Cognitive interference as a possible therapeutic strategy to prevent expression of benzodiazepine withdrawal

Benzodiazepines are usually prescribed for anxiety and sleep disorders in long‐term schedules that may cause drug dependence. Discontinuation after prolonged administration may lead to withdrawal expression, being anxiety the most predominant sign. The context‐dependent associative learning process that underlies diazepam dependence can be interfered by pre‐exposure to the drug administration context, an effect known as latent inhibition. Considering this background, the primary aim of the present investigation is to develop a therapeutic strategy to prevent diazepam withdrawal in male Wistar rats by interfering with this learning process. Nitric oxide is a crucial player in learning and memory, hippocampal synaptic transmission and in diazepam withdrawal. Then, a secondary goal is to determine how latent inhibition could alter functional plasticity and neuronal nitric oxide synthase enzyme (NOS‐1) expression within the hippocampus, by using multi‐unitary cell recordings and Western blot, respectively. Our results indicate that chronic diazepam treated animals under latent inhibition did not show anxiety, or changes in hippocampal synaptic transmission, but a significant reduction in NOS‐1 expression was observed. Accordingly, pharmacological NOS‐1 inhibition resembles behavioral and electrophysiological changes induced by latent inhibition. Contrary, diazepam treated animals under Control protocol expressed anxiety and evidenced an increased hippocampal‐plasticity, without alterations in NOS‐1 expression. In conclusion, manipulation of the contextual cues presented during diazepam administration may be considered as an effective non‐pharmacological tool to prevent the withdrawal syndrome. This behavioral strategy may influence hippocampal synaptic transmission, probably by alterations in nitric oxide signaling pathways in this structure.     

Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

Quantitative electroencephalography from freely moving rats is commonly used as a translational tool for predicting drug‐effects in humans. We hypothesized that drug‐effects may be expressed differently depending on whether the rat is in active locomotion or sitting still during recording sessions, and proposed automatic state‐detection as a viable tool for estimating drug‐effects free of hypo‐/hyperlocomotion‐induced effects. We aimed at developing a fully automatic and validated method for detecting two behavioural states: active and inactive, in one‐second intervals and to use the method for evaluating ketamine, DOI, d‐cycloserine, d‐amphetamine, and diazepam effects specifically within each state. The developed state‐detector attained high precision with more than 90% of the detected time correctly classified, and multiple differences between the two detected states were discovered. Ketamine‐induced delta activity was found specifically related to locomotion. Ketamine and DOI suppressed theta and beta oscillations exclusively during inactivity. Characteristic gamma and high‐frequency oscillations (HFO) enhancements of the NMDAR and 5HT_2A modulators, speculated associated with locomotion, were profound and often largest during the inactive state. State‐specific analyses, theoretically eliminating biases from altered occurrence of locomotion, revealed only few effects of d‐amphetamine and diazepam. Overall, drug‐effects were most abundant in the inactive state. In conclusion, this new validated and automatic locomotion state‐detection method enables fast and reliable state‐specific analysis facilitating discovery of state‐dependent drug‐effects and control for altered occurrence of locomotion. This may ultimately lead to better cross‐species translation of electrophysiological effects of pharmacological modulations.     

基于TNF-α和FABP4蛋白探究长期服用奥氮平导致胰岛素抵抗的作用机制

目的：探究在长期服用奥氮平诱导的胰岛素抵抗过程中，TNF-α和FABP4的相互作用。方法：选择SD大鼠连续灌胃给予奥氮平8周，建立奥氮平诱导胰岛素抵抗的大鼠模型，期间分别对大鼠体质量、空腹血糖（FBG）、空腹胰岛素（Fins）和胰岛素抵抗指数（HOMA-IR）进行测定比较；ELISA测定大鼠血清和白色脂肪中的TNF-α表达量；通过Western Blot对3T3-L1细胞模型中的研究蛋白（FABP4和GLUT4）进行分析比较。结果：与对照组相比，长期服用奥氮平诱导胰岛素抵抗的大鼠血清和白色脂肪内TNF-α表达量显著升高（P<0.05），且在3T3-L1脂肪细胞模型中，随着TNF-α浓度增加，FABP4的表达量显著上升（P<0.05），GLUT4的上膜量显著降低（P<0.05）。结论：长期服用奥氮平可能引起机体产生炎症反应，激活TNF-α的表达，进而上调FABP4蛋白，最终降低GLUT4上膜量，导致胰岛素抵抗的发生。     

Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

分析对比奥氮平与利培酮治疗老年精神分裂症的疗效及安全性

目的：对奥氮平、利培酮治疗老年精神分裂症患者的有效性、安全性进行对比分析。方法：90例老年精神分裂症患者,随机（数字表法）分成观察组和对照组各45例。观察组应用奥氮平治疗,对照组则应用利培酮治疗。以BPRS评分、MCCB评分、TESS评分对2组患者治疗的效果、认知功能、安全性分别进行评价,并对2组患者治疗前、治疗8周后的体质指数（BMI）、血清空腹血糖（FBG）、餐后2 h血糖（2hPBG）、总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、催乳素（PRL）、瘦素（LP）水平进行比较。结果：在BPRS评分方面2组差异无显著性（P>0.05）。2组治疗后的MCCB评分均较治疗前显著上升,且观察组上升更为显著（P<0.05）。观察组的TESS评分显著低于对照组（P<0.05）。2组治疗后的血糖、血脂及BMI水平均较治疗前变化显著,且对照组在TC、TG、LDL-C方面的变化更为显著（P<0.05）。2组治疗后的PRL、LP水平较治疗前显著变化,且对照组变化更为显著（P<0.05）。结论：奥氮平、利培酮治疗老年精神分裂症效果相当,但奥氮平更有助于患者认知功能的改善,不良反应更少,并且对血脂、PRL、LP的影响轻于利培酮,安全性更高。     

奥氮平所致难治性迟发性肌张力障碍1例（英文）

迟发性肌张力障碍是长期使用抗精神病药物所致的一系列锥体外系症状,主要特征包括骨骼肌肉(随意肌)自主运动困难和随后的躯体变形。迟发性肌张力障碍在服用奥氮平患者中罕见,但本文报道中奥氮平正是这名22岁男性精神分裂症患者的促发抗精神病药物,他坚持服用标准剂量的奥氮平大约1年后出现撅嘴、持续不自主斜颈、肌肉疼痛、轴向肌张力障碍和步态不稳的症状。停用奥氮平后,他的症状没有缓解。氯氮平合并丙戊酸镁、维生素E、硫必利和劳拉西泮治疗四个月也没有让肌张力障碍得到任何改善。     

奥氮平联合金刚烷胺治疗精神分裂症首次发病患者的随机双盲对照研究

目的:探讨金刚烷胺添加对奥氮平治疗精神分裂症首次发病患者疗效及脂代谢的影响。方法:采用随机双盲法,将61例精神分裂症首次发病的患者随机分为研究组(31例)和对照组(30例),在奥氮平治疗的基础上,研究组及对照组分别添加金刚烷胺200 mg/d及安慰剂;疗程8周。治疗前及治疗4、8周进行阳性和阴性症状量表(PANSS)及治疗过程中出现的症状量表(TESS)评定,测量体质量,检测血三酰甘油(TG)、低密度脂蛋白(LDL)、总胆固醇(TC)水平。结果:治疗后研究组PANSS阴性症状减分值显著大于对照组(P0.05);TESS评分两组间差异无统计学意义;两组体质量和TG增加值差异无统计学意义;对照组LDL、TC增加值显著大于研究组(P均0.05)。结论:添加小剂量金刚烷胺短期内可明显增加奥氮平对精神分裂症患者阴性症状的改善作用,减少血LDL和TC水平升高;但不能改善奥氮平所致的体质量增加。     

奥氮平连续处理后大鼠中缝背核组织差异表达蛋白的生物信息学分析

目的 分析奥氮平连续处理的大鼠中缝背核蛋白的差异表达,探究奥氮平使用早期导致代谢障碍可能的中枢5-HT机制。方法 将40只SD大鼠随机分配到奥氮平组[灌胃奥氮平1.2 mg/(kg·d）]和对照组（灌胃等量0.9%氯化钠溶液）,两组各分配10只雌性大鼠、10只雄性大鼠。给药1次/d,连续28 d。最后一次给药1 h后处理大鼠,并取大脑中缝背核样本。利用绝对和相对定量同位素标记技术联合液相色谱-串联质谱技术对大鼠中缝背核组织进行蛋白质组学分析,进一步对差异表达蛋白进行GO、KEGG通路、COG、蛋白互作网络分析。另将24只大鼠随机分为4组：2个奥氮平组和2个对照组（6只/组）,类似方法得到大鼠中缝背核样本,根据蛋白质组学数据选择目标基因的表达进行qRT-PCR和Western blot验证。结果 筛选出奥氮平组与对照组大鼠中缝背核差异表达蛋白有72种上调、142种下调。GO注释分析显示,涉及奥氮平的差异表达蛋白参与细胞过程、生物调节、代谢过程、应激反应、多细胞生物过程以及结合、催化活性、分子功能调节、转录调节活性等分子功能。KEGG富集分析显示,涉及奥氮平的差异表达蛋白主要参与流体剪切应力与动脉粥样硬化、5-羟色胺能突触 、丁酸代谢、甲状腺激素合成 和IL-17信号通路等;PPI分析显示,涉及奥氮平的差异表达蛋白Hmgcs2、Cav1、Hsp90b1、Canx、Gnai1、MAPK9和LOC685513(Gng14）位于蛋白质互作网络的节点。qRT-PCR和Western blot结果显示,丁酸代谢和5-羟色胺(5-HT）能突触通路4个基因及其蛋白,其中丁酸代谢的关键调节基因Hmgcs2及其蛋白在药物处理组明显下调（P<0.01）,5-羟色胺2受体调控的Slc6a4、Gnai1基因及其蛋白在药物处理组均出现显著高表达（P<0.05）。结论 奥氮平使用早期可能主要通过调控中缝背核组织Hmgcs2、Cav1、Hsp90b1、Canx、Gnai1、Slc6a4、MAPK9和Gng14等差异表达蛋白以及5-HT能突触通路等,参与大鼠机体代谢障碍的中枢5-HT作用机制。