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Literature is sparse regarding men's attitudes towards male sexual assault and the role that the sexuality of those involved may have. Despite the high prevalence of chemsex and GHB (gamma-hydroxybutyrate) participation among men who have sex with men, no study has yet investigated attitudes towards such. Utilising a community sample of 141 UK men, participants were randomly assigned into one of six conditions based on victim sexuality (heterosexual or homosexual) and the drug used present during the sexual assault (chemsex, chemical submission, or no drugs). All participants completed the Male Rape Victim and Perpetrator Blaming Scale and Victim-Blaming Empathy Scale to measure victim-blame and empathy attributions. Results of a two-way MANOVA revealed a significant difference between participant gender and empathic ratings, with heterosexual participants significantly less likely to empathise than their homosexual counterparts. A non-significant difference was observed between the conditions alongside a non-significant interaction. Nevertheless, results indicate that victims in the chemsex condition, along with heterosexual victims, encountered the greatest victim-blaming attributions and the lowest rates of participant empathy overall. Findings overall appear to indicate a general decline in victim-blame attitudes towards men who have sex with men, though a level of uncertainty was apparent among the sample. Implications and limitations of the work are discussed alongside the importance of future research and psychoeducation interventions. [ABSTRACT FROM AUTHOR]

Sodium oxybate extended-release suspension (LUMRYZ™; hereafter referred to as sodium oxybate ER) represents a promising novel option for the treatment of narcolepsy. It is the first once-nightly sodium oxybate formulation to be approved in the USA for the treatment of cataplexy or excessive daytime sleepiness (EDS) in adults with narcolepsy. Sodium oxybate ER has a pharmacokinetic profile that supports a single bedtime dose. In a pivotal phase 3 trial, once-nightly sodium oxybate ER dose-dependently increased sleep latency during the daytime, reduced cataplexy and daytime sleepiness, and improved disrupted nighttime sleep (DNS) compared with placebo in patients aged ≥ 16 years with narcolepsy. These improvements were statistically significant and clinically meaningful. Most patients who switched from twice-nightly immediate-release sodium oxybate (hereafter referred to as sodium oxybate IR) to once-nightly sodium oxybate ER in an open-label extension/switching study preferred the once-nightly formulation. Once-nightly sodium oxybate ER was generally well tolerated, including over the longer term, with a tolerability profile consistent with that of twice-nightly sodium oxybate IR. Plain Language Summary: Narcolepsy, a disorder of sleep-wake instability, is a lifelong condition characterized primarily by overwhelming and persistent daytime sleepiness. Other symptoms include sudden muscle weakness associated with strong emotions (cataplexy), disturbed nighttime sleep, sleep paralysis, and vivid hallucinations when falling asleep or when awakening. The standard of care for patients with narcolepsy has been sodium oxybate, which requires twice-nightly dosing. Patients take their first dose at bedtime and must then awaken 2.5–4 h later to take their second dose. A less burdensome once-nightly formulation, sodium oxybate extended-release suspension (LUMRYZ™; hereafter referred to as sodium oxybate ER), has been approved for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy. In a clinical trial, patients treated with once-nightly sodium oxybate ER were able to stay awake longer during the day, felt less sleepy in the daytime, had fewer cataplexy attacks, and had less disruption to nighttime sleep than placebo recipients. Sodium oxybate ER was generally well tolerated. Nausea, dizziness, bed-wetting, headache, and vomiting were the most common treatment-related adverse events. Thus, once-nightly sodium oxybate ER represents a promising new option for the treatment of narcolepsy. [ABSTRACT FROM AUTHOR]

Summary: Narcolepsy type 1 is a chronic central disorder of hypersomnolence, and it is frequently accompanied by overweight, but the association between narcolepsy type 1 and eating disorders is controversial. Our study aims to compare patients with narcolepsy type 1 and controls on the symptomatology of eating disorders and to evaluate the association between clinical factors. This is a cross‐sectional study, with consecutive recruitment of patients with narcolepsy type 1 attending the Outpatient Clinic for Narcolepsy at the IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy) for routine follow‐up visits. Healthy subjects from general populations were recruited as controls. Patients underwent a questionnaire‐based assessment using the Eating Disorder Examination Questionnaire (EDE‐Q), Binge Eating Scale (BES), Italian Night Eating Questionnaire (I‐NEQ), Epworth Sleepiness Scale (ESS), and Narcolepsy Severity Scale (NSS). One hundred and thirty‐eight patients with narcolepsy type 1 and 162 controls were enrolled. This study showed that individuals with narcolepsy type 1 reported higher scores on the EDE‐Q, I‐NEQ, and a higher body mass index (BMI) than the controls. The logistic regression analysis results, with EDE‐Q positivity as a dependent variable, demonstrate a significant association with antidepressant drugs, female sex, and the use of sodium oxybate. We found an association between antidepressant drug consumption, the NSS total score, and female sex with BES positivity as the dependent variable. The logistic regression analysis for I‐NEQ positivity found an association with antidepressant drug use. This study shows that patients with narcolepsy type 1 frequently present with comorbid eating disorder symptomatology, mainly night eating syndrome. Investigating the possible presence of eating disorders symptomatology through questionnaires is fundamental during the assessment of patients with narcolepsy type 1. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Discussion and Conclusions In recent years gamma hydroxybutyrate (GHB) use appears to have increased. This study aimed to determine: (i) population rates of GHB‐related death in Australia, 2001–2021; and (ii) whether there have been changes in the characteristics of GHB‐related death in Australia over the period 2001–2023.Retrospective study of all Australian cases in which GHB was a mechanism contributory to death retrieved from the National Coronial Information System (n = 217). Joinpoint regression models were used to analyse trends in overall rates.Death rates were stable between 2001 and 2015 (‘stable period’) (annual percent change [APC] = 3.7) but showed marked acceleration between 2016 and 2021 (‘accelerated period’) (APC = 44.4). Circumstances of death were: unintentional toxicity (81.6%), intentional toxicity (5.1%), self‐harm (6.0%), traumatic injury (7.4%). Compared to the stable period, later cases were slightly older (34.2 vs. 30.7 years, p < 0.05), less likely to be employed (odds ratio [OR] 0.4), but more likely to have substance use problems (OR 3.9), a history of injecting drug use (OR 3.5), mental health problems (OR 3.6), and to have present in their blood at toxicological screening opioids (OR 3.2) and hypnosedatives (OR 3.7). The median blood GHB concentration was 170 mg/L, (range 0–3210), which did not change significantly. There were no differences in major organ pathology, but the proportion with aspiration pneumonia declined (OR 0.4).GHB‐related death rates increased from 2016, accompanied by changes in case characteristics. In recent years GHB use appears to have extended to a population more likely to have substance use problems and use other respiratory depressants. [ABSTRACT FROM AUTHOR]

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Objectives: In overdose, gamma‐hydroxybutyrate (GHB) and its precursors can cause decreased levels of consciousness, coma and death. Here, we aim to describe reported exposure to GHB at four EDs in Sydney, New South Wales (NSW), Australia. Methods: We searched the ED databases of four Sydney metropolitan hospitals for presentations relating to GHB exposure between 2012 and 2021. We calculated annual number of presentations stratified by hospital, age, sex, mode of arrival and triage category. Results: A total of 3510 GHB‐related presentations to ED were recorded across the four hospitals. Data for all hospitals were only available from 2015 onwards and between 2015 and 2021; there was a 114% increase in annual presentations (from 228 to 487). Males represented 68.7% of all presentations and the median age was 31 years (range 16–74 years). There was an increase in the proportion of female presentations between 2012 and 2021 (from 27.9% to 37.9%) along with the severity of presentation over the same period, with the proportion of presentations with a triage category 1 increasing from 19.7% to 34.5%. Conclusions: Increases in recorded absolute number and severity of GHB‐related presentations to Sydney EDs are a major public health concern. There may also be shifts in the demographics of those with GHB‐related presentations. Renewed efforts are required to understand the drivers of these increases to optimally target harm reduction approaches. [ABSTRACT FROM AUTHOR]

A 35-day study investigated the impact of carbon sources and carbon/nitrogen (C/N) ratios on the microbial community of biofloc. For this purpose, we utilized a combination of phospho-lipid fatty acids (PLFAs) profiles and DNA-based sequencing methods to investigate changes in the microbial community composition and structure. The experiment involved three carbon sources including Dextrin (DEX), corn starch (CS) and wheat bran (WB) at two C/N ratios (19 and 30). The results indicated that WB and CS were found to decrease nitrogen metabolite concentration while increasing total suspended solids and bacterial density compared to DEX. The treatments exhibited variations in microbial communities and the use of polymerase chain reaction/ denaturing gradient gel electrophoresis analysis revealed distinct dominant bacterial species linked to carbon sources and C/N ratios. Furthermore, the highest levels of bacteria and protozoa PLFAs biomarkers were observed in the C/N30 ratio and WB treatment while the ratio for poly-β-hydroxybutyrate/PLFAs and fungi biomarkers displayed a decrease. Also, by incorporating the results of PLFAs profile and conducting a principal component analysis, the treatments were categorized into distinct groups based on both the carbon source and C/N ratios. Overall, both methods yield consistent results. PLFAs offered additional insights into the microbial composition beyond bacterial structure while DNA-based analysis provided finer taxonomic resolution. [ABSTRACT FROM AUTHOR]

Introduction Case Presentation Discussion and Conclusions γ‐hydroxybutyrate (GHB) is a GABA‐B agonist that rapidly produces effects that are likened to both alcohol and MDMA/ecstasy. GHB use can lead to neuroadaptation with a characteristic withdrawal syndrome. There is currently a paucity of data on the progression of GHB withdrawal, however, due to the drug's short half‐life it is generally considered to be typically 5–7 days, although some cases can be severe and complicated by life threatening delirium. Here, we present a case of severe GHB withdrawal, which recurred on multiple occasions over 56 days, despite initial clinical stabilisation on each occasion and toxicological evidence of abstinence from GHB between episodes.A male patient in his 30s presented with agitated delirium on a background of severe GHB use disorder with a 15‐year history of daily high dose GHB use. Following 3 hospital admissions over 8 weeks, all requiring intravenous sedation and tracheal intubation, the patient's withdrawal delirium was successfully treated with a slow benzodiazepine and baclofen wean over a period of 6 months. Relapse to GHB use between hospitalisations was excluded toxicologically via blood analysis performed at an institute of forensic pathology.This case highlights that GHB withdrawal can be more prolonged than previously reported in the literature and in some cases may require slow and prolonged tapering of treatment to prevent re‐emergence of delirium. Similar to previous case reports, benzodiazepines and GABA‐B receptor agonists appear to be appropriate drug classes to manage GHB withdrawal. [ABSTRACT FROM AUTHOR]

Thirst is a complex physiological compensatory mechanism but could also be associated with drugs. This association was poorly investigated previously. Using the WHO global pharmacovigilance database, Vigibase®, disproportionality analyses potential associations between exposure to drugs and thirst reports were performed. All reports of thirst in adults between 01/01/2000 and 31/12/2023 were included. Results are expressed as reporting odds ratio (ROR). Analysis of the 3186 reports of thirst (978 'serious') allowed, first, to confirm the association between thirst and exposure to vasopressin antagonists (tolvaptan), lithium, gliflozins (dapagliflozin, empagliflozin), pregabalin and antimuscarinic drugs (glycopyronium, oxybutynin, tiotropium). Second, new safety signals were described with monoamine reuptake inhibitors (antidepressants: duloxetine, venlafaxine; anti‐obesity agent: sibutramine), antipsychotic (olanzapine), glucocorticoid (prednisolone), diuretic (furosemide) drugs as well with ribavirin or sodium oxybate. This study is the first to offer a list of drugs associated with thirst in humans. [ABSTRACT FROM AUTHOR]

Introduction: Low-sodium oxybate (LXB) is approved for treatment of narcolepsy in patients aged 7 years and older and treatment of idiopathic hypersomnia in adults. LXB contains the same active moiety with 92% less sodium than sodium oxybate (SXB). As the indication for oxybate treatment in patients with idiopathic hypersomnia is new and allows for individualized dosing optimization, guidance for beginning LXB treatment is needed. In particular, clinicians may benefit from guidance regarding treatment initiation, dosing/regimen options, potential challenges, and treatment expectations. Additionally, pharmacokinetic profiles differ slightly between both treatments, and further guidance on transitioning from SXB to LXB in patients with narcolepsy may aid clinicians. Methods: An expert panel of five sleep specialists was convened to obtain consensus on recommendations for these topics using a modified Delphi process. Results: Across two virtual meetings, the panel agreed on 31 recommendations with a high degree of consensus that fell into four overarching topics: (1) introducing LXB to patients; (2) initiating LXB for adult narcolepsy and idiopathic hypersomnia; (3) addressing challenges in using LXB; and (4) transitioning from SXB to LXB. The panel recommended that clinicians provide a clear overview of how LXB works for treating symptoms in narcolepsy or idiopathic hypersomnia, as appropriate for their patients, explain safety aspects, and set expectations prior to initiating LXB treatment. Strategies for initial dosing and regimen are provided. Strategies for adjusting the dose, regimen, timing, and consideration of individual factors were developed for specific instances in which patients may have trouble staying asleep or waking up, as well as guidance for addressing potential adverse events, such as nausea, dizziness, anxiety, and depression. Discussion points based on existing literature and clinical experience were included as relevant for each statement. Conclusion: Clinicians may use this resource to guide LXB dosing optimization with patients. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration can require risk evaluation and mitigation strategy (REMS) programs for prescription drugs to ensure the benefits of use outweigh the risks. We conducted a national survey of physicians' experiences prescribing eight REMS‐covered drugs: (1) ambrisentan; (2) bosentan; (3) clozapine; (4) isotretinoin; (5–7) the multiple myeloma (MM) drugs lenalidomide, pomalidomide, thalidomide; and (8) sodium oxybate. Between May 2022 and January 2023, we surveyed 5,331 physician prescribers of these drugs, and 1,295 (24%) returned surveys (range: 149 for bosentan to 226 for MM drugs). Although 765 (68%) respondents thought the certification process provided useful drug information, 757 (67%) wanted materials to include benefit data and 944 (84%) non‐REMS‐related risk data. A majority (704, 63%) thought the safe use requirements facilitated discussion with patients, but a similar number (637, 57%) attributed delayed medication access to these requirements. In multivariable modeling, MM drug and isotretinoin respondents were less likely than sodium oxybate respondents to agree that the certification process provided useful drug information (MM drug: odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.25–0.55; isotretinoin: OR = 0.39, 95% CI = 0.25–0.61), and isotretinoin, clozapine, and bosetan respondents were more likely than sodium oxybate respondents to agree that the safe use requirements often delayed medication access (isotretinoin: OR = 5.83, 95% CI = 3.70–9.19; clozapine: OR = 1.65, 95% CI = 1.08–2.54; bosentan: OR = 1.78, 95% CI = 1.12–2.85). Most physicians believe REMS programs convey useful drug safety information and facilitate discussion with patients but also seek information on benefits and non‐REMS‐related risks and better integration of REMS processes into clinical workflows. [ABSTRACT FROM AUTHOR]

Acute metamfetamine toxicity is characterized by stimulant effects and neuropsychiatric disturbance, which is attenuated by gamma-aminobutyric acid type A receptor agonists including benzodiazepines. We utilized clinical registry data to examine the effect of co-exposure to a gamma-aminobutyric acid type B receptor agonist (gamma-hydroxybutyrate) in illicit drug cases with analytically confirmed exposure to metamfetamine. The Emerging Drugs Network of Australia Victoria is an ethics board-approved prospective registry collecting clinical and analytical data (utilising blood samples) on emergency department illicit drug presentations. Comparison groups were defined by analytically confirmed exposure: lone metamfetamine, metamfetamine plus gamma-hydroxybutyrate, metamfetamine plus benzodiazepine, metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine. Cases with co-exposure to other stimulants or sedatives were excluded. Median metamfetamine blood concentrations were significantly greater in metamfetamine plus gamma-hydroxybutyrate (n = 153, median = 0.20 mg/L, interquartile range: 0.10–0.32 mg/L, 95 per cent confidence interval: 0.20–0.23 mg/L) and metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine (n = 160, median = 0.20 mg/L, interquartile range: 0.10–0.30 mg/L, 95 per cent confidence interval: 0.20–0.30 mg/L) positive groups compared to gamma-hydroxybutyrate negative groups including metamfetamine (n = 81, median = 0.10 mg/L, interquartile range: 0.05–0.21 mg/L, 95 per cent confidence interval: 0.09–0.18 mg/L) and metamfetamine plus benzodiazepine (n = 73, median = 0.10 mg/L, interquartile range: 0.06–0.20 mg/L, 95 per cent confidence interval: 0.09–0.20 mg/L) groups (P < 0.0004). Presenting heart rate in metamfetamine plus gamma-hydroxybutyrate cases (n = 153, median = 72 beats per minute, interquartile range: 63–86 beats per minute, 95 per cent confidence interval: 70–78 beats per minute) was significantly lower than metamfetamine plus benzodiazepine cases (n = 73, median = 84 beats per minute, interquartile range: 73–98 beats per minute, 95 per cent confidence interval: 80–90 beats per minute, P < 0.0001), and lone metamfetamine cases (n = 81, median = 110 beats per minute, interquartile range: 87–131 beats per minute, 95 per cent confidence interval: 93–120 beats per minute, P < 0.0001). Presenting temperature in metamfetamine plus gamma-hydroxybutyrate cases (median = 35.8 °C, interquartile range: 35.0–36.2 °C, 95 per cent confidence interval 35.6–35.9 °C) was significantly lower than metamfetamine plus benzodiazepine cases (median 36.2 °C, interquartile range 35.7–36.6 °C, 95 per cent confidence interval, 36.0–36.4 °C, P = 0.017), and lone metamfetamine cases (median = 36.5 °C, interquartile range: 35.8–37.1 °C, 95 per cent confidence interval: 36.2–36.7 °C, P < 0.0001). Median presenting systolic blood pressure was significantly (P ≤ 0.001) lower in benzodiazepine positive groups (metamfetamine plus benzodiazepine median = 120 mmHg, interquartile range: 109–132 mmHg, 95 per cent confidence interval: 116–124 mmHg and metamfetamine plus benzodiazepine plus gamma-hydroxybutyrate median = 124 mmHg, interquartile range: 110–137 mmHg, 95 per cent confidence interval: 120–129 mmHg). Incidence of sedation (Glasgow Coma Scale less than 9) was significantly greater in metamfetamine plus gamma-hydroxybutyrate cases (63 per cent) compared to metamfetamine plus benzodiazepine cases (27 per cent, P < 0.0001) and lone metamfetamine cases (15 per cent, P < 0.0001). Incidence of agitation was significantly lower in metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine cases (17 per cent, P < 0.0001) and metamfetamine plus gamma-hydroxybutyrate cases (34 per cent, P = 0.0004) compared to lone metamfetamine cases (58 per cent). Differences in gamma-aminobutyric acid type A and B receptor physiology may offer a gamma-aminobutyric acid type B agonist-facilitated alternative pharmacodynamic mechanism able to attenuate metamfetamine stimulant and neuropsychiatric toxicity. Metamfetamine intoxicated patients with analytically confirmed co-exposure to gamma-hydroxybutyrate had significantly reduced heart rate, body temperature and incidence of agitation compared to patients with lone metamfetamine exposure. Metamfetamine intoxicated patients with analytically confirmed co-exposure to a benzodiazepine had significantly reduced systolic blood pressure compared to patients with lone metamfetamine exposure. We hypothesize that gamma-aminobutyric acid type B receptor agonists may be beneficial in the management of acute metamfetamine toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Gamma‐hydroxybutyrate (GHB) use is associated with high risk of accidental overdose. This study examined the pre‐hospital circumstances, demographic characteristics and clinical outcomes of analytically confirmed GHB emergency department (ED) presentations in Western Australia (WA). Methods: This case series was conducted across three WA EDs involved in the Emerging Drugs Network of Australia, from April 2020 to July 2022. Patient demographics, pre‐hospital drug exposure circumstances and ED presentation and outcome characteristics were collected from ambulance and hospital medical records of GHB‐confirmed cases. Results: GHB was detected in 45 ED presentations. The median age was 34 years and 53.3% (n = 24) were female. Most patients arrived at the ED by ambulance (n = 37, 85.7%) and required immediate emergency care (Australasian Triage Score 1 or 2 = 97.8%). One‐third of patients were admitted to intensive care (n = 14, 31.1%). Methylamphetamine was co‐detected in 37 (82.2%) GHB‐confirmed cases. Reduced conscious state was indicated by first recorded Glasgow Coma Scale of ≤8 (n = 29, 64.4%) and observations of patients becoming, or being found, 'unresponsive' and 'unconscious' in various pre‐hospital settings (n = 28, 62.2%). 'Agitated' and/or 'erratic' mental state and behavioural observations were recorded in 20 (44.4%) cases. Discussion and Conclusions: Analytically verified data from ED presentations with acute toxicity provides an objective information source on drug use trends and emerging public health threats. In our study, patients presenting to WA EDs with GHB intoxication were acutely unwell, often requiring intensive care treatment. The unexpectedly high proportion of female GHB intoxications and methylamphetamine co‐ingestion warrants further exploration. [ABSTRACT FROM AUTHOR]

The deterioration of the brain's microvasculature, particularly in the hippocampus, appears to be a very early event in the development of Alzheimer's disease (AD), preceding even the deposition of amyloid-β. A damaged microvasculature reduces the supply of oxygen and glucose to this region and limits the production of energy, ATP. The damage may be a function of the rise with age in the expression and activity of NADPH oxidase (NOX) in these microvessels. This rise renders these vessels vulnerable to the effects of oxidative stress and inflammation. The rise in NOX activity with age is even more marked in the AD brain where an inverse correlation has been demonstrated between NOX activity and cognitive ability. Apocynin, a putative NOX inhibitor, has been shown to block the damaging effects of NOX activation. Apocynin acts as a strong scavenger of H2O2, and as a weak scavenger of superoxide. Like apocynin, sodium oxybate (SO) has also been shown to block the toxic effects of NOX activation. The application of SO generates NADPH and ATP. SO inhibits oxidative stress and maintains normal cerebral ATP levels under hypoxic conditions. Moreover, it acts epigenetically to attenuate the expression of NOX. SO may delay the onset and slow the progress of AD by suppling energy and maintaining an antioxidative environment in the brain throughout the night. The slow wave activity produced by SO may also activate the glymphatic system and promote the clearance of amyloid-β from the brain. [ABSTRACT FROM AUTHOR]

This work refers to the synthesis and characterization of poly (3- hydroxybutyrate)-b-oligo (2-ethyl oxazoline) (oligoEtOx). Cationic ring- opening polymerization of 2-ethyl oxazoline yielded poly (2-ethyl oxazoline) (oligoEtOx) with a hydroxyl end. Carboxylic acid-terminated PHB was reacted with oligoEtOx via dicyclohexylcarbodiimide chemistry to obtain PHB-b- oligoEtOx conjugates. The obtained PHB-b-oligoEtOx conjugates were successfully characterized by 1H- and 13C NMR, FTIR, DSC, and size exclusion chromatography. PHB-b-oligoEtOx conjugates can be promising biologic active materials. [ABSTRACT FROM AUTHOR]

This letter to the editor responds to an article titled "Implications of Oxybate Dosing Regimen for Sleep, Sleep Architecture, and Disrupted Nighttime Sleep in Patients with Narcolepsy: A Commentary" by Rosenberg et al. The authors of the letter discuss the impact of different dosing regimens of sodium oxybate (SXB) on disrupted nighttime sleep (DNS) in patients with narcolepsy. They point out inaccuracies in the article's comparison of immediate-release (IR) SXB and extended-release SXB, and emphasize the importance of using accurate data when considering results from different trials. The authors also discuss the potential effects of concomitant stimulant use and the differences in slow-wave sleep (SWS) between the two dosing regimens. [Extracted from the article]

Als K.-o.-Mittel werden Substanzen bezeichnet, die meist ohne das Wissen der Person, die sie aufnimmt, verabreicht werden und die die Handlungs- und Widerstandsfähigkeit negativ beeinflussen können. Als Substanzen kommen – neben den klassischen Vertretern wie Gamma-Hydroxybuttersäure und Benzodiazepinen – eine große Anzahl weiterer zentral dämpfender Medikamente und besonders Alkohol in Betracht. Auch eine unbeabsichtigte Wechselwirkung bzw. Wirkpotenzierung durch Alkohol kann eine Rolle spielen. Die Nachweisbarkeitsdauer ist – abhängig von der Substanz und ihrer Halbwertzeit – (sehr) kurz, sodass bei Verdacht eine zeitnahe Probenabgabe extrem wichtig ist. Vor allem muss Urin asserviert werden, da hier das Nachweisfenster größer ist. Eine umfangreiche und sensitive Analytik sollte in einem dafür spezialisierten Labor durchgeführt werden. [ABSTRACT FROM AUTHOR]

The systemic administration of sodium oxybate (SXB), the sodium salt of gamma‐hydroxybutyric acid, promotes slow wave activity (SWA, 0.5–4 Hz EEG power) and increases non‐rapid eye movement (NREM) sleep. These effects are mediated by the widely expressed GABAb receptors, and thus, the brain areas targeted by SXB remain unclear. Because slow waves are mainly a cortical phenomenon, we tested here whether systemic SXB promotes SWA by acting directly on the cortex. Moreover, because somatostatin (SOM) + cortical interneurons play a key role in SWA generation, we also assessed their contribution to the effects of SXB. In adult SOM‐Cre mice, the injection of SXB in left secondary motor cortex increased SWA during NREM sleep in the first 30 min post‐injection (11 mice: either sex). SWA, the amplitude and frequency of the slow waves, and the frequency of the OFF periods increased ipsilaterally and contralaterally to the SXB injection in frontal and parietal cortex. All these changes disappeared when the intracortical injection of SXB was preceded by the chemogenetic inhibition of the SOM+ cells. Thus, SXB may promote the slow waves of NREM sleep, at least in part, by acting directly on the cortex, and this effect involves GABAergic SOM+ interneurons. Our working hypothesis is that SXB potentiates the ability of these cells to inhibit all other cortical cell types via a GABAb mechanism, thus promoting the transition from ON to OFF periods during NREM sleep. [ABSTRACT FROM AUTHOR]

Background: Poly-4-hydroxybutyrate (P4HB) is a bioabsorbable mesh with a non-adhesive coating on one side that is being used to reinforce the hiatus during hiatal hernia repair; however, there is limited data regarding its use. The aim of this study was to investigate outcomes after hiatal hernia repair using this mesh at our institution and through a review of the literature. Methods: An institutional review board-approved prospective database was retrospectively reviewed for all patients undergoing hiatal hernia repair from April 2018 to December 2022. A systematic review with meta-analysis was conducted to evaluate outcomes using P4HB coated mesh. Results: In our institutional cohort, there were 230 patients (59 males; 171 females) with a mean follow-up of 20 ± 14.6 months. No mesh-related complications occurred. Hernia recurrence was diagnosed in 11 patients (4.8%) with a median time to recurrence of 16 months. In the systematic review, 4 studies with 221 patients (76 males; 145 females) were included. Median follow-up ranged from 12 to 27 months. Recurrence rate in these studies was reported from 0 to 8.8%, with a total of 12 recurrences identified. Like our institutional cohort, no mesh-related complications were reported. After our recurrences were combined with those from the systematic review, a total of 23 recurrences were included in the meta-analysis. Our meta-analysis revealed a low recurrence rate following hiatal hernia repair with P4HB coated mesh (incidence rate per 100 person-years, 2.82; 95% confidence interval, 1.60, 4.04). Conclusion: P4HB coated mesh is safe and effective for hiatal hernia repairs. [ABSTRACT FROM AUTHOR]

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantage and disadvantages of each agent. • No head-to-head trials have compared different oxybate products or formulations. • Direct comparison of data is complicated by differences in trial designs. • Oxybate improves subjective and objective disrupted nighttime sleep in narcolepsy. • Improvements are observed for both formulations dosed once and twice nightly. [ABSTRACT FROM AUTHOR]

Γ-hydroxybutyric acid (GHB) is widely abused due to its sedative/hypnotic and euphoric effects. In recent years, GHB use has witnessed a notable rise within the LGBTQ+ community. GHB is a substrate of monocarboxylate transporters (MCTs) and exhibits nonlinear toxicokinetics, characterized by saturable metabolism, absorption, and renal reabsorption. This study investigates the impact of exogenous testosterone administration on GHB toxicokinetics and toxicodynamics, exploring the potential of MCT1 inhibition as a strategy to counteract toxicity. Ovariectomized (OVX) females and castrated (CST) male Sprague Dawley rats were treated with testosterone or placebo for 21 days. GHB was administered at two doses (1000 mg/kg or 1500 mg/kg i.v.), and the MCT1 inhibitor AR-C 155858 (1 mg/kg i.v.) was administered 5 min after GHB (1500 mg/kg i.v.) administration. Plasma and urine were collected up to 8 h post-dose, and GHB concentrations were quantified via a validated LC/MS/MS assay. Sleep time (sedative/hypnotic effect) was utilized as the toxicodynamic endpoint. Testosterone treatment significantly affected GHB toxicokinetics and toxicodynamics. Testosterone-treated CST rats exhibited significantly lower renal clearance, higher AUC, and increased sedative effect, while testosterone-treated OVX rats demonstrated higher metabolic clearance. AR-C 155858 treatment led to an increase in GHB renal and total clearance together with an improvement in sedative/hypnotic effect. In conclusion, exogenous testosterone treatment induces significant alterations in GHB toxicokinetics and toxicodynamics, and MCT inhibition can serve as a potential therapeutic strategy for GHB overdose in both cisgender and transgender male populations. [ABSTRACT FROM AUTHOR]

The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study assessed the real-world experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92 % less sodium than SXB). TENOR is a patient-centric, prospective, observational, virtual-format study. Eligible participants included US adults with narcolepsy transitioning from SXB to LXB (±7 days from LXB initiation). Longitudinal data were collected from baseline (taking SXB) through 21 weeks post-transition. TENOR included 85 participants with narcolepsy (type 1, n = 45; type 2, n = 40). Mean (SD) age was 40.3 (13.0) years; the majority (73 %) were female and White (87 %). At study completion, wake-promoting agents were the most common concomitant medications (47 %). Mean (SD) SXB treatment duration was 57.8 (52.1) months; 96 % took SXB twice nightly. After transitioning, 97 % continued on twice-nightly regimens. Mean (SD) dose of both total nightly SXB (n = 85) and baseline LXB (n = 84) was 7.7 (1.5) g; SXB-LXB dose conversions at baseline were gram-for-gram in 87 % of participants. The mean final total nightly dose of LXB was 7.9 g. The most common participant-reported reasons for transitioning included lower sodium content for improved long-term health (93 %), physician recommendation (47 %), to avoid cardiovascular issues (39 %), to avoid side effects (31 %), and to improve control of narcolepsy symptoms (18 %). Most participants transitioned from SXB to LXB using a gram-for-gram strategy. The most commonly cited reason for transition was long-term health benefits due to lower sodium. [Display omitted] • Transition from sodium oxybate to low-sodium oxybate for narcolepsy was evaluated. • Dosing and transition characteristics were examined via questionnaire over 21 weeks. • Most participants switched for long-term health reasons due to low sodium content. • Most switched gram-for-gram, and did not require low-sodium oxybate adjustments. • Dosing was generally maintained at twice-nightly equal dosing after transition. Registry: ClinicalTrials.gov ; Name: A Patient-Centric, Prospective, Observational, Non-Interventional Switch Study of XYWAV in Narcolepsy. URL: https://clinicaltrials.gov/ct2/show/NCT04803786 ; Identifier: NCT04803786. [ABSTRACT FROM AUTHOR]

Bruxism is a movement disorder of uncertain aetiology. Beside local peripheral and central psychological factors, drugs were suspected. Using the World Health Organization (WHO) global pharmacovigilance database, Vigibase®, we investigated through disproportionality analyses potential associations between exposure to drugs and bruxism reports. All reports of bruxism in adults between 01/01/2000 and 31/12/2022 were included. Results are expressed as reporting odds ratio (ROR). Among the 564 reports of bruxism, an association was found with eight antidepressants (first sertraline followed by escitalopram, venlafaxine, vortioxetine, citalopram, paroxetine, fluoxetine, duloxetine) and four antipsychotics (first ziprasidone followed by aripiprazole, olanzapine, risperidone). A signal was also described for oxybate sodium and metoclopramide. For antidepressants, a negative association was found between ROR values and NET (norepinephrine transporter) but not SERT (serotonin transporter) pKi values, suggesting this ADR is more closely linked to norepinephrine than serotonin reuptake inhibition. [ABSTRACT FROM AUTHOR]

Narcolepsy is associated with disrupted nighttime sleep (DNS). Sodium oxybate (SXB; Xyrem®), administered twice nightly, is indicated for the treatment of cataplexy and excessive daytime sleepiness in patients 7 years or older with narcolepsy. Recently, low-sodium oxybate (LXB, Xywav®; for people 7 years of age and older), which contains 92% less sodium than SXB and is dosed twice nightly, and sodium oxybate for extended release (SXB-ER; Lumryz™; for adults), which contains equal sodium to SXB and is dosed once nightly, have also been approved to treat cataplexy or excessive daytime sleepiness in narcolepsy. This paper reviews the evidence regarding the overall impact of oxybate administration, and impact of different oxybate dosing regimens (once nightly, SXB-ER; twice nightly, SXB), on DNS in narcolepsy utilizing polysomnographic data from five clinical trials (three assessing SXB in adults [referred to here as SXB trials 1, 2, and 3], one assessing SXB in children [referred to as the pediatric SXB trial], and one assessing SXB-ER in adults [REST-ON]). Both once-nightly and twice-nightly oxybate regimens similarly improved symptoms of DNS. Regardless of dosing regimen, people with narcolepsy treated with oxybate experience roughly 42–53 arousals and 9–38 awakenings each night, with one of these awakenings on twice-nightly oxybate being due to the second dosing requirement in studies of SXB. Additionally, for SXB, but not SXB-ER, polysomnographic data has been analyzed by half of the night, demonstrating a greater positive impact on sleep architecture in the second half of the night, which might be related to its nonlinear pharmacokinetic profile. We conclude that while once-nightly and twice-nightly oxybate dosing regimens differ in their pharmacokinetic profiles, both improve DNS in patients with narcolepsy to a similar degree. Plain Language Summary: Narcolepsy causes daytime sleepiness and difficulty sleeping (commonly called disrupted nighttime sleep). Sodium oxybate (Xyrem®) and low-sodium oxybate (Xywav®, which contains 92% less sodium than sodium oxybate), are taken twice nightly in patients with narcolepsy. Sodium oxybate for extended release (Lumryz™), which contains as much sodium as sodium oxybate, is taken once per night. All three medications improve narcolepsy symptoms and have the same active ingredient. It is important to understand how well they improve nighttime sleep. This review examined results of five clinical studies looking at disrupted nighttime sleep in people with narcolepsy: three of twice-nightly sodium oxybate in adults (called SXB trials 1, 2, and 3 here), one of twice-nightly sodium oxybate in children (called the pediatric SXB trial here), and one of once-nightly sodium oxybate for extended release in adults (called REST-ON here). No studies specifically investigated disrupted nighttime sleep with twice-nightly low-sodium oxybate in people with narcolepsy. Although the trial designs for these studies were different, both twice-nightly and once-nightly oxybate medications improved sleep similarly, and neither eliminated arousals or awakenings. Certain aspects of sleep improved more during the second half of the night in SXB trials 1 and 3 compared with the first half of the night. Both once-nightly and twice-nightly oxybate medications similarly improve nighttime sleep in people with narcolepsy. Twice-nightly oxybate may be particularly helpful in improving sleep in the second half of the night. [ABSTRACT FROM AUTHOR]

This article discusses the emergence of a new synthetic cathinone called dipentylone in Spain's illicit drug landscape. Synthetic cathinones are being marketed as replacements for amphetamine-derivatives and are often mislabeled as MDMA or used as adulterants. Dipentylone is a stimulant with effects similar to amphetamine and is twice as potent at inhibiting dopamine uptake as cocaine or MDMA. The article presents two cases of patients who unknowingly consumed dipentylone and experienced adverse effects. The study highlights the importance of comprehensive toxicological analysis to identify substances involved in acute drug intoxications. [Extracted from the article]

Idiopathic hypersomnia (IH) is a rare sleeping disorder that is difficult to diagnose, and little is known about its pathophysiology. A defining symptom of IH is excessive daytime sleepiness, which can manifest as narcolepsy-like episodes or as continuous sleepiness. Other symptoms of IH includes sleep inertia and cognitive impairment. Currently, calcium, magnesium, potassium and sodium oxybates is the only FDA approved pharmacological treatment option in the management of IH. Off-label treatment options are recommended by guidelines, with many also being used for the management of narcolepsy. [ABSTRACT FROM AUTHOR]

Background: GHB (gammahydroxybutyrate) and its precursors are popular recreational drugs due to their sedative, anxiolytic and sexually stimulating effects. Their use has been steadily increasing in recent years. The detoxification process is complex and prone to high rates of complications while little is known about the pathophysiology. This study aims to elucidate the characteristics of GHB-addicted patients and to evaluate the risks and complications of GHB withdrawal treatment. Methods: This observational study describes prospectively the socioeconomic status, clinical history and course of inpatient detoxification treatment of a group of 39 patients suffering from GHB substance use disorder. Detoxification treatment took place in a highly specialized psychiatric inpatient unit for substance use disorders. Results: GHB patients were characterised by being young, well-educated and by living alone. More than 50% of the patients had no regular income. The patients were male and female in equal numbers. Detoxification treatment was complicated, with high rates of delirium (30.8%) and high need for intensive care (20.5%). Conclusions: In our sample, GHB users were young, well-educated people and male and female in equal number. Detoxification proved to be dangerous for GHB-addicted patients. The presence of delirium and the need for transfer to an intensive care unit during detoxification treatment was extraordinarily high, even with appropriate clinical treatment. The reasons for this remain unknown. Therefore an intensive care unit should be available for GHB detoxification treatment. Further studies are needed to evaluate the options for prophylactic treatment of delirium during detoxification. [ABSTRACT FROM AUTHOR]

Background: Gamma-hydroxybutyric acid (GHB) at low dosages has anxiolytic effects and promotes REM sleep and low-wave deep sleep. In the U.S., the legal form of GHB is prescribed to adults suffering from narcolepsy-associated cataplexy; the sodium salt of GHB is reserved for alcohol-addiction treatment. GHB is also a molecule of abuse and recreational use, it is a controlled substance in several countries, so gamma-valerolactone (GVL) has frequently been used as a legal substitute for it. GHB's abuse profile is most likely attributable to its anxiolytic, hypnotic, and euphoric properties, as well as its widespread availability and inexpensive/low cost on the illicit market. Methods: Our study is focused on evaluating the potential effects on the mouse brain after repeated/prolonged administration of GHB and GVL at a pharmacologically active dose (100 mg/kg) through behavioral study and immunohistochemical analysis using the markers tetraspanin 17 (TSPAN17), aldehyde dehydrogenase 5 (ALDH5A1), Gamma-aminobutyric acid type A receptor (GABA-A), and Gamma-aminobutyric acid type B receptor (GABA-B). Results: Our findings revealed that prolonged administration of GHB and GVL at a pharmacologically active dose (100 mg/kg) can have effects on a component of the mouse brain, the intensity of which can be assessed using immunohistochemistry. The findings revealed that long-term GHB administration causes a significant plastic alteration of the GHB signaling system, with downregulation of the putative binding site (TSPAN17) and overexpression of ALDH5A1, especially in hippocampal neurons. Our findings further revealed that GABA-A and GABA-B receptors are downregulated in these brain locations, resulting in a greater decrease in GABA-B expression. Conclusions: The goal of this study, from the point of view of forensic pathology, is to provide a new methodological strategy for better understanding the properties of this controversial substance, which could help us better grasp the unknown mechanism underlying its abuse profile. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy. • We investigated the effects of opioids use on narcolepsy symptom severity. • Opioids mainly improved disturbed nocturnal sleep and excessive daytime sleepiness. • Narcolepsy symptom relief was clearest for oxycodone or codeine. • Randomised controlled trials are needed to verify the therapeutic potency of opioids. • Concurrent opioid and sodium oxybate use should be more carefully monitored. [ABSTRACT FROM AUTHOR]

The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study was conducted to provide real-world insight into the experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92% less sodium than SXB). TENOR is a patient-centric, prospective, observational, virtual-format study. Participants were adults with narcolepsy (type 1 or 2) who were transitioning from SXB to LXB treatment (±7 days from LXB initiation). Effectiveness and tolerability data were collected online from baseline (taking SXB) through 21 weeks (taking LXB) via daily and weekly diaries and questionnaires, including the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and the British Columbia Cognitive Complaints Inventory (BC-CCI). TENOR participants (N = 85) were 73% female with a mean (SD) age of 40.3 (13.0) years. Mean (SD) ESS scores decreased numerically throughout the transition from SXB to LXB (baseline: 9.9 [5.2]; week 21: 7.5 [4.7]), with 59.5% and 75.0% of participants having scores in the normal range (≤10) at baseline and week 21, respectively. Mean (SD) FOSQ-10 scores (baseline: 14.4 [3.4]; week 21: 15.2 [3.2]) and BC-CCI scores (baseline: 6.1 [4.4]; week 21: 5.0 [4.3]) also remained stable. The most common symptoms related to tolerability reported by participants at baseline were sleep inertia, hyperhidrosis, and dizziness (45.2%, 40.5%, and 27.4%, respectively), which decreased in prevalence by week 21 (33.8%, 13.2%, and 8.8%, respectively). Findings from TENOR confirm maintenance of effectiveness and tolerability when transitioning from SXB to LXB treatment. [Display omitted] • Transition from high-sodium to low-sodium oxybate for narcolepsy was evaluated. • Effectiveness was maintained following the transition to low-sodium oxybate. • Symptoms related to tolerability remained mostly stable. • This real-world data informs expectations about transitioning to low-sodium oxybate. [ABSTRACT FROM AUTHOR]

Background: Gamma-hydroxybutyrate (GHB) is used at disproportionately high rates within sexuality and gender diverse communities and carries a high risk of overdose. GHB overdose can result in death. Internationally, recent increases in GHB overdoses have been observed. Coronial reviews of GHB-related death highlight the pivotal roles that bystanders to GHB overdose play in preventing fatality. No research has examined, in detail, how bystanders respond to GHB overdose. This qualitative study was conducted among people who use GHB and explored how they responded upon witnessing a GHB overdose experienced by someone else. Methods: Interviews were conducted with 31 sexuality and gender diverse Australian residents reporting three or more occasions of GHB use in the previous 12 months. Participants were asked questions about witnessed GHB overdose, their actions and decision-making processes throughout overdose. Data were analysed thematically. Results: Participants described witnessing GHB overdose, commonly in private settings involving sexualized GHB use. Variable definitions of GHB overdose were reported, ranging from GHB-induced symptoms of distress to comatose intoxication. Drastic actions to keep someone alert and responsive post-GHB ingestion were reported; these included the administration of stimulant substances and citrus. Decisions to call or not call for emergency medical services (EMS) were influenced by many circumstantial variables. In most instances, an EMS call was resisted and response practices deviated from established first aid protocols. Conclusions: GHB overdose prevention and response training programs targeting people who use GHB are urgently required. These education interventions ought to address inaccuracies that inform street remedies for GHB overdose, teach people how to safely check breathing and response, promote basic first aid principles and address barriers to contacting EMS. [ABSTRACT FROM AUTHOR]

In this work, melt blending and co-extrusion techniques have been investigated as functionalization strategies to realize bilayer biodegradable films suitable for food packaging applications, combining enhanced barrier performance, good heat sealability and ductility. The ductile, heat sealable inner layer was realized by mixing Ecovio, a commercial blend based on polylactide (PLA) and polybutylene adipate terephthalate (PBAT) with an amorphous PLA grade; the outer barrier layer, on its side, was realized by blending poly(hydroxybutyrate) (PHB) with a semicrystalline PLA grade. Three different structures were realized changing the relative thicknesses of the two layers, and were characterized for their surface wettability, O2 barrier, heat-sealability and tensile properties. The results highlighted the impact of the bilayer films layout on the functional performance, and pointed out the attractiveness of the developed structures for food packaging applications where barrier to oxygen is critical to reduce oxidative processes. [ABSTRACT FROM AUTHOR]

This study identified patterns of sexualized substance use among gay, bisexual, and other men who have sex with men (gbMSM) and examined associated risk factors for sexually transmitted and blood borne infections (STBBI). Data were from a longitudinal cohort recruited using respondent-driven sampling between Feb-2017 and Feb-2019. Participants reported on events with up to five of their most recent sexual partners. Latent class analysis examined patterns of concurrent substance use 2 h prior to or during sex. Multinomial regression identified demographic, partner-level, and event-level factors associated across 11,877 sexual events reported by 757 participants. Most combinations of substance use were rare, but most drugs were frequently combined with other drugs when they were used prior to or during a sexual event. Six latent classes of concurrent event-level substance use were identified. The referent class (58.8% of events) was characterized by limited use of any drugs. The Common Drug Use class (12.1%) was characterized by use of alcohol, cannabis, and poppers and the Licit Drug Use class (21.6%) was characterized by use of alcohol alone. The Party 'N' Play (PnP) class (2.3%) was characterized by use of crystal methamphetamine GHB, Poppers, and Erectile Drugs; The Multi-use (3.5%) class was characterized by the PnP substances plus alcohol and ecstasy; and the Cannabis + class was characterized by use of Cannabis, Erectile Drugs, and Ecstasy. Relative to the referent class, all other classes were associated with events with more behavioural and network risk factors for STBBIs—highlighting the need for harm reduction interventions for gbMSM who use these drugs. [ABSTRACT FROM AUTHOR]

We reported that gamma-hydroxybutyrate (GHB) is released upon Herpes Simplex Virus Type-1 (HSV-1) acute infection. However, the cellular biochemical processes involved in the production of GHB in infected cells are unclear. This study aims to shed light on the biochemical pathway and the stage within the viral life cycle responsible for the release of GHB in infected cells. UV-inactivation, acyclovir (ACV), and cycloheximide (CHX) treatments were used to inhibit HSV-1 replication at various stages. Vero cells treated with UV-inactivated HSV-1 significantly decreased GHB production. However, ACV or CHX treatments did not affect GHB production. We also showed that inhibition of glycolytic enzyme enolase by sodium fluoride (NaF) significantly reduces GHB production upon infection. This finding suggests that suppression of glycolytic activity negatively affects cellular GHB production. Our data also indicated that succinic semialdehyde dehydrogenase, an enzyme involved in the shunt of the tricarboxylic acid (TCA) cycle to generate succinic acid, was decreased upon infection, suggesting that infection may trigger the accumulation of succinic semialdehyde, causing the production of GHB. Although the precise mechanism has yet to be defined, our results suggest that early events following infection modulates the release of GHB, which is generated through the metabolic pathways of glycolysis and TCA cycle. [ABSTRACT FROM AUTHOR]

Summary: Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ‐hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB‐enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double‐blind cross‐over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography‐defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two‐dimensional, J‐resolved, point‐resolved magnetic resonance spectroscopy (PRESS) localisation at 3‐Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB‐enhanced sleep in all participants in whom good‐quality spectroscopy data were available (n = 16; pFDR < 0.002). Further, global vigilance (10th–90th inter‐percentile range on the PVT) was improved (pFDR < 0.04) and median PVT response time was shorter (pFDR < 0.04) compared to placebo. The data indicate that elevated glutamate in the ACC could provide a neurochemical mechanism underlying SXB's pro‐vigilant efficacy in disorders of hypersomnolence. [ABSTRACT FROM AUTHOR]

Purpose: The US Food and Drug Administration (FDA) Amendments Act of 2007 authorized the FDA to require risk evaluation and mitigation strategy (REMS) programs for drugs with important safety concerns. REMS can have elements to assure safe use (ETASU), such as patient registries, dispensing restrictions, and physician training and certification requirements. We aimed to understand physician experiences with and perceptions of a selection of ETASU REMS. Methods: Physicians prescribing 1 of 4 ETASU REMS-covered drugs: natalizumab, riociguat, sodium oxybate, and vigabatrin. Study design: Descriptive phenomenological study based on semi-structured phone interviews. Data collection/Extraction methods: Qualitative content analysis to summarize physician responses to open-ended questions. Results: Of 31 physicians (14 female), 6 prescribed riociguat, 6 vigabatrin, 7 sodium oxybate, and 12 natalizumab (5 for Crohn's disease, 7 for multiple sclerosis), most demonstrated good understanding of the rationale for and requirements of the ETASU REMS but believed that the programs had limited effect on clinical practice. Some physicians reported that the ETASU REMS made them more comfortable with prescribing covered drugs due to heightened oversight, facilitated discussions about treatment, and were likely more beneficial for non-specialists. Concerns were raised about the administrative effort needed to comply with the programs and the potential misuse of patient health information transmitted to manufacturers. Conclusions: Physicians are generally aware of ETASU REMS and get reassurance from the additional oversight, but the programs can be better integrated into clinical workflows and can be designed to better protect patient health information. [ABSTRACT FROM AUTHOR]

gamma-Hydroxybutyrate (GHB) is an endogenous compound and central nervous system depressant drug used recreationally for its intoxicating effects. In a medico-legal context, the interpretation of blood GHB concentrations can be complicated by its endogenous nature and potential for formation during storage. In Canada, the per se limit for GHB in blood is 5 mg/L. Endogenous GHB concentrations in blood are typically well below 5 mg/L; however, there is a paucity of literature regarding the potential production of GHB in antemortem blood during storage. Changes in GHB concentrations were evaluated over the course of 306 days in preserved and unpreserved antemortem blood stored at 4°C and 21°C. Results were compared to 22 impaired driving cases in Ontario between 2019 and 2022 where GHB was detected in antemortem blood by toxicological analysis at the Centre of Forensic Sciences. Preservative was effective at minimizing GHB production (< 2.5 mg/L) regardless of storage temperature, whereas significant in vitro production of GHB occurred in unpreserved antemortem blood. GHB production occurred rapidly in unpreserved blood stored at 21°C; a significant increase was detected after 5 days. The rate of GHB production in unpreserved blood stored at 4°C occurred more gradually but increased significantly by day 30 and reached a maximum concentration of 10 mg/L at 114 days. In unpreserved blood, GHB concentrations were significantly lower at 4°C compared to 21°C for the first 44 days; however, refrigeration had no significant effect then onward. Blood concentrations of GHB detected in the majority of impaired driving cases were markedly higher than the maximum concentration of 10 mg/L detected in the study; however, in 4 of the 22 cases, concentrations were below 10 mg/L. The results demonstrate that concentrations of GHB less than 10 mg/L in blood collected for the purposes of a drug-impaired driving investigation should be carefully interpreted. [ABSTRACT FROM AUTHOR]

Gamma-hydroxybutyrate (GHB) was a somewhat prevalent club drug two decades ago, but research has been lacking regarding the current epidemiology of use. In this study, prevalence and correlates of past-year GHB use were estimated based on noninstitutionalized US adults participating in the 2015-2020 National Survey of Drug Use and Health (N= 241,675). An estimated 0.05% (95% CI: 0.04-0.07) of adults in the US have used GHB in the past year. Compared to those age 18-25, those age 35-49 were at increased odds for use (aOR = 2.28, 95% CI: 1.02-5.10), and compared to heterosexual men, gay men in particular were at high odds for use (aOR = 27.82, 95% CI: 11.09-69.80). Those identifying as bisexual men (aOR = 3.39, 95% CI: 1.17-9.82) and lesbian/bisexual women (aOR = 3.37, 95% CI: 1.44-7.90) were also at high odds for use. Despite all drugs examined being significant correlates of use in bivariable models (ps < .001), only past-year use of methamphetamine (aOR = 15.68, 95% CI: 7.40-33.25), ketamine (aOR = 8.52, 95% CI: 2.67-27.20), and ecstasy (aOR = 4.41, 95% CI: 1.80-10.75) was associated with increased odds of use in the multivariable model. Results suggest that GHB use is currently rare, but gay men and people who use other party drugs are at particularly high risk for use. [ABSTRACT FROM AUTHOR]

The burden of acute illicit drug use in Australia is largely unknown. Establishing a prospective drug surveillance system in emergency departments using analytical confirmation may facilitate the early identification of emerging drugs. We describe demographic data and acute toxicity patterns, stratified by analytical confirmation of illicit drugs and novel psychoactive substances, to emergency departments in Western Australia. Patients presenting with severe and/or unusual clinical features consistent with recreational drug toxicity were identified across five Western Australian emergency departments participating in the Emerging Drugs Network of Australia between April 2020 and December 2021. Demographic and toxicology patterns in patients with and without analytically confirmed illicit drugs/novel psychoactive substances from blood samples were collected during the emergency department presentation. The cohort included 434 severe and/or unusual toxicology presentations; median age 33 years (first and third quartiles 25–40 years), 268 (61.8%) males. Any substance (illicit, novel psychoactive substance, pharmaceutical) was detected in 405 (93.3%) presentations. Illicit drugs/novel psychoactive substances were detected in 257 (59.2%) presentations, including 73 (28.3%) with more than one confirmed illicit drug/novel psychoactive substance. Frequent illicit drugs identified were metamfetamine (n = 201, 77.9%) and gamma-hydroxybutyrate (n = 30, 11.6%). Forty-eight novel psychoactive substances were detected within 43 (16.7%) presentations. Novel benzodiazepines were most frequently detected (n = 29, 60.4%). Frequent pharmaceuticals detected included diazepam (n = 100, 26.1%) and clonazepam (n = 40, 10.4%). One hundred and fifty-five (35.7%) presentations were discharged home and 56 (12.9%) were admitted to intensive care. Presentations with detected illicit drugs/novel psychoactive substances had a lower median intensive care length of stay compared to presentations without detected illicit drugs/novel psychoactive substances (32.6 h versus 50.8 h respectively, P < 0.001). Integration of clinical and analytic data in patients with severe and/or unusual toxicology presentations via the Emerging Drugs Network of Australia provides insight into illicit drug/novel psychoactive substance use responsible for acute harm across Western Australian emergency departments. [ABSTRACT FROM AUTHOR]

Introduction: Narcolepsy Type 1 (NT1) is a rare hypersomnia of central origin linked to hypocretin deficiency, most frequently arising at pediatric age. NT1 could be associated with endocrine comorbidities involving the neuroendocrine axis, predominantly obesity, and Central Precocious Puberty (CPP). The primary aim of this study is the evaluation of endocrine and auxological parameters at diagnosis and during follow-up in patients with NT1, treated with Sodium Oxybate (SO) or not. Methods: We retrospectively evaluated the auxological, biochemical, and radiological parameters of 112 patients referred to our Center between 2004-2022. The design of our study is cross-sectional at the time of diagnosis followed by a longitudinal follow-up. Results: Our study confirms an increased frequency of CPP and obesity in patients with NT1. At first evaluation, obesity was found in 31.3% of patients, while overweight was found in 25.0%. A diagnosis of CPP was made in 19.6% of patients. Interestingly, this group showed a significantly lower level of CSF-hypocretin (hrct-1) at diagnosis compared to others. We found an improvement in BMI SDS in the SO-treated group compared to untreated patients, and this trend persisted also at 36 months of follow-up (0.0 ± 1.3 vs 1.3 ± 0.4; p<0.03). Sixty-three patients reached their final height, with a median SDS of 0.6 ± 1.1 in boys and 0.2 ± 1.2 in girls. Discussion: To our knowledge, these are the first results regarding the final height in a large series of pediatric patients with NT1, with a normal range of IGF1-SDS levels and stature SDS. [ABSTRACT FROM AUTHOR]

Gamma-hydroxybutyrate (GHB) remains a challenging clinical/forensic toxicology drug. Its rapid elimination to endogenous levels mainly causes this. Especially in drug-facilitated sexual assaults, sample collection often occurs later than the detection window for GHB. We aimed to investigate new GHB conjugates with amino acids (AA), fatty acids, and its organic acid metabolites for their suitability as ingestion/application markers in urine following controlled GHB administration to humans. We used LC–MS/MS for validated quantification of human urine samples collected within two randomized, double-blinded, placebo-controlled crossover studies (GHB 50 mg/kg, 79 participants) at approximately 4.5, 8, 11, and 28 h after intake. We found significant differences (placebo vs. GHB) for all but two analytes at 4.5 h. Eleven hours post GHB administration, GHB, GHB-AAs, 3,4-dihydroxybutyric acid, and glycolic acid still showed significantly higher concentrations; at 28 h only GHB-glycine. Three different discrimination strategies were evaluated: (a) GHB-glycine cut-off concentration (1 µg/mL), (b) metabolite ratios of GHB-glycine/GHB (2.5), and (c) elevation threshold between two urine samples (> 5). Sensitivities were 0.1, 0.3, or 0.5, respectively. Only GHB-glycine showed prolonged detection over GHB, mainly when compared to a second time- and subject-matched urine sample (strategy c). [ABSTRACT FROM AUTHOR]