地西泮对妊娠期大鼠宫颈组织MMP-97/TMP-1表达的影响

目的探讨地西泮促进妊娠期大鼠宫颈成熟和扩张的作用及其可能机制。方法建立妊娠大鼠动物模型,随机分为4组,实验3组,分别为大鼠妊娠11d（中期）及18d（晚期）给予地西低剂量（0．5mg·kg^-1·d^-1）、中剂量（1．0mg·kg^-1·d^-1）、高剂量（2．0mg·kg^-1·d^-1）,给予0．9％生理盐水（2．0mg·kg^-1·d^-1）作为对照组。用蛋白印迹法测定其基质金属蛋白酶9（MMP-9）脸属蛋白酶组织抑制因子1（TIMP-1）的蛋白表达。结果随着妊娠进展宫颈组织MMP-9／TIMP-1表达增加,妊娠晚期较中期MMP-9／TIMP-1表达增加明显（P〈0．05）;妊娠中期不同剂量地西泮组宫颈组织MMP-9／TIMP-1表达与对照组相比无显著性差异：妊娠晚期地西泮中、高剂量组宫颈组织MMP-9／TIMP-1表达均较对照组变化显著（P〈0.01）,而总MMP-9蛋白浓度的表达无显著差异（P〉0.05）。结论一定剂量的地西泮具有增加宫颈组织MMPs活性的作用,从而促进妊娠晚期宫颈成熟和扩张。     

氟马西尼不同给药途径的催醒作用评价

目的 研究氟马西尼不同给药途径对受地西泮和唑吡坦催眠小鼠的催醒作用,评价氟马西尼口服制剂的可行性。方法 首先,昆明种小鼠分别腹腔注射生理盐水和戊巴比妥钠（S+W）、地西泮和戊巴比妥钠（D+W）、唑吡坦和戊巴比妥钠（Z+W）,观察（D+W）组和（Z+W）组能否延长戊巴比妥钠睡眠时间,验证地西泮和唑吡坦的催眠效果;然后提前腹腔注射给药氟马西尼,以小鼠睡眠时间为评价指标,评价其催醒作用;最后考察提前灌胃给药氟马西尼,观察其睡眠时间,评价氟马西尼灌胃给药的催醒作用。结果 与对照组（S+W）相比,地西泮组（D+W）和唑吡坦组（Z+W）能显著延长戊巴比妥钠诱导的小鼠睡眠时间（P<0.001,P<0.05）;提前腹腔注射或灌胃给药氟马西尼,与地西泮组（D+W）和唑吡坦组（Z+W）相比,小鼠的睡眠时间显著缩短（P<0.001,P<0.05）。结论 氟马西尼无论是腹腔注射还是灌胃给药,均能拮抗地西泮和唑吡坦的催眠作用,表明氟马西尼制成的口服制剂,同样能显著发挥药效,为研制氟马西尼口服制剂的可行性提供了依据。     

地西泮预防化学治疗诱导的恶心呕吐75例

目的探讨苯二氮革类药物地西泮联合格拉司琼、地塞米松预防化学治疗诱导的恶心呕吐的疗效和安全性。方法将150例接受化学治疗的肿瘤患者随机分成两组,各75例,对照组采用标准止吐方案格拉司琼联合地塞米松,试验组在对照组基础上加用地西泮,观察两组急性、延迟性和总的恶心呕吐缓解率,并评价治疗期间的毒副反应。结果完全缓解试验组53例（71.62%）,对照组42例（57.53%）,两组比较,X~2=3.19,P〉0.05;急性恶心呕吐缓解试验组57例（77.03%）,对照组55例（75.34%）,两组比较,X~2=0.06,P〉0.05;延迟性恶心呕吐缓解试验组55例（75.68%）,对照组缓解43例（58.90%）,两组比较,X~2=3.93,P〈0.05。两组各项毒副反应无显著性差异（P〉0.05）。结论在应用格拉司琼、地塞米松基础上加用地西泮,可更好地控制化学治疗诱导的延迟性恶心呕吐,提高患者生活质量,值得临床推广。     

Benzodiazepine treatment induces subtype-specific changes in GABAA receptor trafficking and decreases synaptic inhibition

Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA_AR) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an α and γ subunit of GABA_ARs, preferentially enhancing synaptic receptors largely composed of α(1–3, 5), β3, and γ2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA_AR surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of α2 subunit-containing GABA_ARs occurred within 24 h of flurazepam treatment, whereas GABA_ARs incorporating α1 subunits showed little alteration. The GABA_AR surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA_AR surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA_AR endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA_ARs. Together, these data suggest that flurazepam exposure enhances degradation of α2 subunit-containing GABA_ARs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA_AR trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment.     

Antiarrhythmic and proarrhythmic properties of diazepam demonstrated by electrophysiological study in humans

We evaluated the electrophysiological parameters before and after the intravenous infusion of diazepam (0.2 mg/kg) in 20 cardiac patients to investigate the drug's antiarrhythmic effect. Diazepam did not significantly change the arterial pressure. After the intravenous infusion of diazepam, the sinus cycle length significantly shortened from 847 +/- 132 to 747 +/- 155 ms (p less than 0.01). No significant change in the maximal sinus node recovery time was noted. The AH interval at the atrial pacing length of 600 ms shortened significantly from 140 +/- 40 to 127 +/- 39 ms (p less than 0.05). However, there was no significant change after the administration of diazepam in the longest atrial pacing rate associated with Wenckebach conduction in the atrioventricular (AV) node, effective and functional refractory periods of the AV node, HV interval, and QRS width during ventricular pacing at the cycle length of 600 ms. The atrial and ventricular effective refractory periods remained unchanged after the administration of diazepam. Six of the eight patients who showed dual AV nodal refractory period curves in the control study did not demonstrate them after diazepam administration by increasing the atrial or AV node effective refractory period. Thus, diazepam showed significant electrophysiological effects of the heart including shortening of the sinus cycle length, improvement in AV node conduction, and no significant effect on the His-Purkinje or intraventricular conduction and refractoriness of the atrium, AV node and ventricle. On the other hand, diazepam may influence the inducibility of supraventricular reentrant tachycardia incorporating the AV node.     

地西泮单药与联合用药治疗小儿惊厥的疗效对比研究

目的:探讨地西泮单用与联合用药治疗小儿惊厥的临床效果.方法:选取2011年1月~2015年12月在儿科收治的180例惊厥患儿进行回顾性分析,根据治疗方法分为联合组100例和单用组80例,联合组采用地西泮+苯巴比妥治疗,对照组仅采用地西泮治疗,对比两组的治疗效果.结果:治疗前,联合组和单用组的血清NSE、血清NPY水平差异无统计学意义,治疗后24h,两组患儿的血清NSE、血清NPY水平较治疗前均显著的降低,差异具有统计学意义;治疗24h后,联合组患儿的血清NSE、血清NPY水平显著的低于单用组患儿;联合组患儿的给药后的药物起效时间、惊厥停止时间显著的低于单用组患儿,差异具有统计学意义;给药后,联合组治疗显效率42.00%高于单用组的27.50%,联合组患儿治疗效果优于单用组患儿,差异具有统计学意义.结论:地西泮联合苯巴比妥用药治疗小儿惊厥效果较好,并不会增加不良反应的发生率.     

Effects of environmental exposure to diazepam on the reproductive behavior of fathead minnow,Pimephales promelas

Pharmaceutical drugs are continuously discharged into the aquatic environment primarily through wastewater discharge; therefore, their possible effects on wildlife is a reason of concern. Diazepam is a widely prescribed benzodiazepine drug used to treat insomnia and anxiety disorders, and it has been found in wastewater effluents worldwide. The present study tested the effects of diazepam on fecundity and the reproductive behavior of the fathead minnow, Pimephales promelas, a fish that exhibits male parental care. Sexually mature fathead minnows were housed at a ratio of one male and two females per tank and exposed to nominal (measured) concentrations of 0, 0.1 (0.14 ± 0.06), 1.0 (1.04 ± 0.15), 10 (13.4 ± 1.5) µg L^?1 for 21 days. Fish receiving the low diazepam treatment had significantly larger clutches than fish receiving the highest concentration but neither were different from controls. Diazepam exposure was not associated with a significant change in fertilization rate, hatchability or time to hatch, but a trend toward a higher number of eggs/day was observed in fish exposed to the low diazepam concentration relative to those exposed to the medium concentration. There were no significant differences in any of the behaviors analyzed when responses were averaged over time. The results showed that exposure to diazepam at concentrations as high as 13 µg L^?1 did not significantly impact the reproductive behavior of fathead minnow. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 561–568, 2016.     

Tetrazepam drug sensitivity -- usefulness of the patch test

The muscle relaxant tetrazepam may cause severe cutaneous adverse effects. We report 4 cases of varying intensity: Stevens-Johnson syndrome, erythema-multiforme-like exanthema, maculopapular and maculo-urticarial exanthema. Patch testing with tetrazepam (10% in petrolatum) was strongly positive in the 2 patients with severe skin eruptions and weakly positive in the other 2. Oral rechallenge with tetrazepam was positive in 3 patients (1 not done). Diazepam, with a similar chemical structure to tetrazepam, was negative on patch testing and on oral challenge testing in 2 patients. Although the optimal patch test concentration of tetrazepam has still to be determined, it is a useful diagnostic tool to confirm sensitization, particularly in patients with severe bullous eruptions.     

Evidence for a role of inhibition of orexinergic neurons in the anxiolytic and sedative effects of diazepam: A c-Fos study

The classical benzodiazepine diazepam (DZ) induces anxiolysis at low doses and sedation and hypnosis at higher doses. Different brain areas and neuronal populations most likely mediate these different behavioral effects. We used c-Fos immunohistochemistry as an indirect way to study neuronal activation or inhibition induced by DZ at anxiolytic and sedative doses (0.5 and 5 mg/kg, respectively) in various brain areas involved in anxiety, arousal, sedation and addiction in C57BL/6J mice. We also focused on the two neuronal populations, orexinergic and dopaminergic neuronal populations, with the help of double-immunohistochemistry using c-Fos and orexin-A antibodies and c-Fos and tyrosine hydroxylase antibodies. We found that different brain areas of unhabituated mice reacted differently to the mild stress induced by vehicle injection. Also the response to anxiolytic or sedative doses of DZ differed between the areas, suggesting that distinct brain areas mediate the behavioral effects of low and high DZ doses. Our findings propose a role for inhibition of orexin neurons in the anxiolytic and sleep-promoting effects of DZ. In addition, the activation of central amygdala neurons by DZ treatment was associated with anxiolytic and sedative effects. On the other hand, the ventral hippocampus, basolateral amygdala, ventral tegmental area and prefrontal cortex were sensitive even to the mild injection stress, but not to the anxiolytic dose of DZ.     

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticityand depression-like behavior in mice

Whether benzodiazepines(BZD) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain.The present study designed four preclinical experiments to determine the effects of BZD using chronic unpredictable stress model.In Experiment 1,several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests(FST and TST) as well as hippocampal structural plasticity markers.Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 week.In Experiment 2,mice received p.o.administration of three diazepam dosages prior to each variate stress session for 4 week.This treatment significantly antagonized the elevation of stress-induced corticosterone levels.Diazepam 0.5 and 1 mg·kg-1 blocked the detrimental effects of chronic stress.In Experiment 3,after 7 week of stress sessions,daily po diazepam administration during 1 week recovery phase dose-dependently accelerated the recovery of stressed mice.In Experiment 4,1 week diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect,whereas 4 week diazepam administration produced opposite effects.Hence,diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones.Considering the adverse effect of long-term diazepam administration on hippocampal plasticity,the preventive effects of diazepam may depend on the proper dose.Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.