EHMO和模式识别法研究芬太尼衍生物的构效关系

自Hansch等创立QSAR法以来,药物构效关系的研究已获得较大的进展。本文将模式识别法用于芬太尼衍生物构效关系的研究,将该类药物的分子结构看作与生物活性具有对应关系的表现形式——模式,以药物分子结构中有关取代基的多个量子化学参数为数量化的模式向量成分。将已知生物活性的药物作为模式识别训练点,则所得模式识别分类图反映了该类药物的生物活性与其量子化学结构特征参数间的统计学意义的关系。它既可用来探寻高效药物的结构参数,又能预测新设计药物生物活性的等级或类别。     

Designing and Synthesis of Novel Amidated Fentanyl Analogs

Some new amidated fentanyl (=N‐[1‐(2‐phenylethyl)piperidin‐4‐yl]‐N‐phenylpropanamide) analogs with a 4‐(N‐phenylamido)piperidine scaffold and additional amide bonds have been designed and synthesized through Ugi four‐component reaction (Ugi‐4CR). Good‐to‐high yields, diversity‐oriented synthesis, and possible applications in drug discovery are advantages of this approach.     

不同浓度罗哌卡因联合芬太尼行硬膜外分娩镇痛的量效观察

目的探讨罗哌卡因联合芬太尼行硬膜外分娩镇痛的最佳有效浓度。方法选择120例初产妇接受L2-3硬膜外穿刺置管拟行分娩镇痛．按随机数字表法分为0．15％罗哌卡因联合1ug／ml芬太尼（F1组）、0．12％罗哌卡因联合1ug／ml芬太尼（F2组）、0．10％罗哌卡因联合1ug／ml芬太尼（F3组）及0．08％罗哌卡因联合1ug／ml芬太尼（F4组）。监测镇痛过程中阻滞平面和运动阻滞发生情况、VAS、缩富素使用增加例数等。结果F1、F2组运动神经阻滞发生的例数多于F3、F4组（P〈0．05）。F1组缩宫素使用增加例数多于其它3组（P〈0．05）。不同罗哌卡因浓度比较,F4组起效时间最长,明显长于F1、F2、F3组（P〈0．05）。F4组给药后30、60、90min时的VAS明显高于F1、F2、F3组,停药时的VAS明显高于F1组（P〈0．05）。F4组镇痛后30min内第3次宫缩开始每次宫缩对应的VAS明显高于F1、F2、F3组（P〈0．05）。结论罗哌卡因联合1ug／ml芬太尼用于分娩镇痛时,010％是最佳有效浓度,镇痛效果好,运动阻滞轻,安全性高。     

Development of a conformational search strategy for flexible ligands: A study of the potent μ-selective opioid analgesic fentanyl

Summary An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations.The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.     

Fabrication of a new electrochemiluminescent sensor for fentanyl citrate based on glassy carbon microspheres and ionic liquid composite paste electrode

Due to the high performance of glassy carbon in the aspects of mechanical strength, electrical conductivity and high corrosion resistance, etc., glassy carbon has been widely used in the electrochemistry. A new form of glassy carbon, glassy carbon microsphere, was utilized to couple with ionic liquid in preparing a new electrochemiluminescent platform for Ru(bpy)₃Cl₂. Room temperature ionic liquid has been proposed to be very interesting and efficient pasting binder to replace the non conductive organic binders for the fabrication of composite paste electrode. Attributed to the special characteristics of glassy carbon microspheres and room temperature ionic liquid [N-octylpyridium tetrafluoroborate (OPFP)], this new electrochemiluminescent sensor exhibited excellent electrochemiluminescent performance in Ru(bpy)₃²⁺ solution. We first found that fentanyl citrate could increase the ECL of Ru(bpy)₃²⁺, hence an ECL approach was developed for the determination of fentanyl citrate based on this glassy carbon microspheres based electrochemiluminescent platform with high sensitivity. Under the optimized conditions, the enhanced electrochemiluminescent intensity versus fentanyl citrate concentration was linear in the range of 1.0 × 10⁻⁸ to 1.0 × 10⁻⁴ mol L⁻¹ with a detection limit of 8.5 × 10⁻⁹ mol L⁻¹, and the relative standard deviation for 1.0 × 10⁻⁶ mol L⁻¹ fentanyl citrate was 1.90% (n = 10). This protocol has extended the application scopes of glassy carbon material and promoted the application of glassy carbon microspheres in electroanalysis.     

罗哌卡因复合芬太尼硬膜外用药对分娩方式的影响

目的探讨硬膜外罗哌卡因复合芬太尼分娩镇痛对分娩方式的影响。方法回顾7136例具备顺产条件初产妇的最终分娩方式,按产妇意愿分为对照组（A组）4168例及分娩镇痛组（B组）2968例。A组产妇未接受分娩镇痛,B组产妇给予L2~3或L3~4硬膜外阻滞,头向置管后1%利多卡因5ml试验量确定阻滞平面后,予以6~15ml/h持续泵注0.15%罗哌卡因和2μg/ml芬太尼的复合液。记录汇总最终分娩方式及剖宫产原因,评定两组新生儿出生后1、5minApgar评分,评定产妇镇痛后的视觉模拟评分（VAS）及改良Bromage评分。结果B组产妇剖宫产率（20.28%）及产钳使用率（4.38%）明显高于A组（7.70%、2.33%,P＜0.01）;B组第一产程时间延长于A组(P＜0.01）;B组因第一产程延长而行剖宫产比例（64.62%）明显高于A组（42.81%,P＜0.01）;B组胎儿宫内窘迫的比例（12.29%）明显低于A组（31.25%,P＜0.01）;胎头下降停滞及羊水问题、胎位异常比例与A组比较差异均无统计学意义（均P＞0.05）。两组新生儿出生后1、5min的Apgar评分差异无统计学意义（P＞0.05）。B组产妇宫口6、10cm时的VAS评分明显低于A组（P＜0.01）,但两组产妇下肢改良Bromage评分差异无统计学意义（P＞0.05）。结论0.15%罗哌卡因复合2μg/ml芬太尼的硬膜外分娩镇痛可增加产妇剖宫产率、阴道器械助产率及延长第一产程,但对新生儿Apgar评分及产妇下肢肌力无影响。     

Determination of fentanyl in human breath by solid-phase microextraction and gas chromatography–mass spectrometry

Fentanyl, a kind of intravenous narcotic analgesic, is widely used in clinical anesthesia. As a potential pollution, it was detected in both the air of the cardiothoracic operating room and patients' expiratory circuit. However, whether the fentanyl in patients' expiratory circuit is exhaled by patients is unknown. In this study, breath samples were taken from the expiratory circuits of anesthetic machine linked to the patients who received intravenous fentanyl, a solid-phase microextraction (SPME) coupled with gas chromatography–mass spectrometry (GC–MS) method was developed to detect and quantify fentanyl in breath samples. The parameters influencing adsorption (extraction time, temperature,) and desorption (desorption time) of the analyte on the fiber were investigated and validated for method development. The developed method was proved to be simple, easy, and inexpensive and offer high sensitivity and reproducibility. Linear range was obtained from 0.05 ng/mL to 0.8 ng/mL. The limit of detection was 0.01 ng/mL while an interday precision of less than 12.13% (n = 5) could be achieved. Six patients were involved in this study; results showed presence of fentanyl in the breath of patients who received intravenous fentanyl, and fentanyl concentrations in breath varied from 6.00 to 20.89 pg/mL. In conclusion, fentanyl can be exhaled by patients who received intravenous fentanyl.     

Use of single-drop microextraction for determination of fentanyl in water samples

Fentanyl is a very potent synthetic narcotic analgesic. Because of its strong sedative properties, it has become an analogue of illicit drugs such as heroin. Its unambiguous detection and identification in environmental samples can be regarded as strong evidence of its illicit preparation. In this paper we report application of single-drop microextraction (SDME) for analysis of water samples spiked with fentanyl. Experimental conditions which affect the performance of SDME, for example the nature of the extracting solvent, sample stirring speed, extraction time, ionic strength, and solution pH, were optimized. The method was found to be linear in the concentration range 0.10–10 ng mL⁻¹. The limits of quantitation and detection of the method were 100 pg mL⁻¹ and <75 pg mL⁻¹, respectively. This technique is superior to other sample-preparation techniques because of the simple experimental set-up, short analysis time, high sensitivity, and minimum use of organic solvent.     

Determination of midazolam in rabbit plasma by GC and LC following nasal and ocular administration

GC with nitrogen phosphorus detection and HPLC with UV detection were used to determine midazolam (MDZ) levels in rabbit plasma following ocular and nasal administration. For GC with nitrogen phosphorus detection, the analyte was extracted from the plasma using a three‐step liquid–liquid extraction including extraction with an isopropanol/butyl chloride mixture in an alkaline solution, followed by extractions with 1 M HCl, and finally with an alkaline solution of butyl chloride. The recovery of MDZ was dependent on the sample alkalization time prior to the final extraction. The procedure increased the recovery of MDZ up to 99.6%. Improved sample preparation led to a significant increase in the sensitivity of the determination by GC with nitrogen phosphorus detection. The achieved detection limit was 0.34 ng/mL, which is ten times lower than that obtained using HPLC with UV detection. The small plasma volume was another advantage of the GC with nitrogen phosphorus detection method (200 μL per assay). Both administration routes of the anesthetic (nasal and ocular) resulted in comparable plasma MDZ levels. Kinetic simulation of the MDZ plasma was performed for both administration routes.