RESUMEN

PURPOSE: This study examined the applicability of hair analysis as an approach to identify suvorexant (SUV) and lemborexant (LEM) intake by analyzing black hair specimens collected from study participants after a single oral administration. METHODS: Hair specimens were collected form participants who took a single dose of 10 mg SUV or 5 mg LEM. Identification of the dual orexin receptor antagonists (DORAs) and their metabolites was performed by liquid chromatography-tandem mass spectrometry. Reference standards of S-M9 and L-M4, the metabolites of SUV and LEM, respectively, were synthesized in our laboratory. Sectional analysis of 1-mm segments of the single-hair strands was also performed to investigate the incorporation behavior of the drugs into hair. RESULTS: Unchanged SUV and LEM, and their metabolites S-M9 and L-M4 were detected even in the single-hair specimens. Results of the segmental hair analysis showed predominant incorporation of the drugs into hair through the hair bulb region rather than through the upper dermis zone of the hair root. The drug concentrations in the hair specimens, collected about 1 month after intake, were 0.033-0.037 pg/hair strand (0.17-0.19 pg/mg) for SUV and 0.054-0.28 pg/hair strand (0.28-1.5 pg/mg) for LEM. The calculated distribution ratios of the DORAs into hair to the oral doses were much lower than those of benzodiazepines and zolpidem reported in a previous study. CONCLUSIONS: This is the first report of the detection of the DORAs in hair. The incorporation behavior of the DORAs into hair revealed herein are crucial for proper interpretation of hair test results.

RESUMEN

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain ß-amyloid (Aß) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aß deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Trastornos de la Memoria , Ratones Transgénicos , Antagonistas de los Receptores de Orexina , Privación de Sueño , Animales , Privación de Sueño/complicaciones , Privación de Sueño/tratamiento farmacológico , Ratones , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Precursor de Proteína beta-Amiloide/genética , Acetamidas/farmacología , Acetamidas/uso terapéutico , Masculino , Péptidos beta-Amiloides/metabolismo , Aprendizaje/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Receptores de Orexina/metabolismo , Presenilina-1/genética

RESUMEN

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.

Asunto(s)

Modelos Animales de Enfermedad , Hipercapnia , Hipoxia , Ratones Noqueados , Neuronas , Orexinas , Muerte Súbita e Inesperada en la Epilepsia , Animales , Hipercapnia/fisiopatología , Hipercapnia/metabolismo , Hipoxia/metabolismo , Hipoxia/fisiopatología , Orexinas/metabolismo , Ratones , Neuronas/metabolismo , Canal de Potasio Kv.1.1/genética , Canal de Potasio Kv.1.1/metabolismo , Masculino , Ratones Endogámicos C57BL

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Resultado del Tratamiento , Anciano , Antagonistas de los Receptores de Orexina/uso terapéutico , Antagonistas de los Receptores de Orexina/administración & dosificación , Pirrolidinas/uso terapéutico , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Estudios de Seguimiento , Índice de Severidad de la Enfermedad , Imidazoles

RESUMEN

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.

Asunto(s)

Piridinas , Apnea Obstructiva del Sueño , Humanos , Anciano , Estudios Cruzados , Piridinas/uso terapéutico , Pirimidinas/efectos adversos , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/tratamiento farmacológico , Método Doble Ciego

RESUMEN

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.

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Trastornos Relacionados con Sustancias , Humanos , Ratas , Animales , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Zolpidem , Imidazoles , Pirrolidinas , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos Relacionados con Sustancias/tratamiento farmacológico

RESUMEN

For abuse potential assessment, U.S. Food and Drug Administration (FDA) requests that new, brain-penetrating drugs are ideally compared with approved drugs that share the mechanism of action and are judged to have abuse liability by the Drug Enforcement Agency. For development of the dual orexin receptor antagonist (DORA) daridorexant, the FDA recommended conducting a rat drug discrimination paradigm against the approved, schedule IV, DORA suvorexant. Surprisingly, at suvorexant plasma levels up to three-fold the maximum concentration at the highest approved human dose, rats did not learn to discriminate the suvorexant stimulus from vehicle.

Asunto(s)

Azepinas , Antagonistas de los Receptores de Orexina , Humanos , Ratas , Animales , Antagonistas de los Receptores de Orexina/farmacología , Azepinas/farmacología , Triazoles/farmacología , Encéfalo

RESUMEN

Sleep disorders are associated with increased risk of obesity and type 2 diabetes. Lemborexant, a dual orexin receptor antagonist (DORA), is clinically used to treat insomnia. However, the influence of lemborexant on sleep and glucose metabolism in type 2 diabetic state has remained unknown. In the present study, we investigated the effect of lemborexant in type 2 diabetic db/db mice exhibiting both sleep disruption and glucose intolerance. Single administration of lemborexant at the beginning of the light phase (i.e., resting phase) acutely increased total time spent in non-rapid eye movement (NREM) and REM sleep in db/db mice. Durations of NREM sleep-, REM sleep-, and wake-episodes were also increased by this administration. Daily resting-phase administration of lemborexant for 3-6 weeks improved glucose tolerance without changing body weight and glucose-stimulated insulin secretion in db/db mice. Similar improvement of glucose tolerance was caused by daily resting-phase administration of lemborexant in obese C57BL/6J mice fed high fat diet, whereas no such effect was observed in non-diabetic db/m+ mice. Diabetic db/db mice treated daily with lemborexant exhibited increased locomotor activity in the dark phase (i.e., awake phase), although they did not show any behavioral abnormality in the Y-maze, elevated plus maze, and forced swim tests. These results suggest that timely promotion of sleep by lemborexant improved the quality of wakefulness in association with increased physical activity during the awake phase, and these changes may underlie the amelioration of glucose metabolism under type 2 diabetic conditions.

Asunto(s)

Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratones , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ratones Endogámicos C57BL , Sueño , Glucosa/farmacología

RESUMEN

OBJECTIVE/BACKGROUND: To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial. PATIENTS/METHODS: The subjects in these post-hoc analyses were randomized to placebo for 6 months (Time Period [TP]1) in Study E2006-G000-303 (SUNRISE-2; NCT02952820). Following placebo exposure, subjects were re-randomized to LEM5 or LEM10 for another 6 months (TP2). Subject-reported sleep outcomes derived from sleep diaries included sleep onset latency (sSOL), wake after sleep onset (sWASO), sleep efficiency (sSE), and total sleep time (sTST). Magnitude and change rate in parameters were assessed for 7 days before/after initial randomization to placebo and 7 days before/after re-randomization to LEM (6 months later). Month 6 placebo non-responders were assessed for LEM response in TP2 using predetermined responder definitions. Safety was monitored throughout the study. RESULTS: Overall, 321 subjects received placebo; 258 re-randomized subjects received LEM5 (n = 133) and LEM10 (n = 125). Subjective sleep outcomes improved during TP1 with approximately 62 subjects (∼20%) exhibiting a sustained placebo response. Upon re-randomization to LEM, all measures showed an additional incremental benefit, most prominently in sSOL and sTST. Among Month 6 placebo non-responders, 11%-15% subsequently responded to LEM as assessed at Month 12. The safety profile was similar between treatment periods and treatment groups. CONCLUSIONS: These data suggest that even when insomnia symptoms have improved over time with placebo treatment, additional and sustained clinical gains in sleep outcomes are possible with active treatment using lemborexant.

Asunto(s)

Piridinas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Método Doble Ciego , Piridinas/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Sueño , Resultado del Tratamiento

RESUMEN

BACKGROUND: Insomnia is a multi-factorial disorder with conventional treatment options that are not satisfactory for many patients. This metaanalysis analyzed the safety and efficacy of daridorexant. METHODS: An electronic database search for RCTs was conducted on Medline via PubMed, Cochrane, and Clinicaltrials.gov using the terms 'Daridorexant,' 'RCT,' 'Insomnia' trials evaluating the efficacy and/or safety of daridorexant for insomnia were included. The data were synthesized using Cochrane review manager version 5.4.1. Cochrane risk of bias 2.0 tool and GRADEpro-GDT were used to assess the methodological and evidence quality, respectively. RESULTS: Of 109 searched studies, four trials were included. The risk of treatment-emergent adverse events with 25 mg daridorexant [risk ratio (RR) = 1.12 (0.88, 1.43), p = 0.36; I2 = 0%] and 50 mg daridorexant [RR = 1.25 (0.88, 1.79), p = 0.22; I2 = 28%] and serious adverse events with 25 mg [RR = 0.86 (0.23, 3.19), p = 0.82, I2 = 56%] and 50 mg [RR = 1.32 (0.29, 6.08), p = 0.72, I2 = 52%] was comparable to placebo [Moderate quality evidence]. Risk of nasopharyngitis was also comparable to placebo. The efficacy parameters like wake after sleep onset, latency to persistent sleep, and subjective total sleep time showed significant improvement with daridorexant. The risk of bias is low for three studies and some concern for one. CONCLUSION: Daridorexant is a safer and efficacious agent for induction and maintenance of sleep for chronic insomnia. PROSPERO: The registration number is CRD42022335233. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT03575104, NCT03545191, NCT03679884, and NCT02839200).

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Imidazoles , Pirrolidinas/efectos adversos

RESUMEN

Background: Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited. Methods: PubMed, Embase, Cochrane Library, and Clinicaltrials. gov were systematically searched to identify relevant studies published before 31 October 2022. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Results: We pooled 7257 participants from 9 randomized controlled trials (RCTs). Moderate to high certainty evidence demonstrated suvorexant (20 and 40 mg) and daridorexant (10 and 50 mg) as the most effective in latency to persistent sleep (LPS) reduction. Lemborexant at 5 and 10 mg was the most effective in subjective sleep onset time (sTSO) reduction. For wake time after sleep onset (WASO), all drugs except daridorexant 5 mg were more effective than placebo. Lemborexant 5 mg was among the best in subjective WASO (sWASO) (moderate to high certainty) and had the highest surface under the curve ranking area (SUCRA) values for sWASO (100%). For total sleep time (TST), suvorexant and daridorexant, except the respective minimum doses, were more effective than placebo, while suvorexant 40 mg and lemborexant 10 mg may have been the most effective for subjective TST (sTST) (low to very low certainty). Suvorexant 40 mg (RR 1.09), suvorexant 80 mg (RR 1.65), and daridorexant 25 mg (RR 1.16) showed a higher safety risk than placebo. Conclusion: Suvorexant 20 mg, lemborexant 5 mg, lemborexant 10 mg, and daridorexant 50 mg represent suitable approaches for insomnia. Clinical Trial Registration: clinicaltrials.gov, PROSPERO (CRD42022362655).

RESUMEN

Epilepsy is a common neurological disorder, affecting patients of all ages, reducing the quality of life, and associated with several comorbidities. Sleep impairment is a frequent condition in patients with epilepsy (PWE), and the relation between sleep and epilepsy has been considered bidirectional, as one can significantly influence the other, and vice versa. The orexin system was described more than 20 years ago and is implicated in several neurobiological functions other than in controlling the sleep-wake cycle. Considering the relation between epilepsy and sleep, and the significant contribution of the orexin system in regulating the sleep-wake cycle, it is conceivable that the orexin system may be affected in PWE. Preclinical studies investigated the impact of the orexin system on epileptogenesis and the effect of orexin antagonism on seizures in animal models. Conversely, clinical studies are few and propose heterogeneous results also considering the different methodological approaches to orexin levels quantification (cerebrospinal-fluid or blood samples). Because orexin system activity can be modulated by sleep, and considering the sleep impairment documented in PWE, the recently approved dual orexin receptor antagonists (DORAs) have been suggested for treating sleep impairment and insomnia in PWE. Accordingly, sleep improvement can be a therapeutic strategy for reducing seizures and better managing epilepsy. The present review analyzes the preclinical and clinical evidence linking the orexin system to epilepsy, and hypothesizes a model in which the antagonism to the orexin system by DORAs can improve epilepsy by both a direct and a sleep-mediated (indirect) effect.

Asunto(s)

Epilepsia , Calidad de Vida , Animales , Orexinas , Receptores de Orexina/fisiología , Sueño/fisiología , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Antagonistas de los Receptores de Orexina/uso terapéutico , Antagonistas de los Receptores de Orexina/farmacología , Convulsiones/tratamiento farmacológico

RESUMEN

RATIONALE: Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health. OBJECTIVES: This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act. RESULTS: LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks. CONCLUSIONS: LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.

Asunto(s)

Antagonistas de los Receptores de Orexina , Trastornos del Inicio y del Mantenimiento del Sueño , Adulto , Humanos , Sustancias Controladas , Piridinas , Hipnóticos y Sedantes

RESUMEN

INTRODUCTION: Insomnia is a common condition that may be caused by or coexist with other medical or psychological illnesses. Nearly a quarter of a billion people across the globe suffer from insomnia frequently. Lemborexant, a dual orexin receptor antagonist, is a recently authorized hypnotic-based medication for insomnia. The purpose of this systematic review is to further investigate its efficacy and safety profile, with the primary goal of comparing the effects of two FDA-approved doses of lemborexant, 5 mg and 10 mg (LEM5 and LEM10, respectively). MATERIALS AND METHODS: PubMed, Google Scholar, ClinicalTrials.gov, and Cochrane Central were searched for relevant literature, and studies were considered if they compared the efficacy and safety of lemborexant 5 mg to lemborexant 10 mg. This study comprised clinical trials. RESULTS: A total of 6 studies were evaluated for efficacy and safety of lemborexant therapy. They reported a significant betterment in values pertaining to sleep efficacy, sleep onset latency, wake after sleep onset, total sleep time, sleep quality, ISI score, and morning alertness. The results presented a dose-dependent pattern and showed slight variation with the different dosages. The most prevalent side effects noted were somnolence, headaches, and dizziness, with infections like UTIs and upper respiratory tract infections also being commonly reported. The incidence is rather ambiguous and not sincerely dose-dependent. The differences between results for LEM5 and LEM10 do not exhibit a wide variation, although slight dose-dependent alterations are noted. CONCLUSION: Lemborexant is well integrated with the amelioration of sleep disturbances in insomniac patients, as shown by a decrease in eSOL and sWASO and a rise in sSE, sTST, quality of sleep, and morning alertness. Effects last 12 months after therapy.

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Piridinas , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Antagonistas de los Receptores de Orexina/efectos adversos

RESUMEN

STUDY OBJECTIVES: Patients with chronic insomnia may respond differently to therapeutic modalities. This study examined differences in response of individuals with 2 insomnia phenotypes-short sleep duration (I-SSD; < 6 hours) and normal sleep duration (I-NSD; ≥ 6 hours) determined by polysomnography-to treatment with lemborexant and zolpidem tartrate extended-release 6.25 mg (zolpidem ER), compared with placebo. METHODS: Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) was a global, randomized, double-blind, placebo, and active comparator-controlled, parallel-group study comparing lemborexant 5 and 10 mg in individuals aged ≥ 55 years with insomnia disorder. In this analysis, changes in subjective (self-reported) variables based on sleep diaries and objective variables based on polysomnographs were assessed after 1-month administration of study drugs. Data from participants with I-SSD and I-NSD were compared. RESULTS: In the I-SSD subgroup, both lemborexant doses provided significant benefit for sleep-onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) vs placebo; zolpidem ER also provided significant benefit for TST and WASO, but not SOL, on both measures vs placebo. In the I-NSD subgroup, lemborexant and zolpidem ER provided significant benefit for TST and WASO vs placebo objectively but not subjectively; both doses of lemborexant provided significant benefit for SOL vs placebo subjectively, but not objectively. CONCLUSIONS: Both drugs, but lemborexant more consistently, showed subjective and objective benefits compared with placebo in participants with insomnia with objective short sleep duration. However, neither lemborexant nor zolpidem provided consistent benefits for participants with normal sleep duration on sleep-onset and sleep maintenance variables. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/record/NCT02783729; Identifier: NCT02783729. CITATION: Inoue Y, Nishida M, Kubota N, et al. Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings. J Clin Sleep Med. 2023;19(3):519-528.

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Zolpidem , Hipnóticos y Sedantes , Resultado del Tratamiento , Método Doble Ciego

RESUMEN

BACKGROUND AND PURPOSE: A major problem managing alcohol use disorder is the high vulnerability to relapse, even after long periods of abstinence. Chronic alcohol use dysregulates stress responsivity, rendering this system hyporesponsive and making individuals vulnerable to relapse. Orexin (hypocretin) plays a role in diverse physiological processes, including stress. Orexin neurons in the hypothalamus, project to the infralimbic cortex. This study asked does infralimbic cortex orexin transmission play a significant role in stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats. EXPERIMENTAL APPROACH: Male and female rats were trained to self-administer 10% alcohol (3 weeks) and then made dependent via chronic intermittent alcohol vapour exposure. Following extinction (5 days·week-1 at 8 h abstinence for 10 sessions), rats received an intra- infralimbic cortex microinfusion of the OX1/2 antagonist TCS 1102 (15 µg/0.5 µl per side) and then tested for footshock stress-induced reinstatement of alcohol seeking. In a separate cohort, orexin regulation of infralimbic cortex neuronal activity at the time of reinstatement was investigated using ex vivo electrophysiology. KEY RESULTS: TCS 1102 prevented reinstatement in dependent animals only. Moreover, Hcrtr mRNA expression in the hypothalamus and Hcrtr1/2 in the infralimbic cortex increased in alcohol-dependent animals at the time of testing. Dependence dampened basal orexin/OX receptor influence over infralimbic cortex GABAergic synapses (using TCS 1102) allow for greater stimulated orexin effects. CONCLUSION AND IMPLICATIONS: Infralimbic cortex transmission is implicate in stress-induced reinstatement of alcohol-seeking behaviour in subjects with a history of alcohol dependence and show maladaptive recruitment of infralimbic cortex transmission by alcohol dependence.

Asunto(s)

Alcoholismo , Femenino , Ratas , Masculino , Animales , Receptores de Orexina/metabolismo , Orexinas , Etanol/farmacología , Consumo de Bebidas Alcohólicas , Autoadministración , Extinción Psicológica , Comportamiento de Búsqueda de Drogas

RESUMEN

Study objectives: Lemborexant (LEM) is a dual orexin receptor antagonist approved for treating adults with insomnia. We analyzed the efficacy (subjective sleep outcomes) and safety of LEM over 12 months in the subgroup of Asian subjects from Study E2006-G000-303 (Study 303). Methods: Study 303 was a 12-month, randomized, placebo-controlled (first 6 months), double-blind, parallel-group, phase 3 study of adults with insomnia disorder. During the 6-month Period 1, subjects were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10); LEM subjects continued treatment in the following 6-month Period 2. Outcome measures included subject-reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Insomnia Severity Index (ISI), and Patient Global Impression-Insomnia version (PGI-I). Treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 178 Asian subjects (Japanese, n = 161; Chinese, n = 4; other Asian, n = 13) were included. Greater decreases in sSOL and sWASO and increases in sSE and sTST from baseline were observed with LEM vs placebo at 6 months; LEM benefits were sustained through 12 months. Greater decreases in ISI total score were seen with LEM vs placebo at 6 months; improvements from baseline with LEM continued through 12 months. For each PGI-I item, LEM-treated subjects had more positive medication effects than placebo-treated subjects at 6 months; these effects were maintained with LEM in Period 2. TEAEs were generally mild to moderate. Conclusions: LEM improved subjective sleep parameters and was well-tolerated in Asian subjects with insomnia disorder over 12 months. Clinical trial registration: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

RESUMEN

BACKGROUND: The dual orexin receptor antagonist daridorexant did not impact nighttime respiratory function as assessed by the apnea/hypopnea index (AHI) and nocturnal oxygen saturation (SpO2) and improved sleep in patients with mild to moderate obstructive sleep apnea (OSA). These analyses were supplemented with further evaluations of various indices of OSA severity and sleep variables. METHODS: In this randomized, double-blind, placebo-controlled, two-period, crossover study, 50 mg daridorexant or placebo was administered every evening for 5 days to 28 patients with mild to moderate OSA. Treatment differences (daridorexant - placebo) were explored for indices of OSA severity including the number and duration of apneas and hypopneas, mean and lowest nocturnal SpO2, sleep duration during each hour of polysomnography recording, and the number and mean and longest duration of awakenings. RESULTS: After repeated-dose daridorexant, more respiratory events were observed compared to placebo, ie., treatment difference of 16.4 events (90% confidence interval: -0.4, 33.2) which is explained by a longer total sleep time. However, no treatment difference was detected for the longest duration of apneas and hypopneas (1.5 s [-8.3, 11.2] and 8.2 s [-6.6, 23.0], respectively), and lowest SpO2 (0.9% [-0.3, 2.1]). The number of awakenings was similar between daridorexant and placebo while daridorexant shortened the longest duration by 16.2 min (8.5, 23.8). Overall, results were similar after single and repeated dosing for both respiratory and sleep aspects. CONCLUSION: These results suggest safe use of daridorexant in patients with mild to moderate OSA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/NCT03765294.

Asunto(s)

Antagonistas de los Receptores de Orexina , Apnea Obstructiva del Sueño , Estudios Cruzados , Humanos , Imidazoles , Antagonistas de los Receptores de Orexina/efectos adversos , Pirrolidinas , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/tratamiento farmacológico

RESUMEN

Lemborexant is a dual orexin antagonist and is considered a safe and effective hypnotic. Dual orexin antagonists induce physiological sleep by blocking orexin receptors. Although the blockade of orexin signaling has triggered narcolepsy-like symptoms in rodents, there is currently no evidence of lemborexant inducing narcolepsy-like symptoms in humans. We describe the case of a 79-year-old Japanese woman with bipolar depression who experienced lemborexant-induced cataplexy and sleep attack. Her previous results on the Multiple Sleep Latency Test excluded the diagnosis of narcolepsy. She experienced narcolepsy-like symptoms on 2 occasions after she was administered lemborexant, in the context of hyperactive delirium, but not in a relaxed state. Her case suggests that lemborexant could trigger narcolepsy-like symptoms in patients with hyperactive delirium, even those with no history of narcolepsy. This case also emphasizes that clinicians must be very careful when they prescribe lemborexant to patients who experience hyperactive delirium. CITATION: Shibata S, Oda Y, Ohki N, et al. Narcolepsy-like symptoms triggered by lemborexant in the context of hyperactive delirium in a patient with bipolar depression: a case report. J Clin Sleep Med. 2022;18(5):1459-1462.

Asunto(s)

Trastorno Bipolar , Cataplejía , Delirio , Narcolepsia , Trastorno Bipolar/complicaciones , Trastorno Bipolar/tratamiento farmacológico , Delirio/inducido químicamente , Femenino , Humanos , Narcolepsia/tratamiento farmacológico , Antagonistas de los Receptores de Orexina/efectos adversos , Orexinas , Piridinas , Pirimidinas