Structure-guided discovery of orexin receptor-binding PET ligands.

Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [18F]KD23 and [18F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar Ki values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [18F]KD23 and [18F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.

Altered ventilatory responses to hypercapnia-hypoxia challenges in a preclinical SUDEP model involve orexin neurons.

Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1-/- mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1-/- mice have detrimental ventilatory responses. Kcna1-/- mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1-/- mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1-/- mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1-/-mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1-/- mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival.

Pharmacologic Sleep Aids in the Intensive Care Unit: A Systematic Review.

Background: Patients in the intensive care unit (ICU) often experience poor sleep quality. Pharmacologic sleep aids are frequently used as primary or adjunctive therapy to improve sleep, although their benefits in the ICU remain uncertain. This review aims to provide a comprehensive assessment of the objective and subjective effects of medications used for sleep in the ICU, as well as their adverse effects. Methods: PubMed, Web of Science, Scopus, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from their inception until June 2023 for comparative studies assessing the effects of pharmacologic sleep aids on objective and subjective metrics of sleep. Results: Thirty-four studies with 3498 participants were included. Medications evaluated were melatonin, ramelteon, suvorexant, propofol, and dexmedetomidine. The majority of studies were randomized controlled trials. Melatonin and dexmedetomidine were the best studied agents. Objective sleep metrics included polysomnography (PSG), electroencephalography (EEG), bispectral index, and actigraphy. Subjective outcome measures included patient questionnaires and nursing observations. Evidence for melatonin as a sleep aid in the ICU was mixed but largely not supportive for improving sleep. Evidence for ramelteon, suvorexant, and propofol was too limited to offer definitive recommendations. Both objective and subjective data supported dexmedetomidine as an effective sleep aid in the ICU, with PSG/EEG in 303 ICU patients demonstrating increased sleep duration and efficiency, decreased arousal index, decreased percentage of stage N1 sleep, and increased absolute and percentage of stage N2 sleep. Mild bradycardia and hypotension were reported as side effects of dexmedetomidine, whereas the other medications were reported to be safe. Several ongoing studies have not yet been published, mostly on melatonin and dexmedetomidine. Conclusions: While definitive conclusions cannot be made for most medications, dexmedetomidine improved sleep quantity and quality in the ICU. These benefits need to be balanced with possible hemodynamic side effects.

Association between dual orexin receptor antagonists (DORAs) and suicidality: reports to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It remains unknown whether suicidality is attributed to DORAs. We aim to evaluate suicidality associated with DORAs reported to the FDA Adverse Event Reporting System (FAERS). METHODS: The reporting odds ratio (ROR) was determined with trazodone as the control. Significant disproportionate reporting was determined when 95% confidence intervals (CIs) did not encompass 1.0. We used information components (ICs) to calculate the lower limit of the 95% CI (IC025). IC was significantly increased when the IC025 ≥0. RESULTS: Suvorexant (0.025 ROR), lemborexant (0.019 ROR) and daridorexant (0.002 ROR) were significantly associated with lower odds of reported completed suicides compared to trazodone (p < 0.05). There was no significantly increased RORs for the DORAs regarding suicidal ideation, depression suicidal, suicidal behavior and suicide attempts. Nonsignificant associations between all parameters of suicidality were observed for each DORA using IC025. CONCLUSION: We did not find a significant association between any parameter of suicidality captured in the FAERS for each DORA. All persons treated for insomnia pharmacologically/non-pharmacologically should be evaluated for emergence/worsening of any suicidality aspect.

Efficacy of Lemborexant in Adults ≥ 65 Years of Age with Insomnia Disorder.

BACKGROUND: Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5 mg (LEM5) and 10 mg (LEM10) in the subgroup age ≥ 65 years with insomnia. METHOD: Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18 years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated. RESULTS: In this subgroup of older adults (≥ 65 years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. CONCLUSIONS: Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65 years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016).

Insomnia is a common sleep disorder associated with significant difficulties, particularly in older adults. Although there are many drug treatments available, some are associated with the important risk of side effects and may not adequately treat sleep maintenance (ability to stay asleep), which is a frequent sleep complaint in older people. Lemborexant has been approved in multiple countries for the treatment of adults with insomnia based on studies that show lemborexant improved adults' ability to fall asleep and stay asleep and is well tolerated. To examine the long-term benefit of lemborexant, we investigated subject-reported benefits and safety of lemborexant in older (≥ 65 years) adults who participated in a 1-year study. The results showed that within the first few days of taking lemborexant, and lasting through 12 months of treatment, nightly lemborexant improved nighttime sleep (that is, it reduced the time it took to fall asleep, reduced the time awake during the night, and increased total sleep time) more than placebo. Morning alertness improved more in older adults who took lemborexant compared with placebo. In addition, those who took lemborexant also reported that their insomnia symptoms were less severe and they had less fatigue compared with placebo. Lemborexant was well tolerated in older adults. These results suggest that lemborexant may be a good option for older adults with insomnia disorder.

Emerging and upcoming therapies in insomnia.

Insomnia, commonly treated with benzodiazepine (BZD) receptor agonists, presents challenges due to associated serious side effects such as abuse and dependence. To address these concerns, many researches have been conducted to develop and advance both pharmacological and non-pharmacological interventions. Dual orexin receptor antagonists (DORAs), which include suvorexant, daridorexant and lemborexant, have recently been approved by United States Food and Drug Administration (US FDA) as a novel pharmacotherapeutic alternative. Unlike BZD receptor agonists that act as positive allosteric modulators of the gamma-aminobutyric acid type A subunit alpha 1 receptor, DORAs function by binding to both orexin receptor types 1 and 2, and inhibiting the action of the wake-promoting orexin neuropeptide. These drugs induce normal sleep without sleep stage change, do not impair attention and memory performance, and facilitate easier awakening. However, more real-world safety information is needed. Selective orexin-2 receptor antagonists (2-SORAs) is under clinical developments. This review provides an overview of the mechanism of action in relation to insomnia, pharmacokinetics, efficacy and safety information of DORAs and SORA. According to insomnia management guidelines, the first-line treatment for chronic insomnia is cognitive behavioral therapy for insomnia (CBT-I). Although it has proven effective in improving sleep-related quality of life, it has several restrictions limitations due to a face-to-face format. Recently, prescription digital therapy such as Somryst® was approved by US FDA. Somryst®, a smartphone app-based CBT-I, demonstrated meaningful responses in patients. However, digital limitations may impact scalability. Overall, these developments offer promising alternatives for insomnia treatment, emphasizing safety, efficacy, and accessibility.

Orexin-1 Receptor Antagonist SB-334867 Enhances Formalin-Induced Nociceptive Behaviors in Adult Male Rats.

Background: Orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. Neurons that produce orexin are scattered mediolaterally within the Dorsomedial Hypothalamus (DMH) and the lateral hypothalamus. In the current research, we assessed the impact of prolonged application of the antagonist of Orexin Receptor 1 (OXR1) on nociceptive behaviors in adult male rats. Methods: Sixteen Wistar rats received subcutaneous (s.c.) injections of the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle repetitively from Postnatal Day 1 (PND1)-PND30. On the 30th day following the final application of the OXR1 antagonist formalin-provoked pain was evaluated by injecting formalin. Results: Administration of the OXR1 antagonist in the long-term augmented the formalin-provoked nociceptive behaviors in interphase and phase II of the formalin-induced pain. Conclusion: Current results showed that the continued inhibiting OXR1 might be implicated in formalin-induced nociceptive behaviors. Therefore, the present study highlighted the effect of orexin on analgesia.

Lemborexant-induced interstitial lung disease: A case report.

We report the first case of drug-induced interstitial lung disease attributed to lemborexant. A 66-year-old man reported to our hospital with the acute onset of cough and breathlessness with ground-glass opacity on radiological examination. Symptoms were identified after taking lemborexant for 2 consecutive days. The patient had undergone lemborexant treatment 2 years prior and had exhibited no symptoms at that time. The drug-induced lymphocyte stimulation test for lemborexant was positive. He showed rapid improvement upon treatment with steroid. With the rise in prescriptions of lemborexant for insomnia, lemborexant should be considered as a possible cause of drug-induced interstitial lung disease.

The Role of the Orexin System in Craniocerebral Trauma-Induced Epilepsy in Mice.

BACKGROUND: Following traumatic brain injury (TBI), an imbalance arises in the central nervous system within the hippocampus region, resulting in the proliferation of mossy cell fibers, causing abnormal membrane discharge. Moreover, disruptions in cellular neurotransmitter secretion induce post-traumatic epilepsy. Extensive experimental and clinical data indicate that the orexin system plays a regulatory role in the hippocampal central nervous system, but the specific regulatory effects are unclear. Therefore, further experimental evaluation of its relevance is needed. OBJECTIVE: This study aims to investigate the effects of orexin receptor agonists (OXA) on the seizure threshold and intensity in controlled cortical impact (CCI) mice, and to understand the role of the orexin system in post-traumatic epilepsy (PTE). METHODS: Male C57BL/6 mice weighing 18-22 g were randomly divided into three groups: Sham, CCI, and CCI+OXA. The three groups of mice were sequentially constructed with models, implanted with electrodes, and established drug-delivery cannulas. After a 30-day recovery, the Sham and CCI groups were injected with physiological saline through the administration cannulas, while the CCI+OXA group was injected with OXA. Subsequently, all mice underwent electrical stimulation every 30 minutes for a total of 15 times. Epileptic susceptibility, duration, intensity, and cognitive changes were observed. Concurrently, the expression levels and changes of GABAergic neurons in the hippocampus of each group were examined by immunofluorescence. RESULTS: Injecting OXA into hippocampal CA1 reduces the threshold of post-traumatic seizures, prolongs the post-discharge duration, prolongs seizure duration, reduces cognitive ability, and exacerbates the loss of GABAergic neurons in the hippocampal region. CONCLUSIONS: Based on the results, we can find that injecting OXA antagonists into the CA1 region of the hippocampus can treat or prevent the occurrence and progression of post-traumatic epilepsy.

Orexin Receptor Antagonists as Adjunct Drugs for the Treatment of Depression: A Mini Meta-Analysis.

Introduction: There is growing interest in the efficacy of orexin receptor antagonists (ORA), one of the new psychopharmacological agents used in the treatment of insomnia, in other psychiatric disorders such as depression. Methods: This meta-analysis was conducted in accordance with PRISMA requirements. Literature searches were conducted using PubMed, Scopus and EBSCO (Medline) databases. Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). No date restrictions were used. The random effects model was used for analyses with I2 values above 50% and fixed effects model was used for analyses with I2 values below 50%. Results: In the acute phase, ORAs had no significant effect on core, sleep-adjusted and total symptoms of depression respectively; Standardized Mean Difference (SMD) for random effect -0.422, 95% CI [-0.90; 0.06], p=0.089, I2=62.4%; SMD for random effect -0.375, 95% CI [-1.24; 0.49], p=0.400; I2=66.6% and SMD for random effect -0.477, 95% CI [-0.97; 0.01], p=0.059; I2=83.1%). However, they had a significant effect on core and total symptoms of depression in the early period respectively; SMD for fixed effect=-0.228, 95% CI [-0.44; -0.01], p=0.036, I2=9.1%; and SMD for fixed effect=-0.186, 95% CI [-0.37; -0.001], p=0.048, I2=0.0%, respectively). Conclusion: The results of this meta-analysis suggest that ORAs may provide direct antidepressant efficacy when added to existing antidepressant treatment and may also have indirect antidepressant effects through improvement in sleep symptoms. Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed.

Early experience with the new DORA daridorexant in patients with insomnia disorder and comorbid mental disturbances: Results of a naturalistic study with 3 months follow-up.

Insomnia disorder may affect mental health, increasing suicidal risk. Targeting insomnia is crucial in the clinical practice. Sixty-six consecutive patients with insomnia disorder according with the DSM-5-TR criteria were treated with the dual orexin receptor antagonist, daridorexant 50 mg. Baseline (T0), 1 month (T1) and 3 month (T2) evaluations were performed. Insomnia severity (Insomnia Severity Index), mood, anxiety symptoms and suicidal risk (Beck Depression Inventory-II, Young Mania Rating Scale, Self-Reported Anxiety Scale, Suicidal Ideation Scale), dysfunctional insomnia-cognitive factors and pre-sleep arousal (Dysfunctional Beliefs About Sleep, Pre-Sleep Arousal Scale) were evaluated. The final sample included 66 patients (n = 36, 54% females, mean age 60 ± 13.6 years). Most of them, 64%, suffered from insomnia disorder comorbid with unipolar/bipolar depression, anxiety disorders and substance use disorders. Repeated ANOVA analyses showed that Insomnia Severity Index, Dysfunctional Beliefs About Sleep and Pre-Sleep Arousal Scale total score decreased across time (F = 68.818, p < 0.001; F = 47.561, p < 0.001; F = 28.142, p < 0.001, respectively). Similarly, Beck Depression Inventory-II, Self-Reported Anxiety Scale, Young Mania Rating Scale, and Suicidal Ideation Scale significantly decreased over time (p < 0.001). Predictors of insomnia remission (Insomnia Severity Index < 8) at T1 were improvement of Insomnia Severity Index at T1 (F = 60.205, p < 0.001), and improvement of Dysfunctional Beliefs About Sleep at T1 (F = 4.432, p = 0.041). Insomnia remission at T2 was best predicted by improvement of Dysfunctional Beliefs About Sleep at T2 (F = 3.993, p = 0.023). Multiple-regression models showed that clinical improvement of Beck Depression Inventory-II was best predicted by improvement in Dysfunctional Beliefs About Sleep at T1 and T2, manic symptoms by Insomnia Severity Index at T2, anxiety symptoms by Dysfunctional Beliefs About Sleep, Insomnia Severity Index and somatic Pre-Sleep Arousal Scale at T1 and T2. With the caution of a naturalistic design, early experience with daridorexant showed that by targeting insomnia it may be possible to improve not only insomnia symptoms but also comorbid symptoms.

Danavorexton (TAK-925): an orexin receptor 2 agonist as a new 'arousal' agent.

A preclinical study in animals has further characterised a new 'arousal' agent. Danavorexton (TAK-925) is an agonist for orexin receptor 2 where it promotes recovery from inhalational and i.v. anaesthesia and opioid sedation. Although danavorexton reverses opioid sedation, it does not compromise analgesia. This could be a useful addition to the postoperative drug cupboard.

Daridorexant treatment for chronic insomnia: a real-world retrospective single-center study.

INTRODUCTION: Chronic insomnia disorder (CID) significantly impacts well-being and daily functioning. Daridorexant, a double orexin receptor blocker, has shown efficacy in randomized clinical trials and has been recently approved for the treatment of CID in adult patients. This retrospective observational study aimed to describe real-world data on daridorexant effectiveness and safety in adult patients with CID. METHODS: Consecutive patients initiating on-label daridorexant at the Sleep Medicine Centre, University Hospital of Rome Tor Vergata were enrolled. Baseline and 30-day follow-up (FU) evaluations included patients' and CID characteristics, comorbidities, and clinicians' and patients' subjective ratings of changes with the Clinical and Patient Global Impression-Improvement scores (CGI-Is and PGI-Is), as well as Insomnia Severity Index (ISI) scores in a subgroup of patients. RESULTS: Sixty-nine patients initiated 50-mg daily dosage. At FU, 58% of both patients and clinicians rated CID as improved on CGI-Is and PGI-Is, with no differences based on comorbidities, sex, or number of previous medications. No significant predictors of CGI-Is and PGI-Is improvement were identified. At FU, ISI scores (n = 24) significantly decreased from 18.25 ± 3.21 to 12.08 ± 6.12 (Z = 8.000; p < 0.001). Of these, eight patients (33.3%) had absence of insomnia symptoms, and no patients reported a worsening in ISI score categories. CONCLUSIONS: This study suggests daridorexant to be effective and safe in real-world CID treatment whether used as a first-ever treatment, switch, or add-on, as reflected by subjective and objective measures and the absence of serious treatment-related adverse events. Future research on larger cohorts should explore daridorexant potential across diverse patient characteristics.

Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX2R coupled Gq signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys.

BACKGROUND: Delayed emergence from general anaesthesia, opioid-induced sedation, and opioid-induced respiratory depression is associated with perioperative complications. We characterised the preclinical effects of the orexin receptor 2 (OX2R)-selective agonist danavorexton (TAK-925) on emergence from anaesthesia and reversal of fentanyl-induced sedation, respiratory depression, and analgesia. METHODS: Emergence from isoflurane- or propofol-induced anaesthesia and fentanyl-induced sedation were investigated by righting reflex, rotarod, and electroencephalography in rats or monkeys. Fentanyl-induced respiratory depression was assessed by arterial blood gas analysis and whole-body plethysmography in rats and monkeys. Analgesia was evaluated using formalin- and skin incision-induced pain models in rats. RESULTS: Danavorexton shortened emergence from isoflurane- or propofol-induced anaesthesia and from fentanyl-induced sedation at 1 (P=0.005), 3 (P=0.006), and 3 mg kg-1 s.c. (P=0.022), respectively, by righting reflex in rats. Danavorexton (10 mg kg-1 s.c.) accelerated recovery from isoflurane-, propofol- and fentanyl-induced motor impairment in separate rotarod tests in rats (P=0.008, P=0.007, P=0.017, respectively), and reversed anaesthesia and fentanyl-induced delta-power increases. Danavorexton shortened emergence (return of righting reflex) from isoflurane- or propofol-induced anaesthesia at 1 (P=0.002) and 3 mg kg-1 (P=0.004), respectively, in cynomolgus monkeys. Danavorexton (10 mg kg-1 s.c.) reversed fentanyl-induced increase in Pco2 (P=0.006), and decrease in Po2 (P=0.015) and pH (P<0.001) in rats, and at 3 mg kg-1 s.c. reversed fentanyl-induced increase in Pco2 (P=0.007), and decrease in Po2 (P=0.013) and SO2 (P=0.036) in monkeys. Danavorexton increased minute volume and tidal volume in fentanyl-treated animals. Danavorexton at ≤10 mg kg-1 s.c. did not compromise fentanyl analgesia in rat formalin- and skin incision-induced pain models. CONCLUSIONS: Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia.

A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea.

STUDY OBJECTIVES: To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA). METHODS: E2006-A001-113 (Study 113; NCT04647383) was a double-blind, two-period crossover, placebo-controlled study in adults (ages ≥ 45 to ≤ 90 years, n = 33) with moderate (apnea-hypopnea index [AHI] score ≥ 15 to < 30 events/h, n = 13) or severe (AHI ≥ 30 events/h, n = 20) OSA. Participants were randomized to lemborexant 10 mg (LEM10) or placebo (PBO) for two treatment periods of 8 nights with a ≥ 14-day washout period. AHI and peripheral oxygen saturation were evaluated after treatment on Day 1 (after a single dose) and Day 8 (after multiple doses). RESULTS: No significant differences in AHI were observed after single and multiple doses of LEM10 compared with PBO in participants with moderate to severe OSA (least-squares mean: single-dose LEM10, 41.7; PBO, 44.8; multiple-dose LEM10, 44.9; PBO, 45.7). In addition, there were no significant differences between treatments in peripheral oxygen saturation (least-squares mean: single-dose LEM10, 93.0; PBO, 93.1; multiple-dose LEM10, 93.1; PBO, 93.4). Further, there were no significant differences between treatments in percentage of total sleep time with peripheral oxygen saturation < 90%, < 85%, or < 80%. No significant differences were observed between treatments when AHI and peripheral oxygen saturation outcomes were analyzed by OSA severity. Altogether, 6/33 (18.2%) participants receiving LEM10, vs 3/33 (9.1%) PBO, reported treatment-emergent adverse events, mostly mild in severity. CONCLUSIONS: LEM10 demonstrated respiratory safety and was well tolerated with single-dose and multiple-dose administration in participants with moderate to severe OSA. This suggests that LEM may be a treatment option for patients with OSA and comorbid insomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Participants With Moderate to Severe Obstructive Sleep Apnea and in Adult and Elderly Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04647383; Identifier: NCT04647383. CITATION: Cheng JY, Lorch D, Lowe AD, et al. A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea. J Clin Sleep Med. 2024;20(1):57-65.

The orexin receptor 2 (OX2R)-selective agonist TAK-994 increases wakefulness without affecting cerebrospinal fluid orexin levels in cynomolgus monkeys.

Orexin A (OX-A) and orexin B are neuropeptides produced in orexin neurons located in the lateral hypothalamus that exert multiple biological functions through the activation of orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) throughout the central nervous system. OX1R and OX2R have distinct functions: OX1R is involved in reward seeking, whereas OX2R has a pivotal role in sleep/wake regulation. OX2R-selective agonists are in development as novel therapeutic agents for the treatment of hypersomnia. However, their potential to induce orexin release, which may indirectly stimulate both OX1R and OX2R in vivo, is unclear. Herein, we assessed the effects of the OX2R-selective agonist TAK-994 on wakefulness and orexin release in monkeys. Oral administration of TAK-994 at 10 mg/kg in the beginning of the sleep phase (zeitgeber time [ZT] 12) significantly increased wakefulness time in monkeys but did not increase OX-A levels in monkey cisternal cerebrospinal fluid (CSF). Moreover, oral administration of TAK-994 (10 mg/kg) during the active phase (ZT1) did not increase OX-A levels in monkey CSF. These findings indicate that the OX2R agonist TAK-994 selectively activates OX2R in vivo and would not robustly induce spontaneous orexin release during the daytime or nighttime in monkeys.

Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis.

STUDY OBJECTIVES: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. METHODS: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. RESULTS: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. CONCLUSION: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.

Clinical usefulness of dual orexin receptor antagonism beyond insomnia: Neurological and psychiatric comorbidities.

Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results.

Abuse potential assessment of the dual orexin receptor antagonist daridorexant in rats.

BACKGROUND: Drugs that act on the central nervous system (CNS) and have sedative effects can lead to abuse in humans. New CNS-active drugs often require evaluation of their abuse potential in dedicated animal models before marketing approval. Daridorexant is a new dual orexin receptor antagonist (DORA) with sleep-promoting properties in animals and humans. It was approved in 2022 in the United States and Europe for the treatment of insomnia disorder. AIMS: Nonclinical evaluation of abuse potential of daridorexant using three specific rat models assessing reinforcement, interoception, and withdrawal. METHODS: Reinforcing effects of daridorexant were assessed in an operant rat model of intravenous drug self-administration. Similarity of interoceptive effects to those of the commonly used sleep medication zolpidem was tested in an operant drug discrimination task. Withdrawal signs indicative of physical dependence were evaluated upon sudden termination of chronic daridorexant treatment. Rat experiments were conducted at a dose range resulting in daridorexant plasma concentrations equaling or exceeding those achieved at the clinically recommended dose of 50 mg in humans. RESULTS: Daridorexant had no reinforcing effects, was dissimilar to zolpidem in the drug discrimination task, and did not induce any withdrawal-related signs upon treatment discontinuation that would be indicative of physical dependence. OUTCOMES: Daridorexant showed no signs of abuse or dependence potential in rats. Our data indicate that daridorexant, like other DORAs, has a low potential for abuse in humans.