氟马西尼对苯二氮（艹卓）类药物的拮抗作用观察

氟马西尼化学名为8-氟-5,6-二氢-5-甲基-6-氧代-4 H-咪唑并-［1,5-α］［1,4］苯并二氮（艹卓）-3-甲酸乙酯。氟马西尼对苯二氮（艹卓）类类（ BDZ）受体有很强的亲和力,可竞争性地拮抗BDZ与受体结合,从而消除BDZ的药理作用［1］。笔者对地西泮（安定）或咪达唑仑（咪唑安定）复合静脉全麻术后的4例患者运用氟马西尼拮抗其麻醉苏醒延迟,观察其效果,现报道如下。     

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。     

苯二氮卓受体在依托咪酯致小鼠学习记忆障碍中的作用

目的：观察苯二氮卓受体拮抗剂氟马西尼（flumazenil,Flu）对依托咪酯（etomidate,Eto）所致遗忘作用的影响。方法：昆明种小鼠48只,随机分为4组：生理盐水＋脂肪乳（intralipid）组（NS＋Z组）,生理盐水＋依托咪酯组（NS＋Eto组）,氟马西尼＋脂肪乳组（Flu＋Z组）,氟马西尼＋依托咪酯组（Flu＋Eto组）。训练前20min皮下注射氟马西尼（0.1mg/kg）或生理盐水（0.1mL/10g）,训练前5min腹腔注射脂肪乳（0.12mL/10g）或依托咪酯（3mg/kg）。在跳台实验和避暗实验中观察氟马西尼对依托咪酯导致遗忘小鼠错误次数（errortimes,ET）、跳台潜伏期（step down latency,SDL）和步入潜伏期（step through latency,STL）的影响。结果：氟马西尼可减少依托咪酯所致遗忘小鼠的ET、延长SDL和STL。结论：苯二氮卓类（benzodiaz-epines,BDZ）受体可能是依托咪酯致小鼠遗忘作用的重要靶位。     

口服镇静催眠药中毒患者药物治疗性分析

目的 比较两种药物联合应用治疗镇静催眠药中毒治疗效果的优劣。方法 根据我院急诊科临床用药情况将2016年1月~2018年12月收治的59例镇静催眠药中毒患者分为纳洛酮、氟马西尼联合治疗组（A组）;醒脑静、氟马西尼联合治疗组（B组）,比较两组患者GCS（格拉斯哥昏迷评分）、苏醒时间、住院时间、不良反应等,分析两种联合用药情况的优劣。结果 两组患者治疗后GCS（格拉斯哥昏迷评分）、苏醒时间、住院时间差异具有统计学意义（P<0.05）,B组治疗效果优于A组。结论 醒脑静、氟马西尼联合治疗镇静催眠药中毒,能明显缩短住院时间,效果优于纳洛酮和氟马西尼。     

高龄患者全麻术后氟马西尼对呼吸和认知功能的影响

氟马西尼是苯二氮艹卓类(BDZ)选择性拮抗药,常用于全麻手术后的催醒.我们将氟马西尼用于高龄患者全麻术后,并与应用安慰剂进行效果比较,观察二者对患者呼吸和认知功能的影响.     

氟马西尼对抗丙泊酚减弱小鼠学习记忆功能的影响

目的:考察苯二氮受体拮抗剂氟马西尼对丙泊酚所致学习记忆功能减弱的影响。方法:昆明种小鼠40只,随机分为对照组、丙泊酚组、氟马西尼组和氟马西尼+丙泊酚组。训练前20 min皮下注射氟马西尼或生理盐水,训练前10 min腹腔注射脂肪乳或丙泊酚。在跳台实验和避暗实验中观察氟马西尼对丙泊酚导致健忘小鼠错误次数、跳台潜伏期和步入潜伏期的影响。结果:氟马西尼可减少丙泊酚所致健忘小鼠的错误次数,延长跳台潜伏期和步入潜伏期。结论:苯二氮类受体可能是丙泊酚致小鼠学习记忆功能减弱的重要靶位之一。     

比较氟马西尼和纳洛酮在急性苯二氮卓类药物中毒治疗中的疗效观察

目的:研究比较苯二氮卓类受体拮抗剂氟马西尼和阿片受体拮抗剂纳洛酮在急性苯二氮卓类(BZDs)药物中毒患者中的治疗作用。方法随机将60例急性BZDs中毒患者分为氟马西尼组,纳洛酮组和常规治疗组,每组均为20例。疗效分析采用Glasgow—Pittsburgh昏迷观察量表(G—PCS评分)。结果氟马西尼组治疗后1、3和8小时G—PCS得分较治疗前分别增加4．7 7．05 10．05纳洛酮组G—PCS得分分别增加1．45 3．05 9．6常规治疗组G—PCS得分分别增加0．8 2．15 3．8差异具有显著性。结论氟马西尼和纳洛酮治疗急性BZDs中毒均有明显疗效,二者8小时后症状改善无明显差异,但氟马西尼在催醒方面明显优于纳洛酮。     

氟马西尼药物伍用下在5%葡萄糖注射液中的稳定性

氟马西尼（flumazenil）为一种咪哇苯二氮注类衍生物，可竞争性地与苯二氮近受体结合，从而桔抗或逆转苯二氮a类药物的中枢抑制作用。临床常用于苯二氮这类药物镇静，全身麻醉后或特护（ICU）病人的催醒，经常与其它药物合用。本文报道在室温下氟马西尼与氨条碱、盐酸多巴酚丁胺、盐酸多巴胺、盐酸西咪替丁、法莫替丁、盐酸雷尼替丁、肝素钠、盐酸利多卡因和盐酸普鲁卡因胺在5％葡萄糖注射液中的配伍稳定性。将氟马西尼！．0mg分别加入50mL5％葡萄糖注射液和各含有上述9种药物的SOmL50葡萄糖注射液中。室温下（23℃）放置24h，于0，2，48…     

七氟醚介导的神经元自噬抑制对幼年大鼠神经发生和学习记忆功能的影响

目的 探讨七氟醚对幼龄大鼠学习记忆功能的影响及机制。方法 48只幼鼠随机分为对照组、七氟醚-1 h组、七氟醚-3 h组与七氟醚-3 h＋雷帕霉素（20 mg/kg,于麻醉前连续ip 3 d）组,每组12只。麻醉当天,对照组幼鼠吸入氧气混合氮气3 h,七氟醚组以含3%七氟醚的混合气体麻醉1 h或3 h。4周后,应用Morris水迷宫检测幼鼠学习与记忆功能;使用电子透射显微镜观察神经元自噬;采用BrdU免疫荧光法观察幼鼠海马组织中神经元新生;Western blotting法检测幼鼠海马组织中NeuN、DCX、PI3K、mTOR、LC3-II/LC3-I和Beclin-1蛋白表达。结果 与对照组比较,七氟醚-3 h组幼鼠逃避潜伏期显著增加（P<0.05）,穿越平台次数显著减少（P<0.05）,靶象限停留时间显著减少（P<0.05）;与七氟醚-3 h组比较,雷帕霉素显著缩短幼鼠逃避潜伏期（P<0.05）,增加测试中穿越平台次数（P<0.05）与靶象限停留时间（P<0.05）。与对照组比较,七氟醚-3 h组幼鼠齿状回中神经元新生显著减少（P<0.05）,神经元新生相关蛋白NeuN与DCX表达显著降低（P<0.05）;海马组织中PI3K表达显著降低（P<0.05）,且mTOR蛋白表达显著增加（P<0.05）,而LC3-II/LC3-I与Beclin-1表达显著下调（P<0.05）,造成自噬小体显著减少（P<0.05）。与七氟醚-3 h组比较,雷帕霉素显著增加NeuN与DCX蛋白表达（P<0.05）,显著提高PI3K蛋白表达（P<0.05）,显著下调mTOR表达（P<0.05）,显著上调LC3-II/LC3-I与Beclin-1表达（P<0.05）,显著增加自噬小体的形成。结论 七氟醚通过下调PI3K,增加mTOR表达,抑制LC3-II/LC3-I与Beclin-1表达,减少自噬小体形成并抑制神经元新生,最终诱导幼鼠学习和记忆功能障碍。     

孟鲁司特联合丙酸氟替卡松对变应性鼻炎患儿的临床疗效及免疫功能评价

目的 评价孟鲁司特联合丙酸氟替卡松对变应性鼻炎患儿的临床疗效及免疫调节作用。方法 收集2014年1月－2016年12月惠州市中心人民医院第一分院收治的变应性鼻炎患儿140例,使用数字法随机分为丙酸氟替卡松单药治疗对照组和孟鲁司特联合丙酸氟替卡松治疗观察组,每组70人。ELISA法检测免疫球蛋白IgE、白介素（IL）-17、IL-10因子表达。比较两组的临床疗效和临床不良反应。结果 治疗前两组症状体征评分无显著差异,治疗后均较治疗前有显著降低（P<0.01）,且观察组评分降低作用显著优于对照组（P<0.05）;对照组临床有效率为80.0%,显著低于观察组的94.3%（P<0.05）;治疗前两组IgE、IL-17和IL-10表达无显著差异,治疗后两组IgE和IL-17表达显著降低、IL-10表达显著升高（P<0.01）,且观察组对IgE和IL-17的减低作用以及对IL-10的升高作用优于对照组（P<0.05）。IgE表达与IL-17呈显著正相关（r=0.392,P<0.05）,与IL-10呈显著负相关（r=-0.364,P<0.05）。观察组不良反应发生率为14.3%,对照组的为11.4%,治疗期间两组临床不良反应发生率无显著差异。结论 孟鲁司特钠联合丙酸氟替卡松治疗小儿变应性鼻炎临床疗效显著,使用安全,调节IL-17/IL-10因子失衡可能是其起效的作用机制。     

Altered gamma-aminobutyric acid/benzodiazepine interaction after chronic diazepam exposure

Binding to components of the GABA/benzodiazepine receptor complex was examined in cortical membranes from rats treated for 3 weeks with continuously releasing diazepam pellet implants. Chronic diazepam treatment resulted in a decrease in the ability of GABA to inhibit benzodiazepine inverse agonist binding. The amount of binding of benzodiazepine agonist, antagonist, and inverse agonist to benzodiazepine recognition sites was unaltered by the chronic treatment, as were the potencies of these benzodiazepine ligands in inhibiting agonist (3H-flunitrazepam) binding. Chloride channel binding (35S-TBPS) was also unchanged by chronic diazepam treatment. A change in GABA/benzodiazepine coupling and/or a decreased effectiveness of GABA may be responsible for the desensitization of GABA/benzodiazepine interaction.     

Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence

We described characteristics of subjects with benzodiazepine dependence that was typically complicated by harmful and hazardous alcohol use or high benzodiazepine doses, and assessed predictors of successful discontinuation of benzodiazepines for this group. Seventy-six patients who participated in a randomized clinical trial of two different gradual withdrawal treatment approaches were assessed. The trial was conducted between February 1995 and July 1999. The mean age +/- SD of subjects was 40.0 +/- 9.6 years, 55% were male, 38% were married or cohabiting, and 70% had received more than nine years of education. The median benzodiazepine dose was 35 mg/day (range 2.5-180) in diazepam equivalents. The median duration of benzodiazepine use was 84 (range 8-360) months. Subjects with lower benzodiazepine doses and no previous withdrawal attempts were more successful at benzodiazepine discontinuation. Cluster B personality/borderline personality disorder was associated with an inability to stop benzodiazepine use and with "dropping out" of treatment. Alcohol use-related disorders or other psychiatric diagnoses were not associated with outcome. Further studies on predictors of successful benzodiazepine discontinuation in different populations are required. Patients manifesting cluster B personality/borderline personality disorder and benzodiazepine dependence may need concomitant treatment for their personality disorders to benefit from benzodiazepine discontinuation treatment.     

Effects of peripheral-type benzodiazepine receptor ligands on Ehrlich tumor cell proliferation

Peripheral-type benzodiazepine receptors have been found throughout the body, and particularly, in high numbers, in neoplastic tissues such as the ovary, liver, colon, breast, prostate and brain cancer. Peripheral-type benzodiazepine receptor expression has been associated with tumor malignity, and its subcellular localization is important to define its function in tumor cells. We investigated the presence of peripheral-type benzodiazepine receptors in Ehrlich tumor cells, and the in vitro effects of peripheral-type benzodiazepine receptors ligands on tumor cell proliferation. Our results demonstrate the presence of peripheral-type benzodiazepine receptor in the nucleus of Ehrlich tumor cells (85.53+/-12.60%). They also show that diazepam and Ro5-4864 (peripheral-type benzodiazepine receptor agonists) but not clonazepam (a molecule with low affinity for the peripheral-type benzodiazepine receptor) decreased the percentage of tumor cells in G0-G1 phases and increased that of cells in S-G2-M phases. The effects of those agonists were prevented by PK11195 (a peripheral-type benzodiazepine receptor antagonist) that did not produce effects by itself. Altogether, these data suggest that the presence of peripheral-type benzodiazepine receptor within the nucleus of Ehrlich tumor cells is associated with tumor malignity and proliferation capacity.     

Autoradiographic demonstration of the selectivity of two 1-N-trifluoroethyl benzodiazepines for the BZD-1 receptors in the rat brain

Receptor autoradiographic techniques have been used to demonstrate the selectivity of two trifluoroethyl-containing benzodiazepines for one of the subtypes of benzodiazepine receptor. Indirect localization of the binding sites for quazepam and halazepam was accomplished by using the ability of these compounds to displace [3H]-flunitrazepam binding. The appropriate binding parameters were selected on the basis of initial studies aimed at identifying the binding characteristics of several benzodiazepine compounds in comparison with the triazolopyridine CL218,872. Autoradiographic analysis of the benzodiazepine sites displaceable with quazepam and halazepam revealed the two benzodiazepine compounds preferentially labeled receptor sites in regions of the brain dominated by the type 1 benzodiazepine receptor subtype. Thus, quazepam and halazepam preferentially bind to benzodiazepine type-1 receptors in lamina IV of the cerebral cortex, the zona incerta, substantia nigra and the cerebellum.     

Predictors of Benzodiazepine Discontinuation in Subjects Manifesting Complicated Dependence

We described characteristics of subjects with benzodiazepine dependence that was typically complicated by harmful and hazardous alcohol use or high benzodiazepine doses, and assessed predictors of successful discontinuation of benzodiazepines for this group. Seventy-six patients who participated in a randomized clinical trial of two different gradual withdrawal treatment approaches were assessed. The trial was conducted between February 1995 and July 1999. The mean age ±SD of subjects was 40.0±9.6 years, 55% were male, 38% were married or cohabiting, and 70% had received more than nine years of education. The median benzodiazepine dose was 35 mg /day (range 2.5–180) in diazepam equivalents. The median duration of benzodiazepine use was 84 (range 8–360) months. Subjects with lower benzodiazepine doses and no previous withdrawal attempts were more successful at benzodiazepine discontinuation. Cluster B personality/borderline personality disorder was associated with an inability to stop benzodiazepine use and with “dropping out” of treatment. Alcohol use–related disorders or other psychiatric diagnoses were not associated with outcome. Further studies on predictors of successful benzodiazepine discontinuation in different populations are required. Patients manifesting cluster B personality/borderline personality disorder and benzodiazepine dependence may need concomitant treatment for their personality disorders to benefit from benzodiazepine discontinuation treatment.     

High density of benzodiazepine binding sites in the substantia innominata of the rat

In order to study the neuronal basis of the pharmacological interactions between benzodiazepine receptor ligands and cortical cholinergic turnover, we examined the regional distribution of specific benzodiazepine binding sites using in vitro autoradiography. In the basal forebrain, the substantia innominata contained a high density of [3H]lormetazepam (LMZ) binding sites (Bmax = 277 fmol/mg tissue; Kd = 0.55 nM). The label could be displaced by diazepam (IC50 = 100 nM), the benzodiazepine receptor antagonist beta-carboline ZK 93426 (45 nM) and the partial inverse agonist beta-carboline FG 7142 (540 nM). It is hypothesized that the amnesic effects of benzodiazepine receptor agonists are exerted through benzodiazepine receptors which are situated on cholinergic neurons in the substantia innominata and are involved in a tonic inhibition of cortical acetylcholine release. The benzodiazepine receptor antagonist ZK 93426 may exert its nootropic effects via benzodiazepine receptors in the substantia innominata and, consequently, by disinhibiting cortical acetylcholine release.     

Opioid benzodiazepine tifluadom and drug-induced hyperactivity in mice: lack of benzodiazepine-like effects

The opioid benzodiazepine, tifluadom, and the benzodiazepine tranquilizer, diazepam, were compared for their influence on morphine and scopolamine-induced locomotor stimulation in mice. Diazepam enhanced drug-induced hyperactivity, while tifluadom had no effect or reduced locomotor activity. The results demonstrate that tifluadom, a benzodiazepine compound possessing opiate-like analgesic properties, is devoid of either benzodiazepine or morphine-like effects in activity tests.     

Differential antagonism of the anticonflict effects of typical and atypical anxiolytics

Selected benzodiazepine and non-benzodiazepine agents were studied alone or in the presence of benzodiazepine antagonists in the shock-induced suppression of drinking (SSD) procedure in rats. The disinhibitory activity of chlordiazepoxide, CL218,872, zopiclone and CGS 9896 was antagonized by two benzodiazepine antagonists, RO-15-1788 and CGS 8216. In contrast, the disinhibitory activity of fenobam, meprobamate, phenobarbital and tracazolate was not antagonized by either RO 15-1788 and CGS 8216. From these data it is apparent that the anticonflict activity of agents that bind to benzodiazepine receptors is blocked by benzodiazepine antagonists. In contrast, the activity of anxiolytics that are not displacers are unaffected even at higher doses.     

Benzodiazepine agonist and inverse agonist coupling in GABAA receptors antagonized by increased atmospheric pressure

Past work found that exposure to 12 times normal atmospheric pressure (ATA) of helium-oxygen gas (heliox) selectively antagonizes (uncouples) and differentiates allosteric coupling in GABA(A) receptors initiated by benzodiazepines versus neurosteroids. The present study tested the hypothesis that pressure can differentiate coupling initiated by a spectrum of benzodiazepine receptor ligands by measuring the effects of pressure on benzodiazepine ligand modulation of GABA-activated 36Cl(-) uptake in mouse brain membranes. 12 ATA completely antagonized allosteric modulation by: benzodiazepine receptor agonists diazepam and flunitrazepam; Type-1 selective benzodiazepine receptor agonist zolpidem and the benzodiazepine receptor partial inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha][1,4]benzodiazepine-3-carboxylate (Ro15-4513). The similar, non-competitive-like characteristics of pressure antagonism of these ligands suggest common structural/functional elements underlying their coupling. Pressure also antagonized allosteric modulation by the benzodiazepine receptor inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), but the antagonism was not complete and appeared to be surmountable (competitive-like) suggesting unexpected differences in coupling for DMCM versus Ro15-4513. These studies represent the first attempt to use pressure as a tool to dissect benzodiazepine receptor coupling. The results suggest that there is a common, pressure antagonism sensitive structural/functional element underlying coupling for benzodiazepine receptor ligands and that coupling for the full inverse benzodiazepine receptor agonist DMCM differs from coupling for benzodiazepine receptor agonists and benzodiazepine receptor partial inverse agonists.     

Facilitation of benzodiazepine binding by sodium chloride and GABA

An endogenous substance was found which facilitated benzodiazepine binding and was subsequently identified as GABA. The facilitation of benzodiazepine binding produced by GABA obeyed Michaelis — Menten Kinetics and Scatchard analysis revealed that this facilitation was due to an increased affinity of the benzodiazepine receptor. Sodium chloride itself increased benzodiazepine binding and also markedly enhanced the facilitation caused by GABA, by a further increase in the affinity of the benzodiazepine receptor. The enhancement of the GABA effect produced by sodium chloride showed sigmoidal kinetics indicating cooperativity, no evidence could be found for the involvement of sodium-dependent GABA binding in this interaction.