应激在抑郁症失眠中的作用和常用应激动物模型的睡眠特点

抑郁症导致的失眠常表现为睡眠中断和早醒, 慢波睡眠 (slow wave sleep, SWS) 减少或消失以及快速动眼 (rapid eye movement, REM) 睡眠潜伏期缩短。这些异常特征与应激引起的下丘脑-垂体-肾上腺 (hypothalamic-pituitary-adrenal, HPA) 轴去抑制亢进导致的睡眠异常极为相似, 提示两者之间可能有密切的联系。因此由应激引起的动物模型, 如创伤后应激障碍和慢性温和不可预知应激等模型, 可用来评价抗抑郁和改善睡眠的药物, 并为深入研究抑郁及伴发的失眠机制提供比较可靠的平台。本文重点阐述抑郁症失眠的特点、可能的病理生理机制、常用应激动物模型的建立方法并分析其睡眠结构。     

失眠动物模型研究进展

催眠药物是对失眠症进行对因和对症治疗的首选药物。设计和选择良好的动物模型是催眠药物从临床前基础研究过渡到临床研究的关键环节之一。该文从模型制作的不同理论根据(中医理论和西医理论)出发,对近年来催眠药物研究所用的失眠动物模型的造模机制、具体方法、优缺点及适用情况作一简要综述。     

Update on emerging drugs for insomnia

In recent years, there has been no evidence that the problem of chronic insomnia has faded in the least in US adults; on the contrary, a recent estimate of annual lost productivity due to insomnia was $63.2 billion dollars. However, the proportion of insomniacs who are treated continues to be low, indicating the need for continued development and dissemination of effective therapies. Hypnotic drug development has arguably become more focused in recent years, particularly upon the highly anticipated novel target, the orexin (hypocretin) system. Merck's suvorexant (MK-4305) is the first compound of the so-called dual orexin receptor antagonist (DORA) class expected to be submitted for FDA approval, with a new drug application anticipated in 2012. While there has also been some new activity in the modulation of well-characterized targets with well-characterized agents, such as CNS histamine receptors with low-dose doxepin, a decades-old antidepressant and GABA_A with sublingual zolpidem, experience with melatonin and serotonin modulators suggests that other targets also exist. Diversifying insomnia drug targets may expand possibilities for customizing hypnotic administration to individualized patient presentation and mechanistic underpinnings. In addition, it may offer improved avenues for combining medications with non-drug treatments such as cognitive behavioral therapy for insomnia (CBT-I).     

Zolpidem for insomnia

Background: Recently, mycophenolic acid drugs have gained interest in the treatment of autoimmune diseases. However, only limited pharmacokinetic data are available on enteric-coated mycophenolate sodium in non-transplant indications. Objective: This study compared the pharmacokinetics of mycophenolic acid from enteric-coated mycophenolate sodium in patients with autoimmune disease and renal transplant recipients. Methods: Twelve autoimmune disease patients (mainly with antineutrophil cytoplasmic antibody-associated vasculitis) and 11 stable renal transplant patients, all of whom had been on enteric-coated mycophenolate sodium for ≥ 10 weeks, received an oral dose of enteric-coated mycophenolate sodium of 720 mg under fasting conditions. Blood samples for the determination of mycophenolic acid in the plasma were collected over 24 h. Results. Overall, no significant difference was found between both groups for their 0 – 12 h and 0 – 24 h areas under the concentration–time curve, C_max, T_max, C_{0 h}, C_{12 h} and C_{24 h}, although the mean C_max was numerically higher by 39% in the autoimmune disease patients (autoimmune disease 27.3 ± 17.4 mg/l and renal transplant 19.6 ± 15.7 mg/l). Patients on concomitant ciclosporin tended to have a lower mycophenolic acid exposure than patients on a non-ciclosporin regimen. The intersubject variabilities in the mycophenolic acid pharmacokinetics were high in both patient populations (around 40% for the area under the curve values). Both groups exhibited a weak and non-significant correlation between their mycophenolic acid trough (C_{12 h}) levels and mycophenolic acid 0 – 12 h area under the curve (autoimmune disease r = 0.482 and renal transplant r = 0.138), whereas in the autoimmune disease group the mean C_{1.5 h} and C_{2 h} concentrations provided a satisfactory association with the 0 – 12 h area under the curve (for both r > 0.7 and p < 0.001). Conclusion: These data suggest that mycophenolic acid exposure (in terms of the area under the curve) from enteric-coated mycophenolate sodium is comparable in autoimmune disease and renal transplant patients. The mycophenolic acid trough levels did not reflect the systemic exposure to mycophenolic acid adequately; a limited sampling strategy for estimating mycophenolic acid exposure in autoimmune disease patients should include times around C_{1.5 h} and/or C_{2 h} reflecting T_max if further studies confirm its usefulness.     

Comparison of zopiclone and flurazepam treatments in insomnia

In this double-blind study the efficacy and safety of two doses (7·5 and 11·25 mg) of zopiclone were compared to that of flurazepam (30 mg) in 60 insomniac patients divided into three groups. After an initial 4-day washout period, placebo was administered single-blind to all patients followed by 24 consecutive days of either one of the three drug levels. No significant difference was shown between the two zopiclone dosages at any time during the study for sleep efficacy and psychomotor performance. Compared to flurazepam, zopiclone was slightly less effective for sleep induction and sleep soundness variables. However, flurazepam was constantly worse than zopiclone for daytime performance. This study shows that both zopiclone dosages are shown to be active and safe in the treatment of insomnia, and exhibit a true advantage over flurazepam by its low incidence of residual effects.     

Advances in the management of insomnia

Insomnia is a prevalent disorder, altering night time sleep, daytime mood and performance. Current treatment strategies, used separately or in combination, include pharmacological, circadian, behavioural and cognitive therapy. An increased diversity of available hypnotics with different potency, pharmacodynamic and pharmacokinetic profiles and improved side effect profiles provides more flexibility in designing individual treatment strategies. Melatonin, a pineal hormone with acute sleep-promoting and chronobiotic properties, allows additional possibilities in treating insomnia and circadian sleep disorders. Current studies of processes involved in normal sleep regulation and pathophysiology of insomnia should result in the development of new medications based on physiological mechanisms of sleep.     

老年性痴呆动物模型研究进展

老年性痴呆 (Alzheimersdisease ,AD )是一种进行性的神经退行性疾病 ,临床主要表现为中枢认知功能障碍 ,老年斑、淀粉样蛋白沉积及神经元纤维缠结 (NFT)是其脑部主要的病理学特征。由于AD的发病机制尚不清楚 ,给AD模型动物的研制带来了很大困难。自然衰老动物模型、损毁模型、脑室注射模型及自身免疫模型虽表现有中枢学习记忆功能的衰退 ,但缺乏AD脑内特征性的病理学变化。转基因模型虽然是十分有希望的模型 ,但目前的转基因模型尚不能全面反映AD的特征。因此 ,迄今为止还没有一个能够准确反应AD特征的理想的动物模型。比较而言 ,SAMP8是一个较好的AD替代模型 ,它既有AD学习记忆功能障碍的特征 ,又有部分AD病理学的特征。目前自身免疫模型和转基因模型已成为AD模型研究的新热点。研究并建立可靠的AD动物模型对于探明AD的发病机制以及防治药物的研究均具有重要的意义     

正常和便秘模型动物排便实验研究进展

近年来用多种方法成功地在大鼠、家兔、狗与猴等动物体内建立了若干新的便秘动物模型与排便实验方法。本文简要介绍这些模型的制作方法及其在药物研究中的应用:药物性便秘动物模型包括阿米替林所致猕猴便秘模型,吗啡所致家兔便秘模型,溴莫尼定和吗啡所致雪貂弛缓性与痉挛性便秘模型,洛哌丁胺所致大鼠便秘模型及对结肠黏液影响的研究;正常动物排便实验包括正常家兔与狗排便实验及清醒猴胃肠收缩活动测量。这些便秘模型制备方法,将有益于抗便秘药物研究时的选择应用。     

Use of zolpidem 10 mg as a benzodiazepine substitute in 84 patients with insomnia

The antagonistic effects of zolpidem 10 mg on withdrawal symptoms caused by abrupt or gradual discontinuation (half-dose over 4 nights) of triazolam 0·25 mg in patients with chronic insomnia, who had been receiving regular treatment for over one month, were assessed in a randomized, double-blind, placebo-controlled clinical trial in general practice. Eighty-four patients were enrolled, mostly women (67·9%), with a mean age of 54·3±11·0 years. Twenty-one different general practitioners were solicitated for the recruitment. The subjects were randomized into four groups, and all received triazolam 0·25 mg during the run-in phase from day 1 (D1) to day 3 (D3). The following treatments were given from D4 to D7: triazolam 0·125 mg+zolpidem 10 mg (Group 1); zolpidem 10 mg (Group 2); placebo (Group 3); or triazolam 0·125 mg+placebo (Group 4). Groups 1 and 2 received zolpidem 10 mg from D7 to D24, while Groups 3 and 4 received placebo. Finally, all four groups received placebo (blind withdrawal phase) from D25 to D28. The following assessment criteria were used: clinical global impression (CGI) scale completed by the practitioner; patient questionnaire based on routine sleep criteria, wakefulness and daytime alertness. Secondary criteria were sleep diaries and visual analogue scales. Study drop-outs were reported and explained. The effectiveness/tolerance ratio was found to be statistically significant using the CGI (p<0·007) in favour of zolpidem 10 mg. There was no significant difference in patients subjective assessment between the groups except for nightmares (p<0·04) less frequent in patients receiving zolpidem. Zolpidem was found to be more effective than placebo at D21 (CGI) according to sleep diaries; the zolpidem group showed a statistically significant difference as compared to the three other concerning four sleep parameters: number of awakenings, anxiety, sleep duration, energy. Drop-out rates were significantly lower in the zolpidem group than in other ones (p<0·01). Abrupt and gradual triazolam withdrawal over 4 nights induced withdrawal symptoms. Equally no specific phenomena were observed at the end of the trial during the blind withdrawal phase. This study shows that zolpidem 10 mg improves sleep quality and reduces withdrawal symptoms after abrupt or gradual discontinuation of triazolam 0·25 mg in chronic patients with chronic insomnia. Copyright © 1998 John Wiley & Sons, Ltd.