失眠治疗新药物双重食欲素受体拮抗剂daridorexant最新研究进展

治疗失眠障碍的药物种类繁多,然而当前市场上的失眠药物并不能完全满足临床需求。作为新型治疗失眠障碍的药物,双重食欲素受体拮抗剂(DORAs)与传统促眠药物有着不同的作用机制,它可以通过拮抗食欲素受体兴奋传导通路,选择性地影响大脑的睡眠/觉醒机制,能够避免常见传统促眠药物的一系列不良反应,并可有效改善睡眠障碍,在老年患者及青少年神经发育障碍患者中的失眠治疗效果均可观。最新研发的双重食欲素受体拮抗剂达利雷生(daridorexant)在全球已经开展了一系列临床研究,数据显示其不仅可以改善失眠障碍患者的夜间失眠症状和日间功能,且安全性和耐受性良好。本综述将对双重食欲素受体拮抗剂daridorexant的疗效、安全性以及各个研究阶段的临床数据进行总结。     

食欲素受体拮抗剂治疗失眠

目的为治疗失眠症新方法即食欲素受体拮抗剂的深入研究及临床运用提供参考。方法通过web of knowledge、scifinder和pubmed等外文数据库查阅相关文献44篇并对其进行分析与总结。结果现有的治疗方法包括认知行为治疗法(cognitive-behavioral therapy,CBT-I)和药物治疗两大类。由于CBT-I法需花费大量的时间和精力而药物干预法存在许多不良反应,所以在临床中运用都受限。近年来研究发现食欲体系可调节睡眠-醒觉体系,食欲素拮抗剂是一类新型的治疗失眠症的药物且副作用小,现已有大批量的食欲素受体拮抗剂用于失眠的研究。结论食欲素受体拮抗剂是治疗失眠的一类新方法。     

治疗成人失眠症的双重食欲素受体拮抗剂daridorexant

daridorexant是一种双重食欲素受体拮抗剂(dual orexin receptor antagonist, DORA),于2022年1月10日被美国FDA批准上市(商品名：Quviviq),用于治疗以入睡困难和/或睡眠维持困难为特征的失眠症成人患者。与传统镇静类催眠药物不同,daridorexant通过与双重食欲素受体的特异性结合抑制觉醒食欲素神经肽的作用。本文对其作用机制、药效学、药动学、安全性及临床研究进行综述。     

食欲素受体拮抗剂用于治疗酒精依赖的研究进展

酒精依赖是长期过度饮酒导致中枢神经系统紊乱的一种慢性、复发性脑部疾病,是全世界范围内严重的公共卫生问题,已给全球造成了巨大的社会和经济负担.目前用于治疗酒精依赖的药物有限,这些药物的临床疗效虽可以部分获得肯定,但不良反应同样突出.食欲素作为一种参与调节机体摄食、睡眠-觉醒和能量平衡的神经肽,在酒精等物质成瘾中也发挥着重...     

食欲素受体拮抗剂的研究进展

食欲素(orexin)是下丘脑外侧orexin神经元合成和分泌的神经肽,包括orexin-A和orexin-B.Orexin受体是G蛋白耦联受体,有两种亚型:OX1R和OX2R.近年来,食欲素受体及其拮抗剂的研究越来越受到重视,已发现食欲素受体拮抗剂对失眠、肥胖、抑郁症、药物成瘾等疾病具有治疗作用,为人类寻找上述疾病的治疗提供了新的思路.目前,食欲素受体拮抗剂,尤其是双重食欲素受体拮抗剂(DORAs)用来治疗失眠成为研究的热点,已有1个上市药品Suvorexant及处于临床Ⅲ或Ⅱ期研究的药物,发展前景广阔.本文对食欲素受体拮抗剂的研究进展进行综述,以期对该类药物的研究开发和使用有所帮助.     

达利雷生临床应用专家共识及监管建议

失眠障碍对患者及社会造成了沉重的负担,国内亟须疗效及安全性俱佳、滥用风险低、可及性理想、可长期使用、有效改善日间功能的非管制类创新机制催眠药。作为美国FDA及欧洲EMA批准上市的双重食欲素受体拮抗剂(dual orexin receptor antagonist, DORA),达利雷生(daridorexant)针对失眠患者展现出良好的疗效及安全性,可改善日间功能,且无明确的耐药性、依赖性及滥用证据,其公共卫生风险显著低于被列入《精神药品品种目录》的苯二氮■类药物和γ-氨基丁酸(γ-aminobutyric acid, GABA)能“Z类药物”。综合多方面证据,针对达利雷生的药监管理力度宜与该药可能产生的临床及公共卫生效益相权衡,以更好地满足人民群众的失眠治疗需求。     

双重食欲素受体拮抗剂类催眠药物的结构优化策略

食欲素受体拮抗剂,特别是双重食欲素受体拮抗剂（DORAs）,具有良好的镇静催眠效果,是近十年来新型镇静催眠药物研发的重点方向。较为经典的DORAs类药物有阿莫伦特、苏沃雷生、莱博雷生、达利多雷生等,DORAs类药物大部分是以U型分子骨架为基础对骨架上的模块进行改造,结构改造的核心目标是提高拮抗活性,此外还包括降低亲脂性、降低酶的时间依赖性抑制、降低药物外流比、提高脑浓度及降低P-糖蛋白的易感性。     

治疗成人失眠新药Dayvigo的研究现状

Dayvigo是美国食品药品监督管理局于2019年12批准的一种用于治疗成人失眠的新型双食欲素受体拮抗药,化学成分为lemborexant.临床研究结果显示Davigo能够显著改善失眠患者的入睡速度与睡眠维持时间.现对其作用机制、药理毒理研究、临床研究结果、安全性、有效性、注意事项等作一综述.     

新型血管紧张素Ⅱ受体和内皮素受体双重拮抗剂研究进展

简要介绍新型血管紧张素Ⅱ和内皮素受体双重拮抗剂的研究开发近况，并讨论其作用机制及构效关系。血管紧张素受体和内皮素受体双重拮抗剂以AngⅡ和ET-1之间的双向正反馈机制作为其治疗高血压的主要靶点。此类化合物对AngⅡ受体和ET-1受体兼有拮抗作用，因此有可能比单一的血管紧张素受体或内皮素受体拮抗剂疗效好，适应范围更广。     

Orexin 受体拮抗剂：治疗失眠的新途径

Orexin受体有2种亚型,即orexin-1受体和oerxin-2受体,为下丘脑外侧神经元中的2个G蛋白偶联受体,其内源性配体分别为orexin—A和-B。研究发现,动物或人的orexin神经元损伤后会引起嗜睡症,且orexin受体在调节睡眠-觉醒周期方面发挥重要作用。因此,开发orexin受体拮抗剂,成为改善睡眠和治疗失眠的-条新途径。简介orexin及其受体,综述orexin信号通路对睡眠-觉醒的调控作用与机制以及orexin受体拮抗剂的研究与开发。     

Neurogenesis-Independent Antidepressant-Like Effects on Behavior and Stress Axis Response of a Dual Orexin Receptor Antagonist in a Rodent Model of Depression

Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2′-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.     

雄激素受体拮抗剂普克鲁胺——具有双重作用机制的抗COVID-19新药

普克鲁胺是由开拓药业研发的第2代雄激素受体拮抗剂。针对COVID-19,该药具有双重作用机制,能通过下调血管紧张素转换酶2和跨膜丝氨酸蛋白酶2阻断新冠病毒侵入宿主细胞,并可抑制急性炎症、减轻细胞因子诱导的组织/器官损伤,对轻症、中症或重症COVID-19均有治疗效果。简介了普克鲁胺治疗COVID-19的机制与临床研究进展,旨在为COVID-19的新药研发与临床治疗提供思路。     

用于治疗失眠的褪黑激素受体激动剂研究进展

褪黑激素为一种内源性生理物质,可通过激动褪黑激素受体MT1和MT2来调节昼夜节律及睡眠质量。MT1和MT2由此成为失眠治疗药物的潜在靶点。介绍褪黑激素的作用机制,以及可用于治疗失眠的褪黑激素受体激动剂的研究进展,并初步探讨其构效关系。     

Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats

Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)_A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABA_A modulators from DORA-22, an analog of the DORA MK-6096, in Sprague–Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound''s ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.     

Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists: A New Paradigm for Treating Sepsis and Other Diseases

Sepsis remains the most common cause of death in intensive care units in the USA, with a current estimate of at least 750,000 cases per year, and 215,000 deaths annually. Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury. Endotoxin (lipopolysaccharide from Gram-negative bacteria, or LPS) has been implicated as a major cause of this syndrome. Inflammatory shock as a consequence of LPS release remains a serious clinical concern. In humans, inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages, which can cause fever, shock, organ failure and death. A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria, including blockage of one or more of the cytokines induced by LPS. Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor, TLR4. This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling, in vitro pre-clinical and in vivo clinical evaluation of TLR4 antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction.     

内皮素受体拮抗剂治疗肺动脉高压症临床评价

目的：伴随对肺动脉高压症发病机制的解释，一类内皮素受体桔抗剂于近期问市，本文阐述其在治疗肺动脉高压症的进展与临床评价，方法：采用国内、外文献综述方法。结果及结论：内皮素受体拮抗剂近年来进展迅猛，其抑制ET-1的收缩血管和促进细胞增殖作用，使动脉高压和心力衰竭问题已不再难于逾越，成为解脱肺动脉高压症之门一把金“药匙”．     

Mood Therapeutics: Novel Pharmacological Approaches for Treating Depression

Introduction: Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders.

Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non-pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States.

Expert commentary: Of these novel targets, the most promising – and the ones for whom the most evidence exists – appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders.     

内皮素受体拮抗剂治疗肺动脉高压的研究进展

近年来肺动脉高压的药物治疗多从调控内源性血管收缩因子（如内皮素-1、血栓素A2）和增殖介质（前列腺素和一氧化氮）的失衡入手。本文综述了基于内皮素-1途径的内皮素受体拮抗剂,如波生坦、安立生坦以及新近上市的macitentan,该类药物具有全身副作用小和口服优势,日益受到关注。     

养血清脑颗粒治疗失眠的临床观察

目的:观察养血清脑颗粒治疗失眠的临床疗效。方法:入组76例失眠患者,给予养血清脑颗粒每日3次,每次1袋治疗,4周为1疗程,治疗2个疗程。观察治疗前及治疗第4周、8周末的情况,用阿森斯失眠量表评定疗效。结果:治疗4周后失眠和认知功能障碍总有效率分别为63.15%和53.95%,治疗8周后失眠和认知功能障碍总有效率分别为89.47%和85.53%。结论:多数患者服药8周后失眠及认知功能障碍均有缓解。