Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. (1/173)

Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.  (+info)

Zopiclone use during pregnancy. (2/173)

QUESTION: One of my patients, whom I had treated with a 2-week course of zopiclone for insomnia, conceived while using the medication. She is concerned. How should I advise her? ANSWER: Based on available, albeit limited, evidence, zopiclone does not appear to be a major human teratogen.  (+info)

Characterization of the interaction of zopiclone with gamma-aminobutyric acid type A receptors. (3/173)

Zopiclone is a cyclopyrrolone that is used clinically as a hypnotic. Although this drug is known to interact with neuronal gamma-aminobutyric acid type A receptors, its binding site(s) within the receptor oligomer has been reported to be distinct from that of the classical benzodiazepines. After photoaffinity labeling with flunitrazepam, receptors in rat cerebellar membranes showed differentially reduced affinity for flunitrazepam and zopiclone by 50- and 3-fold, respectively. Because histidine 101 of the alpha-subunit is a major site of photolabeling, we have made specific substitutions of this residue and studied the consequences on the binding properties of zopiclone and diazepam using recombinant alpha1beta2gamma2-receptors transiently expressed in tsA201 cells. Both compounds showed similar binding profiles with receptors containing mutated alpha-subunits, suggesting a similar interaction with the residue at position 101. At alpha1beta2gamma3-receptors, flunitrazepam affinity was dramatically decreased by approximately 36-fold, whereas the affinity for zopiclone was decreased only 3-fold, suggesting a differential contribution of the gamma-subunit to the binding pocket. Additionally, we used electrophysiological techniques to examine the contribution of the gamma-subunit isoform in the receptor oligomer to ligand recognition using recombinant receptors expressed in Xenopus oocytes. Both compounds are agonists at alpha1beta2gamma2- and alpha1beta2gamma3-receptors, with flunitrazepam being more potent but less efficacious. In summary, these data suggest that histidine 101 of the alpha1-subunit plays a similar role in ligand recognition for zopiclone, diazepam, and flunitrazepam.  (+info)

Mechanism-based pharmacokinetic/pharmacodynamic modeling of the electroencephalogram effects of GABAA receptor modulators: in vitro-in vivo correlations. (4/173)

A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model for neuroactive steroids, comprising a separate characterization of 1) the receptor activation process and 2) the stimulus-response relationship, was applied to various nonsteroidal GABAA receptor modulators. The EEG effects of nine prototypical GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one beta-carboline) were determined in rats in conjunction with plasma concentrations. Population PK/PD modeling revealed monophasic concentration-EEG effect relationships with large differences in potency (EC50) and intrinsic activity between the compounds. The data were analyzed on the basis of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the assumption of a single and unique stimulus-response relationship. The model converged yielding estimates of both the apparent in vivo receptor affinity (KPD) and the in vivo intrinsic efficacy (ePD). The values of KPD ranged from 0.41 +/- 0 for bretazenil to 436 +/- 72 for clobazam and the values for e(PD) from -0.27 +/- 0 for methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate to 0.54 +/- 0.02 for diazepam. Significant linear correlations were observed between KPD for unbound concentrations and the affinity in an in vitro receptor bioassay (r = 0.93) and between e(PD) and the GABA-shift in vitro (r = 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABAA receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABAA receptor modulators behave as partial agonists relative to neuroactive steroids.  (+info)

Effect of zaleplon, a non-benzodiazepine hypnotic, on melatonin secretion in rabbits. (5/173)

Melatonin, a major hormone secreted by the pineal gland, is known to play an important role in regulation of the circadian rhythm. (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (zaleplon) is a non-benzodiazepine hypnotic that acts via the benzodiazepine site of the GABA(A) receptor. In the present study, we investigated the effect of zaleplon on melatonin secretion in rabbits using RIA and compared the effect to triazolam and zopiclone. Zaleplon increased a dose-dependent concentration of melatonin in rabbit plasma collected at 30 min after intravenous administration at doses of 1 and 2 mg/kg. The zaleplon-induced increase in plasma melatonin level was not blocked by flumazenil, a benzodiazepine-receptor antagonist. In contrast, triazolam and zopiclone failed to affect the plasma melatonin level. We also investigated the effect of zaleplon on intracellular cAMP in rat pinealocytes. Consequently, zaleplon had no effect on the intracellular cAMP levels in rat pinealocytes. These results of the present studies suggest that zaleplon may promote melatonin secretion and the elevation of plasma levels of melatonin may suggest an influence of zaleplon on chronobiology.  (+info)

Dependence on legal psychotropic drugs among alcoholics. (6/173)

AIMS: Dependence on legal psychotropic drugs (PTD) has been reported to have increased in alcoholics, but previous studies report conflicting results concerning the rate of increase and clinical characteristics. The aim of the present study was first, to assess the dependence rate of PTD among alcoholics in open and institutionalized care, and to compare these populations with the general population, and second, to assess rates and doses of high- and low-dose PTD-dependence among alcoholics. METHODS: In 1997, alcoholics in open and institutionalized care were asked to anonymously fill in a questionnaire on their drug use and dependence. Healthy controls were included. The number of attending subjects was 130 open-care alcoholics at the Department of Alcohol and Drug Diseases in Malmo, Sweden; 23 alcoholics in institutionalized care at Karlsvik Rehabilitation Centre in Hoor, Sweden; and 120 healthy controls at Vardcentralen Kirseberg, a primary health care centre located in a Malmo area. The approximate attendance rate was 75, 70 and 95%, respectively. The questionnaire was based on DSM-IV criteria for dependence. RESULTS: The total rate of PTD-dependent alcoholics was higher in the institutionalized group (35%) than in the open-care setting (14%): difference in proportions (p(1)-p(2) 21%; 95% CI: 1%, 41%). Alcoholics were more often PTD-dependent (17%) than were healthy controls (2%), (p(1)-p(2) 15%; 95% CI: 9%, 21%). Benzodiazepines (BZD) were the most common PTD. Only four out of a total of 23 BZD-dependent alcoholics developed high-dose BZD-dependence. Those subjects were also misusing other drugs, including cannabis. CONCLUSIONS: We conclude that alcoholism is associated with legal PTD-dependence and illegal drug misuse. High-dose BZD-dependence is infrequent among BZD-dependent alcoholics.  (+info)

Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats. (7/173)

The encephalographic (EEG) properties of zaleplon were investigated in comparison with those of other sedative hypnotics in conscious rats with chronically implanted electrodes. The oral administration of zaleplon (0.25-1.0 mg/kg), triazolam (0.0625-0.25 mg/kg), zopiclone (1.0-4.0 mg/kg), brotizolam (0.0625-0.25 mg/kg), and nitrazepam (0.125-0.5 mg/kg) lengthened the total sleep in a dose-dependent manner. On distribution of sleep-wakefulness stages, zaleplon, in particular, increased the slow wave deep sleep (SWDS), whereas triazolam, brotizolam, and nitrazepam increased the slow wave light sleep (SWLS) in a dose-dependent manner. Zopiclone significantly increased the SWDS at a dose of 2 mg/kg and both the SWLS and the SWDS at a dose of 4 mg/kg. All tested hypnotics caused no influence on fast wave sleep (FWS) at doses tested. The appearance of the sleep-inducing activity of zaleplon was more rapid than those of any compounds tested, and zaleplon significantly increased the relative EEG power density in the delta frequency band over that of triazolam at 20 and 30 min after the administration in the spectral analysis. Therefore, the present findings suggest that the non-benzodiazepine zaleplon can be expected to exhibit high practical potential as a hypnotic and is characterized by an increase in SWDS with rapid onset of hypnotic action.  (+info)

Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride). (8/173)

Two novel N-methyl-d-aspartate (NMDA) antagonists with unique chemical structures, EAA-090 (2-[8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride), were compared with CGS-19755 (Selfotel) in ligand binding, electrophysiology, and neuroprotection assays. CGS-19755, EAA-090 and EAB-318 inhibited [(3)H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding to NMDA receptors with IC(50) values of 55, 28, and 7.9 nM, respectively. All three compounds decreased the duration of spontaneous synaptic currents and inhibited NMDA-activated currents in rat hippocampal neurons. IC(50) values for inhibition of current induced by 10 microM NMDA were 795, 477, and 69 nM for CGS-19755, EAA-090, and EAB-318, respectively. The NMDA antagonists protected chick embryo retina slices and cultured rat hippocampal and cortical neurons from glutamate- and NMDA-induced neurotoxicity. In experiments in which different NMDA receptor splice variants and subtypes were expressed in Xenopus oocytes, all three antagonists preferentially blocked NMDA-elicited currents mediated by N-methyl-d-aspartate receptor (NR)1 splice variants containing the N-terminal insertion. They also favored NR2A-versus NR2B- or NR2C-containing NMDA receptors, with EAA-090 showing the greatest selectivity. EAA-090 was 10 times more potent at blocking NR2A-versus NR2B- or NR2C-containing NMDA receptors. In addition to being the most potent NMDA antagonist, EAB-318 inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. The combination of NMDA and AMPA/kainate block enabled EAB-318 to protect neurons against ischemia induced cell death.  (+info)