中枢神经系统疾病及其药物与蛋白质组学研究进展

阐述中枢神经系统疾病及其药物蛋白质组学研究的最新进展。蛋白质组学是后基因组时代的一门重要学科 ,是从整体水平对蛋白质进行综合分析 ,目前已广泛应用于临床和生物医学各个领域。蛋白质组学研究有助于阐明CNS疾病发生、发展、转归的网络机制 ,寻找疾病特异性蛋白质 ,针对疾病靶点定向合成药物 ,构建分子药理模型 ,高通量地筛选和评价药物的效应及毒副作用。可以预见 ,蛋白质组学将为CNS疾病的诊断、监测和药物研制起到不可估量的作用     

Vitamin D and the central nervous system

Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases.     

P-糖蛋白介导的中枢神经系统药物相互作用

P-糖蛋白(P—gp)属于ATP结合盒转运体超家族成员之一,是目前研究较多的一类转运体,它广泛分布于人体的肠、肝、肾、等部位的管腔上皮细胞和脑毛细血管内皮细胞上。由于临床使用的大多数药物都是P—gp底物和或调节剂,容易引起相应的药物相互作用。本文重点介绍了P—gp与血脑屏障、P—gp对中枢神经系统(CNS)药物作用的研究进展、P—gp介导的相互作用及在中枢神经系统上产生的药物效应或副作用。     

Discontinued drugs in 2006: central and peripheral nervous system drugs

This perspective describes compounds that target the central and peripheral nervous system, whose development was discontinued in 2006 and which were being developed for the treatment of a range of neurological disorders, including chronic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and anxiety. These discontinued candidates are described by disease area, based on information available from the Pharmaprojects database.     

The toxic effect of opioid analgesics on human sperm motility in vitro

Opioid analgesics are the most common therapeutic analgesic for acute pain. In this study, the toxicological and pharmacological features of a group of opioid analgesics were characterized by the motility of human sperm. Aliquots of sperm were incubated with various concentrations of opioid analgesics in vitro. Computer-assisted sperm analysis was used to assess sperm motility at 15 minutes, 2 hours, and 4 hours after drug addition to the medium. Butorphanol and dezocine showed marked reduction of motility after incubation with sperm for 15 minutes. Butorphanol was more effective than dezocine in immobilizing sperm. Other opioids studied, such as fentanyl, alfentanil, and sufentanil, showed only partial inhibitory activity. Based on the data reported herein, we have found that butorphanol and dezocine exert a sperm-immobilizing effect. However, fentanyl, alfentanil, and sufentanil exhibit only partial inhibition of sperm motility. Given the increasing use of opioids and their potential effect on sperm motility, these findings are greatly relevant to male reproductive health.     

原发性中枢神经系统淋巴瘤32例临床分析

目的 探讨原发性中枢神经系统淋巴瘤（PCNSL）临床特点、诊治方案及临床疗效。方法 回顾性分析1990年1月～2004年12月收治的PCNSL32例。结果 1例经立体定向活检确诊,31例手术确诊。31例手术中全切或近全切除28例（90％）,大部切除3例（10％）,无手术死亡病例。病理检查：B细胞型淋巴瘤30例,T细胞型淋巴瘤2例。术后临床症状改善22例（69%）,稳定6例（19％）,症状加重4例（12％）。术后辅以放射治疗25例,联合化疗9例。结论 PCNSL为少见恶性肿瘤,早期诊断,并进行有效的综合治疗是延长PCNSL患者生存期和改善生存质量的关键。     

中枢神经系统的药代动力学参数及其意义

血脑屏障可阻碍药物进入中枢神经系统。本文系统介绍了中枢神经系统的药代动力学研究常用的几个参数:PS积、内清除率(Kin,CLin,)、外清除率(Kout,CLout)、T1/2eq,in、摄取百分比(%ID/g)、脑/血分配系数(Kp,Kp,u和Kp,uu),游离药物表观分布容积(Vu,brain)和脑内药物半衰期(T1/2,brain)。其中,PS积用来评价药物通过血脑屏障的能力、内清除率(Kin,CLin,)、外清除率(Kout,CLout)、T1/2eq,in、T1/2,brain用来描述药物进出中枢神经系统内的速度;%ID/g、Kp,uu用来评价药物进入大脑的程度;Vu,brain评价药物在脑内的分布特点。     

铅对中枢神经系统功能及母体铅负荷对子代中枢神经系统发育的影响

采用猕猴作为实验对象进行了铅对中枢神经系统功能以及母体铅负荷对于代中枢神经系统发育的影响的实验研究。实验发现染铅组母猴脑铅和脑组织脂质过氧化物含量明显高于对照组（Ｐ＜０．０５），中枢神经递质５－ＨＴ含量降低。仔猴的观察指标改变与母猴相似。结果提示接触５～１５ｍｇ／ｋｇ剂量的醋酸铅可导致中枢神经细胞膜和功能的损害，并可发生中枢神经系统功能的改变。母体铅可经胎盘和乳汁传递至子代，长期铅接触可致子代脑发育不良。     

加锡果宁的中枢抑制作用

加锡果宁(Ed)在1/20～1/8 LD_(50)剂量下对小鼠可明显缩短巴比妥或安定的翻正反射消失潜伏期和延长睡眠时间,增强乙醚的麻醉作用,减少自发活动。对某些镇痛药也有增强作用,使家兔脑电呈高幅慢波。延长大鼠总睡眠和慢波睡眠时间,与ip 30mg/kg戊巴比妥钠的作用强度相似,但Ed抑制异相睡眠时间比戊巴妥钠更强。     

Effects of maternal chlorpromazine on offspring nervous system development.

Administration of chlorpromazine (7 mg/kg/day) to rat dams from day 8 of pregnancy until the pups were weaned produced small but statistically significant decreases in litter size and birth weight. The difference in pup weight was no longer present at the time of weaning. The offspring of chlorpromazine-treated dams were less able to maintain body temperature in response to restrained cold stress as determined when they were 60–65 days of age. They also incorporated significantly less¹⁴C from tyrosine into heart norepinephrine during acute cold exposure. No differences in incorporation of ¹⁴C into norepinephrine from tyrosine were evident when the animals were not subjected to cold stress. Similarly treated offspring did not have an increase in superior cervical ganglion tyrosine hydroxylase activity after 48 hr of cold exposure while the offspring of control dams did have a significant increase in the activity of this enzyme. These data suggest that maternal administration of chlorpromazine produces a permanent alteration in the ability of the offspring to respond to cold stress and that this deficit is related to an alteration in nervous system development.     

The central nervous system effects, pharmacokinetics and safety of the NAALADase-inhibitor GPI 5693

AIM: The aim was to assess the central nervous system (CNS) effects, pharmacokinetics and safety of GPI 5693, an inhibitor of a novel CNS-drug target, NAALADase which is being evaluated for the treatment of neuropathic pain. METHODS: This was a double-blind, placebo-controlled, exploratory study in healthy subjects receiving oral GPI 5693 single ascending doses of 100, 300, 750, 1125 mg with a placebo treatment randomly interspersed. An open-label, parallel extension examined the effects of food and sex on the pharmacokinetics of 750, 1125 and 1500 mg doses. Blood samples were collected for pharmacokinetic and biochemical/haematological safety analysis, vital signs, ECG and adverse event checks were performed regularly up to 48 h postdose. Postdose CNS effects were assessed using eye movements, adaptive tracking, electroencephalography (EEG), body sway and Visual Analogue Scales (VAS). RESULTS: CNS effects were mainly observed after the 1125 mg dose, showing a significant decrease of adaptive tracking performance, VAS alertness and VAS mood, and an increase of EEG occipital alpha and theta power. Gastro-intestinal (GI) adverse effects were frequent at higher doses. No clinically significant changes in vital signs or ECG were noted during any of the treatments. The therapeutically relevant concentration range (950-11 100 ng ml(-1)) as determined from animal experiments was already reached after the 300 mg dose. C(max) after the 300 mg and 750 mg dose was 2868 and 9266 ng ml(-1) with a t(1/2) of 2.54 and 4.78 h, respectively. Concomitant food intake (with the 750 mg and 1125 mg doses) reduced C(max) by approximately 66% and AUC by approximately 40%. With concomitant food intake, the dose-normalized C(max) also decreased significantly by -5.6 (CI: -2.6 to -8.7) ng ml(-1) mg(-1). The pharmacokinetic variability was largest after the 300 mg and 750 mg dose, resulting in a SD of approximately 50% of the C(max). CONCLUSION: NAALADase inhibition with GPI 5693 was safe and tolerable in healthy subjects. Plasma concentrations that were effective in the reversal of hyperalgesia in the chronic constrictive injury animal model of neuropathic pain were obtained at doses of 300, 750 and 1125 mg in the fasted state. Comcomitant food intake reduced C(max) and AUC. CNS effects and GI AEs increased in incidence over placebo only at the 1125 mg dose.     

中枢认知功能有关基因

中枢学习记忆功能障碍是衰老及老年性痴呆病人的典型特征之一。大量研究初步表明中枢学习记忆的生理和病理过程受基因调控,已发现多种基因及其产物与中枢学习记忆的生理及病理过程有密切的关系。即刻早期基因家族作为“第三信使”参与调节神经细胞内信号转导而与学习记忆密切相关,其中ｃ ｆｏｓ的表达与学习记忆功能的变化具有密切关系。神经细胞粘附分子、ｅｐｅｎｄｙｍｉｎ及ＧＡＰ ４３基因参与和影响突触的可塑性与重建及细胞间粘附连接。ＣＲＥＢ能激活与学习记忆密切相关的基因,在长时记忆（ＬＴＭ）过程中起重要作用。此外,ｂｃｌ ２、ＩＣＥ、ｐ５３、及ｈｓｐ等基因参与了神经元的信号转导及凋亡等过程,与学习记忆过程也有一定的联系。因此,寻找和研究学习记忆功能有关基因对从基因水平阐明中枢学习记忆功能的调控机制具有重要意义。     

反相HPLC快速测定微量人血清中7种中枢神经抑制药

本文采用简便的RP—HPLC 条件和萃取方法,9min 内同时测定微量血清(<100μl)中7种中枢神经抑制药。样品用三氯甲烷/乙酸乙酯(100∶2v/v萃取,N_260℃吹干。色谱柱:Spherisorb-C_(18)(4.0mm×150mm),流动相为MeOH/H_2O(45/55v/v)1.0ml/min 在220nm 检测。最小检出限≤35ng/ml,回收率在93.1%～98.3%,变异系数=1.6%。本法简便、快速、灵敏、准确。适于临床对配伍或交叉用药时的血浓度监测。     

Evaluation of effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system

It has been shown that vasoconstrictive drugs such as ephedrine derivatives are able to decrease systemic absorption of drugs administered by mucosal surfaces. The present paper set out to evaluate in the rat model the effect of co-administered nasal ephedrine on the absorption of GR138950 in a simple and in a pectin self-gelling formulation. It was hypothetised that a decrease in nasal systemic absorption would lead to an increase in direct nose-to-brain transport as demonstrated by the drug concentration in the olfactory lobes of the brain. It was found that ephedrine administered nasally with the drug in a simple aqueous solution resulted in a significant increase in nasal systemic absorption and also an increase in brain delivery; however, this trend was not observed with the pectin formulations. The pectin formulation with ephedrine resulted in lower systemic absorption of GR138950 and lower brain uptake compared to the simple solution formulation containing ephedrine.     

系统性红斑狼疮合并中枢神经系统病变28例临床研究

目的 对系统性红斑狼疮(SEE)合并中枢神经系统(CNS)病变的临床特点、诊治经验进行研究。方法 对我院28例有CNS病变的SLE住院及专科门诊的病人进行回顾性分析。结果 在SLE发病2年内起病者占75％：活动期病人24例：焦虑、抑郁等为主要表现者占31．2％。其次为癫痫占21．4％;60％病人脑脊液检查异常：影像学主要表现为梗塞、出血、脑萎缩等。治疗后18例病情好转,死亡6例。结论 SLE合并CNS病变临床表现多样,其诊断主要依靠临床表现、脑脊液及影像学检查：治疗应强调个体化原则。     

短肽类药物与中枢神经系统疾病

中枢神经系统疾病的治疗一直是医学领域的难题。传统药物无法防治急慢性中枢神经系统损伤、阿尔采末病、帕金森病、癫痫等中枢神经系统疾病。医学界一直在致力于寻找治疗中枢神经系统疾病的新药。短肽类药物是近年来研究的热点。人工合成的联接蛋白43模拟肽、载脂蛋白E模拟肽、神经营养因子模拟肽、神经细胞黏附分子模拟肽、金属硫蛋白模拟肽、促红细胞生成素模拟肽等短肽类药物对中枢神经系统疾病的治疗价值已获得证实。该文对短肽类药物在中枢神经系统疾病治疗中的研究进展进行了全面分析综述。     

炎症小体与中枢神经系统疾病

炎症小体是一蛋白复合物,能够识别不同刺激信号,活化后能诱导免疫和炎症应答。NLRP3炎症小体是中枢神经系统中研究最广泛的炎症小体。小胶质细胞、血管周围的巨噬细胞和脑膜巨噬细胞均能表达炎症小体,而炎症小体与急性脑部感染、急性无菌性脑损伤、帕金森病和阿尔茨海默病等的发生发展有密切关系。基于炎症小体与中枢神经系统疾病相关的机制探索和靶向药物开发是目前的研究热点。     

反式曲马朵及反式氧去甲基曲马朵对映体在大鼠中枢神经系统的分布

目的：研究反式曲马朵（trans-T)及其活性代谢产物反式氧去甲基曲马朵（M1）对映体的中枢神经系统分布。方法：大鼠ip单剂量的盐酸trans-T或M1后,采用高效毛细管电泳（HPCE）法测定血清和不同脑组织中trans-T及M1对映体的浓度,脑组织包括脑脊液、大脑皮层、纹状体、下丘脑、小脑、延髓。结果：大鼠ip盐酸trans-T后,在血清及所有测试脑组织中,（＋）－trans-T的浓度均高于（－）－trans-T的浓度;在所有测试脑组织中,（＋）－M1的浓度均低于（－）－M1的浓度;trans-T和（＋）－M1对映体的浓度以大脑皮层中最高,脑脊液中最低。大鼠ip M1后,在血清及所有测试脑组织中,（＋）－M1的浓度均高于（－）－M1的浓度;M1对映体的浓度以大脑皮层中最高,脑脊液中最低。结论：在血清和不同脑组织中,trans-T及M1对映体的浓度是有区别的;trans-T及M1在中枢神经系统的分布具有立体选择性;大鼠ip M1与trans-T后,M1在中枢神经系统分布的立体选择性是不同的。     

MRI对原发性中枢神经系统淋巴瘤的诊断价值探讨

目的探讨磁共振成像(MRI)对原发性中枢神经系统淋巴瘤(PCNSL)的诊断价值。方法 50例疑似原发性中枢神经系统淋巴瘤患者,随机分为对照组与研究组,各25例。对照组患者接受CT检查,研究组患者接受MRI检查。分析所有患者的手术病理结果;对比两组患者对病灶的检测准确率。结果 50例患者均接受手术病理确诊,对照组患者中有64个病灶,边界清晰的38个,边界较为清晰的19个,边界模糊不清的7个;所有病灶均未出现出血以及钙化,仅有18个病灶周围未见水肿;研究组患者中有73个病灶,边界清晰的43个,边界较为清晰的21个,边界模糊不清的9个;所有病灶均未出现出血以及钙化,仅有20个病灶周围未见水肿。研究组患者的病灶、边界清晰、边界较为清晰、病灶周围未见水肿的检测准确率分别为95.89%、95.35%、95.24%、95.00%,均高于对照组的73.44%、78.95%、63.16%、55.56%,差异有统计学意义(P<0.05);研究组边界模糊不清的检测准确率为100.00%,与对照组的71.43%比较,差异无统计学意义(P>0.05)。结论原发性中枢神经系统淋巴瘤采用进行MRI诊断,结合患者的个体情况,可对于确诊原发性中枢神经系统淋巴瘤有一定的提示作用,同时MRI还能探查到患者的病灶具体情况,为患者临床治疗方案提供参考依据,该诊断方式值得推广。     

原发性中枢神经系统淋巴瘤的MRI表现

目的研究原发性中枢神经系统淋巴瘤的MRI表现。方法回顾性分析7例PCNSL患者的MRI表现。结果单发病灶4例,多发病灶3例,共11个病灶,其中分布于额叶4个,顶叶、颞叶、小脑半球各2个,胼胝体1个。T1WI呈低或稍低信号,T2WI呈高信号或稍高信号,FLAIR呈高信号或稍高信号,DWI高信号。增强扫描病灶明显均匀强化,可见＂缺口征＂（2个）和＂尖角征＂（1个）,3个病灶邻近脑膜可见异常强化。伴囊变坏死5个,出血2个。轻-中度水肿8个,重度水肿3个。结论原发性中枢神经系统淋巴瘤的MRI表现有一定的特征性,但对于不典型的病例还较难做出正确诊断。