地西泮固体脂质纳米粒的制备及大鼠经鼻腔给药的药动学研究

 目的 制备地西泮固体脂质纳米粒,评价其制剂学性质,并探讨其经鼻腔给药后的药动学过程。方法 用高温乳化-低温固化法制备地西泮固体脂质纳米粒,考察了其包封率、体外释药、粒径分布、Zeta电位和形态;大鼠经鼻腔给予固体脂质纳米粒或静脉给予地西泮注射液后经股动脉插管采集血样,采用HPLC测定血药浓度,以DAS1.0软件估算药动学参数。结果 制备的地西泮固体脂质纳米粒形态为类球形,平均粒径为(104.4±0.56 nm;Zeta电位为(-18.50±0.98 mV;包封率为(98.8±3%。经鼻腔给药后,地西泮固体脂质纳米粒的t_max为11 min,ρ_max为(0.33±0.01 μg·mL^-1,绝对生物利用度为67.01%。结论 鼻腔给予地西泮固体脂质纳米粒后吸收迅速,绝对生物利用度较高,有望成为治疗癫痫持续状态的新型制剂。     

不同剂量地西泮治疗酒依赖戒断综合征疗效和副作用比较

目的:比较不同剂量地西泮治疗酒依赖戒断综合征的疗效和副作用。方法:将94例酒依赖戒断综合征患者随机分为高(38%(V/V)白酒500 ml.d-1=地西泮40 mg.d-1)、中等(38%(V/V)白酒500 ml.d-1=地西泮30mg.d-1)、低(38%(V/V)白酒500 ml.d-1=地西泮20 mg.d-1)剂量三组,按不同换算模式计算地西泮剂量。用酒精戒断综合征评定量表(AWS)评定疗效。用自编的《地西泮替代治疗副作用记录单》详细记录治疗过程中出现的不良事件。结果:治疗后d1,d2,d3,d5各组与治疗前AWS评分比较,除低剂量组治疗d1与治疗前比较差异无显著性外(P>0.05),其余各组各天差异均有显著性(P=0.001)。治疗后高、中等剂量组之间AWS评分差异无显著性(P>0.05)。治疗d1,d2,d3高、中等剂量组AWS评分明显低于低剂量组,差异有显著性(P<0.001)。治疗d5三组间AWS评分差异无显著性(P>0.05)。治疗中出现的不良事件记录显示,高剂量组较低剂量组过度镇静,肌无力共济失调的发生率明显高,差异均有显著性(χ2=8.036,P=0.008;χ2=4.778,P=0.041)。结论:高、中等剂量地西泮治疗酒依赖戒断综合征较低剂量疗效好,高、中等剂量组副作用虽较低剂量组明显,但未见严重毒副作用。     

Effect of single-use versus combined-use moschus and diazepam on expression of amino acid neurotransmitters in the rat corpus striatum

The present study analyzed expressional changes of excitatory neurotransmitters and inhibitory neurotransmitters in the rat corpus striatum after single-use and combined-use diazepam and Chinese herb moschus. The influence of moschus on the central nervous system was analyzed, in particular whether moschus increased penetration of other drugs into the brain. Reverse-phase high-performance liquid chromatography, which included pre-column derivation with orthophthaladehyde detection, showed varied increased levels of excitatory neurotransmitters, including aspartate and glutamate, and inhibitory neurotransmitters, including glycine and Y-aminobutyric acid, in the corpus striatum after treatment with moschus alone, diazepam alone, or a combination of both. Compared with the diazepam group, aspartate levels significantly decreased at 30 and 60-105 minutes after combined treatment with moschus, while glutamate significantly increased at 45 and 75-105 minutes, glycine levels significantly increased at 105 minutes, and γ-aminobutyric acid increased at 30 and 75-105 minutes. These findings suggested that moschus increased the inhibition effects of diazepam on the brain.     

Benzodiazepine Receptor Agonists Cause Drug-Specific and State-Specific Alterations in EEG Power and Acetylcholine Release in Rat Pontine Reticular Formation

Study Objectives:

Benzodiazepine (BDZ) and non-benzodiazepine (NBDZ) hypnotics enhance GABAergic transmission and are widely used for the treatment of insomnia. In the pontine reticular formation (PRF), GABA inhibits rapid eye movement (REM) sleep and acetylcholine (ACh) release. No previous studies have characterized the effects of BDZ and NBDZ hypnotics on ACh release in the PRF. This study tested 2 hypotheses: (1) that microdialysis delivery of zolpidem, eszopiclone, and diazepam to rat PRF alters ACh release in PRF and electroencephalographic (EEG) delta power and (2) that intravenous (IV) administration of eszopiclone to non-anesthetized rat alters ACh release in the PRF, sleep, and EEG delta power.

Design:

A within- and between-groups experimental design.

Setting:

University of Michigan.

Patients or Participants:

Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 57).

Interventions:

In vivo microdialysis of the PRF in rats anesthetized with isoflurane was used to derive the concentration-response effects of zolpidem, eszopiclone, and diazepam on ACh release. Chronically instrumented rats were used to quantify the effects of eszopiclone (3 mg/kg, IV) on ACh release in the PRF, sleep-wake states, and cortical EEG power.

Measurements and Results:

ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam. EEG delta power was increased by zolpidem and diazepam but not by eszopiclone administered to the PRF. Eszopiclone (IV) decreased ACh release in the PRF of both anesthetized and non-anesthetized rats. Eszopiclone (IV) prevented REM sleep and increased EEG delta power.

Conclusion:

The concentration-response data provide the first functional evidence that multiple GABA_A receptor subtypes are present in rat PRF. Intravenously administered eszopiclone prevented REM sleep, decreased ACh release in the PRF, and increased EEG delta power. The effects of eszopiclone are consistent with evidence that ACh release in the PRF is lower during NREM sleep than during REM sleep, and with data showing that cholinergic stimulation of the PRF activates the cortical EEG.

Citation:

Hambrecht-Wiedbusch VS; Gauthier EA; Baghdoyan HA; Lydic R. Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation. SLEEP 2010;33(7):909-918.     

Use of phenytoin, phenobarbital, or diazepam during pregnancy and risk of congenital abnormalities: a case-time-control study

PURPOSE: Case-control studies are often used to examine putative teratogenic drug effects during organogenesis but these studies are subject to confounding by indication, recall, and participation bias. The case-time-control approach is less susceptible to these sources of bias. We studied congenital abnormalities following exposure to phenytoin, phenobarbital, and diazepam in early pregnancy, i.e., second and third month, compared to mid-pregnancy, i.e., fifth and sixth month of pregnancy. METHODS: We analyzed data from the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996) in a case-time-control study. RESULTS: The study included 22 843 children with congenital abnormalities (cases) and 38 151 children with no abnormalities (controls). Overall, odds ratio (OR) for congenital abnormalities after exposure to one of the three drugs in early pregnancy was 1.2 (95% confidence interval (CI): 1.0-1.4). Among children exposed to phenytoin OR for congenital abnormalities was 3.7 (95%CI: 0.3-49.6), for children exposed to phenobarbital the OR was 1.1 (95%CI 0.7-1.7), and for diazepam, OR for congenital abnormalities was 1.2 (95%CI: 1.0-1.4). CONCLUSIONS: The associations we found between the drugs examined and congenital abnormalities were either only borderline significant or not statistically significant. The case-time-control study provides an interesting way of using existing case-control data to study rare side effect of drugs taken during pregnancy.     

Genetic epistasis in female suicide attempters

Background

Complex behaviors such as suicidal behavior likely exhibit gene–gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction).

Methods

Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18 years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models.

Results

Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%–62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI) = 7.74(4.60–13.37)] in females.

Conclusions

Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters.     

安神方治疗广泛性焦虑障碍临床观察

目的观察安神方治疗广泛性焦虑障碍(GAD)的临床疗效。方法将120例GAD患者随机分为治疗组和对照组,每组60例,分别给予口服安神方和地西泮治疗,疗程均为4周。以汉密尔顿焦虑量表(HAMA)和副反应量表(TESS)评价疗效和不良反应。结果治疗4周后,两组HAMA分值均比治疗前明显降低,差异有统计学意义(P均<0.01);但两组间比较差异无统计学意义。治疗组与对照组TESS量表评分比较差异有统计学意义(P<0.05)。结论安神方治疗GAD安全、有效且不良反应较小,值得进一步研究推广。     

Distinct α GABA(A)R subunits influence structural and transcriptional properties of CA1 hippocampal neurons

The hippocampus is recognized as a major telencephalic area modulating learning and episodic memory through the activation of its different subregions. The various functional properties of Ammon's horn 1 (Cornu Amonis 1; CA1) area have been shown to rely on GABAergic and Glutamat- (Glu)-ergic neuronal signals during both postnatal and adult stages. For this purpose, it was the aim of the present study to establish whether certain alpha GABA(A)R subunits (alpha(2,5)) were capable of modifying CA1 structural and functional features via their interaction with specific NMDA receptor subunits such as NR1 during early development stages of the hibernating hamster (Mesocricetus auratus). Indeed, in vitro addition of the selective alpha(2,5) GABA(A)R agonist diazepam (DZP; alpha(2,5)) accounted for early neuronal formations that were blocked by its antagonist flumazenil (FLM). In particular, the former drug caused very great (p<0.001) increases of dendritic sprouting and branching processes mainly at day in vitro (DIV) 3, while its effects still continued to be responsible for moderate (p<0.05) increases of axonal length during the entire culture period. Contextually, DZP was also responsible for a very great up-regulated expression of neuritic NR1 and MAP2 together with a great (p<0.01) increase of synaptophysin at DIV7. Overall, this first study suggests a specifically tight cross-talking relationship of GABAergic/Gluergic mechanisms operating during CA1 neuronal development, which may bring us closer to the identification of more selective therapeutic targets for hippocampal-linked neurological disorders.     

安定-氯胺酮麻醉及烧伤的应激和炎症反应的比较

目的 :观察烧伤、安定 -氯胺酮麻醉对正常小鼠肝组织糖皮质激素受体和血清炎性细胞因子的作用 ,比较麻醉与创伤对应激和炎症反应的不同影响。方法 :雄性BALB/c小鼠 ,随机分为正常对照组、烧伤组、麻醉组。烧伤组背部 15%～ 2 0 %Ⅲ°烧伤 ,麻醉组采用安定 -氯胺酮麻醉 ,安定 0 4mg/kg ,氯胺酮 10mg/kg。烧伤或麻醉后 4h采用放免法测定血清皮质酮浓度 ,ELISA测定血清肿瘤坏死因子α(TNF -α)、白介素lβ(IL -lβ)、白介素 10 (IL -10 )水平 ,用Westernblot在蛋白质水平测定肝组织糖皮质激素受体。结果 :烧伤组、麻醉组与正常对照组相比血清皮质酮浓度明显升高 ,肝组织糖皮质激素受体明显降低 ,而麻醉组血清皮质酮浓度明显低于烧伤组 ,肝组织糖皮质激素受体水平明显高于烧伤组 ;烧伤组血清F -a、IL -lβ、IL -10比正常对照组显著增高 ,而麻醉组与正常对照组间无明显差异。 结论 :烧伤与安定 -氯胺酮麻醉均可引起小鼠血清皮质酮明显升高 ,其受体在蛋白质水平明显降低 ,但麻醉的影响明显小于创伤 ,并且烧伤可引起炎性细胞因子明显升高 ,而麻醉并无影响 ,揭示麻醉可引起机体一定的应激反应 ,但比创伤引起的应激和炎症反应程度轻