Dimdazenil: First Approval.

Dimdazenil (Junoenil®) is a small-molecule, oral, partial positive allosteric modulator of the gamma-aminobutyric acid (GABA)A receptor that is being developed by Zhejiang Jingxin Pharmaceutical in collaboration with Evotec for the treatment of insomnia. Dimdazenil is designed to overcome issues associated with full GABAA receptor agonists, such as tolerance, withdrawal symptoms and associated adverse effects. On 29 November 2023, dimdazenil oral capsules received approval in China for the short-term treatment of insomnia. This article summarizes the milestones in the development of dimdazenil leading to this first approval for insomnia.

The effective perospirone augmentation with clonazepam for treatment-resistant burning mouth syndrome: A case report.

Burning mouth syndrome (BMS) is characterized by burning sensations in the oral region without corresponding abnormalities and is often accompanied by uncomfortable sensations. Herein, we present cases of BMS in which the remaining uncomfortable sensations improved with perospirone augmentation with clonazepam. Case 1: A 61-year-old man complained of a burning pain in his tongue, a sensation of dryness and discomfort as if his tongue was sticking to a palatal plate. With the diagnosis of BMS, psychopharmacotherapy was initiated with amitriptyline. At the dose of amitriptyline 50 mg, the pain lessened but uncomfortable sensations persisted. Further attempts to alleviate symptoms by combining aripiprazole with amitriptyline, aripiprazole with mirtazapine, or aripiprazole with clonazepam were limited; however, nearly all symptoms were relieved by a combination of perospirone 8.0 mg with clonazepam 1.5 mg. Case 2: A 51-year-old woman complained of a burning sensation along with oral dryness and crumb-like feeling on her tongue. She was diagnosed with BMS and began treatment with amitriptyline. Her burning sensation improved at the dose of 25 mg, but uncomfortable sensations persisted. Augmentation of amitriptyline with aripiprazole, aripiprazole either with valproate, mirtazapine, or clonazepam failed to produce a significant improvement. However, a regimen of perospirone 6.0 mg and clonazepam 1.5 mg relieved the crumb-like sensation and pain and culminated in a stabilized condition. The reported cases suggested that multiple approaches targeting the dopaminergic circuit in basal ganglia involving the serotoninergic and GABA systems, through the administration of perospirone with clonazepam is an effective adjunctive treatment for the remaining uncomfortable sensations in patients with BMS.

Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial.

Importance: Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. Objective: To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD. Design, Setting, and Participants: This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019. Interventions: Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks. Main Outcomes and Measures: Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments. Results: Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo. Conclusions and Relevance: In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD. Trial Registration: ClinicalTrials.gov Identifier: NCT02978326.

Safety, Tolerability, and Pharmacokinetics of Multiple Repeated Oral Doses of the α2/3/5-Subtype Selective GABAA -Positive Allosteric Modulator PF-06372865 in Healthy Volunteers.

Multiple-dose pharmacokinetics (PK) and safety were investigated in this phase 1 study of PF-06372865, a positive allosteric modulator of α2/3/5 subunit-containing γ-aminobutyric acid A receptors (NCT03351751). In 2 cohorts (7-8 PF-06372865 and 2 placebo in each cohort), healthy adult subjects received twice-daily oral doses of PF-06372865 for 21 days, which included titration in the first 7 days, followed by a maintenance dose of 25 mg twice daily (Cohort 1) and 42.5 mg twice daily (Cohort 2) for 14 days. Serial PK samples were collected on days 1 and 21. Nineteen subjects were assigned to study treatments; 18 completed the study. Approximate dose-proportional increases in maximum plasma concentratin and area under the plasma concentration-time curve over the dosing interval were observed. PF-06372865 was rapidly absorbed with a median time to maximum concentration of 1 to 2 hours following both single- and multiple-dose administration. Mean terminal elimination half-life on day 21 was approximately 11 hours in both cohorts. All adverse events were mild; the most frequently reported was dizziness. After titration, there were no reports of somnolence. There were no clinically significant safety findings, including a lack of withdrawal symptoms on discontinuation of treatment. These results demonstrate that PF-06372865 is safe and well tolerated at doses estimated to achieve high receptor occupancy (>80%), a profile differentiated from nonselective benzodiazepines.

Pharmacological uses of flumazenil in benzodiazepine use disorders: a systematic review of limited data.

BACKGROUND: The estimated annual prevalence of drug use disorders is as high as 3%, underpinning the need to continually develop more effective treatments. Central nervous system dysregulation, contributing to acute and post-withdrawal syndromes, has traditionally been managed with benzodiazepines; however, a small but growing body of data indicate that the GABAA receptor antagonist, flumazenil, may offer some advantages over traditional management. AIM: To review the literature on the safety and efficacy of flumazenil in benzodiazepine use disorders and identify gaps in the literature. METHOD: A systematic method was used to identify randomised control trials. Where randomised control trials existed, non-randomised control trials were included to supplement findings. RESULTS: Eleven flumazenil trials were included with varying doses, frequencies and routes of administration. The evidence for flumazenil alone showed generally a reduction in withdrawal symptoms with the exception of one study where withdrawal symptoms initially increased. Flumazenil plus benzodiazepine tapering was assessed in one randomised control trial and a series of non-randomised control trials. Randomised control trial results showed that flumazenil plus benzodiazepine tapering was superior at reducing withdrawal symptoms compared to benzodiazepine tapering alone and placebo. Flumazenil was associated with no serious adverse events; however there remains a risk of seizures. CONCLUSION: Although flumazenil shows promising efficacy in the management of benzodiazepine use disorders and withdrawal, more randomized control trials are required before a definitive recommendation can be made around its use.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator.

RATIONALE: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. OBJECTIVES: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). METHODS: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. RESULTS: In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. CONCLUSIONS: Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors.

The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABAAR) and increased N-methyl-d-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). We hypothesized that trafficking of synaptic GABAAR and glutamate receptors is maladaptive and contributes to the pharmacoresistance to antiseizure drugs; targeting these components should ameliorate the pathophysiological consequences of refractory SE (RSE). We review studies of rodent models of cholinergic-induced SE, in which we used a benzodiazepine allosteric GABAAR modulator to correct loss of inhibition, concurrent with the NMDA antagonist ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDAR-dependent. Models included lithium/pilocarpine-induced SE in rats and soman-induced SE in rats and in Es1-/- mice, which similar to humans lack plasma carboxylesterase, and may better model soman toxicity. These model human soman toxicity and are refractory to benzodiazepines administered at 40 min after seizure onset, when enough synaptic GABAAR may not be available to restore inhibition. Ketamine-midazolam combination reduces seizure severity, epileptogenesis, performance deficits and neuropathology following cholinergic-induced SE. Supplementing that treatment with valproate, which targets a non-benzodiazepine site, effectively terminates RSE, providing further benefit against cholinergic-induced SE. The therapeutic index of drug combinations is also reviewed and we show the improved efficacy of simultaneous administration of midazolam, ketamine and valproate compared to sequential drug administration. These data suggest that future clinical trials should treat both the lack of sufficient inhibition and the excess excitation that characterize RSE, and include early combination drug therapies. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Severe Benzodiazepine Use Disorder in a 16-Year-Old Adolescent: A Rapid and Safe Inpatient Taper.

We describe the case of a 16-year-old boy with a 1-year history of severe benzodiazepine misuse. After being denied access to several treatment programs and hospital centers that felt unprepared to manage benzodiazepine use disorder and withdrawal in an adolescent, the patient was admitted to a tertiary pediatric unit for rapid inpatient tapering and detoxification. The patient was hospitalized for 13 days and received decreasing doses of diazepam under close monitoring of withdrawal symptoms. The taper was well tolerated, and the patient was transferred to a youth residential substance use treatment center, where he completed a successful 2-month placement. This case highlights the lack of adolescent-friendly facilities allowing safe tapering of rapid-acting benzodiazepines in North America. Given high rates of benzodiazepine misuse among youth and the risks associated with benzodiazepine misuse and withdrawal, there is a critical need for more research, provider training, and dedicated resources in this area.

Suppressing effect of the novel positive allosteric modulator of the GABAB receptor, COR659, on locomotor hyperactivity induced by different drugs of abuse.

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABAB receptor. Similarly to all GABAB PAMs tested to date, COR659 has been reported to suppress different alcohol-related behaviors in rodents. The present study was designed to assess whether the anti-addictive properties of COR659 extend to drugs of abuse other than alcohol. Specifically, it investigated the effect of COR659 on cocaine-, amphetamine-, nicotine-, and morphine-induced locomotor hyperactivity in mice. To this aim, independent groups of CD1 mice were acutely pretreated with COR659 (0, 10, and 20 mg/kg; i.p.), then acutely treated with cocaine (0 and 10 mg/kg, s.c.), amphetamine (0 and 5 mg/kg; s.c.), nicotine (0 and 0.05 mg/kg; s.c.), or morphine (0 and 20 mg/kg; s.c.), and finally exposed for 60 min to a photocell-equipped motility cage. When given alone, both doses of COR659 were ineffective on spontaneous locomotor activity. Pretreatment with COR659 reduced, or even suppressed, the increase in motility counts induced by cocaine, amphetamine, nicotine, and morphine. Since locomotor hyperactivity is an attribute common to drugs of abuse, the results of the present study constitute the first line of evidence on the extension of the preclinical, anti-addictive profile of COR659 to cocaine, amphetamine, nicotine, and morphine.

A Systematic Review of Intravaginal Diazepam for the Treatment of Pelvic Floor Hypertonic Disorder.

This systematic review evaluates the efficacy of intravaginal diazepam in treating chronic pelvic pain and sexual dysfunction associated with high-tone pelvic floor dysfunction. A literature search was conducted in Medline and Web of Science, including articles from the database's inception to July 2019. The search identified 126 articles, and 5 articles met study inclusion criteria: 2 observational reviews and 3 small randomized, controlled trials (RCTs) evaluating intravaginal diazepam for high-tone pelvic floor dysfunction. The 2 observational studies identified subjective reports of improvement in sexual function for a majority of women, 96% and 71%, in each study. However, there were no statistical differences between Female Sexual Function Index (FSFI) and Visual Analog Scale (VAS) scores for pain identified. One RCT found no significant changes between groups in median FSFI or VAS scores, and a second RCT found no significant changes between groups in 100-mm VAS scores. The third RCT demonstrated that compared with placebo, treatment with transcutaneous electrical nerve stimulation and intravaginal diazepam for women with vestibulodynia and high-tone pelvic floor dysfunction yielded significant differences in reduction of dyspareunia (P ≤ .05), ability to relax pelvic floor muscles after contraction (P ≤.05), and current perception threshold values at a 5-Hz stimulation related to C fibers (P < .05), but no significant changes in 10-cm VAS scores. Intravaginal diazepam may be helpful in women with a specific diagnosis of high-tone pelvic floor dysfunction, but more and larger studies are needed to confirm these potential effects.

Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. METHODS: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. SIGNIFICANCE: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population.

Apremilast regulates acute effects of ethanol and other GABAergic drugs via protein kinase A-dependent signaling.

Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam. Apremilast prolonged rotarod ataxia induced by zolpidem, propofol, and loreclezole, shortened recovery from diazepam, but had no effect on ataxia induced by gaboxadol or etomidate. The PKA inhibitor H-89 blocked apremilast's ability to prolong the sedative-hypnotic effects of ethanol, gaboxadol, and propofol and to prolong ethanol- and propofol-induced ataxia. H-89 also blocked apremilast's ability to shorten the sedative-hypnotic and ataxic effects of diazepam. The ß1-specific antagonist, salicylidene salicylhydrazide (SCS), produced faster recovery from ethanol- and diazepam-induced ataxia, but did not alter propofol- or etomidate-induced ataxia. SCS shortened the sedative-hypnotic effects of ethanol and diazepam but not of propofol. In Xenopus oocytes, a phosphomimetic (aspartate) mutation at the PKA phosphorylation site in ß1 subunits decreased the maximal GABA current in receptors containing α1 or α3, but not α2 subunits. In contrast, phosphomimetic mutations at PKA sites in ß3 subunits increased the maximal GABA current in receptors containing α1 or α2, but not α3 subunits. The GABA potency and allosteric modulation by ethanol, propofol, etomidate, zolpidem, flunitrazepam, or diazepam were not altered by these mutations. We propose a model whereby apremilast increases PKA-mediated phosphorylation of ß1-and ß3-containing GABAA receptors and selectively alters acute tolerance to ethanol and GABAergic drugs.

Thiopental sodium loaded solid lipid nano-particles attenuates obesity-induced cardiac dysfunction and cardiac hypertrophy via inactivation of inflammatory pathway.

This work evaluates solid lipid nanoparticles of thiopental sodium against obesity-induced cardiac dysfunction and hypertrophy and explores the possible mechanism of action. TS loaded SLNs were formulated by hot-homogenization and solvent diffusion method. TS-SLNs were scrutinized for entrapment efficiency, drug loading capacity, gastric stability, particle size, in vitro drug release. Mice were feed with the normal chow or high-fat diet for 08 weeks to induce obesity and primary cardiomyocytes. The therapeutic effects of thiopental sodium in the high fat diet (HFD) induced cardiac hypertrophy. Systolic blood pressure (SBP) was estimated at a regular time interval. At the end of the experimental study, systolic pressure left ventricular, LV end-diastolic pressure and rate of increase of LV pressure and antioxidant, apoptosis, cytokines and inflammatory scrutinized. HFD induced group mice exhibited a reduction in the body weight and enhancement of cardiac hypertrophy marker and dose-dependent treatment of thiopental sodium up-regulation the body weight and down-regulated the cardiac hypertrophy. Thiopental sodium significantly (p < .001) dose-dependently altered the antioxidant, biochemical, cardiac parameters and remodeling. Thiopental sodium significantly (p < .001) dose-dependently reduced the SBP. Thiopental sodium altered the apoptosis marker, pro-inflammatory cytokines, inflammatory parameters along with reduced the p38-MAPK level. The cardiac protective effect of thiopental sodium shed light on future therapeutic interventions in obesity and related cardiovascular complications via inflammatory pathway.

Bolus infusion scheme for the adjustment of steady state [11C]Flumazenil levels in the grey matter and in the blood plasma for neuroreceptor imaging.

The use of hybrid PET/MR imaging facilitates the simultaneous investigation of challenge-related changes in ligand binding to neuroreceptors using PET, while concurrently measuring neuroactivation or blood flow with MRI. Having attained a steady state of the PET radiotracer using a bolus-infusion protocol, it is possible to observe alterations in ligand neuroreceptor binding through changes in distribution volumes. Here, we present an iterative procedure for establishing an administration scheme to obtain steady state [11C]flumazenil concentrations in grey matter in the human brain. In order to achieve a steady state in the shortest possible time, the bolus infusion ratio from a previous examination was adapted to fit the subsequent examination. 17 male volunteers were included in the study. Boli and infusions with different weightings were given to the subjects and were characterised by kbol values from 74 â€‹min down to 42 â€‹min. Metabolite analysis was used to ascertain the value of unmetabolised flumazenil in the plasma, and PET imaging was used to assess its binding in the grey matter. The flumazenil time-activity curves (TACs) in the brain were decomposed into activity contributions from pure grey and white matter and analysed for 12 â€‹vol of interest (VOIs). The curves highlighted a large variability in metabolic rates between the subjects, with kbol â€‹= â€‹54.3 â€‹min being a reliable value to provide flumazenil equilibrium conditions in the majority of the VOIs and cases. The distribution volume of flumazenil in all 12 VOIs was determined.

Adverse Drug Reaction: Midazolam-Induced Extrapyramidal Symptoms: A Case Report.

Midazolam is commonly used for sedation during procedures because of its relative safety and predictability. Still, some rare undesirable medication reactions have been described. We report a case in which midazolam given before a peripheral nerve block caused acute onset dyskinetic extrapyramidal symptoms. These symptoms ultimately resolved following reversal of the midazolam with flumazenil. Given the widespread and multidisciplinary use of midazolam, practitioners should be aware of the potential for rare adverse reactions and be prepared to manage these scenarios.

Patterns of neural activity in the mouse brain: Wakefulness vs. General anesthesia.

In light of the general shift from rats to mice as the leading rodent model in neuroscience research we used c-Fos expression as a tool to survey brain regions in the mouse in which neural activity differs between the states of wakefulness and pentobarbital-induced general anesthesia. The aim was to complement prior surveys carried out in rats. In addition to a broad qualitative review, 28 specific regions of interest (ROIs) were evaluated quantitatively. Nearly all ROIs in the cerebral cortex showed suppressed activity during anesthesia. Subcortically, however, some ROIs showed suppression, some showed little change, and some showed increased activity. The overall picture was similar to the rat. Special attention was devoted to ROIs significantly activated during anesthesia, as such loci might actively drive the transition to anesthetic unconsciousness rather than responding passively to inhbitory agents distributed globally (the "wet blanket" hypothesis). Twelve such "anesthesia-on" ROIs were identified: the paraventricular hypothalamic nucleus, supraoptic nucleus, tuberomamillary nucleus, lateral habenular nucleus, dentate gyrus, nucleus raphe pallidus, central amygdaloid nucleus, perifornical lateral hypothalamus, ventro-lateral preoptic area, lateral septum, paraventricular thalamic nucleus and zona incerta. The same primary anti-FOS antibody was used in all mice, but two alternative reporter systems were employed: ABC-diaminobenzidine and the currently more popular AlexaFluor488. Fluorescence tagging revealed far fewer FOS-immunoreactive neurons, sounding an alert that the reporter system chosen can have major effects on results obtained.

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring.

BACKGROUND: An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus. OBJECTIVES: This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice. METHODS: In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2 014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic-clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated. RESULTS: In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5-76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5-15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p < 0.001) and generalized tonic-clonic seizure (Cox proportional-hazard model p = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42-0.60; p < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%). CONCLUSION: We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1-2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.

Single- and Multiple-Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies.

ASP8062 is an orally active γ-amino-butyric acid type B (GABAB ) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first-in-human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single-dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty-six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration-time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half-life were 1-4 hours and ∼40-50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2-fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.