Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study

AIMS: The aim of this study was to evaluate the effects of flumazenil on hepatic encephalopathy in patients with liver cirrhosis. PATIENTS AND METHODS:. In the double blind randomized, placebo controlled study, 54 patients with hepatic encephalopathy grade III-IV were randomly assigned to receive either flumazenil 2 mg iv (group A) or placebo (group B); conventional treatment with branched-chain amino acid, saline, glucose, and lactulose was administered in both groups. A 24-hour observation period was established. Clinical improvement was defined as a 3 point decrease in the Glasgow coma score at any time within 24 hours. RESULTS: Clinical improvement was obtained in 22/28 patients in group A and in 14/26 in group B (p<0.05); improvement was observed within the first six hours in 21/22 patients in group A and only in 3/14 in group B. Mortality rate was not different between group A and B; however, all 6 non-responders in group A and only 5 out of 12 in group B died within 24 hours. Among patients with post-bleeding encephalopathy, 11 out of 17 in group A and only 2 out of 14 in group B improved (p<0.001). CONCLUSIONS: Flumazenil may exert a beneficial effect in a subset of patients with acute hepatic encephalopathy; encephalopathy associated with bleeding is more likely to respond to flumazenil; responders to the treatment usually improve within the first 6 hours while lack of response usually represents a bad prognostic sign.     

Yohimbine increases the binding potential for [11C]flumazenil in the monkey brain

Summary. We evaluated the impact of yohimbine administration on benzodiazepine (BDZ) receptor binding in the central nervous system of non-human primates (rhesus monkeys). Estimates of the binding potential (B_max/K_d) of BDZ receptors were made following intravenous administration of yohimbine, an α₂-adrenoceptor antagonist. Positron emission tomography was used in conjunction with [¹¹C]flumazenil (Ro 15-1788), a tracer for central BDZ receptor binding activity. The effects of yohimbine were compared with a control condition in which saline was administered. Yohimbine significantly increased the binding potential in the hippocampus, as assessed using a Student's t-test with Bonferroni correction. The result that the administration of yohimbine readily induces an increase in the binding potential for BDZ receptors in the primate brain suggests that the presence of an anxiety state potentiates the effect of anxiolytics. Accepted August 10, 2001     

Radioautographic Evidence that the GABAA Receptor Antagonist SR 95531 is a Substrate Inhibitor of MAO-A in the Rat and Human Locus Coeruleus

The locus coeruleus (LC), a major noradrenergic nucleus in the brain, probably has a functional role in the regulation of anxiety states as well as vigilance, attention, learning and memory. LC neurons are under the inhibitory control of γ-aminobutyric acid (GABA) via ionotropic GABA_A receptors. However, to date, little is known of the receptor binding characteristics of these neurons. In the present investigation we therefore examined by receptor radioautography the localization of the binding sites for different components of the GABA_A receptor complex in the rat and human LC. Both rat and human LC neurons have a high density of binding sites for the pyridazinyl-GABA derivative [³H]SR 95531 (gabazine, a GABA_A receptor antagonist for low affinity GABA recognition sites). However, at the concentrations used, no binding sites in the LC were detectable for the benzodiazepine receptor antagonist [³H]flumazenil, the GABA_A receptor agonist (for high affinity sites) [³H]muscimol or the ionophore ligand [³⁵S]t -butyl bicyclophosphorothionate (TBPS). Unexpectedly, the pharmacological specificity of [³H]SR 95531 binding to the LC differed markedly from that to most brain regions (IC₅₀ values for GABA and RU 5135 respectively in the LC were > 10^-2 and 10^-3 M; and, for example, in the dentate gyrus the most labelled structure after the LC, 8 × 10^-7 and 1.8 × 10^-9 M). These differences prompted the further characterization of [³H]SR 95531 binding in the LC, revealing a significant affinity for monoamine oxidase type A (MAO-A), which is highly concentrated in this nucleus. In a competition binding study, a reduction of up to 25% of the [³H]SR 95531 binding was observed with MAO-A but not MAO-B inhibitors, at concentrations which produce maximum but selective enzyme inhibition. Correspondingly, 2 h after the oral administration of supramaximal doses of the MAO-A inhibitors moclobemide and Ro 41 -1049 (but not the MAO-B inhibitor lazabemide) the in vitro binding of [³H]SR 95531 was markedly reduced (by 77 and 82% of controls respectively). Moreover, enzyme radioautography with [³H]Ro 41 -1049 revealed that SR 95531 has a significant affinity for MAO-A (ICgo values were 10^-5 and 4x 10^-6 M in the LC and dentate gyrus respectively) but not for MAO-B ([³H]lazabemide binding). Altogether, these findings suggest that the high-affinity binding of [³H]SR 95531 to the LC mainly reflects its affinity for MAO-A, which questions its utility as a selective ligand for low-affinity GABA recognition sites in the CNS. It remains to be seen whether the dual pharmacological profile of SR 95531 (desinhibition of LC neurons and facilitation of noradrenergic transmission) can be exploited as a principle in the development of new anxiolytics or antidepressants.     

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。     

氟马西尼对老年全麻术后患者的催醒作用

目的探讨氟马西尼用于老年全麻术后催醒的临床效果。方法择期全麻下行上腹部手术患者60例,随机分为两组：实验组（给予氟马西尼）和对照组（给予安慰例1,观察两组患者术后清醒程度评分、神经功能评分以及两组术后不良反应发生率。结果实验组注射氟马西尼10min后清醒程度评分、神经功能评分均明显高于对照组（P〈0．05）;其不良反应虽高于对照组,但无统计学意义。结论老年全麻患者术后注射适量氟马西尼可以迅速安全的催醒,副作用发生少。     

Antipsychotic and sedative effects of the leaf extract of Crassocephalum bauchiense (Hutch.) Milne-Redh (Asteraceae) in rodents

ETHNOPHARMACOLOGICAL RELEVANCE: Crassocephalum bauchiense (Hutch.) Milne-Redh (Asteraceae) has been used as a medicine for the treatment of epilepsy, insomnia, dementia and psychotic disorders in Cameroonian traditional medicine. AIM OF THE STUDY: This study was designed to examine whether the aqueous extract and the alkaloid fraction prepared from the leaves of Crassocephalum bauchiense possess antipsychotic and sedative properties in rodents. MATERIALS AND METHODS: The rectal temperature of mice was recorded with a probe thermometer at a constant depth. Novelty-induced rearing behavior is used to evaluate a central excitatory locomotor behavior in mice. The antipsychotic effects of the extracts were assessed using the apomorphine animal model of psychosis. The catalepsy test was tested based on the ability of the leaves extracts of Crassocephalum bauchiense to alter the duration of akinesia by placing the naive mice with both forelegs over a horizontal bar. The extracts of Crassocephalum bauchiense effects were evaluated on sodium pentobarbital-induced sleeping time. In addition, gamma-aminobutyric acid concentrations in the brain treated mice were also estimated. RESULTS: The aqueous extract and the alkaloid fraction from Crassocephalum bauchiense caused dose-dependent inhibition of novelty-induced rearing behavior, decreased the apomorphine-induced stereotypy and fighting, and had significant fall of the body temperature. The aqueous extract prolonged the sodium pentobarbital sleeping time. This prolongation was not reversed by bicuculline, a light-sensitive competitive antagonist of GABA(A) receptors complex. However, the effect of the aqueous extract on sodium pentobarbital-induced sleeping time was blocked by N-methyl-β-carboline-3-carboxamide, a partial inverse agonist of the benzodiazepine site in the GABA(A) receptor complex and flumazenil, a specific antagonist of the benzodiazepine site in the GABAA receptor complex. In biochemical experiments, the concentration of the inhibitory amino acid, gamma-aminobutyric acid, was significantly increased in the brain of animals treated with the aqueous extract of Crassocephalum bauchiense and sodium valproate. CONCLUSIONS: The results show that the antipsychotic and sedative properties of Crassocephalum bauchiense are possibly mediated via the blockade of dopamine D-2 receptors and GABAergic activation, respectively. However, pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for these neuropharmacological actions and also to identify the active substances present in the extracts of Crassocephalum bauchiense.     

Changes in GABAA receptor properties in amygdala kindled animals: in vivo studies using [11C]flumazenil and positron emission tomography

Purpose: The purpose of the present investigation was to quantify alterations in GABA_A receptor density in vivo in rats subjected to amygdala kindling. Methods: The GABA_A receptor density was quantified by conducting a [¹¹C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA_A receptors. Subsequently, the concentration‐time curves of FMZ in blood [using high‐pressure liquid chromatography with UV detector (HPLC‐UV) or high‐performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET‐scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain. Results: The GABA_A receptor density (B_max) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA_A receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K_D) was not changed, but the total volume of distribution in the brain (V_Br), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood–brain barrier. Conclusions: Both the GABA_A receptor density (B_max), and possibly also the blood–brain barrier transport of FMZ (V_Br) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA_A receptor density in a rat model of epilepsy in vivo.     

安定联合氟马西尼用于无痛胃镜检查术的疗效观察

目的 为探讨无痛胃镜麻醉用药选择的多样性，我院选择安定联合氟马西尼应用于无痛胃镜检查中，并观察其临床疗效。方法 接受无痛胃镜检查患者70例，随机分为I、Ⅱ两组。I组给予丙泊酚麻醉，2mg／kg，iv；Ⅱ组给予安定0．2～0．6mg／kg梯次静脉给药，检查完毕立即给予氟马西尼0．5～1．0mg静脉注射以催醒。结果 I、Ⅱ组在麻醉后心率、清醒时间上差异无统计学。麻醉深度体动率、起效时间、术中呛咳发生率I组优于Ⅱ组。I组呼吸暂停率高于Ⅱ组。结论 虽然安定有部分缺陷，但因其安全性高等优点，一样可在临床推广。     

Midazolam for patients undergoing upper gastrointestinal endoscopy: a prospective, single-blind and randomized study to determine the appropriate amount and time of initiation of endoscopy

BACKGROUND AND AIMS: Midazolam is currently the most used sedative agent in endoscopy. The present study was designed to examine the appropriate dose of midazolam, time of initiation of endoscopy after midazolam infusion, and to prove the necessity of flumazenil as an antidote. METHODS: One hundred and eighty patients undergoing diagnostic gastroscopy were assigned three different amounts of intravenous midazolam in prospective, single-blinded and randomized setting as follows: (i) group I 0.03 mg/kg midazolam; (ii) group II 0.06 mg/kg midazolam; and (iii) group III 0.09 mg/kg midazolam. Endoscopy was initiated 30, 60 and 90 s after infusion of midazolam within each group. After endoscopy, patients were divided into two groups, one receiving flumazenil and one placebo in a double-blind fashion. The ease of the procedure, the conscious sedative state, the paradoxical response, the level of satisfaction and anterograde amnesia were assessed using a 100 mm visual analog scale. RESULTS: The endoscopist's assessments were not changed by the different doses of midazolam; however, significant differences were observed in the paradoxical responses (P < 0.05). The level of satisfaction with endoscopy was notably different between group I and the other two groups (P < 0.05). Amnesia was boosted according with increasing doses of midazolam (P < 0.05). The time until discharge after endoscopy was significantly different between group III and the other two groups (P < 0.05) and the discharge time was reduced in the flumazenil subgroup compared with the placebo subgroup in group III (P < 0.05). Group II (0.06 mg/kg) reported good levels of satisfaction, fewer paradoxical responses and short discharge time without any side-effects. Comparing the time of initiation of endoscopy (at 30, 60 and 90 s after midazolam) in each group, there were no significant differences in the level of satisfaction, conscious sedative state and amnesia. CONCLUSIONS: Midazolam should be administered at a dose of 0.06 mg/kg and the endoscopy should be initiated 30 s after midazolam injection for appropriate effects without any side-effects. Flumazenil is not necessary, except in the case of the use of a high dose (above 0.09 mg/kg) of midazolam.     

Intrasubject correlation between static sean and distribution volume images for [11C]flumazenil PET

Accumulation of [11C]flumazenil (FMZ) reflects central nervous system benzodiazepine receptor (BZR). We searched for the optimal time for a static PET scan with FMZ as semi-quantitative imaging of BZR distribution. In 10 normal subjects, a dynamic series of decay-corrected PET scans was performed for 60 minutes, and the arterial blood was sampled during the scan to measure radioactivity and labeled metabolites. We generated 13 kinds of "static scan" images from the dynamic scan in each subject, and analyzed the pixel correlation for these images versus distribution volume (DV) images. We also analyzed the time for the [11C]FMZ in plasma and tissue to reach the equilibrium. The intra-subject pixel correlation demonstrated that the "static scan" images for the period centering around 30 minutes post-injection had the strongest linear correlation with the DV image. The ratio of radioactivity in the cortex to that in the plasma reached a peak at 40 minutes after injection. Considering the physical decay and patient burden, we conclude that the decay corrected static scan for [11C]FMZ PET as semi-quantitative imaging of BZR distribution is to be optimally acquired from 20 to 40 minutes after injection.