Number, Duration, and Distribution of Wake Bouts in Patients with Insomnia Disorder: Effect of Daridorexant and Zolpidem.

BACKGROUND: Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with insomnia. The objective of this post hoc analysis was to explore the effect of daridorexant on the number, duration, and distribution of night-time wake bouts, and their correlation with daytime functioning. METHODS: Adults with insomnia disorder were randomized 1:1:1:1:1:1 to placebo, zolpidem 10 mg, or daridorexant 5, 10, 25, or 50 mg in a phase II dose-finding study, and 1:1:1 to placebo or daridorexant 25 or 50 mg in a pivotal phase III study. We analyzed polysomnography data for daridorexant 25 and 50 mg, zolpidem 10 mg, and placebo groups. Polysomnography was conducted at baseline, then on Days 1/2, 15/16, and 28/29 in the phase II study, and Months 1 and 3 in the phase III study. The number, duration, and distribution of wake bouts (≥ 0.5 min) were assessed. RESULTS: Data from 1111 patients (phase II study: daridorexant 50 mg [n = 61], zolpidem 10 mg [n = 60], placebo [n = 60]; phase III study: daridorexant 25 mg [n = 310], daridorexant 50 mg [n = 310], placebo [n = 310]) were analyzed. Long wake bouts were defined as > 6 min. Compared with placebo, daridorexant 50 mg reduced overall wake time (p < 0.05; all time points, both studies), the odds of experiencing long wake bouts (p < 0.001; Months 1 and 3, phase III study), and the cumulative duration of long wake bouts (p < 0.01; all time points, both studies). Reductions in long wake bouts were sustained through the second half of the night and correlated with improvements in daytime functioning. An increase in the cumulative duration of short wake bouts was observed with daridorexant 50 mg (p < 0.01 vs placebo, Months 1 and 3, phase III study); this was uncorrelated with daytime functioning. CONCLUSION: Daridorexant reduced the number and duration of longer wake bouts throughout the night compared with placebo, corresponding with improved daytime functioning. CLINICAL TRIALS: Clinicaltrials.gov NCT02839200 (registered July 20, 2016), NCT03545191 (registered June 4, 2018).

Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator.

Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50-79 years of age) were randomized in a placebo- and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.

Effectiveness of different activated irrigation techniques on debris and smear layer removal from curved root canals: a SEM evaluation.

This study evaluates the effectiveness of different activated irrigation techniques on removal of debris and smear layer from curved root canals. Ninety mandibular molars with a root canal curvature between 20 and 40 degrees were assigned to 4 groups (n = 20): syringe irrigation (SI), passive ultrasonic activation (PUI), sonic activation with EDDY (ED) or EndoActivator (EA) and a control group. Mesiobuccal root canals were prepared to size 40, 0.04 and irrigated with NaOCl (3%) according to the respective technique. Roots were split longitudinally and subjected to scanning electron microscopic analysis. Presence of debris and smear layer was evaluated using 5-grade scoring systems with 200× and 1000× magnification, respectively. Data were analysed with nonparametric analysis for ordinal longitudinal data (α = 5%). Activation of the irrigant significantly improved smear layer removal (P < 0.05). Regarding debris, only activation with EA and ED was significantly more effective than SI (P < 0.05). No activation technique was able to eliminate debris and smear layer completely from curved root canals.

Health-related quality of life, psychosocial work conditions, and absenteeism in an industrial sample of blue- and white-collar employees: a comparison of potential predictors.

PROBLEM: There is a scarcity of data simultaneously evaluating the relationship of health behavior, health perception, work characteristics, and demographic variables with sickness absenteeism in industrial employees. METHOD: Predictors and possible confounders (smoking, physical activity, alcohol intake, age, gender, body mass index, income) were regressed against frequency indices and the time lost index derived from the day-to-day absence data of 1524 employees at a manufacturing plant in Germany. Frequency indices were the number of sick-leave spells of 1, 2-3, 4-5, and >5 days within 1 year. RESULTS/CONCLUSION: Effort-reward imbalance, lack of support by supervisors or coworkers, negative affectivity, exhaustion, and impaired health perception were significantly associated with absence spells and the time lost index. Job demands and job control as well as overcommitment were unrelated to absenteeism indices. Multivariate models suggest mediation through impaired health-related quality of life.

Subcutaneous interferon Beta-1a in pediatric multiple sclerosis: a retrospective study.

To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon ß-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon ß-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon ß-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon ß-1a (44 and 22 µg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates.