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Introduction Many patients have difficulties achieving hypnotic discontinuation due to anxiety that arises when they knowingly reduce their hypnotic dose or withhold it entirely. This study tested a blinded tapering approach to reduce patients’ anxiety and help them discontinue their hypnotics. Methods The study sample included 78 (M age = 55.2 ± 12.8 yrs.; 65.4% women) users of benzodiazepine and benzodiazepine receptor agonists. Following baseline assessments, enrollees first completed 4 sessions of cognitive behavioral insomnia therapy (CBTI). Subsequently they were randomized to one of three 20-week, double-blinded tapering protocols wherein their medication dosage either remained unchanged (CTRL) or was reduced by 25% or 10% every two weeks. At the end of the 20-week period the study blind was eliminated and those who completed one of the two blinded tapering protocols entered a 3-month follow-up period, whereas CTRL participants were offered an open label taper before completing the follow-up. Results Among those who completed one of the blinded tapering protocols, 92.9% totally discontinued their medication use by the end of the 20-week tapering phase, whereas 77.3% in the CTRL group discontinued hypnotic use by the end of their open label tapering. At follow-up 72.1% of those who completed blinded tapering remained medication free whereas only 52% of those who underwent open-label tapering remained medication free. Comparisons at follow-up showed those who received the open-label taper continued to use hypnotics on average 2.06 nights/week compared to .051 times per week for the blinded taper group (p = .042). The average weekly diazepam equivalent dose of medication used by the open label tapering group was 11.29 mg whereas the weekly dose for the blinded tapering group was 3.22 (p = .069). Conclusion CBTI combined with blinded hypnotic tapering is a promising treatment approach for helping hypnotic users overcome their medication dependence. Support (if any) National Institute of Drug Abuse, Grant # R34 DA042329-01

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA sub(A) receptors (GABA sub(A)Rs) containing alpha 2 subunits ( alpha 2-GABA sub(A)Rs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal alpha 2-GABA sub(A)Rs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABA sub(A)R-mutated mice, which either lack alpha 2-GABA sub(A)Rs specifically from the spinal cord, or, which express only benzodiazepine-insensitive alpha 2-GABA sub(A)Rs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all alpha 2-GABA sub(A)Rs were benzodiazepine insensitive. The major ( alpha 2-dependent) component of GABA sub(A)R-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal alpha 2-GABA sub(A)Rs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target alpha 2-GABA sub(A)Rs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions.

GABA^sub A^ receptor mediated inhibition plays an important role in modulating the input/output dynamics of cerebellum. A characteristic of cerebellar GABA^sub A^ receptors is the presence in cerebellar granule cells of subunits such as [alpha]6 and δ which give insensitivity to classical benzodiazepines. In fact, cerebellar GABA^sub A^ receptors have generally been considered a poor model for testing drugs which potentially are active at the benzodiazepine site. In this overview we show how rat cerebellar granule cells in culture may be a useful model for studying new benzodiazepine site agonists. This is based on the pharmacological separation of diazepam-sensitive [alpha]1 [beta]2/3 γ2 receptors from those which are diazepam-insensitive and contain the [alpha]6 subunit. This is achieved by utilizing furosemide/Zn^sup 2+^ which block [alpha]6 containing and incomplete receptors.[PUBLICATION ABSTRACT]

Background Remimazolam besylate is a newer benzodiazepine with characteristics of quick onset of effects, short maintenance and recovery times without accumulation in tissues. This trial was conducted to confirm the efficacy and safety of remimazolam besylate versus propofol during hysteroscopy. Methods Patients undergoing hysteroscopy were randomly assigned to either the remimazolam (Group R) or the propofol group (Group P). Group R was administered an induction dose of 0.2 mg/kg and a maintenance dosage of 1.0 mg/kg/h. In Group P, propofol was started at 1.5–2.0 mg/kg and then maintained at 3.0–6.0 mg/kg/h. After remimazolam besylate or propofol induction, remifentanil was infused using a target-controlled infusion system with a target concentration of 1.5 ng/ml and titrated during the procedure. The incidence rates of injection pain, low oxygen saturation (SpO 2 ) and adverse effects in both groups were compared. Results Eighty-two patients were included in this study. The incidence of adverse events in Group R (3.7%) was significantly lower than that in Group P (36.6%) ( p  < 0.001). The incidence of injection pain in Group P (80.5%) was much higher than that in Group R (2.4%) ( p  < 0.001). The incidence of other adverse events, such as low SpO 2 , bradycardia, and hypotension in Group R was lower than that in Group P ( p  < 0.05). Conclusions Remimazolam besylate proves to be a safer alternative for anesthesia during hysteroscopy. Moreover, adverse events caused by propofol, such as low SpO 2 and injection pain, are largely avoided. Trial registration This study was approved by the Clinical Research Ethics Committee of Mengcheng County No. 1 People’s Hospital (2020MYL20003) and registered at http://www.chictr.org.cn (15/09/2020, ChiCTR-2000038252 ). The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

In a randomized trial involving patients with high-risk vascular disease, the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers but was not associated with a lower rate of cardiovascular events than placebo. Pharmacologic reduction of the low-density lipoprotein (LDL) cholesterol level with statins substantially decreases the risks of death and complications from cardiovascular causes. 1 , 2 Considerable interest has focused on the identification of approaches that might further reduce cardiovascular-event rates among high-risk patients. 3 Epidemiologic studies have shown inverse associations between high-density lipoprotein (HDL) cholesterol levels and cardiovascular outcomes, 4 – 6 a correlation that persists despite treatment with statins. 7 Nevertheless, therapeutic interventions that raise the HDL cholesterol level have not been shown to reduce cardiovascular risk. Cholesteryl ester transfer protein (CETP) modulates the transfer of esterified cholesterol from HDL to apolipoprotein B–containing lipoproteins. 8 Two . . .

MRI-based measurements of surface cortical thickness (SCT) have become a sensitive tool to quantify changes in cortical morphology. When comparing SCT to histological cortical thickness maps, a good correspondence can be found for many but not all human brain areas. Discrepancies especially arise in the sensory motor cortex, where histological cortical thickness is high, but SCT is very low. The aim of this study was to determine whether the relationship between cortical thickness and neuronal density is the same for different cytoarchitectonic areas throughout homo- and heterotypical isocortex. We assessed this relationship using high-resolution [[super]18F]-labelled flumazenil (FMZ) PET and SCT-mapping. FMZ binds to the benzodiazepine GABA sub(A receptor complex which is localized on axo-dendritic synapses, with a cortical distribution closely following the local density of neurons. SCT and voxelwise FMZ binding potential (BP) sub(N)D) were assessed in ten healthy subjects. After partial volume correction, two subsets with a differential relationship between SCT and BP sub(ND were identified: a fronto-parietal homotypical subset where neuronal density is relatively constant and mainly independent of SCT, and a subset comprising heterotypical and mainly temporal and occipital homotypical regions where neuronal density is negatively correlated with SCT. This is the first in-vivo study demonstrating a differential relationship between SCT, neuronal density and cytoarchitectonics in humans. These findings are of direct relevance for the correct interpretation of SCT-based morphometry studies, in that there is no simple relationship between apparent cortical thickness and neuronal density, here attributed to FMZ binding, holding for all cortical regions.)

A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB). In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control). Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time–concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time–concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB Cmax values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively). The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.

The addition of olanzapine to a neurokinin receptor blocker, a serotonin receptor blocker, and dexamethasone markedly improved the control of nausea and vomiting in previously untreated patients receiving highly emetogenic chemotherapy. Chemotherapy-induced nausea and vomiting are associated with a significant deterioration in quality of life and are perceived by patients as major adverse effects of cancer treatment. 1 The use of 5-hydroxytryptamine type 3 (5-HT 3 ) receptor antagonists, 2 dexamethasone, 2 and neurokinin-1 (NK 1 ) receptor antagonists 3 – 9 has significantly improved the control of this troublesome side effect. International guidelines 10 – 12 recommend combinations of these agents to prevent chemotherapy-induced nausea and vomiting in patients receiving moderately or highly emetogenic chemotherapy. Nonetheless, nausea remains a major problem for many patients. 1 , 2 Olanzapine is approved by the Food and Drug Administration (FDA) as an . . .

The optimal sedation strategy for gastrointestinal endoscopy remains debated. This study compared the efficacy and safety of remimazolam combined with etomidate versus propofol for procedural sedation during gastrointestinal endoscopy. This single-center, randomized controlled clinical trial was performed from March 2024 to April 2024. A total of 262 patients scheduled to undergo gastrointestinal endoscopy were randomly assigned to receive remimazolam-etomidate (RE) or remimazolam-propofol (RP). The primary outcome was the incidence of respiratory depression. Secondary outcomes included the results of sedation and recovery. The safety results mainly include the incidence of hypotension, bradycardia, tachycardia, painful injection and muscular tremor. Statistical analyses included t-tests, Mann-Whitney U tests, and χ² tests for group comparisons, with subgroup analyses and multivariable logistic regression to assess the robustness of primary outcome. Respiratory depression occurred in 20.0% (25/125) of RE patients versus 32.3% (40/124) of RP patients (OR=0.52; 95% CI = 0.29-0.93; p = 0.028). There was a statistically significant difference in the distribution of the number of airway interventions between the two groups (p = 0.043), with 18 patients (14.5%) in the RP group requiring three airway interventions and only seven patients (5.6%) in the RE group. Hypoxemia occurred in three patients (2.4%) in the RE group and in five patients (4.0%) in the RP group. Hypotension was observed in 23.2% of patients sedated with RE versus 36.3% of patients sedated with RP (p = 0.024). Remimazolam-etomidate demonstrated a superior safety profile, with reduced respiratory depression and hemodynamic instability compared to remimazolam-propofol, suggesting its potential as a safer alternative for gastrointestinal endoscopy sedation. This trial was prospectively registered at the Chinese Clinical Trial Registry (ChiCTR2400085904) prior to patient enrollment.