Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo*

Greenblatt, David J.; Harmatz, Jerold S.; Moltke, Lisa L. von; Ehrenberg, Bruce L.; Harrel, L.; Corbett, Kathleen E.; Counihan, Molly; Graf, Jennifer A.; Darwish, Mona; Mertzanis, Polyxane; Martin, Paul T.; Cevallos, William; Shader, Richard I.

doi:10.1016/s0009-9236(98)90139-4

Cited by 114 publications

(119 citation statements)

References 24 publications

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“…Thus morning testing occurred 9.5 h after zolpidem-ER dosing and 5.5 h after zaleplon dosing which is approximately 1.5 h after drug should have been eliminated based on pharmacokinetic data. 23,24 Both time intervals are consistent with prior studies of SDMC involving overnight sleep. 5,6 Polysomnography (PSG) was conducted at each of the 3 overnight visits with bedtime at the subject's reported typical bedtime and time in bed held constant at 8 hours.…”

Section: Experimental Design and Proceduressupporting

confidence: 85%

“…The two hypnotics have similar mechanisms of action, both binding preferentially to the α-1 benzodiazepine receptor subunit, 22 although their durations of action differ. Zolpidem-ER has an estimated duration of action of 6-8 h, with a t 1/2 of 2.8 h and a t max of 1.5 h. 23 In contrast, zaleplon has an estimated duration of action of 3-4 h due to rapid absorption and elimination, with t 1/2 and t max both approximately one h. 24 These doses were chosen because, at the time of study, they were the recommended therapeutic doses for treatment of insomnia. In addition, residual morning sedation has not been detected with either drug at these doses when administered at bedtime, 25,26 or with zaleplon 10 mg when administered as little as 4 h before wake time (middle-of-the-night dosing).…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

Hall-Porter

Schweitzer

Eisenstein

et al. 2014

Journal of Clinical Sleep Medicine

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Results: ANOVA revealed a signifi cant condition effect for the WPT (p = 0.025) and a trend for the FTT (p = 0.067), which was signifi cant when sex was added to the model (p = 0.014). Improvement in memory performance following sleep was lower with bedtime dosing of zolpidem-ER compared to placebo and middle-of-the-night dosing of zaleplon. There were no differences between placebo and zaleplon. Conclusions:The results suggest that in some circumstances hypnotics may have the potential to reduce the degree of sleep-dependent memory consolidation and that drug-free sleep early in the night may ameliorate this effect. S C I E N T I F I C I N V E S T I G A T I O N SA growing body of evidence demonstrates that sleep promotes memory consolidation in healthy individuals.1-3 Numerous studies using various designs and memory tasks have consistently found that memory consolidation (i.e., improvement on a given memory task from initial training/test to retest) is significantly greater after a period of sleep than a period of wake. This is commonly referred to as sleep-dependent memory consolidation (SDMC). 4 For example, improvements on a procedural memory fi nger-tapping task were observed after a night of sleep but not after 4-, 8-, or 12-hour daytime periods without sleep. 5,6 Studies examining declarative memory consolidation, such as with a word pair association task, also demonstrate improvements in performance after sleep.7 In addition to improvements in memory following overnight sleep, memory consolidation is also enhanced during naps as short as 45 minutes. Improvements in procedural 8,9 and declarative 10 memory occur with naps, but not following similar durations of wakefulness. These fi ndings suggest that memory consolidation that occurs during wakefulness is enhanced during sleep.Synaptic plasticity, which refers to structural or functional neural changes in response to stimuli, 2 is thought to be the cellular substrate underlying the processes of memory formation and consolidation.11 Sleep has been found to enhance plasticity in animals, 12 which is consistent with the idea that sleep enhances memory consolidation. In humans, fMRI studies have shown that sleep-dependent learning of a motor skill task is accompanied by changes in multiple brain areas, BRIEF SUMMARYCurrent Knowledge/Study Rationale: Few studies have investigated the impact of hypnotic medication on sleep-dependent memory consolidation. This study compared the effect of differing time of exposure to two hypnotics on the sleep-dependent consolidation of declarative and non-declarative memory. Study Impact: This study contributes to the research surrounding sleep-dependent memory and hypnotics, indicating that hypnotic exposure during most of the night may reduce sleep-dependent memory consolidation; whereas hypnotic exposure only during the second half of the night appears to have no effect.

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Section: Experimental Design and Proceduressupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

Hall-Porter

Schweitzer

Eisenstein

et al. 2014

Journal of Clinical Sleep Medicine

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“…Preliminary experiments had determined 30 min to be an optimal incubation time for formation of both metabolites. Clinical concentrations for zaleplon are in the low micromolar range (Greenblatt et al, 1998); however, it was determined from this study that a 20 M zaleplon incubation concentration was necessary to produce both metabolites in a readily measurable amount. Zaleplon concentrations greater than 50 M did not result in a corresponding increase in either metabolite.…”

Section: Resultsmentioning

confidence: 84%

Hydralazine As a Selective Probe Inactivator of Aldehyde Oxidase in Human Hepatocytes: Estimation of the Contribution of Aldehyde Oxidase to Metabolic Clearance

Strelevitz

Orozco²,

Obach³

2012

Drug Metab Dispos

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ABSTRACT:Aldehyde oxidase (AO) metabolism could lead to significant underestimation of clearance in prediction of human pharmacokinetics as well as unanticipated exposure to AO-generated metabolites, if not accounted for early in drug research. We report a method using cryopreserved human hepatocytes and the time-dependent AO inhibitor hydralazine (K I ‫؍‬ 83 ؎ 27 M, k inact ‫؍‬ 0.063 ؎ 0.007 min

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“…The advantages of these newer agents over benzodiazepines seem to result from their mode of interaction with the GABA A receptor combined with a reduced duration of action. Thus, for example, zolpidem has a moderate affinity for ␣1-containing GABA A receptors in radioligand binding experiments (10 -100 nM; Arbilla et al, 1985;Smith et al, 2001;Sullivan et al, 2004), is fully efficacious (Smith et al, 2001;Sullivan et al, 2004), has selectivity for GABA A receptors containing the ␣1 subunit (Damgen and Luddens, 1999;Smith et al, 2001), produces sedative activity in animals that is mediated through ␣1 subunit-containing GABA A receptors , and has a half-life in rodents and humans after oral administration of 2 to 3 h (Gaudreault et al, 1995;Greenblatt et al, 1998). Zopiclone displays a similar efficacy profile in animal tests (Perrault et al, 1990), but it has only marginal selectivity for GABA A receptors containing the ␣1 subunit (Damgen and Luddens, 1999;Smith et al, 2001) and its half-life in humans of 3.5 to 6.5 h (Fernandez et al, 1995) has been associated with next day hangover effects, including impaired driving ability (Bocca et al, 1999;Vermeeren et al, 2002).…”

mentioning

confidence: 99%

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Foster¹,

Pelleymounter²,

Cullen³

et al. 2004

J Pharmacol Exp Ther

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Indiplon (NBI 34060;-pyrazolo[1,5-␣]pyrimidin-7-yl]phenyl]acetamide), a novel pyrazolopyrimidine and high-affinity allosteric potentiator of GABA A receptor function, was profiled for its effects in rodents after oral administration. In mice, indiplon inhibited locomotor activity (ED 50 ϭ 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED 50 ϭ 6.1 mg/kg p.o.) and zaleplon (ED 50 ϭ 24.6 mg/kg p.o.), a sedative effect that was reversed by the benzodiazepine site antagonist flumazenil. Indiplon inhibited retention in the mouse passive avoidance paradigm over a dose range and with a temporal profile that coincided with its sedative activity. Indiplon, zolpidem, and zaleplon were equally effective in inhibiting locomotor activity in the rat and produced dose-related deficits on the rotarod. In a rat vigilance paradigm, indiplon, zolpidem, and zaleplon produced performance deficits over a dose range consistent with their sedative effects, although indiplon alone showed no significant increase in response latency. Indiplon produced a small deficit in the delayed nonmatch to sample paradigm at a dose where sedative effects became apparent. Indiplon was active in the rat Vogel test of anxiety, but it showed only a sedative profile in the mouse open field test. The pharmacokinetic profile of indiplon in both rat and mouse was consistent with its pharmacodynamic properties and indicated a rapid T max , short t 1/2 , and excellent blood-brain barrier penetration. Therefore, indiplon has the in vivo profile of an efficacious sedative-hypnotic, in agreement with its in vitro receptor pharmacology as a high-affinity allosteric potentiator of GABA A receptor function, with selectivity for ␣1 subunit-containing GABA A receptors.

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Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo*

Abstract: Benzodiazepine agonist effects of zaleplon and zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic dose (10 mg of either drug), agonist effects of zolpidem exceeded those of zaleplon.

Cited by 114 publications

References 24 publications

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

Hydralazine As a Selective Probe Inactivator of Aldehyde Oxidase in Human Hepatocytes: Estimation of the Contribution of Aldehyde Oxidase to Metabolic Clearance

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

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