PubMed · 16173660
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Daniel F Kripke. 2005. Selective publication.. https://pubmed.ncbi.nlm.nih.gov/16173660/
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BACKGROUND: Commonly used methods for detecting benzodiazepines (BZPs) and BZP-like substances, such as zolpidem and zopiclone, may not detect low concentrations of these drugs. We developed a liquid chromatographic-tandem mass spectrometric method for identifying these drugs and their relevant metabolites. METHODS: We extracted BZPs from urine by solid-phase extraction with a mixed-mode phase (OASIS HLB cartridges). Chromatographic separation was performed with a Waters XTerra MS C18 [150 x 2.1 mm (i.d.); bead size, 5 microm] reversed-phase column with deuterated analogs of the analytes as internal standards (IS). Detection was performed with a triple-quadruple mass spectrometer that monitored 2 specific transitions per compound in the electrospray, positive-ion selected-reaction monitoring mode. We tested this technique on urine samples from 12 healthy volunteers and 1 forensic sample obtained in a case of alleged drug-facilitated sexual assault. RESULTS: Chromatographic separation was achieved within 18 min. The linear dynamic ranges extended from 0.02 or 0.1 microg/L (depending on the drug or metabolite) to 50 microg/L. Extraction recovery (range) was 77%-110%. Limits of detection were < or = 0.05 microg/L. No ion suppression was seen except for alprazolam, for which baseline decreased by almost 20%. In the forensic urine sample, the method detected alprazolam (3.5 microg/L) and its characteristic metabolite, alpha-hydroxyalprazolam (0.17 microg/L). CONCLUSION: This method measured low concentrations of BZPs and BZP-like substances and might be useful for analyses of urine in suspected drug-facilitated sexual assault cases.
A simple, reliable HPLC method using fluorescence detection (excitation 307 and emission 483 nm) was developed and validated for simultaneous quantitation of zopiclone and its metabolite desmethylzopiclone in human plasma. Following a single-step liquid-liquid extraction, the analytes and internal standard (zaleplon) were separated using an isocratic mobile phase on a reversed-phase C18 column. The lower limit of quantitation was 3 ng/mL for zopiclone and 6 ng/mL for desmethylzopiclone with a relative standard deviation of less than 5%. A linear dynamic range of 3-300 ng/mL for zopiclone and of 6-500 ng/mL for desmethylzopiclone was established. This HPLC method was validated with between-batch precision of 1.7-4.2% and 3.2-7.5% for zopiclone and desmethylzopiclone respectively. The between-batch accuracy was 99.4-111.5% and 101.6-104.8% for zopiclone and desmethylzopiclone, respectively. Frequently coadministered drugs did not interfere with the described methodology. Stability of zopiclone and desmethylzopiclone in plasma was excellent, with no evidence of degradation during sample processing (autosampler) and 30 days' storage in a freezer. This validated method is simple and repeatable enough to be used in pharmacokinetic studies.
OBJECTIVE: This paper reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of the nonbenzodiazepine cyclopyrrolone agent eszopiclone in the management of adult patients with insomnia. METHODS: Recent studies, abstracts, reviews, and consensus statements published in English were identified through searches of MEDLINE (1966-December 2005), International Pharmaceutical Abstracts (1970 December 2005), and PharmaProjects (1990-December 2005) using the search terms eszopiclone, cyclopyrrolone, insomnia, nonbenzodiazepine, and zopiclone enantiomer. Selected information provided by the manufacturer of eszopiclone was included, as were all pertinent clinical trials. RESULTS: Eszopiclone is rapidly absorbed after oral administration, with Tmax achieved within approximately 1 hour and a terminal-phase elimination half-life of approximately 6 hours. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Eszopiclone is extensively metabolized by oxidation and demethylation. In vitro studies have indicated that the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; therefore, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Eszopiclone is excreted in the urine as racemic zopiclone at <10% of the orally administered dose. Six Phase III clinical trials were identified that evaluated the safety profile and efficacy of eszopiclone, 1 in healthy subjects with transient insomnia and 5 in patients with primary chronic insomnia (3 in younger adults and 2 in the elderly). In the trials in younger adults, eszopiclone significantly improved sleep efficiency, sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened weekly, total sleep time, and quality and depth of sleep compared with placebo (P<0.05). In the trials in elderly patients, who received eszopiclone 2 mg or placebo for 2 weeks, eszopiclone was associated with significantly shorter sleep latency compared with placebo (P<0.004), as well as a significant decrease in the cumulative number of naps (P<0.05). The most commonly reported drug-related, dose-responsive adverse event in clinical trials of eszopiclone 2 and 3 mg was bitter taste (17% and 34%, respectively), followed by dizziness (5% and 7%) and dry mouth (5% and 7%). Somnolence occurred at an incidence of 4% to 9% with both doses. Tolerance or rebound insomnia was not reported. CONCLUSIONS: Eszopiclone represents an effective and well-tolerated option for the treatment of insomnia. In the absence of published studies comparing eszopiclone with similar hypnotic agents (eg, zolpidem, zaleplon, zopiclone), it is not yet possible to evaluate its efficacy relative to other agents used for insomnia.