol. 5-HTP thus had a significant impact on the pharmacokinetic profile of Gaboxadol.
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intestinal Gaboxadol absorption via pat1 slc36a1 modified absorption in vivo following co administration of l tryptophan
British Journal of Pharmacology, 2009Co-Authors: Mie Larsen, Rene Holm, Klaus Gjervig Jensen, Birger Brodin, Carsten Uhd NielsenAbstract:Background and purpose: Gaboxadol has been in development for treatment of chronic pain and insomnia. The clinical use of Gaboxadol has revealed that adverse effects seem related to peak serum concentrations. The aim of this study was to investigate the mechanism of intestinal absorption of Gaboxadol in vitro and in vivo. Experimental approach: In vitro transport investigations were performed in Caco-2 cell monolayers. In vivo pharmacokinetic investigations were conducted in beagle dogs. Gaboxadol doses of 2.5 mg·kg−1 were given either as an intravenous injection (1.0 mL·kg−1) or as an oral solution (5.0 mL·kg−1). Key results: Gaboxadol may be a substrate of the human proton-coupled amino acid transporter, hPAT1 and it inhibited the hPAT1-mediated L-[3H]proline uptake in Caco-2 cell monolayers with an inhibition constant Ki of 6.6 mmol·L−1. The transepithelial transport of Gaboxadol was polarized in the apical to basolateral direction, and was dependent on Gaboxadol concentration and pH of the apical buffer solution. In beagle dogs, the absorption of Gaboxadol was almost complete (absolute bioavailability, Fa, of 85.3%) and Tmax was 0.46 h. Oral co-administration with 2.5–150 mg·kg−1 of the PAT1 inhibitor, L-tryptophan, significantly decreased the absorption rate constant, ka, and Cmax, and increased Tmax of Gaboxadol, whereas the area under the curve and clearance of Gaboxadol were constant. Conclusions and implications: The absorption of Gaboxadol across the luminal membrane of the small intestinal enterocytes is probably mediated by PAT1. This knowledge is useful for reducing Gaboxadol absorption rates in order to decrease peak plasma concentrations.
