Orexin Receptor Research Articles

The efficacy and safety of dual orexin receptor antagonists in obstructive sleep apnea: A systematic review and meta-analysis of randomised controlled trials.

Dual orexin receptor antagonists (DORAs) are indicated for the treatment of insomnia disorder. However, DORAs may change sleep parameters, thus having adverse effects on patients with obstructive sleep apnea (OSA). This meta-analysis clarified the impact of DORAs in OSA treatment on sleep architecture and respiratory parameters. We systematically searched PubMed, Embase, and Cochrane Central databases for randomised control trials published up to May 2024. The search focussed on studies discussing the effects of DORAs on sleep architecture in patients with OSA. Nonrandomised studies were excluded. A meta-analysis using a random-effects model was performed. The patients were categorised into subgroups based on the treatment protocol (single or multiple dosages). The Cochrane risk of bias tool for randomised trials assessed the risk of bias. Our meta-analysis included four randomised placebo-controlled trials, encompassing 126 patients with a mean age of 49.1 years. The effects of DORAs on sleep architecture and respiratory parameters were examined. The main findings were as follows: DORAs significantly increased the total sleep time and improved sleep efficiency. However, they did not affect rapid eye movement sleep. DORAs also showed a trend towards decreased wake after sleep onset and did not increase the apnea-hypopnea index. DORAs did not increase the percentage of total sleep time with oxygen saturation lower than 90% and 85% compared with placebo, respectively. Furthermore, DORAs were not associated with significantly higher adverse effects compared with placebo. This meta-analysis demonstrated that DORAs improve sleep and do not impair nighttime respiratory function in patients with OSA.

Brook-Oxidation Reaction of Acylsilanes: General Access to α-Ketoamides and α-Ketothioamides.

A novel chemoselective Brook-oxidation reaction of acylsilanes initiated by the carbamoyl anion has been successfully developed for the first time. This method enables the synthesis of diverse α-ketoamides and α-ketothioamides under transition metal-free and strong oxidant-free conditions with high yields and high chemoselectivity. It also demonstrates tolerance toward a wide range of functional groups. The synthetic utility of this process is underscored by its successful application in the synthesis of an orexin receptor antagonist from acylsilane, highlighting its potential for the development of novel therapeutic agents and further exploration in synthetic chemistry.

Abstract 4118332: Suvorexant is associated with the reduced risk of feart failure rehospitalization in elderly patients with heart failure and insomnia

Background: Research that compares the safety of orexin receptor antagonists and other types of hypnotics prescribed to elderly patients with heart failure (HF) and insomnia remains lacking. This study aimed to compare an orexin receptor antagonist, Suvorexant, with benzodiazepines or Z-drugs for insomnia treatment and investigate the risk of HF-related rehospitalization in elderly patients with HF and insomnia. Methods: A national administrative claims database from April 2008 to December 2020 was utilized and analyzed. The study population, consisting of 1,159,937 patients aged ≥65 years, was randomly sampled from the database. Patients were then selected based on specific inclusion and exclusion criteria. Exposures were identified based on the classification of the first prescribed hypnotic. The follow-up period was continued considering the prescription interval and grace period. The end of follow-up was censored based on multiple criteria, including outcome occurrences (i.e., HF rehospitalization) and hypnotic classification changes. Kaplan–Meier survival analysis and Cox proportional hazards models were used. Hazard ratios were adjusted by propensity scores derived from patients’ background factors. Results: The analysis included 1,858 elderly who had their first HF-related hospitalization. They were categorized into Suvorexant, benzodiazepines and Z-drugs groups (N=490, 606 and 762, respectively). The average age for all participants was 82.7 ± 7.6 years, which is similar across three groups. Kaplan-Meier curves indicated a higher trend of HF-rehospitalization risk for benzodiazepines and Z-drugs groups than for Suvorexant. The adjusted hazard ratios were 2.77 (95% confidence intervals [CI]: 1.17-6.52) for benzodiazepines and 2.98 (95% CI: 1.33-6.68) for Z-drugs. Conclusion: Compared with benzodiazepines and Z-drugs, the use of suvorexant for insomnia treatment in elderly patients with HF indicates a potential for the reduced risk of rehospitalization due to HF exacerbation. The results of this study provide valuable information for the selection of hypnotics in elderly HF patients with concurrent insomnia.

LITERATURE REVIEW ON ANALYTICAL METHODS FOR QUANTIFICATION OF SUVOREXANT

This review summarizes various analytical methods reported for the quantification of suvorexant, a novel dual orexin receptor antagonist used for the treatment of insomnia. The methods discussed include chromatographic techniques such as HPLC-MS/MS, GC-MS, and HPTLC. The review highlights the sensitivity, specificity, and linearity range of these methods. Additionally, the review explores the formulation and tissue distribution of suvorexant.

Daridorexant as a new dual orexin receptor antagonist for insomnia - a literature review

Introduction and purpose of review: Insomnia is a prevalent disorder responsible for multiple negative effects on human health. Its treatment involves both non pharmacological and pharmacological methods, however many common insomnia medications are recommended not to be used long term. Daridorexant is a new dual orexin receptor inhibitor, recently approved by the EMA for use in the European Union. The aim of this study is to present current knowledge concerning daridorexantsafety, efficacy and general characteristics. Methods: Pubmed database literature review has been performed. Relevant studies regarding daridorexant and insomnia have been assessed. Product characteristics available on EMA, FDA and Idorsia Pharmaceuticals websites have also been inspected. Current state of knowledge: Studies suggest that daridorexant is generally safe and significantly improves the night-time and daytime functioning of people suffering from insomnia, by enabling them to fall asleep in shorter periods of time and stay asleep for longer. It increases time spent in both REM and non-REM phases proportionally and does not disturb physiological sleep architecture. It shows no residual effects in the morning and can be used long-term, with no reduced efficacy and with no signs of physical dependence or withdrawal symptoms. It rarely leads to serious adverse effects and is contraindicated only in a few groups of patients. Conclusions: Daridorexant is a recently approved dual orexin receptor inhibitor with a promising long-term use safety and efficacy profile. As it is a new medication, further investigation concerning the side effects observed over time should be advised.

Medical Professionals and Pharmacological Intervention for the Treatment of Insomnia: A Cross-Sectional Study

Abstract Objective To explore the preferences of medical practitioners concerning various medications and other remedies to manage insomnia, and to ascertain whether these preferences are associated with their respective medical specialties. Materials and Methods Employing the snowball sampling technique, we administered two versions of a questionnaire to an international group of medical professionals, including trainees and specialists from diverse medical backgrounds. Results Zopiclone, zolpidem, and mirtazapine were evaluated as the most effective treatments for insomnia, while physicians would typically avoid using other tricyclic antidepressants, dual orexin receptor antagonists, and tryptophan for insomnia treatment. Noteworthy statistical correlations between physicians' specialty and preferred drug therapy, were observed in three out of five cases: 1) first-line drug treatment for short-term intervention against insomnia; (2) second-line treatment for long-term intervention; and 3) cases involving the elderly. Discussion Psychiatrists demonstrated a greater preference for antipsychotics and antidepressants for the treatment of insomnia compared with other physicians. Conversely, other medical professionals exhibited a preference for benzodiazepines and Z-drugs (zopiclone and zolpidem). Although Z-drugs were evaluated as the most effective in the treatment of insomnia, in the clinical practice, physicians administer or would administer antidepressant or antipsychotic drugs more often (mirtazapine and quetiapine respectively). Regarding Dual Orexin Receptor Antagonists (DORAs), the high prevalence of “Do not know/No opinion” answers implies that our sample was not familiar with this innovative treatment.

Structure-Affinity-Pharmacokinetics Relationships of Novel 18F-Labeled 1,4-Diazepane Derivatives for Orexin 1 Receptor Imaging.

The orexin 1 receptor (OX1R) has been suggested to be involved in the reward and autonomic nervous systems. Positron emission tomography (PET) of OX1R contributes to elucidating its role and developing new drugs. However, there are no useful PET probes for in vivo imaging of OX1R. Here, we newly designed and synthesized 18F-labeled 1,4-diazepane derivatives and evaluated their utilities as OX1R PET probes. In particular, BTF showed high and selective binding affinity for OX1R. In a biodistribution study using normal mice, [18F]BTF exhibited brain uptake, and radioactivity in the brain was significantly decreased by preinjection of unlabeled BTF. In a PET/CT study, it was suggested that [18F]BTF has the potential to visualize high-expression regions of OX1R in the normal mouse brain. Collectively, [18F]BTF has the fundamental features of an OX1R PET probe, and further studies may lead to the development of more useful probes.

Spatial mRNA expression patterns of orexin receptors in the dorsal hippocampus.

Orexins are wake-promoting neuropeptides that originate from hypothalamic neurons projecting to widespread brain areas throughout the central nervous system. They modulate various physiological functions via their orexin 1 (OXR1) and 2 (OXR2) receptors, including sleep-wake rhythm but also cognitive functions such as memory formation. Here, we provide a detailed analysis of OXR1 and OXR2 mRNA expression profiles in the dorsal hippocampus as a key region for memory formation, using RNAscope multiplex in situ hybridization. Interconnected subareas relevant for cognition and memory such as the medial prefrontal cortex and the nucleus reuniens of the thalamus were assessed as well. Both receptor types display distinct profiles, with the highest percentage of OXR1 mRNA-positive cells in the hilus of the dentate gyrus. Here, the content of OXR1 mRNA per cell was slightly modulated at selected time points over a 12h light/ 12 dark light phase. Using RNAScope and quantitative polymerase chain reaction approaches, we began to address a cell-type specific expression of OXR1 in hilar GABAergic interneurons. The distinct expression profiles of both receptor subtypes within hippocampal subareas and circuits provide an interesting basis for future interventional studies on orexin receptor function in spatial and contextual memory.

Pharmacological Management of Sleep-Wake Disturbances in Delirium.

Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep-wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep-wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions.

The Orexin OX2 Receptor-Dependent Pathway Is Implicated in the Development of Overactive Bladder and Depression in Rats Exposed to Corticosterone.

In the present study, we wanted to check whether TCS OX2 29 (TCS), a potent selective antagonist of OX2 receptors, would have positive effects in an animal model of detrusor overactivity co-existed with the depression-like state in Wistar male rats. The forced swim test with the measurement of spontaneous locomotor activity, conscious cystometry, determination of c-Fos expression in central micturition areas, and a set of biochemical analyses (with the use of urine, hippocampus, bladder urothelium, and detrusor muscle of tested animals) were carried out. The outcomes showed that a 7-day administration of TCS (3 mg/kg/day, subcutaneously) normalizes the cystometric parameters corresponding to overactivity of the detrusor and reverses the pro-depressive response. Furthermore, the antagonism of OX2 receptors restored the abnormal levels of overactive bladder markers (i.e., ATP, CGRP, OCT3, TRPV1, ROCK1, and VAChT), diminished neuronal overactivity in central micturition areas (i.e., pontine micturition center, ventrolateral periaqueductal gray, and medial preoptic area) as well as restored the altered hippocampal levels of CRF, cytokines (IL-1β, IL-6, IL-10, and TNF-α), and growth factors (BDNF and NGF) that reflected biochemical disturbances detected in depressed people. It seems that our findings open new perspectives regarding the implication of the orexin system in the functioning of the urinary bladder and in the pathophysiology of depression.

The distribution of Hypocretin/Orexin receptor mRNA in the mouse and human brain

Hypocretin (Hcrtr, HCRTR) / orexin (OX) receptors modulate a range of neurobiological functions and are drug targets for several disorders. Mapping the distribution of receptors in the brain can inform their function and guide targeting of specific disorders. Although studied in rodents, orexin receptor distribution has remained relatively unexplored in humans, and thus there is also a paucity of comparative anatomy. The aim of this study was therefore to map the distribution of hypocretin/orexin receptor mRNA in selected regions of the mouse and human brain by non-radioactive in situ hybridization (ISH) using digoxigenin (DIG)-labelled cRNA anti-sense probes. Data revealed both distinct and overlapping patterns of distributions of Hcrtr1/HCRTR1 and Hcrtr2/HCRTR2 mRNA suggesting that the functions of the orexin system are mediated differently by each receptor. In the mouse brain, the highest expression of Hcrtr1 mRNA was in the locus coeruleus (LC) whereas Hcrtr2 mRNA was most abundant in the lateral hypothalamus (LH). The human caudate nuclei showed significant expression of both HCRTR1 and HCRTR2 mRNA, whereas the mouse predominantly expressed Hcrtr2 mRNA. The noradrenergic neurons of the human LC showed high signals for both HCRTR1 (71.7%) and HCRTR2 (81.5%) mRNA. Expression of HCRTR2 mRNA in non-noradrenergic human LC cells was also notable. The distribution pattern in mouse and human brains is consistent with the involvement of the orexin system in arousal and the sleep/wake cycle in both species, however, variations in receptor subtype expression profiles suggests that species differences in responses to orexin receptor ligands may be expected.

Fentanyl demand and seeking in female rats: Role of the orexin system and estrous cycle

The orexin system plays a major role in drug reward. Orexin-1 receptor (OxR1) blockade reduces fentanyl demand in males. However, there are a number of sex differences in the orexin system, and it is unclear how OxR1 antagonism would decrease fentanyl demand in females. Furthermore, the relationships between the estrous cycle and fentanyl intake are yet to be delineated.Here, we conducted a behavioral economics (BE) procedure in female rats to assess the effects of the OxR1 antagonist SB-334867 on fentanyl demand before and after short-(ShA), long- (LgA) or intermittent-access (IntA) self-administration of fentanyl; we also tested the effect of SB-334867 on cued reinstatement of fentanyl seeking. Finally, we measured the impact of the estrous cycle on fentanyl demand, intake and seeking.Results showed that in females SB-334867 did not consistently modulate demand for fentanyl before or after chronic access periods. However, SB-334867 at 30mg/kg reduced the number of active lever presses during cued-reinstatement of fentanyl seeking. We also found that fentanyl self-administration disrupted estrous cyclicity, in particular proestrus epochs, an effect that depended on short versus chronic access. Furthermore, extended access to fentanyl shifted the role of progesterone from facilitation of fentanyl demand during short periods, to attenuation of fentanyl demand after long term exposure. These results indicate that an orexin-based therapy in women for treating opioid use disorder must consider prior drug history as well as cycle phase.

Evaluation of the effects of a team-based systematic prevention and management program for postoperative orthopedic older patients: A retrospective cohort study.

This study aimed to evaluate a team-based systematic prevention and management program for delirium (a multicomponent intervention addressing potentially modifiable risk factors based on the DELirium Team Approach [DELTA]) in older patients undergoing orthopedic surgery within a real-world clinical setting. The DELTA program was initiated at our hospital in January 2019. A retrospective before-after study was conducted during a preintervention period (January 1, 2017 to December 31, 2018) and a postintervention period (January 1, 2020 to December 31, 2021) at orthopedic wards of an advanced acute care hospital in Japan. A total of 787 inpatients were evaluated before the preintervention period, and 833 inpatients were evaluated after the postintervention period. After the DELTA program's implementation, a significant decrease in benzodiazepine receptor agonist prescriptions (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.29-0.53) and an increase in prescriptions of either melatonin receptor agonists or dual orexin receptor antagonists (OR, 3.83; 95% CI, 2.49-5.88) were observed. However, no significant difference was observed in the incidence of falls, self-extubation, or required level of medical and nursing care, including risky behavior and inability to follow medical or care instructions following the intervention, despite a reduction in the length of hospital stay and institutionalization. Implementing the DELTA program for older patients undergoing orthopedic surgery contributed to optimizing the prescription of hypnotics; however, the impact on other patient outcomes, such as falls, self-extubation, and required level of medical and nursing care was limited.

Short-Term Efficacy and Safety of Suvorexant and Lemborexant: A Retrospective Study.

Given the risks of long-term benzodiazepine use, safer alternatives like orexin receptor antagonists (ORAs) are needed for insomnia treatment. This study aims to compare suvorexant and lemborexant, focusing on early-stage sleep duration as an efficacy measure and fall incidence as a safety measure. We included patients admitted to our hospital between April 1, 2022and December 31, 2022, who were newly prescribed suvorexant or lemborexant, excluding patients taking other concomitant sleep medications or antipsychotics. Primary and secondary endpoints were sleep duration during the first three days after taking the medications and the incidence of falls, respectively. We analyzed data from 48 and 57 patients taking suvorexant and lemborexant, respectively. When compared with that in the pre-treatment period, sleep duration was significantly longer on days 2 and 3 in the suvorexant group, and on all three days in the lemborexant group. On day 1 of drug administration, the lemborexant group had a significantly longer sleep duration than the suvorexant group (5.10 ± 1.84 vs. 5.93 ± 1.90 h, respectively; P = 0.017). Zero (0.0%) and three (5.3%) falls occurred in the suvorexant and lemborexant groups, respectively (P = 0.248). Lemborexant exerted a potent inhibitory effect on orexin 2 receptors, which could explain the longer sleep duration experienced by patients taking this drug on the first day of treatment.

Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders.

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.

Orexins mitigate obesity-associated dysfunctions in mice.

Obesity is a chronic disease that affects more than 400 million adults with severe comorbidities. The search for new treatments to reduce its negative consequences is necessary. Orexins are hypothalamic neuropeptides involved in various physiological processes related to obesity. The aim of this study was to investigate the consequences of chronic orexin-A treatment in mouse models. Female wild-type C57BL/6 mice that were obesity-prone or obesity-resistant and mice that were deficient for orexin receptors were fed with a high-fat diet. Glucose tolerance, indirect calorimetry, expression of brain neuropeptides and receptors, microglial activation, and microbiota were determined to evaluate the role of orexins on metabolic flexibility. Orexin-A reduces weight gain in obesity-prone mice. This reduction is associated with a decrease in body fat, food intake, steatosis, and insulin resistance, as well as alterations of intestinal microbiota composition. A decreased expression of orexin receptors and neuropeptides involved in food intake was also observed in the hypothalamus. Our data support the notion that orexin receptor signaling is involved in different aspects of energy metabolism and can mitigate several dysfunctions associated with obesity, suggesting that orexin receptors can represent new targets for obesity treatment.

Stimulation of kappa opioid receptors in the nucleus accumbens promotes feeding behavior in mice: Acute restoration of feeding during anorexia induced by 5-fluorouracil

Though μ and δ opioid receptors are reported to regulate energy homeostasis, any role for κ opioid receptors in these processes remains unclear. The present study investigated the role of κ opioid receptors in regulation of feeding behavior and plasma glucose levels using nalfurafine, a κ opioid receptor agonist used clinically. Systemic injection of nalfurafine increased food intake under non-fasted conditions, but not after food deprivation, and this effect was inhibited by the κ opioid receptor antagonist norbinaltorphimine. In contrast, nalfurafine did not affect plasma glucose levels. I.c.v. injection of nalfurafine increased food intake, whereas systemic injection of nalfurafine methiodide, which does not penetrate the blood brain barrier, was without effect. In addition, nalfurafine tended to increase preproorexin mRNA in the hypothalamus. However, neither the orexin OX1 receptor antagonist YNT-1310 nor the non-selective orexin receptor antagonist suvorexant inhibited the increase in food intake induced by nalfurafine. While nalfurafine injected into the lateral hypothalamus did not affect food intake, nalfurafine injected into the nucleus accumbens increased food intake, which was inhibited by norbinaltorphimine. Finally, we examined the effect of nalfurafine on anorexia induced by the anti-cancer agent 5-fluorouracil. Reduced food intake at 2 days following 5-fluorouracil administration was alleviated across the first 3 h following daily injection of nalfurafine, though daily food intake was not influenced. These results indicate that nalfurafine promotes feeding behavior through stimulation of κ opioid receptors in the nucleus accumbens and may be a candidate for reducing anorexia due to anti-cancer agents.

Effects of Approved Pharmacological Interventions for Insomnia on Mood Disorders: A Systematic Review.

Insomnia can be a contributing factor, a comorbid disorder, or a transdiagnostic element to several mental disorders, including mood disorders (MDs). A recent meta-analysis has already shown the effectiveness of cognitive behavioral treatment (CBT) for insomnia that is comorbid with MDs. This work aimed to systematically review data on pharmacological insomnia treatment in the context of MDS. In agreement with the current guidelines, pharmacological interventions for insomnia include gamma-aminobutyric acid (GABA)A receptor agonists such as short-medium acting benzodiazepines and benzodiazepine receptor agonists - Z-drugs, melatonergic receptors agonists, specifically melatonin 2 mg Prolonged Release (PR) and ramelteon, and dual orexin receptors antagonists (DORA) such as daridorexant, lemborexant, and suvorexant. A systematic search was carried out on PUBMED database, according to the PRISMA Guidelines. Thirty-three papers, 15 on gabaergic receptor agonists, 14 on melatonergic receptor agonists and 4 on DORA, were selected. Available data suggests that the treatment of insomnia symptoms with specific pharmacological options can improve both insomnia and comorbid conditions. Specifically, eszopiclone and melatonin 2 mg PR have demonstrated promising outcomes. Moreover, daridorexant and suvorexant, both belonging to the DORA class, have demonstrated efficacy in treating insomnia and mood symptoms. To summarize, current literature would suggest that targeting insomnia could potentially regulate the sleep system and, as such, improve mood symptoms.

Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant

Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.

Insomnia in ambulatory care: A clinical review.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. One-third to one-half of ambulatory care patients report insomnia. The objective of this clinical review is to detail the many causes and evidence-based treatment options for insomnia in outpatients and to recommend screening and summarize evidence for the place in therapy of prescription and nonprescription treatments. This work provides an overview of the literature on insomnia regarding causes, patient assessment, and nonpharmacological and pharmacological treatments. Patients who present with insomnia should be assessed for sleep apnea, restless legs syndrome, narcolepsy, and all contributing medications as well as medical, psychiatric, and substance use disorder diagnoses. The type of insomnia, namely difficulty falling asleep, difficulty maintaining sleep, and early morning awakening with resulting functional impairment, should be documented in addition to whether insomnia is short term or persistent. Cognitive behavioral therapy for insomnia (CBT-I) or digital CBT-I is first-line treatment for all patients with insomnia irrespective of the cause or type. Nonprescription treatments such as antihistamines or melatonin are for select populations. Prescription hypnotics are best utilized on an as-needed basis or for nightly use for less than 6 weeks. Z-hypnotics are safe and effective for insomnia in persons with depression or an anxiety disorder but should be avoided in older individuals or if there is respiratory or cognitive impairment. Orexin receptor antagonists are effective for sleep initiation and maintenance in healthy persons or if there is mild cognitive impairment, but they require further study in individuals with psychiatric and medical diagnoses. Trazodone is the most prescribed off-label treatment due to its efficacy for sleep initiation and maintenance and its lack of abuse potential. Insomnia treatment should be guided by patient age, diagnoses, and type of insomnia. Pharmacological treatments should be used at the lowest effective dose for the shortest duration of time.