Regulation of neuronal differentiation in neuron-enriched primary cultures from embryonic rat cerebra by platelet activating factor and the structurally related glycerol ether lipid, dodecylglycerol.

Primary cultures enriched in neurons dissociated from embryonic rat cerebra were used to demonstrate that platelet activating factor and the structurally related ether glycerolipid, dodecylglycerol, are readily taken up in small amounts by neurons and that they stimulate the differentiation of neurons. The stimulation of neuronal differentiation was observed as a precocious development of axon-like extensions which correlated with a concentration-dependent increase in neuronal-specific enzyme activities. This stimulation of morphological and neurochemical factors by either platelet activating factor or dodecylglycerol was almost completely abolished by triazolam, a known inhibitor of platelet activating factor function. Neither platelet activating factor nor dodecylglycerol at the concentrations used to achieve stimulation of neuronal differentiation compromised the plasma membrane, as indicated by the lack of leakage of cytoplasmic lactic acid dehydrogenase.     

短效催眠药唑吡坦和三唑仑对人体前庭功能的影响

目的 :探讨两种短效催眠药唑吡坦和三唑仑对人体前庭功能的影响 ,为在应急条件下对飞行员服用该药提供试验依据。方法 :8名受试者 ,采用三阶段交叉双盲给药设计方法 ,分别交叉服用三唑仑 (0 .2 5mg)、唑吡坦 (10mg)、安慰剂 ,每次间隔 1周 ,在服药前 1h及服药后1、2、3、4、6、8、10h分别进行一组前庭功能测试 ,包括视动性眼震 (OKN)、前庭眼动反射 (VOR)、前庭眼动反射固视抑制 (VOR -Fix)、视前庭眼动反射 (VVOR)。结果 :与安慰剂组比较 ,服用唑吡坦和三唑仑后均能显著降低VOR、OKN、SPT增益 ,在服药 2h后降到最低〔VOR :(0 .5 1± 0 .0 4 ) ,(0 .5 2± 0 .0 5 )vs (0 .6 7± 0 .13) ;OKN :(0 .32± 0 .0 2 ) ,(0 .6 2± 0 .0 6 )vs (0 .82± 0 .0 7) ;SPT :(0 .71± 0 .14 ) ,(0 .6 6± 0 .0 6 )vs (0 .93± 0 .0 3)〕。其中唑吡坦对OKN增益的降低要强于三唑仑 ,但这种影响持续时间不长 ,在服药 6h后即消失。两种短效催眠药对VVOR增益、SPT相位及VOR -Fix均无明显影响。结论 :唑吡坦及三唑仑对人体前庭功能具有一定的影响 ,但这种影响持续时间较短 ,对人体的空间定向及平衡能力无残留后遗效应     

Effects of small dose of brotizolam on P300

Nine healthy men (mean age, 22.2 years) participated in two experimental sessions cross-overed randomly in a double blind manner; one with a placebo and the other with 0.125 mg of brotizolam (BTZ) administered in the morning. Resting electroencephalogram and event-related potential under oddball paradigm was recorded before and 1, 2, 4, 6 and 8 h after the administration. Mean 30-msec bin amplitude from 240 msec to 450 msec after the stimulus was compared between placebo and drug sessions in order to observe P300. Brotizolam reduced the amplitude of P300 at 6 h after administration. It was noted that the effects of BTZ were most marked at Fz.     

Triazolam premedication

A randomised, double blind study, of 58 female patients undergoing laparoscopic investigation was carried out to compare triazolam 0.25 mg, lorazepam 2 mg, or placebo as oral premedication. Each patient was assessed by only one of the authors both pre- and postoperatively with regard to anxiolysis, sedation and rapidity of recovery. Triazolam and lorazepam were each associated with a significant reduction in anxiety compared to the initial assessment, whereas placebo had no anxiolytic effect. Sixty minutes after premedication, patients who had received triazolam were significantly more sleepy than patients given placebo or lorazepam. Two hours after the operation, the patients who had had triazolam or lorazepam were significantly more sleepy than those who received placebo. However, at 6 hours postoperatively there was no difference between triazolam and placebo, whilst those who had been given lorazepam were still significantly more sleepy than those given placebo. Triazolam appears to offer advantages over either lorazepam or placebo in patients who require rapid recovery, sedation and reduction in pre-operative anxiety.     

A pharmacodynamic study of quazepam and triazolam

A double-blind single oral dose study in 10 healthy volunteers was performed during the day to compare the diurnal effects of quazepam (15 mg) and triazolam (0.25 mg) on psychomotor performance. The central effect of the two benzodiazepines was assessed by means of a computer analysis of visually guided saccadic eye movements (SEM), critical flicker fusion threshold (CFFT), and choice reaction time (CRT). The results obtained suggest that: computer analysis of SEM is more sensitive than CRT and CFFT to detect sedative drug effects at a subclinical level; the presumed equipotent doses of quazepam and triazolam tested do not show the same sedative activity; the minimal impairment produced by quazepam on CNS function does not seem to be related to the property to bind to BZ1 receptors; the pharmacodynamic profile of quazepam seems to be characteristic of a “non-sedative” agent, while triazolam behaves as a “sedative” benzodiazepine.     

COMPARATIVE EFFECTS OF ZOPICLONE, TRIAZOLAM AND PLACEBO ON MEMORY AND PSYCHOMOTOR PERFORMANCE IN HEALTHY VOLUNTEERS

This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.     

三唑仑药物的固相萃取和气相色谱法的研究

本文建立了新型安眠镇静药三唑仑的气相色谱分析方法。采用固相柱ＧＤＸ４０３提取净化，ＧＣ／ＮＰＤ法分析送检样品中的三唑仑，并用ＳＫＦ５２５Ａ作为内标进行质量控制。进行了茶水中添加三唑仑的实验研究，确立了提取净化的最佳ｐＨ值范围和提取溶剂（淋洗剂）。结果表明，该方法灵敏度高，最小检测量小于５ｎｇ，２０ｍｌ茶水中添加１０μｇ三唑仑的回收率大于７０％。并报道了几例案例的应用情况。     

Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model

1. Prediction of metabolic clearance in extreme individuals rather than the ‘average human’ is becoming an attractive tool within the pharmaceutical industry.

2. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CL_int) data from in vitro metabolic data and back-calculation from in vivo clearance data. Second, the sensitivity of predicted in vivo variability to changes in variability for physiological parameters (e.g. liver weight, haematocrit, CYP3A abundance). Finally, reported estimates of variability in hepatic CYP3A4 abundance (coefficient of variation (CV) 95%) were refined by separating experimental from interindividual variability using a repeat measurement protocol in 52 human liver samples.

3. Using in vitro metabolic data, predicted clearances were within 2-fold of observed for triazolam and midazolam. Clearance of alprazolam was overpredicted by 2.0- to 3.7-fold. Use of in vivo CL_int values improved prediction of intravenous clearance to within 2-fold of observed for all drugs.

4. Initially, the variability in clearance was overestimated for all drugs (by 1.8- to 3.6-fold). Use of a reduced hepatic CYP3A4 CV of 41%, representative of interindividual variability alone improved predictions of variability in clearance for all drugs to within 2-fold of observed.

     

三唑仑片在正常人体的药代动力学

 目的 研究在中国人中三唑仑(triazolam)片的血药浓度测定方法及药代动力学。方法 8名健康男性志愿者,单次服用 0.5 mg三唑仑片,在不同时间点取静脉血,血浓度采用气相色谱色谱法(GC)测定。药代动力学参数采用3P87程序计算。结果 三唑仑片的主要药代动力学参数Ka,AUC_0～7,c_max,t_max,t_1/2,CL/F分别为(2.33±0.84)h^-1,(11.00±3.75)ng·h·ml^-1,(3.95±0.74)ng·ml^-1,(0.92±0.37)h,(1.20±0.39)h,(0.049±0.017)L·h^-1。结论 三唑仑片在体内能迅速吸收并很快消除,这与其临床作用是一致的。