Benzodiazepine dependence and its treatment with low dose flumazenil

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABA_A benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.     

Chronic diazepam treatment: Effect of dose on development of tolerance and incidence of withdrawal in an animal test of anxiety

The effect of the treatment dose of diazepam was assessed on the rate of development of tolerance to diazepam's effects on rat behaviour in the elevated plus-maze test of anxiety. Tolerance developed more rapidly when treatment was with the higher dose: after 14 days when rats were given 2·5 mg/kg/day, but not until 21 days when they were given 1 mg/kg/day. When rats were tested undrugged 36 h after the last of 14 daily doses of diazepam (2·5 mg/kg) they showed behavioural changes indicating increased anxiety. Rats tested at this time with a lower dose of diazepam (1 mg/kg) also showed changes indicating increased anxiety compared with the control scores. This indicates that a more gradual tapering of doses would be necessary to avoid withdrawal responses.     

Diazepam prevents progression of kindled alcohol withdrawal behaviour

The purpose of the present experiment was to study the kindling hypothesis of alcohol withdrawal stating that exposure to repeated episodes of alcohol withdrawal results in an increased severity of subsequent withdrawal reactions. Two groups of male Wistar rats were subjected to 13 episodes of 2 days severe alcohol intoxication and 5 days alcohol withdrawal. Animals in the control group (n=80) developed clinical withdrawal signs following each intoxication episode. In the diazepam group (n=80) the withdrawal reactions during episodes 1–9 were blocked by intraperitoneal diazepam administration (0–30 mg/kg) 8, 11 and 15 h into withdrawal. During episode 10–13 diazepam treatment was terminated and convulsive withdrawal behaviour was observed 9–15 h after last alcohol dose. The probability of seizure activity during these four withdrawal episodes was calculated as 0.239 and 0.066 in the control and the diazepam groups, respectively. Based on Monte Carlo simulation techniques, this difference was found to be statistically significant (P<0.05). No differences in the non-convulsive alcohol withdrawal symptoms tremor, hyperactivity and rigidity were detected between controls and diazepam animals after diazepam treatment. It was concluded that the increased convulsive behaviour in the control group was caused by cumulated kindling-like cerebral alterations during the previous repeated alcohol withdrawal phases.     

Effects of benzodiazepine receptor antagonist, flumazenil, on antinociceptive and behavioural responses to the elevated plus-maze in mice

Brief exposure to an elevated plus-maze has been shown to induce antinociception in male mice, a reaction that is not attenuated by manipulations of opiate receptors but which is fully blocked by diazepam. The present study examined the effects of the benzodiazepine receptor antagonist, flumazenil (5–20 mg/kg), on behavioural and antinociceptive responses to the elevated plus-maze in male DBA/2 mice. The results showed that, in the absence of an effect on total arm entries or rearing, flumazenil increased the time spent on the closed arms of the maze (an anxiogenic profile) and significantly enhanced antinociception induced by the elevated plus-maze. Data are discussed in relation to an “endogenous ligand theory” and it is concluded that the present findings are consistent with the proposed involvement of anxiety in at least certain forms of adaptive inhibition of pain.     

A placebo controlled study of flumazenil in bronchoscopic procedures

Methods A double-blind, randomized, placebo controlled trial of the efficacy of flumazenil was conducted in 22 consecutive patients admitted for bronchoscopy. Sedation was induced by inhvidually titrated amounts of intravenous diazepam (mean ± s.d., 15.75 ± 4.4 mg). Post bronchoscopy, patients received up to 1 mg of the benzohazepine antagonist flumazenil (Anexate®) or placebo intravenously. Clinical scores for the degree of sedation, orientation in time and space, co-operation and anterograde amnesia were used. These, together with three psychometric tests were performed twice prior to bronchoscopy and on eight occasions in the following 24 h. The psychometric tests were: Tapping Test (TT), Simple Reaction Time (SRT) and Critical Flicker Fusion (CFF) and these were carried out using the automated Multipsy test system.
Results The level of co-operation, orientation in time and space and anterograde amnesia were similar in both groups pre-and-post procedure. However compared with the pre-bronchoscopy assessment, the maximum degree of apparent sedation was significantly less in the flumazenil group in the first 4 h. In support of this, the patients in the flumazenil group also showed a significantly greater proficency with the TT and CFF test post bronchoscopy (P<0.05). There was no difference in the incidence of side effects and flumazenil was well tolerated.
Conclusions In this highly controlled setting, the use of flumazenil (Anexate®) was shown to be safe and effective in aiding recovery from benzodiazepine facilitated bronchoscopy and as such provides an additional level of safety for this procedure.     

Reduced Concentrations of Plasma Diazepam in Chronic Alcoholic Patients Following an Oral Administration of Diazepam

Abstract: Diazepam (tensopam®) 10 mg was given orally to 12 chronic alcoholic patients, at the beginning of the alcohol-free period and to 14 controls. Diazepam in the plasma was determined gaschromatographically with a ⁶³Ni-EC detector. During the absorption phase the plasma levels of diazepam were reduced to 44% at 2 hours (P < 0.01) and 32% at 3.5 hours (P < 0.001) in alcoholic patients compared with respective values of normal subjects. The reduced values, found in the alcoholic patients, may be due to disturbances in the gastro-intestinal absorption of diazepam, or to processes involving the portal vein or liver. Some alcoholic patients received a simultaneous treatment with neuroleptic or hypnotic drugs.     

地西泮在体鼻腔吸收动力学及薄荷醇对其吸收促进作用的研究

目的：研究地西泮鼻腔吸收的主要影响因素、吸收动力学及促透剂薄荷醇对其吸收的影响。方法：建立家兔在体鼻腔循环吸收的动物模型,取样时间为0、5、10、15、30、45、60、75、90 min,计算药物吸收速率常数K、吸收半衰期（t1/2）及药物吸收率。研究在鼻腔灌流液体积、循环液流速和pH值一定的条件下,地西泮的质量浓度、吸收促进剂薄荷醇对地西泮鼻腔吸收的影响。结果：在鼻腔灌流液体积为5 ml,循环液流速2.0 ml/min,循环液的pH值在5.9～6.1的中性吸收环境下,地西泮质量浓度在0.25～1.00 g/L时,随着地西泮质量浓度的增加,药物吸收速率常数K增加不明显,t1/2及药物吸收率变化不大;薄荷醇含量为0.2%时对地西泮鼻腔吸收有最佳的促进效果[药物吸收速率常数K为（0.442 4±0.002 3）/h],且能加快地西泮的吸收[t1/2为（0.32±0.07）h）],缩短地西泮的t1/2;0.2%～0.4%范围内,随薄荷醇质量浓度的增加,药物吸收速率常数K反而减小。结论：地西泮可以经鼻腔吸收,鼻腔吸收的机制为被动扩散;0.2%薄荷醇能促进地西泮的鼻腔吸收。     

高效液相色谱法测定 地西泮中毒患者血浆与尿中地西泮浓度

［摘要］目的建立高效液相色谱法测定血浆与尿中地西泮浓度。方法采用Agilent Eclipse XDB C18色谱柱(4.6 mm×150 mm, 5 μm )，以甲醇 水（65：35）为流动相，流速1.0 mL·min-1，检测波长254 nm。结果地西泮和内标物出峰时间分别为3.5 和7.3 min，分离效果较好；血浆样品中地西泮3种浓度（4.0，8.0，16.0 μg·mL 1）日内和日间RSD均＜6%，尿样中地西泮3种浓度（4.0，8.0，16.0 μg·mL 1）日内和日间RSD均＜5%；血浆中地西泮回收率为95.63%～98.33%，尿样中地西泮回收率为88.33%～95.33%，血清及尿样样品线性范围为2.0～64.0 μg·mL 1，相关系数0.995 8。血浆、尿样品地西泮最低检出限分别为2.0及1.5 μg·mL 1。结论该条件可对地西泮中毒患者进行药物快速检测并定量分析。     

Ethanol dependence in the rat: Temporal changes in neuroexcitability following withdrawal

Electrodes were chronically implanted in the dorsal hippocampus of rats. Pretreatment levels of neural excitability were assessed by determining the duration of direct hippocampal electrical stimulation sufficient to induce forelimb clonus in each rat. Following baseline measurements the rats were administered an alcohol or sucrose-containing liquid diet and 19–22 days later were withdrawn. Two postwithdrawal stimulation sessions were conducted on each animal. Separate groups of ethanol-dependent and control rats were given primary stimulation sessions at 8 h, 24 h, 72 h, or 1 week postwithdrawal. Secondary stimulation sessions were conducted 1 week or 2 weeks postwithdrawal.The results from the primary stimulations indicated that ethanol-dependent animals exhibited significant neural hyperexcitability for at least 72 h, but not 1 week, postwithdrawal. Results from the secondary stimulations demonstrated the presence of a relative neural hypoexcitability in ethanol-dependent groups as compared to controls. The pattern of results suggests, however, that the observed relative neural hypoexcitability was not the direct result of ethanol withdrawal.     

RP-HPLC法用于地西泮片剂的含量测定

[目的 ]建立一种 RP- HPL C法用于地西泮片的含量测定。 [方法 ]采用 Diam onsil(钻石 ) C1 8柱 (2 5 0 mm×4 .6 mm ,5μm) ,流动相为甲醇 -水 (70∶ 30 ) ,流速为 1.0 ml/ min,紫外检测波长 2 5 4 nm ,对地西泮片剂进行含量检测 ,并采用紫外分光光度法进行对比实验。 [结果 ]地西泮的保留时间为 13.4 m in,其浓度在 4 0～ 2 4 0μg/ m l范围内线性关系良好 (r=0 .9999,n=6 ) ,平均回收率为 98.73% (n=5 ) ,RSD为 0 .2 8%。[结论 ]RP- HPL C法简便快速 ,定量准确 ,重复性好 ,可作为地西泮片剂的含量测定方法。     

氟马西尼的药理、药效和剂型应用进展

氟马西尼作为苯二氮GFDA1（BDZ）受体拮抗剂,能特异性结合中枢BDZ受体,减少γ-氨基丁酸（GABA）的释放,从而拮抗BDZ类、非BDZ类药物引起的抗焦虑、镇静催眠、麻醉等作用。根据其作用靶点和方式,就目前氟马西尼在临床、科研上的应用和剂型进展做一综述。     

不同厂家安定片的体外溶出度比较

采用转篮法研究了四个厂家6个批号安定片的体外溶出度,实验数据用威布尔分布模型拟合,求得Td、T50、m.结果表明:不同厂家生产的安定片溶出度差异显著(P<0.01),而同一厂家生产的不同批号的安定片溶出度无明显差异。     

苯二氮类药物依赖及其防治

苯二氮类药物(BZD)主要用于治疗焦虑和失眠,长期使用可导致躯体及精神依赖。BZD依赖的发生机制与γ-氨基丁酸和谷氨酸等中枢神经递质有关。药物选择、给药方法和个体差异是BZD依赖的影响因素。BZD依赖表现为药物耐受性增加、戒断症状和心理依赖。BZD依赖的治疗包括停药、药物辅助治疗、替代治疗、中西医结合治疗和心理治疗。     

The effect of the benzodiazepine antagonist,flumazenil, on psychometric performance in acute ethanol intoxication in man

Summary The effect on cognitive and psychomotor performance of the benzodiazepine (BZD) antagonist, flumazenil, in antagonising the central effect, of ethanol in man has been investigated. Eight healthy adult male volunteers, aged 23 to 32 years, participated in the study. Following a loading infusion, stable blood ethanol levels with a mean value of 1.6 g·l^–1 were produced by a maintenance infusion. When stable blood levels of ethanol were reached, 5.0 mg flumazenil/placebo was administered intravenously, and after 15 and 75 min a test battery evaluating psychomotor and cognitive functions was applied.The test battery was sensitive to the test model, but no significant improvement in the test scores could be demonstrated following the administration of flumazenil.It is concluded that flumazenil has no influence on psychomotor functions in acute ethanol intoxication.     

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。     

Diazepam and decision making in the rat: negative evidence for reduced tolerance to reward delay

A laboratory decision-making paradigm was developed in which changes in behavioural planning in response to delays in reward delivery could be studied in the rat. The problem given was to choose between three behavioural options, lever-pressing or running into one of two arms fitted to the experimental chamber, in order to obtain rewards (water). Basically, the animal received rewards with a certain probability when pressing the lever. At certain random intervals, reward delivery by lever-presses was stopped. To restart the system, the animal had to abandon lever-pressing and run out into one of the arms. The arm lengths could be varied, and a time-delay for restarting the system could be introduced into one of the arms. These manipulations changed the arm preference so that a long arm, or an arm with a time delay, was avoided. It was specifically investigated whether the benzodiazepine diazepam selectively lowered the tolerance to accept reward delay. Such an effect of benzodiazepines has previously been proposed. After diazepam 1 mg/kg, the number of lever-presses before running into an arm and number of behavioural interruptions were increased, and interpreted to show a deficit in information processing and/or decision making. No evidence for a selective effect of diazepam to reduce tolerance to reward delays could be detected.     

丙泊酚、地西泮用于心脏电复律术前麻醉的效果评价

目的评价丙泊酚、地西泮用于心脏电复律术前麻醉的效果。方法将35例行心脏电复律术的患者随机分为实验组18例和对照组17例,分别应用丙泊酚和地西泮进行术前麻醉并对两组患者麻醉起效时间、苏醒时间和定向力恢复时间、术后不良反应进行比较。结果实验组麻醉起效时间明显快于对照组(P<0.01),术后苏醒时间和定向力恢复时间时间明显短于对照组(P<0.01);实验组术后不良反应较对照组明显减少(P<0.05)。结论丙泊酚用于心脏电复律麻醉起效快,效果好,不良反应少。     

反相HPLC法测定血浆中氯胺酮和安定浓度

采用HPLC法测定了家兔血浆中氯胺酮、安定的浓度,线性范围分别为0.125～5.0μg/ml;0.025～1.0μg/ml。检测最低浓度分别为50ng/ml、2.5ng/ml;日内日间误差<6.5％。药动学研究表明:氯胺酮、安定分别为一室线性、二室线性开放模型。     

Effect of flumazenil on the memory-enhancing properties of (−)-nicotine in rodents

The effect of the benzodiazepine-receptor antagonist flumazenil on the facilitatory effect of (?)-nicotine on memory in septal-lesioned rats in a spatial task and in the inhibitory avoidance test in mice was investigated. In the two-platform spatial discrimination test, septallesioned rats exhibited a significant number of errors in comparison to sham animals, an effect that can be reversed by the administration of (?)-nicotine during the training phase. Flumazenil did not affect the performance of septal-lesioned rats but it blocked the facilitatory effect of (–)-nicotine on lesioned rats. In the inhibitory avoidance test in mice,(?)-nicotine as well as flumazenil facilitated retention of the test at 0.62 and 10 μmol/kg, respectively. However, a low-noneffective dose of flumazenil blocked the memory enhancing effect of (?)-nicotine. The blockade of the facilitatory effect of (?)-nicotine by flumazenil in normal and septal-lesioned animals suggests that the cognitive effect of (?)-nicotine requires the activation of benzodiazepine receptors. © 1994 Wiley-Liss, Inc.     

Absorption of Diazepam in Man Following Rectal and Parenteral Administration

Abstract Serum concentrations of diazepam and N-desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121-200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62-186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50±17 per cent (mean±S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.