The Orchestra Nocturne: Description For Six New Katydid Species From India (Orthoptera: Tettigoniidae).

The paper describes six new species from three genera of Tettigoniidae. The paper evaluates the status of Hexacentrus Serville 1831, Phyllomimus Stl 1873 and Euconocephalus Karny 1907. Diagnostic characters for new members of each genus are described along with additional information about the ecology and distribution of species. Keys to all species of each genus is presented. Of the six, three namely H. sylavanus sp. nov., E.helleri sp. nov and E. brevicornis are recorded only from Assam. One species, E.latipennis is recorded from Arunachal Pradesh and one species P.midoriyae is recorded from both locations. One species E. malabaricum is recorded from the Alappuzha district, in Kerala. The paper also demonstrates the importance of acoustic signals in taxonomic studies.

Occurrence of Z-drugs, benzodiazepines, and ketamine in wastewater in the United States and Mexico during the Covid-19 pandemic.

Z-drugs, benzodiazepines and ketamine are classes of psychotropic drugs prescribed for treating anxiety, sleep disorders and depression with known side effects including an elevated risk of addiction and substance misuse. These drugs have a strong potential for misuse, which has escalated over the years and was hypothesized here to have been exacerbated during the COVID-19 pandemic. Wastewater-based epidemiology (WBE) constitutes a fast, easy, and relatively inexpensive approach to epidemiological surveys for understanding the incidence and frequency of uses of these drugs. In this study, we analyzed wastewater (n = 376) from 50 cities across the United States and Mexico from July to October 2020 to estimate drug use rates during a pandemic event. Both time and flow proportional composite and grab samples of untreated municipal wastewater were analyzed using solid-phase extraction followed by liquid chromatography-tandem mass spectrometry to determine loadings of alprazolam, clonazepam, diazepam, ketamine, lorazepam, nordiazepam, temazepam, zolpidem, and zaleplon in raw wastewater. Simultaneously, prescription data of the aforementioned drugs were extracted from the Medicaid database from 2019 to 2021. Results showed high detection frequencies of ketamine (90 %), lorazepam (87 %), clonazepam (76 %) and temazepam (73 %) across both Mexico and United States and comparatively lower detection frequencies for zaleplon (22 %), zolpidem (9 %), nordiazepam (<1 %), diazepam (<1 %), and alprazolam (<1 %) during the pandemic. Average mass consumption rates, estimated using WBE and reported in units of mg/day/1000 persons, ranged between 62 (temazepam) and 1100 (clonazepam) in the United States. Results obtained from the Medicaid database also showed a significant change (p < 0.05) in the prescription volume between the first quarter of 2019 (before the pandemic) and the first quarter of 2021 (pandemic event) for alprazolam, clonazepam and lorazepam. Study results include the first detections of zaleplon and zolpidem in wastewater from North America.

Rapid Extraction and Qualitative Screening of 30 Drugs in Oral Fluid at Concentrations Recommended for the Investigation of DUID Cases.

A rapid, simple extraction method followed by qualitative screening using liquid chromatography-tandem mass spectrometry (LC-MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council's Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid-liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid-buffer mix collected in a Quantisal™ device, followed by LC-MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory.

Exposure via biotransformation: Oxazepam reaches predicted pharmacological effect levels in European perch after exposure to temazepam.

It is generally expected that biotransformation and excretion of pharmaceuticals occurs similarly in fish and mammals, despite significant physiological differences. Here, we exposed European perch (Perca fluviatilis) to the benzodiazepine drug temazepam at a nominal concentration of 2 µg L-1 for 10 days. We collected samples of blood plasma, muscle, and brain in a time-dependent manner to assess its bioconcentration, biotransformation, and elimination over another 10 days of depuration in clean water. We observed rapid pharmacokinetics of temazepam during both the exposure and depuration periods. The steady state was reached within 24 h of exposure in most individuals, as was complete elimination of temazepam from tissues during depuration. Further, the biologically active metabolite oxazepam was produced via fish biotransformation, and accumulated significantly throughout the exposure period. In contrast to human patients, where a negligible amount of oxazepam is created by temazepam biotransformation, we observed a continuous increase of oxazepam concentrations in all fish tissues throughout exposure. Indeed, oxazepam accumulated more than its parent compound, did not reach a steady state during the exposure period, and was not completely eliminated even after 10 days of depuration, highlighting the importance of considering environmental hazards posed by pharmaceutical metabolites.

Amelioration of cyclosporine-induced testicular toxicity by carvedilol and/or alpha-lipoic acid: Role of TGF-ß1, the proinflammatory cytokines, Nrf2/HO-1 pathway and apoptosis.

Cyclosporine is an immunosuppressive agent that is used to prevent organ rejection after organ transplantation. Due to the widespread use of this type of surgery, the effect of cyclosporine on reproduction and fertility should have a specific interest. Our aim was to assess the effect of carvedilol and/or alpha-lipoic acid on cyclosporine-induced testicular toxicity in rats. Sixty male Wistar rats were divided into six equal groups: Control; cyclosporine; cyclosporine + carvedilol; cyclosporine + alpha-lipoic acid; cyclosporine + carboxymethyl cellulose; and cyclosporine + carvedilol +alpha-lipoic acid. Food intake, testis weight, testicular functions, serum testosterone, luteinizing hormone and follicle-stimulating hormone were measured. Also, testicular tissue 3 ß-hydroxysteroid dehydrogenase, 17 ß- hydroxysteroid dehydrogenase, paroxonase-1, proinflammatory cytokines, transforming growth factor beta-1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Heme oxygenase-1 (HO-1) content and sperm characteristics were determined. Parts of the testes were subjected to histopathological and electron microscopic examination. The carvedilol/alpha-lipoic acid combination restored the food intake, testicular weight and functions, sperm characteristics, hormonal profile and the antioxidant defences compared to the use of each of these drugs alone. Also, this combination significantly ameliorated inflammation (P < .05) and induced significant increase in tissue Nrf2/HO-1 content (P < .05) and significant improvement of the histopathological and electron microscopic picture (P < .05) compared to the use of each of these drugs alone. So, carvedilol/alpha-lipoic acid combination might represent a novel therapeutic strategy to ameliorate testicular damage induced by cyclosporine.

Evaluation of an activated carbon disposal system for safe disposal of model prescription sedative medications.

Lack of a safe and convenient disposal method for expired and unused medications may lead to many problems such as accidental exposure, intentional misuse, and food and water contamination. Activated carbon can offer safe disposal of medications due to its highly porous structure, which exerts strong physical adsorption forces with chemicals. This study aimed to evaluate the efficiency of an activated carbon-based drug disposal system for deactivating three model sedative prescription medications. Deactivation was performed by mixing the medication, activated carbon, and tap water. Desorption was evaluated by exposing the deactivation system to wash-out solutions. Rapid, precise, accurate, and sensitive HPLC-UV method for each drug was successfully developed, validated and employed. Results of the 28-day deactivation study showed that on average, more than 94.00% of drugs were rapidly deactivated within 8 hours. All drugs reached more than 99.00% deactivation by the end of 28-day period. Desorption study demonstrated that all medications were retained by the system, with insignificant amount of drug (0.25%) leached into the washout solutions within 24 hours. In conclusion, activated carbon rapidly and successfully deactivated the medications tested, suggesting activated carbon-based drug disposal system provides a convenient, secure, and effective method for unused medication.

Melatonin, temazepam and placebo in hospitalised older patients with sleeping problems (MATCH): a study protocol of randomised controlled trial.

INTRODUCTION: Hospitalised older patients frequently suffer from inadequate sleep, which can lead to patient distress and delayed recovery from acute illness or surgical procedure. Currently, no evidence-based treatments exist for sleeping problems in hospitalised older patients. Benzodiazepines, such as temazepam, are regularly prescribed by physicians, although they have serious side effects; for older patients in particular. Melatonin is proposed as a safe alternative for sleeping problems in hospitalised older patients, but the efficacy of melatonin is unclear in this population. Therefore, the aim of this study is to investigate the effects of melatonin and temazepam compared with placebo on sleep quality among hospitalised older patients with sleeping problems. METHODS AND ANALYSIS: This study is a multicentre, randomised, placebo-controlled trial. A total of 663 patients will be randomised in a 1:1:1 fashion to receive either melatonin (n=221), temazepam (n=221) or placebo (n=221). The study population consists of hospitalised patients aged 60 years and older, with new or aggravated sleeping problems for which an intervention is needed. The primary outcome is sleep quality measured with the Leeds Sleep Evaluation Questionnaire (LSEQ). Secondary outcomes include sleep parameters measured with actigraphy and medication-related adverse effects. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of the Academic Medical Centre Amsterdam, (No 2015_302). Study findings will be disseminated through presentations at professional and scientific conferences and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6908; Pre-results.

Investigating tissue bioconcentration and the behavioural effects of two pharmaceutical pollutants on sea trout (Salmo trutta) in the laboratory and field.

Pharmaceuticals entering aquatic ecosystems via wastewater effluents are of increasing concern for wild animals. Because some pharmaceuticals are designed to modulate human behaviour, measuring the impacts of exposure to pharmaceuticals on fish behaviour has become a valuable endpoint. While laboratory studies have shown that pharmaceuticals can affect fish behaviour, there is a lack of understanding if behaviour is similarly affected in natural environments. Here, we exposed sea trout (Salmo trutta) smolts to two concentrations of two pharmaceutical pollutants often detected in surface waters: temazepam (a benzodiazepine, anxiolytic) or irbesartan (an angiotensin II receptor blocker, anti-hypertensive). We tested the hypothesis that changes to behavioural traits (anxiety and activity) measured in laboratory trials following exposure are predictive of behaviour in the natural environment (downstream migration). Measures of anxiety and activity in the laboratory assay did not vary with temazepam treatment, but temazepam-exposed fish began migrating faster in the field. Activity in the laboratory assay did predict overall migration speed in the field. In contrast to temazepam, we found that irbesartan exposure did not affect behaviour in the laboratory, field, or the relationship between the two endpoints. However, irbesartan was also not readily taken up into fish tissue (i.e. below detection levels in the muscle tissue), while temazepam bioconcentrated (bioconcentration factor 7.68) rapidly (t1/2 < 24 h). Our findings add to a growing literature showing that benzodiazepine pollutants can modulate fish behaviour and that laboratory assays may be less sensitive at detecting the effects of pollutants compared to measuring effects in natural settings. Therefore, we underscore the importance of measuring behavioural effects in the natural environment.

The effect of temazepam on assessment of severity of obstructive sleep apnea by polysomnography.

PURPOSE: To determine the effect of temazepam on assessment of the severity of obstructive sleep apnea (OSA) by polysomnography (PSG). METHODS: Analysis of diagnostic laboratory-PSG studies was performed in OSA patients who were administered temazepam (10 mg) to facilitate sleep ("temazepam group", n = 73) and in OSA patients (matched for age, gender, body mass index and study date) in whom temazepam was not administered ("control group", n = 73). Sleep- and respiratory-related variables were compared between the groups for the (i) first 3 h of study following temazepam in the temazepam group (when peak blood concentration is expected) or following lights out in the control group, and (ii) entire study duration. RESULTS: Within the first 3 h, no differences in sleep-related variables were observed between the groups. Over the entire study duration, the temazepam group had a reduced total sleep time compared to the control group, likely due to the overnight sleep difficulties that led to its use. Whether measured during the first 3 h of study or over the entire study duration, no significant differences were detected between the groups for any respiratory-related variable, including apnea hypopnea index, arousal index, oxygen desaturation, apnea index, hypopnea index, and event duration. When patients were considered in terms of OSA severity, decreased arousal index was noted in the temazepam group over the entire study duration, but only in those with severe OSA. CONCLUSION: Oral administration of 10 mg of temazepam during the course of PSG does not systematically affect assessment of the severity of OSA by PSG.

Withdrawal from long-term use of zopiclone, zolpidem and temazepam may improve perceived sleep and quality of life in older adults with primary insomnia.

Long-term use of benzodiazepines or benzodiazepine receptor agonists is widespread, although guidelines recommend short-term use. Only few controlled studies have characterized the effect of discontinuation of their chronic use on sleep and quality of life. We studied perceived sleep and quality of life in 92 older (age 55-91 years) outpatients with primary insomnia before and after withdrawal from long-term use of zopiclone, zolpidem or temazepam (BZDA). BZDA was withdrawn during 1 month, during which the participants received psychosocial support and blindly melatonin or placebo. A questionnaire was used to study perceived sleep and quality of life before withdrawal, and 1 month and 6 months later. 89 participants completed the 6-month follow-up. As melatonin did not improve withdrawal, all participants were pooled and then separated based solely on the withdrawal results at 6 months (34 Withdrawers. 55 Nonwithdrawers) for this secondary analysis. At 6 months, the Withdrawers had significantly (P < 0.05) shorter sleep-onset latency and less difficulty in initiating sleep than at baseline and when compared to Nonwithdrawers. Compared to baseline, both Withdrawers and Nonwithdrawers had at 6 months significantly (P < 0.05) less fatigue during the morning and daytime. Stress was alleviated more in Withdrawers than in Nonwithdrawers (P < 0.05). Satisfaction with life and expected health 1 year later improved (P < 0.05) in Withdrawers. In conclusion, sleep disturbances, daytime fatigue and impaired quality of life may resolve within 6 months of BZDA withdrawal. These results encourage withdrawal from chronic use of benzodiazepine-type hypnotics, particularly in older subjects.

Long-term persistence of withdrawal of temazepam, zopiclone, and zolpidem in older adults: a 3-year follow-up study.

BACKGROUND: Studies on persistence of benzodiazepine agonist (BZDA) withdrawal in older outpatients are few, and few studies on long-term persistence over years have yet been published. To describe the persistence of temazepam, zolpidem, and zopiclone (BZDA) withdrawal among older outpatients at 3 years from the beginning of withdrawal, as well as any changes in use of other medications. METHODS: 92 outpatients (≥55 years) with primary insomnia, long-term BZDA use as hypnotics (mean duration of BZDA use 9.9 ± 6.2 years), and willingness to withdraw from BZDAs each received either melatonin or a placebo nightly for one month. During this period, BZDAs were meant to be gradually withdrawn. Sleep hygiene counselling and psychosocial support were provided. Three years later, use of BZDAs and other medications was determined by interview and confirmed from medical records. RESULTS: Of the original 92 outpatients, 83 (90%) participated in the 3-year survey (mean follow-up 3.3 ± 0.2 years). The number of BZDA-free participants decreased from 34 (37%) at 6 months to 26 (28%; intention-to-treat) at 3 years, that of irregular BZDA users decreased from 44 (48%) at 6 months to 27 (29%) at 3 years, while that of regular users increased from 11 (12%) at 6 months to 30 (33%) at 3 years (P = 0.001). Those who were regular BZDA users at 3 years had at baseline (before withdrawal) higher BMI (P = 0.001) than did other participants. At 3 years, the total number of medications remained unchanged for non-users (P = 0.432), but increased for the irregular (P = 0.011) and regular users (P = 0.026) compared to baseline. At 3 years, compared to baseline, use of antidepressants, dopamine agonists, melatonin, and NSAIDs/paracetamol was significantly more common in the whole cohort, but their use did not differ between the BZDA-user subgroups. Randomization to melatonin or placebo during BZDA withdrawal was unrelated to BZDA-withdrawal result. CONCLUSIONS: At 3 years after withdrawal, the number of BZDA-free participants had decreased, but still one-third of the subjects remained BZDA-free, and one-third had reduced their use. Successful BZDA withdrawal did not lead to any increase in total number of medications; use of symptomatic medications in the whole cohort, however, did increase.

Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem.

Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data are lacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousal threshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep.21 individuals with and without OSA (18-65 years) completed 84 detailed sleep studies after receiving temazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind, placebo-controlled, crossover trial (ACTRN12612001004853).The arousal threshold increased with zolpidem and zopiclone versus placebo (mean±sd -18.3±10 and -19.1±9 versus -14.6±7 cmH2O; p=0.02 and p<0.001) but not with temazepam (-16.8±9 cmH2O; p=0.17). Genioglossus muscle activity during stable non-REM sleep and responsiveness during airway narrowing was not different with temazepam and zopiclone versus placebo but, paradoxically, zolpidem increased median muscle responsiveness three-fold during airway narrowing (median -0.15 (interquartile range -1.01 to -0.04) versus -0.05 (-0.29 to -0.03)% maximum EMG per cmH2O epiglottic pressure; p=0.03). The upper airway critical closing pressure did not change with any of the hypnotics.These doses of common hypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airway muscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airway narrowing with zolpidem.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

GABAA receptor positive allosteric modulators (GABAA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABAA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABAA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABAA receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABAA receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABAA receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine.

Screening of benzodiazepines in thirty European rivers.

Pharmaceuticals as environmental contaminants have received a lot of interest over the past decade but, for several pharmaceuticals, relatively little is known about their occurrence in European surface waters. Benzodiazepines, a class of pharmaceuticals with anxiolytic properties, have received interest due to their behavioral modifying effect on exposed biota. In this study, our results show the presence of one or more benzodiazepine(s) in 86% of the analyzed surface water samples (n = 138) from 30 rivers, representing seven larger European catchments. Of the 13 benzodiazepines included in the study, we detected 9, which together showed median and mean concentrations (of the results above limit of quantification) of 5.4 and 9.6 ng L-1, respectively. Four benzodiazepines (oxazepam, temazepam, clobazam, and bromazepam) were the most commonly detected. In particular, oxazepam had the highest frequency of detection (85%) and a maximum concentration of 61 ng L-1. Temazepam and clobazam were found in 26% (maximum concentration of 39 ng L-1) and 14% (maximum concentration of 11 ng L-1) of the samples analyzed, respectively. Finally, bromazepam was found only in Germany and in 16 out of total 138 samples (12%), with a maximum concentration of 320 ng L-1. This study clearly shows that benzodiazepines are common micro-contaminants of the largest European river systems at ng L-1 levels. Although these concentrations are more than a magnitude lower than those reported to have effective effects on exposed biota, environmental effects cannot be excluded considering the possibility of additive and sub-lethal effects.

Pentobarbital in the context of possible suicides: Analysis of a Case.

Pentobarbital is a barbiturate, acting as a central nervous system depressant (CNS), being used for its anticonvulsant, sedative, hypnotic and anaesthetic properties. Barbiturates were replaced by benzodiazepines, leading to a decrease in poisoning cases with these compounds. However, pentobarbital is still used in many countries as an anaesthetic in veterinary medicine. Due to its properties, this compound is sought after by people who wish to commit suicide, acquiring it on the black market. The authors present an unusual fatal pentobarbital intoxication case, in a 37 years-old male salesperson, with no known connection with the veterinary field, being more difficult to obtain this compound. Toxicological results in cardiac blood revealed the presence of pentobarbital (111mg/L), ethanol (0.94g/L), diazepam (33ng/mL), nordiazepam (50ng/mL), oxazepam (3.3ng/mL), temazepam (5.3ng/mL), and metoclopramide. No illicit drugs were detected. Pentobarbital analysis in urine and gastric content was also positive, as well as its presence in the glass powder and in the bottle residue sent to the laboratory. In the present case, it was possible to conclude that the death was a suicide due to pentobarbital intoxication in association with other depressants of the CNS (benzodiazepines and ethanol). It is important to search pentobarbital in routine toxicological analyses, since it is one of the drugs most frequently mentioned by entities defending "painless death", advising the simultaneous use of metoclopramide for emesis avoidance.

Deposition of diazepam and its metabolites in hair following a single dose of diazepam.

Only sporadic data are available on hair concentrations of diazepam and some of its metabolites (nordazepam, oxazepam, and temazepam) following a single controlled dose. The aim of this study was to investigate the deposition of diazepam and its metabolites in human hair after eight healthy volunteers (four women and four men, ages 24-26, East Asian) consumed 10 mg of diazepam. Hair was collected from all volunteers 1 month after exposure, and also 2 months post-exposure from men and 10 months post-exposure from women. Diazepam and the complete metabolite profile, including oxazepam glucuronide and temazepam glucuronide, were measured by ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with limits of quantifications (LOQs) of 0.5-2.5 pg/mg for diazepam, nordazepam, oxazepam, and temazepam, and of 10 pg/mg for oxazepam glucuronide and temazepam glucuronide. There were no differences by gender in the amounts of diazepam or metabolites found. The concentration of the main metabolite nordazepam was consistently higher than that of diazepam at both 1 and 2 months after consumption. Oxazepam and temazepam traces were found in some volunteers' hair, but the glucuronides were not detected. Diazepam and nordazepam levels at 10 months post-exposure were extremely low (near the LOQ), indicating drug loss by personal hygiene and physical handling. To our knowledge, this is the first single-dose diazepam study using black hair and the first study to include measurements of oxazepam glucuronide and temazepam glucuronide in human hair.

Investigation of the effect of mobile phase composition on selectivity using a solvent-triangle based approach in achiral SFC.

Defining a method development methodology for achiral drug impurity profiling in SFC requires a number of steps. Initially, diverse stationary phases are characterized and a small number of orthogonal or dissimilar phases are selected for further method development. In this paper, we focus on a next step which is the investigation of the modifier composition on chromatographic selectivity. A solvent-triangle based approach is used in which blends of organic solvents, mainly ethanol (EtOH), propanol (PrOH), acetonitrile (ACN) and tetrahydrofuran (THF) mixed with methanol (MeOH) are tested as modifiers on six dissimilar stationary phases. The tested modifier blends were composed to have equal eluotropic strengths as calculated on bare silica. The modifier leads to minor changes in terms of elution order, retention and mixture resolution. However, varying only the modifier composition on a given stationary phase does not lead to the creation of dissimilar systems. Therefore the modifier composition is an optimization parameter, with the stationary phase being the factor determining most the selectivity of a given mixture in achiral SFC.

Melatonin, hypnotics and their association with fracture: a matched cohort study.

OBJECTIVES: although melatonin prescribing in England has been increasing in recent years, there have been no large scale studies on the safety of melatonin compared to other medical treatments for insomnia. The primary aim of this study was to examine the association between exposure to melatonin, hypnotic benzodiazepines (temazepam, nitrazepam) or Z-drugs (zolpidem, zopiclone) and fracture risk. DESIGN: retrospective cohort study. SETTING: 309 general practices contributing to The Health Improvement Network (THIN) between 2008 and 2013. PARTICIPANTS: 1,377 patients aged 45 years and older prescribed melatonin; 880 patients prescribed hypnotic benzodiazepines; 1,148 patients prescribed Z-drugs and 2,752 unexposed controls matched by age, gender and practice. MAIN OUTCOME: fracture following prescription of study drugs ascertained from practice records. RESULTS: the unadjusted hazard ratios for fracture during the follow-up period were 1.90 (95% CI 1.41-2.57) for melatonin, 1.70 (95% CI 1.18-2.46) for hypnotic benzodiazepines and 2.03 (95% CI 1.45-2.84) for Z-drugs. After adjustment for 26 covariates, the hazard ratios were 1.44 (95% CI 1.01-2.04) for melatonin, 1.26 (95% CI 0.82-1.92) for hypnotic benzodiazepines and 1.52 (95% CI 1.04-2.23) for Z-drugs. Only patients with three or more melatonin prescriptions had elevated risk. The mean time to fracture was 1.04 years and there was no significant difference in mean time to fracture between the cohorts. CONCLUSIONS: in this large cohort of patients attending UK primary care, prescriptions for melatonin and Z-drugs were associated with a significantly increased risk of fracture. With the use of melatonin increasing steadily overtime, this study adds to the literature on the safety profile of this drug.