Peripubertal Diazepam Administration Prevents the Emergence of Dopamine System Hyperresponsivity in the MAM Developmental Disruption Model of Schizophrenia

Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period.     

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.     

长期应用地西泮对豚鼠耳蜗微音器电位的影响

目的观察长期应用地西泮对豚鼠耳蜗微音器电位的影响。方法采用逐渐增加剂量的方法皮下注射地西泮3个月后停药,10d后用不同强度的短声刺激诱发微音器电位产生,测量诱发微音器电位产生的阈值,用共聚焦显微镜测量耳蜗毛细胞内Ca2+浓度的变化。结果应用地西泮3个月后停药,与对照组相比,引起豚鼠微音器电位产生的阈值明显降低,微音器电位的幅度显著增加,记录出自发的微音器电位,毛细胞内Ca2+浓度降低。结论长期应用地西泮后豚鼠耳蜗对声刺激的敏感性增加可能与毛细胞内Ca2+浓度降低有关。     

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.     

氯氟乙酯(25例)和地西泮(23例)治疗焦虑障碍的疗效和安全性比较

目的 :评价氯氟乙酯治疗焦虑障碍的疗效和安全性。方法 :采用双盲、双模拟、随机、平行对照研究。完成 4wk治疗的病人共 4 8例。其中试验组 (氯氟乙酯组 ) 2 5例 ,对照组 (地西泮组 ) 2 3例。试验组早、午餐后服氯氟乙酯安慰剂及地西泮安慰剂各 1片 ,晚餐后服氯氟乙酯 2mg及地西泮安慰剂各 1片 ;对照组早、午、晚餐后服氯氟乙酯安慰剂及地西泮 2 .5mg各 1片 ,疗程为 4wk。结果 :治疗 4wk后 ,试验组的HAMA总分显著降低 ,HAMA减分率达 (5 9± 2 5 ) % ,临床总有效率达72 % ,与对照组相比无显著意义 (P >0 .0 5 )。试验组的不良反应的发生率为 8% ,与对照组相比无显著意义 (P >0 .0 5 )。结论 :氯氟乙酯治疗焦虑障碍的疗效 ,与地西泮相似 ,无明显不良反应。     

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。     

地西泮对基础麻醉时戊巴比妥钠用量的影响

目的 :评价房颤患者行同步电复律时地西泮对戊巴比妥钠使用剂量的影响。方法 :回顾分析风湿性心脏病机械瓣膜置换术后合并房颤患者 43例 ,其中组 ( 14例 )患者静脉推注地西泮 10 m g后给予戊巴比妥钠 ,组 ( 2 9例 )患者静脉推注地西泮 2 0 m g后给予戊巴比妥钠 ,比较两组患者意识丧失及睫毛反射消失所需戊巴比妥钠用量。结果 :组 患者静脉推注戊巴比妥钠剂量为 ( 90 .2± 60 .1) mg,组 患者静脉推注戊巴比妥钠剂量为 ( 5 0 .6± 3 5 .7) mg,组 戊巴比妥钠剂量用量明显少于组 ,P<0 .0 5。结论 :房颤同步电复律基础麻醉时适量使用地西泮可明显减少戊巴比妥钠的用量     

Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol

1 Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double-blind, placebo controlled six-way cross over experiment in 12 healthy volunteers, aged 19−26 years.
2 Bretazenil (0.5  mg), diazepam (10  mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target-blood concentration of 0.5  g l⁻¹ or a control infusion of 5% w/v glucose at 1 week intervals.
3 CNS effects were evaluated between 0 and 3.5  h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales.
4 Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol>diazepam+alcohol≥bretazenil> diazepam>alcohol>placebo.
5 There were no consistent indications for synergistic, supra-additive pharmacodynamic interactions between alcohol and bretazenil or diazepam.
6 Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests.
7 No significant pharmacokinetic interactions were found.
8 Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.     

Lack of pharmacokinetic interaction of pantoprazole with diazepam in man

Pantoprazole, a substituted benzimidazole, is a potent and well tolerated inhibitor of the gastric H⁺,K⁺-ATPase with a low potential to inhibit cytochrome P450. In this randomized, placebo-controlled two-period crossover study, 12 healthy volunteers received placebo (reference) and 240 mg of pantoprazole (test) i.v. within 2  min once daily for 7 days each. On day 4 of either period, a 1  min bolus of diazepam (0.1  mg  kg⁻¹ body weight) was additionally injected. Pantoprazole was well tolerated and did not cause clinically relevant changes in heart rate, blood pressure, ECG and routine clinical laboratory parameters. There was no effect on diazepam clearance (0.021  l  h⁻¹  kg⁻¹ for test and reference) and elimination half-life (36.8  h for test, 40.4  h for reference). Diazepam metabolism to desmethyldiazepam was not affected by pantoprazole. In conclusion, pantoprazole and diazepam may be administered concomitantly without dose adjustment even when high doses of pantoprazole are required.