血府逐瘀丸治疗老年2型糖尿病伴失眠的临床疗效及其对认知功能的影响

目的:探究血府逐瘀丸治疗老年2型糖尿病伴失眠患者的临床疗效及其对认知功能影响。方法:选取43例我院收治的老年2型糖尿病伴失眠患者,将其随机分为实验组及对照组。对照组21例予地西泮治疗,实验组22予血府逐瘀丸治疗。观察两组治疗前后失眠症状及认知功能的变化情况。结果:治疗后,实验组总有效率(86.4%)高于对照组(61.9%),其差异经比较有统计学意义(P0.05);两组匹兹堡睡眠质量指数量表(PSQI)评分均较治疗前显著降低(P0.05),与对照组相比,实验组PSQI评分较低(P0.05),空腹血糖水平较低(P0.05),蒙特利尔认知评估量表(MoCA)评分较高(P0.05)。结论:血府逐瘀丸可有效降低老年2型糖尿病伴失眠患者的血糖水平,提升睡眠质量,改善失眠及认知功能障碍。     

Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (−)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (−)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid T_max and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9–2.0 h. Thus, (−)-3h (ORN0829; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia.     

针灸对肝郁化火型失眠患者NE 及PKC, BDNF表达水平的影响

目的:探究针刺对肝郁化火型失眠患者血清中去甲肾上腺素(NE)含量及蛋白激酶C(PKC)、脑源性神经营养因子(BDNF)基因表达水平的影响。方法:选取我院针灸科收治失眠,肝郁化火型住院患者,共120例。随机分为两组,对照组60例予以枣仁安神胶囊治疗;治疗组60例,在对照组基础上予以针刺四神聪穴(百会穴前后左右各相去1寸)。检测并比较患者血清中NE含量,RT-PCR检测脑组织中PKC、BDNF基因表达水平。结果:与治疗前相比,两组患者的NE水平均降低,PKC、BDNF水平均升高(P0.05);与对照组相比,实验组患者的NE水平较低,PKC、BDNF水平较高(P0.05),实验组患者的治疗总有效率较高(P0.05)。结论:针刺能够明显降低肝郁化火型失眠患者血清中NE水平,升高脑组织中PKC及BDNF基因转录水平,对临床有指导意义。     

Synthesis and evaluation of carbon-linked analogs of dual orexin receptor antagonist filorexant

Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.     

阿戈美拉汀联合舍曲林治疗抑郁症伴失眠的疗效及对睡眠质量评分、多导睡眠监测参数和血清神经递质的影响

摘要 目的：观察阿戈美拉汀联合舍曲林治疗抑郁症伴失眠的疗效及对睡眠质量评分、多导睡眠（PSG）监测参数和血清神经递质的影响。方法：选取2020年4月~2021年12月期间来贵州省第二人民医院就诊的80例抑郁症伴失眠患者作为观察对象,采用随机数字表法分为实验组和对照组各40例,对照组患者接受舍曲林治疗,实验组患者接受阿戈美拉汀联合舍曲林治疗,对比两组疗效、匹兹堡睡眠质量指数（PQSI）评分、PSG相关指标参数、汉密尔顿抑郁量表（HAMD）评分、血清神经递质水平变化,记录两组治疗期间不良反应发生情况。结果：实验组的临床总有效率为90.00%（36/40）,高于对照组的67.50%（27/40）,差异有统计学意义（P<0.05）。两组治疗8周后PSQI、HAMD评分均下降,且实验组的变化程度大于对照组（P<0.05）。两组治疗8周后睡眠总时间（TST）、睡眠效率（SE）、非快速眼动睡眠阶段3+4的百分比（SWS）、快速眼动睡眠阶段睡眠时间（RT）增加,非快速眼动睡眠阶段1的百分比（S1）、非快速眼动睡眠阶段2的百分比（S2）减少,且实验组的变化程度大于对照组（P<0.05）。两组治疗8周后去甲肾上腺素（NE）、5-羟色胺（5-HT）水平均升高,且实验组的升高程度大于对照组（P<0.05）。两组不良反应发生率组间对比未见差异（P>0.05）。结论：阿戈美拉汀联合舍曲林治疗抑郁症伴失眠,可有效改善抑郁和失眠症状,同时还可调节血清神经递质水平,是一个较为安全可靠的治疗方案。     

Intramolecular fluorescence resonance energy transfer (FRET) sensors of the orexin OX1 and OX2 receptors identify slow kinetics of agonist activation

Intramolecular fluorescence resonance energy transfer (FRET) sensors able to detect changes in distance or orientation between the 3rd intracellular loop and C-terminal tail of the human orexin OX(1) and OX(2) G protein-coupled receptors following binding of agonist ligands were produced and expressed stably. These were directed to the plasma membrane and, despite the substantial sequence alterations introduced, in each case were able to elevate [Ca(2+)](i), promote phosphorylation of the ERK1/2 MAP kinases and become internalized effectively upon addition of the native orexin peptides. Detailed characterization of the OX(1) sensor demonstrated that it was activated with rank order of potency orexin A > orexin B > orexin A 16-33, that it bound antagonist ligands with affinity similar to the wild-type receptor, and that mutation of a single residue, D203A, greatly reduced the binding and function of orexin A but not antagonist ligands. Addition of orexin A to individual cells expressing an OX(1) sensor resulted in a time- and concentration-dependent reduction in FRET signal consistent with mass-action and potency/affinity estimates for the peptide. Compared with the response kinetics of a muscarinic M(3) acetylcholine receptor sensor upon addition of agonist, response of the OX(1) and OX(2) sensors to orexin A was slow, consistent with a multistep binding and activation process. Such sensors provide means to assess the kinetics of receptor activation and how this may be altered by mutation and sequence variation of the receptors.     

Differences in pharmacokinetic and electroencephalographic responses to caffeine in sleep-sensitive and non-sensitive subjects

The present study investigated pharmacokinetic and electroencephalographic responses to caffeine (140 mg) in two groups of healthy volunteers reporting, or not, caffeine-related sleep disturbances. Significant differences in caffeine consumption and smoking habits were observed between the two groups. Plasma samples were taken from each subject before (T0) and after caffeine intake at 0.5, 1, 2, 4, 6 and 24 h. Three pharmacokinetic parameters: half-life (t1/2), maximum time (Tmax) and maximum plasma concentration (Cmax) were calculated from caffeine plasma concentration measurements determined by reversed phase HPLC analysis. Caffeine-sensitive subjects showed significantly greater half-life values when calculated on 24 h after the administration than tolerant subjects (p<0.05). Since the elimination kinetics were similar on the first 6 h after caffeine administration, the increased caffeine clearance observed overnight, when smoking was resumed in the control group, may indicate a short delay for the induction of hepatic cytochrome, reported here for the first time. Electrophysiological responses to caffeine, including vigilance and cortical activity, were assessed by ambulatory electroencephalographic (EEG) recorded during a period of 6 h before and after caffeine consumption. Following caffeine intake, the caffeine-intolerant subjects presented an increase in vigilance levels with faster peak alpha, beta frequency and lower delta and theta power when compared to tolerant subjects. Pharmacokinetic parameters and EEG data showed significant differences between sleep-sensitive and control subjects. These variations may be, in part, explained by cigarette smoking and the higher caffeine intake observed in the subjects of the control groups while caffeine sleep-sensitive subjects have a significantly lower caffeine intake, as already reported in previous studies on patients with sleep disturbances.     

Association of rest–activity and light exposure rhythms with sleep quality in insomnia patients

ABSTRACT

The relevance of altered rest-activity rhythm (RAR) and light exposure rhythm (LER) in insomnia patients under natural conditions remains unclear. The aim of this study was to compare the parametric and nonparametric circadian variables of RAR and those of LER under natural conditions between insomnia patients and normal controls (NC) in a community-dwelling setting. The relationship of the nonparametric variables with sleep quality was also explored in both groups. Participants above 18 years old were recruited from three Public Health Centers in a rural area of Korea. Actigraphy (Actiwatch 2; Philips Respironics, Murrysville PA, USA) recording was conducted for 7 days. Subjects were eligible for our study if they had an insomnia disorder (ID) for at least 1 month. Actigraphy data of 78 normal control (NC) subjects (Age, 55.95 ± 13.22 years) and 104 patients with insomnia disorder (ID) (Age, 62.14 ± 12.34 years) were included for the analysis. Acrophases and amplitudes of RAR and LER were estimated using cosinor analysis. Interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA) of these rhythms were determined using nonparametric methods. Parametric cosinor and nonparametric variables of RAR and LER were compared between the NC and ID groups. Generalized linear models (GLMs) were applied to evaluate the main effects of group and each nonparametric variable as well as a group by each variable interaction on the sleep onset latency (SOL), sleep efficiency (SE), and wake after sleep onset (WASO) reflecting sleep quality. Among sleep parameters, the ID group showed significantly lower SE and greater WASO than the NC group. There were no significant differences in the acrophase and amplitude of RAR and LER between the two groups. There were no significant differences in IV, IS, and RA of RAR and LER between the two groups either. GLMs for RAR revealed a significant interaction between the group and IS on the SOL (β = ?46.39, p < 0.01), indicating a negative relationship of the IS with SOL in ID unlike its positive relationship in NC. There were no significant main effects of IV on the SOL, SE, and WASO, but significant main effects of RA on the SE and WASO (β = 63.65 and β = ?221.43, respectively, p < 0.01). GLMs for LER revealed no significant main effects of IS, IV or RA on the SOL, SE, and WASO, but significant interactions between group and RA on the SE and WASO (β = 56.17 and β = ?171.93, respectively, p < 0.05), indicating a stronger positive relationship of the RA with SE in ID compared to NC, and a negative relationship of the RA with WASO in ID, unlike its positive relationship in NC. Although our study did not reveal group differences in circadian variables of RAR and LER, it suggested that the regularity of RAR could be positively associated with sleep initiation, while the robustness of LER could be positively associated with sleep maintenance in insomnia patients.     

重复经颅磁刺激联合阿普唑仑治疗失眠症伴焦虑患者的效果分析

摘要 目的：研究重复经颅磁刺激以及阿普唑仑联用治疗失眠症伴焦虑患者的效果。方法：选择2015年1月～2019年12月我院神经内科收治的81例失眠症伴焦虑患者,将其随机分为两组。对照组每晚在睡前30 min服用阿普唑仑0.8 mg,观察组联用重复经颅磁刺激。比较两组的临床疗效,治疗前后焦虑评分、生活质量和睡眠质量评分的变化。结果：治疗后,观察组的有效率为95.00 %,明显高于对照组(73.17 %,P<0.05);两组焦虑评分均较治疗前明显降低(P<0.05),心理领域、社会领域、环境领域和生理领域评分均较治疗前明显升高(P<0.05),且观察组的焦虑评分和心理领域、社会领域、环境领域、生理领域评分明显优于对照组(P<0.05);两组的睡眠持续性、主观睡眠质量、睡眠障碍、日间功能、睡眠潜伏期、安眠药物和入睡时间评分均较治疗前明显升高(P<0.05),且观察组以上指标均明显高于对照组(P<0.05)。结论：重复经颅磁刺激以及阿普唑仑联用治疗失眠症伴焦虑患者的效果明显优于单用阿普唑仑治疗,其能有效减轻其焦虑程度,提高患者生活质量及睡眠质量。     

失眠症的中医证候分析与中药治疗概况

失眠症是指持续相当长时间的对睡眠的质和量不满意的状况,可引起精神无法集中、思考能力减退、警觉力与判断力下降、免疫功能低下、内分泌紊乱等,还与感冒、抑郁症、糖尿病、肥胖、中风、心脏病和癌症的发生有关。现代社会,随着生活水平的提高,体力劳动减少,脑力劳动增加,工作及精神压力日益加重,很多失眠患者情志不畅的表现尤为突出。经过临床观察,我们发现五脏气机失调在失眠症的辨证论治中占有主导作用,因此对失眠及失眠症的研究与治疗就成为重要课题。