Disease relevance of zolpidem

• Zolpidem in progressive supranuclear palsy [1].
• Zolpidem in Parkinson's disease [2].
• Zolpidem-induced macropsia in anorexic woman [3].
• Effect of zolpidem on the efficacy of continuous positive airway pressure as treatment for obstructive sleep apnea [4].
• The was no significant difference between placebo and zolpidem nights in the apnea + hypopnea index (P: 4.8 +/- 1.4 versus Z : 2.7 +/- 0.47 events/hour), oxygen desaturation index (1.46 +/- 0.53 versus 0.81 +/- 0.29 desaturations/hour), or the lowest SaO2 (91.4 +/- 0.6 versus 91.0 +/- 0.7%) [4].

Psychiatry related information on zolpidem

• CONCLUSIONS: Benzodiazepines and zolpidem produced reliable improvements in commonly measured parameters of sleep in patients with chronic insomnia [5].
• Test for catatonia with zolpidem [6].
• Paradoxically, DZP, which, unlike zolpidem, acts at alpha5-containing GABA(A)-Rs, increases the locomotor activity of SI mice [7].
• Furthermore, none of the respiratory parameters were significantly affected by zolpidem in any sleep stage [8].
• No clinically relevant differences were found between zolpidem and triazolam for memory, psychomotor performance, postural sway, or adverse effects [9].

High impact information on zolpidem

• Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy [5].
• Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem [10].
• Chimeric or mutant gamma subunits were coexpressed with alpha1 and beta2 in human embryonic kidney 293 cells to localize amino acid residues responsible for the reduced zolpidem affinity [11].
• We show here that the hemoglobin (Hb) metabolites hemin and protoporphyrin IX (PPIX) interact with the BZ site on the gamma-aminobutyric acid (GABA(A)) receptor and enhance inhibitory synaptic transmission in a manner similar to diazepam and zolpidem [12].
• Based on in silico zolpidem docking, three residues within loop F, gamma2Glu189, gamma2Thr193, and gamma2Arg194, emerge as being important for stabilizing zolpidem in the BZD binding pocket and probably interact with other loop F residues to maintain the structural integrity of the BZD binding site [13].

Chemical compound and disease context of zolpidem

• A case of parenteral zolpidem dependence with opioid-like withdrawal symptoms [14].
• Furthermore, suppression of distress USVs by zolpidem may involve BZ/alpha1 receptors and a nonanxiolytic mechanism, such as hypothermia [15].
• The ability of zolpidem, but not triazolam or diazepam, to suppress USVs and augment hypothermia was antagonized by beta-CCt, whereas the increase in motor incoordination engendered by zolpidem, triazolam, and diazepam was not sensitive to beta-CCt administration [15].
• METHOD: Single and repeated (7 day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg) or placebo were administered at bedtime in a crossover design to 23 patients (9 men and 14 women aged 38.8+/-2.0 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) primary insomnia [16].
• Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo [17].

Biological context of zolpidem

• In this study, the effects of rifampin on the pharmacokinetics and pharmacodynamics of zolpidem were studied [18].
• RESULTS: Kinetics of zaleplon and zolpidem were not significantly related to dose [19].
• All granule cell GABAR currents were uniformly sensitive to Zn2+ (IC50 = 29 microM), diazepam (EC50 = 158 nM), zolpidem (EC50 = 75 nM), and dimethoxyl-4-ethyl-beta-carboline-3-carboxylate (IC50 = 60 nM) [20].
• Hence, alpha 5 beta 3 gamma 3 recpetors are not a major fraction of the native zolpidem-insensitive receptors, even though their genes are colocalized on mouse chromosome 7 and on human chromosome 15 [21].
• Short- and long-term memory (paired words associate and pictures test), psychomotor performances (critical flicker fusion frequency, choice reaction time, digit symbol substitution test), and postural sway were evaluated before and 1.5, 4, 6, and 8 h after the administration of a single dose of zolpidem (10 mg), triazolam (0.25 mg), and placebo [9].

Anatomical context of zolpidem

• This prevalence was directly probed by zolpidem displacement experiments in alpha2-alpha1 double immunopurified receptors (K(i) = 295 +/- 56 nM and 200 +/- 8 nM in hippocampus and cortex, respectively) [22].
• However, using zolpidem, three different BZD receptors have been identified by binding displacement experiments in membranes [23].
• The distribution of the high- and low-affinity binding sites for zolpidem was similar to that of type I and type II subtypes in cerebellum, prefrontal cortex, and adult cerebral cortex [23].
• The high- and low-affinity binding sites for zolpidem seemed to have a similar high degree of coupling, except in spinal cord [23].
• In the present study, we found increased BZ receptor levels in C57BL/6 mice in the central and basolateral nuclei of the amygdala as well as the locus coeruleus using either flunitrazepam (nonselective) or zolpidem (alpha1 subtype selective) as radioligands [24].

Associations of zolpidem with other chemical compounds

• However, zaleplon had more rapid elimination (apparent elimination half-life [t1/2] of 1 hour) and higher apparent oral clearance (approximately 4300 mL/min) than zolpidem (t1/2, 2.0 to 2.2 hours; apparent oral clearance, 340 to 380 mL/min) [19].
• The imidazopyridine zolpidem (Ambien) is one of the most commonly prescribed sleep aids in the United States (Rush, 1998) [13].
• In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells [25].
• Expression of specific GABAA, receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem [26].
• Placebo, zolpidem (5, 10, and 20 mg/70 kg), triazolam (0.125, 0.25, and 0.50 mg/70 kg), and temazepam (15, 30, and 60 mg/70 kg) were administered orally in a randomized, double-blind, cross-over design [27].

Gene context of zolpidem

• We conclude that the formation of alcohol derivatives of zolpidem is rate-limiting and principally mediated by CYP3A4 [28].
• CONCLUSIONS: The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition [29].
• Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro [29].
• The distinct affinities of recombinant receptors for CI 218,872 suggested that the alpha 5 beta 3 gamma 2 receptor is the dominant zolpidem-insensitive GABAA receptor in the brain [21].
• Here, we have tested the effects of zolpidem on the hippocampus of gamma2 subunit (gamma2F77I) point mutant mice [30].

Analytical, diagnostic and therapeutic context of zolpidem

• STUDY SELECTION: Studies using randomized, double-blind, placebo-controlled, parallel or crossover designs with benzodiazepines or zolpidem in adults younger than 65 years with chronic insomnia (modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for primary insomnia) were selected for review [5].
• In this study, we used radioligand binding techniques, gamma2/alpha1 chimeric subunits (chi), site-directed mutagenesis, and molecular modeling to identify additional gamma2 subunit residues important for high-affinity zolpidem binding [13].
• Evaluation of EEG cyclic alternating pattern during sleep in insomniacs and controls under placebo and acute treatment with zolpidem [31].
• This review traces the history of insomnia drug therapies from chloral hydrate and the barbiturates through the benzodiazepines and explores the newest selective benzodiazepine receptor agonists, including zolpidem and zaleplon [32].
• In an attempt to explain this discrepancy, we examined the ability of zolpidem to differentiate BZR subtypes in vivo in primate brain using positron emission tomography [33].

References