咪达唑仑鼻用凝胶喷雾剂的镇静催眠作用研究

目的：对咪达唑仑鼻用凝胶喷雾剂的镇静催眠作用进行初探。方法：采用镇静、催眠实验,考察味达唑仑通过经鼻腔给药途径对小鼠自发活动和对戊巴比妥钠催眠作用的影响,以及对小鼠抬举双前肢的影响。结果：咪达唑仑鼻用凝胶喷雾剂经鼻腔给药后,可明显降低小鼠的自主活动次数,并具有良好的量效关系;可极显著地使阂下剂量戊巴比妥钠导致小鼠的入睡只数增加;各剂量组均可明显缩短给予戊巴妥钠阈上剂量后小鼠的入睡时间并延长其睡眠时间;可明显减少2min内小鼠的抬举双前肢的次数．结论：味达唑仑鼻用凝胶喷雾剂具有明显的镇静催眠作用．     

达唑仑与盐酸戊乙奎醚对小鼠学习记忆获得和巩固及再现的影响

目的 探讨咪达唑仑(Mid)、盐酸戊乙奎醚(Pen)对小鼠学习记忆的获得、巩固和再现的影响。方法120只昆明种小鼠分成4组，每组30只。分别为M组：给予Mid 1 mg•kg^-1；P组：给予Pen 0.2 mg•kg^-1；M+P组：给予Mid 1 mg•kg^-1＋Pen 0.2 mg•kg^-1；NS组：给予等量0.9%氯化钠溶液。上述各组再随机分成3个亚组，均为10只，分别参加记忆的获得、巩固和再现实验。另取30只小鼠作阳性对照，每组10只。分别为S组：给予阳性对照药物东莨菪碱2 mg•kg^-1；SN组：给予亚硝酸钠125 mg•kg^-1；A组：给予30%乙醇。所有药物注射容积均为0.1 mL•（10 g）^-1。用避暗实验的错误次数和潜伏期作为评估小鼠学习记忆的指标。训练前给药测定药物对小鼠记忆获得的影响：训练前30 min，各组分别腹腔注射Mid、Pen、Mid+Pen或0.9%氯化钠溶液；训练前15 min，S组腹腔注射阳性对照药东莨菪碱。训练后立即给药测定药物对小鼠记忆巩固的影响：各组训练后立即腹腔注射Mid、Pen、Mid+Pen或0.9%氯化钠溶液；SN组训练后立即皮下注射阳性对照药亚硝酸钠。测验前给药测定药物对记忆再现的影响：测验前30 min分别腹腔注射 Mid、阳性对照药30%乙醇灌胃；测验前15 min分别腹腔注射Pen或0.9%氯化钠溶液。结果单用Mid或合用Pen对记忆的获得和巩固均有抑制作用，而对记忆的再现无抑制作用；Mid合用Pen与单用Mid比较，虽不加重记忆获得的抑制，却明显抑制记忆的巩固；单用Pen不抑制记忆的获得、巩固和再现。结论Mid和Pen对记忆的抑制作用有利于防止术中知晓.     

咪达唑仑和丙泊酚对儿童七氟烷麻醉苏醒期躁动的影响

目的：观察咪达唑仑和丙泊酚对儿童七氟烷麻醉苏醒期躁动（EA）的影响。方法：选择120例行先天性斜视矫正手术的患儿,按随机数字表法均分为氯化钠注射液组（S组）、咪达唑仑组（M组）和丙泊酚组（P组）。所有患儿静脉麻醉后,M组给予咪达唑仑0．05mg／kg,静脉注射;P组给予丙泊酚1mg／kg,静脉注射;S组给予0．9％氯化钠注射液2ml,静脉注射。记录3组患儿诱导时间、麻醉维持时间、术中平均动脉压（MAP）、心率（HR）及呼吸频率（RR）;记录3组患儿苏醒和出麻醉后恢复室（PACU）时间及患儿苏醒期躁动（PAED）评分;记录所有患儿镇痛评分（CHIPPs）及EA发生率;观察3组患儿不良反应发生情况。结果：3组患儿术中诱导时间、麻醉维持时间、MAP、HR、RR、苏醒时间、出PACU时间、CHIPPs比较差异均无统计学意义（P〉0．05）。M组患儿和P组患儿EA发生率及PAED评分比较差异无统计学意义（P〉0．05）,但较S组患儿EA发生率和PAED评分均显著降低,差异有统计学意义（P〈0．05）。3组患儿治疗期间均未见明显不良反应发生。结论：咪达唑仑和丙泊酚可降低七氟烷麻醉患儿EA发生率和PAED评分,提高患儿复苏质量和安全,且不延长苏醒和出PACU时间,具有较好的临床疗效。     

咪达唑仑用于椎管内麻醉穿刺产生镇静与遗忘作用的合适剂量与给药时机

目的 寻求咪达唑仑对椎管内麻醉穿刺时产生镇静、遗忘作用的合适给药时机和剂量.方法 将240例ASAⅠ级患者分为椎管内麻醉穿刺操作前（A）组和操作后（B）组各120例;每大组又随机分为4小组,分别静脉给予0.01（M1组）,0.03（M2组）,0.1 mg•kg 1（M3组）咪达唑仑和0.9%氯化钠溶液（NS）组,每组30例.记录用药后警觉 镇静（OAA/S）评分和手术后1 h遗忘评分（AS）.结果OAA/S评分：A组和B组不同剂量M组与NS组比,OAA/S评分秩次差异有显著性;M2、M3组与M1组,M3组与M2组比较,镇静程度增加（P＜0.05）.B组中M2、M3组分别与A组中M2、M3组比较,镇静程度增加（P＜0.05）; AS评分：A组不同剂量M组与NS组比较,各剂量M组遗忘程度大于NS组（P＜0.05）;M2、M3组与M1组比较,遗忘程度增加（P＜0.05）;M2和M3组遗忘程度相似（P＞0.05）;B组：M1 、M2组与NS组遗忘程度相似（P＞0.05）;M1 、M2和NS组分别与M3组比,M3组遗忘程度增加（P＜0.05）;B组中M3组遗忘程度不如A组中M3组（P＜0.05）.结论 椎管内麻醉穿刺操作前,0.03 mg•kg 1咪达唑仑静脉给药可以产生良好的镇静、遗忘作用,而对呼吸、循环影响较轻.     

丙泊酚对线粒体功能影响的研究进展

丙泊酚输注综合征（propofol infusion syndrome,PRIS）是一种罕见但危及生命的并发症。虽然有证据显示PRIS的病理机制可能是丙泊酚引起的线粒体疾病,然而其分子机制并不明确,并且丙泊酚对损伤的心肌细胞和神经细胞线粒体功能还具有一定保护作用。因此本文对丙泊酚引起的不同细胞线粒体功能变化及机制进行一综述,分别阐述丙泊酚对心肌细胞线粒体、神经细胞线粒体及肝脏细胞线粒体的作用机制,以期为丙泊酚对线粒体影响的药理机制学研究提供理论依据。     

The Antinociceptive Effects of Midazolam on Three Different Types of Nociception in Mice

Antinociceptive effects of systemically administered midazolam remain controversial. The present study was performed to investigate its antinociceptive effects on different types of nociception in mice. Four different doses of midazolam (1, 3, 10, and 30 mg/kg) were administered intraperitoneally (i.p.). Saline was used as a control. The hot plate test, tail pressure test, acetic acid writhing test, the running wheel test, and the balance beam test were performed following the drug administration. In the hot plate test and tail pressure test, i.p. midazolam produced significant antinociceptive effects with the 50% effective dose (ED₅₀) of 3.46 mg/kg [confidence interval (CI), 1.99 – 6.01 mg/kg] and 3.52 mg/kg (CI, 2.77 – 4.47 mg/kg), respectively. In the acetic acid writhing test, i.p. midazolam also produced significant antinociceptive effects. In the running wheel test, no mice stopped running after saline or midazolam at 1, 3, or 10 mg/kg, but all mice stopped running 30 and 45 min after i.p. administration of midazolam at 30 mg/kg. In the balance beam test, 30 min after i.p. administration of saline or midazolam at 1, 3, and 10 mg/kg, all mice were able to stay on the beam for 90 s, none of them could with midazolam at 30 mg/kg. In conclusion, systemically administered midazolam had antinociceptive effects on acute thermal, acute mechanical, and acute inflammatory-induced nociception in mice. The antinociceptive potency of midazolam was the same for both acute thermal-induced nociception and mechanical-induced nociception.     

Biochemical and Mechanical Characterization of Enzyme-Digestible Hydrogels

Albumin-cross-linked hydrogels were prepared by free radical polymerization using 1-vinyl-2-pyrrolidinone as a monomer and functionalized albumin as a crosslinking agent. The degree of chemical cross-linking was controlled by varying the degree of albumin functionality and the concentration of albumin. With emphasis placed on the potential use of these hydrogels for long-term oral drug delivery, gel characterization studies examined both the swelling and the mechanical properties in the absence and presence of pepsin. In the absence of pepsin, the equilibrium swelling ratio in simulated gastric fluid ranged from 17 to 55, depending on the degree of albumin functionality and the albumin concentration. Swelling was pH dependent at pH's greater than 7. The uptake of solvent into the dried hydrogels was determined to be Fickian. The integrity of swelling gels was dependent on the concentration of the functionalized albumin as well as on the degree of albumin functionality. In the presence of pepsin, a predominance of either surface or bulk degradation was observed, depending on the functionality of the albumin used as a cross-linker. Gel integrity during pepsin degradation also showed a marked dependence on the albumin functionality.     

Oral Single Doses of Erythromycin and Roxithromycin May Increase the Effects of Midazolam on Human Performance

Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule form were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam + erythromycin impaired digit symbol substitution and letter cancellation, and triazolam + roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg + erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg + erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg + roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg. Our results suggest that sedation produced by hypnotic doses of midazolam is enhanced by erythromycin and perhaps by roxithromycin after single oral doses. The combined effects of triazolam together with erythromycin and roxithromycin were unclear, partly due to the relatively lower dose of triazolam.     

Midazolam, a short-acting benzodiazepine, resets the circadian clock of the hamster

Treatment with the short-acting benzodiazepine, triazolam, has been found to induce changes in both behavioral and endocrine circadian rhythms in hamsters. The objective of this study was to determine if these effects of triazolam could be generalized to other short-acting benzodiazepines. Therefore, the effects of midazolam on the biological clock of the hamster were examined in detail. A phase-response curve and a dose-response curve were measured to determine the effects of a single intraperitoneal injection of midazolam on the circadian clock of hamsters free-running in constant light. Midazolam injections produced maximal phase advances at circadian time (CT) 6 and 9 and maximal phase delays at CT 15 and 21. Doses of 2.5 mg or larger produced phase shifts that were significantly different from those produced by the vehicle controls. In addition, the phase-shifting effects of midazolam were completely blocked by administration of the benzodiazepine receptor antagonist, RO 15-1788, indicating that the phase-shifting actions of midazolam are mediated via benzodiazepine receptors. These results indicate that the previously reported effects of triazolam on the circadian clock can be generalized to other short-acting benzodiazepines.     

舒芬太尼联合咪达唑仑用于机械通气患者镇静的临床观察

目的：评价机械通气时采用舒芬太尼与咪达唑仑联合镇静的效果和安全性。方法：选择ICU中需要镇静的机械通气患者106例,随机分为舒芬太尼-咪达唑仑组（MSF组）、咪达唑仑组（M组）。两组均在给予负荷剂量后用微量注射泵持续静脉泵入药物方式镇静。监测用药初期（0、15、30 min）两组患者呼吸及循环参数的变化,以后每2小时评估镇静深度,以MAAS镇静评分3分、ATICE人机顺应性评分≥3分为镇静目标,优先保证人机顺应性进行药物输注速度的调整;并于24 h停药后观察苏醒时间、相关并发症、用药量及镇静满意度和人机顺应性满意度。结果：两组患者的基线参数比较差异均无统计学意义（P〉0.05）;两组镇静15 min和30 min的心率、呼吸频率、气道峰压明显低于用药前（P〈0.05,P〈0.01或P〈0.001）;MSF组收缩压较镇静前下降（P〈0.05）,但两组舒张压镇静前后无明显变化（P〉0.05）;M＋F组的镇静满意程度、人机顺应满意程度明显高于M组（P〈0.01,P〈0.05）。M＋F组的恢复时间明显短于M组（P〈0.01）;MSF组咪达唑仑的用药量少,相关并发症少。结论：机械通气患者使用舒芬太尼联合咪达唑仑镇静具有良好的镇静效果,提高人机顺应性,适当改善通气效果,且用药安全。     

Benzodiazepine receptor ligand actions on GABA responses. Beta-carbolines, purines

The effects of several beta-carboline and purine ligands for benzodiazepine receptors were studied upon GABA (4-aminobutyric acid) responses and upon diazepam enhancement of GABA responses, using mouse spinal cord neurons in dissociated cell culture. While the potent convulsant beta-carboline DMCM (methyl-6,7-dimethyoxy-4-ethyl-carboline-3-carboxylate), reduced GABA responses, methyl-carboline-3-carboxylate (beta CCMe) and the corresponding ethyl ester (beta CCEt) did not alter GABA responses. The propyl ester (beta CCPr) enhanced GABA responses in a concentration-dependent fashion, while both beta CCMe and beta CCPr blocked diazepam enhancement of GABA responses. beta CCPr may thus have partial agonist activity. Two purines with moderate benzodiazepine receptor affinity, 1-methylisoguanosine (MeIG) and 6-dimethylaminopurine (DMAP), weakly enhanced GABA responses. MeIG also significantly antagonized diazepam enhancement of GABA responses. Inosine and hypoxanthine had no apparent actions upon GABA responses or upon diazepam enhancement of such responses. The results with beta-carbolines are consistent with their behavioural profile in vivo and with neurochemical studies of their effects upon GABA-benzodiazepine receptor complexes. Furthermore, certain purines are also able to interact with these complexes.     

Midazolam: kinetics and effects on memory, sensorium, and haemodynamics.

This study aimed not only to compare the pharmacokinetics of oral and intravenous doses of the new water-soluble benzodiazepine, midazolam, but also to study the effects on haemodynamics, sensorium, and memory performance. Eight normal human volunteers each received a single 15 mg dose of midazolam base orally and intravenously in randomized sequence 2 weeks apart. Serial venous samples were obtained for 12 h after dosing. Vital signs, sensorium testing and memory testing using word lists were also performed. Computerized non-linear least squares curve-fitting of the two-compartment open model to the oral and intravenous data simultaneously yielded the following estimates: V1, 0.33 1 kg-1, VdSS, 1.08 1 kg-1, t1/2,lambda, 0.10 h, t1/2,Z, 1.89 h, ka 1.17 h-1 and bioavailability, 49%. The intravenous dose decreased the systolic pressure 22 mm Hg during the first half-hour and the oral dose had 50% less effect. Most subjects became drowsy halfway through the infusion and were only rousable to voice by its end. The sensorium was clear by 2-3 h. After oral dosing the peak sensorium effects of ataxia-dysarthria were seen at 30 min and had cleared by 2 h. Memory testing showed that memory acquisition was markedly impaired for at least 90 min after the intravenous dose and slight recovery was apparent at this time after the oral dose. Memory performance was proportionately more impaired than the sensorium score. We conclude that: midazolam kinetics are characterized by rapid absorption, but incomplete bioavailability and rapid elimination, midazolam intravenously may lower blood pressure significantly, and the level of consciousness correlates poorly with the degree of memory impairment.     

早期给予右美托咪定对重症监护酒精戒断综合征患者苯二氮

摘 要 目的：评估右美托咪定的早期给予对重症监护酒精戒断综合征患者苯二氮卓类药物需求的影响。方法: 重度酒精戒断综合征成年患者60例,随机分成A、B两组,每组30例。A组接受苯二氮卓类药物的同时早期给予右美托咪定,B组只接受常规苯二氮卓类药物治疗。记录患者第一次注射右美托咪定后24 h对苯二氮卓类药物的累计需求量、ICU和住院时间、机械通气情况、低血压和心率过缓发生率等。 结果: A组患者注射后24 h 对苯二氮卓类药物的需求明显低于B组[（8.6±1.2）mg vs (25.6±4.9)mg, P<0.05]。两组患者使用机械通气的例数相近,但A组患者插管持续时间明显低于B组[（24.9±3.1)h vs(48.8±6.9) h, P<0.05]。A组患者相对于B组表现出更高的心动过缓发生率（57% vs13%, P<0.05）。结论:作为治疗戒酒综合征的辅助用药,早期给予右美托咪定可显著降低ICU患者对苯二氮卓类药物的需求。     

Midazolam effects on prepulse inhibition of the acoustic blink reflex

AIMS: The eye-blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenuated by presentation of a weak stimulus before the 'startle-eliciting' stimulus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the application of benzodiazepines altered the magnitude of PPI in healthy male volunteers. METHODS: In an open-label noncontrolled investigation, the effect of the benzodiazepine agonist midazolam on PPI was assessed in the absence and presence of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing concentrations of midazolam were studied (0. 02, 0.06, 0.14 mg kg-1 h-1 ). A final 60 min period during the administration of flumazenil (0.004 mg kg-1 h-1 ) and while the agonist was still present was also studied. Drug was administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) response of the right orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were randomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 65 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calculated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects participated in the study, two of them were excluded from the statistical analysis because startle responses could not be reliably elicited (final sample size n=9). RESULTS: The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal Emax model, giving an Emax of 0.65+/-0.13, an ED50 of 33.9+/-10.9 ng ml-1 and gamma of 3.5+/-1.0. During infusion of flumazenil and in the presence of midazolam, the magnitude of PPI increased by 0.11 (95% CI, 0-0.22, P相似文献   

Benzodiazepine agonist-type activity of raubasine, a rauwolfia serpentina alkaloid

Raubasine produced a dose-related inhibition of specific [3H]flunitrazepam binding to rat brain membranes. Scatchard analyses revealed a significant increase in the affinity constant but no change in the number of binding sites, suggesting that raubasine acts as a competitive inhibitor. Raubasine also inhibited the in vivo binding of [3H]flunitrazepam to mouse brain sites. Behavioral studies showed raubasine to possess anticonvulsant properties against pentylenetetrazol- and bicuculline-induced convulsions in mice. These effects were inhibited by the benzodiazepine antagonist, Ro 15-1788. The results suggest that raubasine interacts directly at benzodiazepine sites with a benzodiazepine agonist-type activity.     

Midazolam cue in rats: Effects of Ro 15-1788 and picrotoxin

The discriminative stimulus effect of midazolam, a short-acting benzodiazepine, was used for testing the effects of drugs thought to act as antagonists at different sites in the proposed benzodiazepine receptor complex. Rats were trained in a standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. The benzodiazepine receptor antagonist Ro 15-1788 blocked the discriminative effect of midazolam but did not influence generalization to pentobarbitone (7.5 mg/kg). The indirect GABA antagonist picrotoxin attenuated both generalization to pentobarbitone and its response rate-reducing effect. Picrotoxin had no effect on the discriminative effect of midazolam at 0.4 mg/kg but it blocked the effect of 01 mg/kg. Even in doses which reduced overall response rates, nicotine did not block discrimination of midazolam (0.4 mg/kg). The results are consistent with models which postulate a GABA-linked ion channel which is a site of action for barbiturates and which is downstream of the benzodiazepine receptor itself.     

Antagonism of Soman-Induced Convulsions by Midazolam,Diazepam and Scopolamine

ABSTRACT

The effects of midazolam (MDZ), diazepam (DZ) and scopolamine (SCP) therapies on soman-induced electrocorticogram (ECoG) and biceps femoris electromyogram (EMG) activities and brain lesions were assessed in male rats. Animals received pyridostigmine (26 μg/kg, im) 30 min before soman (87.1 μg/kg, im) followed by therapy consisting of atropine (1.5 mg/kg) admixed with 2-PAM (25 mg/kg, im) 1 min later; MDZ (0.5 mg/kg), DZ (1.77 mg/kg) or SCP (0.43 mg/kg) was administered im at 1 min after the onset of convulsions (CVs). Typically, within 5 min after soman the ECoG profile changed to a fullblown, spike-and-dome epileptiform (SDE) pattern followed by CVs and increased amplitude of EMG activity. Treatment with SCP restored ECoG and EMG profiles by 30 min. At 2 hr after exposure only 1 animal demonstrated a slight abnormality in ECoG activity which was normal at 24 hr. Similarly, DZ and MDZ restored EcoG and EMG profiles by 30 min; however, in contrast to SCP, 83% of the animals demonstrated reappearance of SDE 2 hrs after soman. SCP therapy also enabled rats to move about in their cages by 30 min post treatment. In contrast, DZ- and MDZ-treated rats remained incapacitated as late as 2 hr post-exposure. Animals were euthanized at 24 hr, and the extent of soman-induced brain lesions was determined by light microscopic analysis. When present, brain lesions were minimal in SCP-treated rats. The mean brain lesion scores across all experimental conditions ranked as follows: soman control > MDZ > DZ≥ SCP = saline control. These observations suggest that SCP may be highly effective in severe soman intoxication.