Effect of discontinuation of lemborexant following long-term treatment of insomnia disorder: Secondary analysis of a randomized clinical trial.

Discontinuing long-term pharmacotherapy for insomnia can result in rebound insomnia or withdrawal symptoms and suboptimal treatment. Post hoc analyses evaluated rebound insomnia and withdrawal symptoms among the subset of subjects from a phase III, 12-month, global, multicenter, randomized, double-blind, parallel-group study who completed 12 or 6 months of active treatment and follow-up period. Study E2006-G000-303 (Study 303) included adults (N = 655) with subjective sleep-onset latency ≥30 min and/or subjective wake-after-sleep onset ≥60 min at least three times weekly during the 4 weeks before enrollment. Subjects were randomized 1:1:1 to lemborexant 5 mg (LEM5) or 10 mg (LEM10) or placebo for 6 months. Thereafter, for an additional 6 months, LEM5- and LEM10-treated subjects continued lemborexant and the placebo group was rerandomized 1:1 to LEM5 or LEM10. Month 12 was followed by abrupt discontinuation and a 2-week end-of-study follow-up. Using daily electronic sleep diaries, patients reported (subjective) sleep end points (sleep-onset latency, wake-after-sleep onset, sleep efficiency, and total sleep time). Withdrawal symptoms were assessed using the Tyrer Benzodiazepine Withdrawal Symptoms Questionnaire (T-BWSQ). Sleep outcome improvements with lemborexant at month 12 were generally maintained throughout the 2-week off-treatment period wherein <20% of subjects experienced significant worsening of insomnia symptoms versus screening. There was no evidence of withdrawal symptoms by T-BWSQ following lemborexant discontinuation. This analysis demonstrates rebound insomnia is unlikely to occur with lemborexant, and its effectiveness is maintained after abrupt discontinuation without placebo replacement following 6-12 months of treatment.

A Chemical Modulator of p53 Transactivation that Acts as a Radioprotective Agonist.

Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives, that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses, including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seem to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacologic upregulation of radioprotective p53 target genes is an effective strategy for addressing the gastrointestinal syndrome. Mol Cancer Ther; 17(2); 432-42. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."