Esmirtazapine maleate

Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia.

Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively.

Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0-62.5; P < .0001) at months 4-6. There was no evidence of residual effects on next-day alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events.

Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation.

Registry: ClinicalTrials.gov; Name: A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002); URL: https://clinicaltrials.gov/ct2/show/NCT00631657; Identifier: NCT00631657; and Registry: ClinicalTrials.gov; Name: Twenty-Six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007); URL: https://clinicaltrials.gov/ct2/show/NCT00750919); Identifier: NCT00750919.

This work presents the development of an enantioselective method to quantify chiral drugs (CDs) in surface water and its application in the Douro River estuary monitoring. Different classes of CDs were targeted, including 23 compounds, namely beta-blockers, antidepressants, one beta₂-adrenergic agonist, non-steroidal anti-inflammatory drugs, stimulants, and some illicit drugs as cocaine (COC) and its metabolites, and amphetamines. The analytical method was based on an innovative application of solid phase extraction (SPE), followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a triple quadrupole analyzer. The ground-breaking approach of SPE consists in the use of Oasis^® MCX cartridges to pre-concentrate 500 mL of water samples, allowing the simultaneous extraction of acidic, basic and neutral analytes, rather than the conventional recovery of basic compounds only. Two chiral columns were used for enantiomeric separation in reverse elution mode, a Chirobiotic™V and a Pirkle type Whelk-O^®1, for basic and acidic compounds, respectively. The method validation demonstrated good linearity (r² > 0.99), selectivity and sensitivity, with method detection limits between 0.01 and 2.66 ng L^-1 and method quantification limits between 0.02 and 5.71 ng L^-1. The developed method was successfully applied to monitor daily variations along one week in surface waters collected in 5 locations of the Douro River estuary. Tramadol (TRM) and its metabolite N-desmethyltramadol (NDT), presented high concentrations near the affluent of a tributary river, while the second eluted enantiomer of O-desmethyltramadol (ODT) was found at high concentrations at the mouth of the Douro River. The metabolite NDT was quantified at higher concentrations than TRM. Venlafaxine (VNF) was found at high concentrations near the affluent of the same tributary river, but its metabolite, O-desmethylvenlafaxine (ODV), was found at concentrations 3 times higher. COC was found every day at all sampling points along the estuary, with slight variations.