抗抑郁药米氮平的新合成方法

目的：合成抗抑郁药米氮平。方法：以N-甲基乙醇胺、氧化苯乙烯和2-氨基烟酸为原料，经亲核开环、氯代、碱化、还原、胺烷基化和环合6步制得了抗抑郁药米氮平。结果：文献报道的相应各步反应条件得以优化，产率由22．6％提高到49．5％，各中间体及产物经红外光谱、核磁共振氢谱确证。结论：本方法简化了操作步骤，优化了反应条件，降低了成本，提高了收率。     

关于抑制抑郁药物米氮平的合成方法分析

目的：制成抑制抑郁药米氮平（m irtazapine）。方法以氧化苯乙烯、N-甲基乙醇胺、2-氨基烟酸等为原料，经过开环、氯代、碱化、还原以及氨烷基化和环合六步制成抑制抑郁药物米氮平。结果制作步骤反应条件得以优化，产出率提高。结论采用此方法缩减了操作步骤，优化了反应条件，提高了效益，取得了良好的效果。     

米氮平的合成工艺改进

目的 研究抗抑郁药米氮平的合成工艺。方法 以2-氯-3-氰基吡啶和1-甲基-3-苯基哌嗪为起始原料，经烷基化、水解、还原、分子内傅克烷基化4步反应合成目标化合物米氮平。结果与结论 目标化合物的结构经元素分析、IR、¹H-NMR 、¹³C-NMR、MS谱数据确证。改进后的工艺，操作简单，生产成本低廉，总收率由文献的46%提高到60%，更适合工业化生产。     

氯沙坦的合成

目的：探索氨沙坦新的合成方法。方法：以戊腈为原料，经3步反应制备中间体4，以2-氰基-4＇-甲基联苯为原料，经3步反应制备中间体8。中间体4与8经N-烷基化反应、还原反应、脱三苯甲基合成了目标化合物氯沙坦。结果：目标物经红外光谱、核磁共振氢谱、质谱和元素分析确证其化学结构，以戊腈计总收率达51.8％。结论：该方法原料易得，操作简便，易于工业化生产。     

咪喹莫特的合成

目的：研究抗病毒药咪喹莫特的合成。方法：以邻氨基苯甲酸为起始原料经缩合、环合、氯化、还原、N-氧化,氨基化等反应合成咪喹莫特。结果：合成的咪喹莫特收率为39％（以3-硝基4-羟基喹啉计）。经元素分析、MS、UV、IR、HNMR等测试确证了结构。结论：本方法合成咪喹莫特原料价廉易得,适合工业化生产。     

N-[5-氨基水杨酰基]甘氨酸的合成

[目的]改进N-[5-氨基水杨酰基]甘氨酸的合成方法，使之更适合工业化生产，[方法]以5-硝基水杨酸为起始原料合成N-[5-氨基水杨酰基]甘氨酸，经缩合，还原和水解等三步反应合成了N-[5-氨基水杨酰基]甘氨酸。[结果]较文献报道工艺简单，反应条件温和。产物结构经红外光谱，核磁共振氢谱及质谱确证。[结论]此合成路线是完全可行的。     

抗癌药雷替曲塞的合成

目的研究抗癌药雷替曲塞的合成。方法以2-噻吩甲醛为起始原料,经硝化、氧化、酯化、还原、氨基保护、N-甲基化、水解、缩合、脱保护、N-烷基化、水解11步反应合成雷替曲塞。结果与结论总收率为12.9%,其结构经核磁共振氢谱、质谱确证。     

米氮平治疗老年经皮冠状动脉介入术后抑郁患者的疗效观察

目的：观察米氮平对老年经皮冠状动脉介入治疗术（PCI）术后抑郁患者的疗效及安全性。方法：将80例老年PCI术后抑郁患者分为米氮平治疗组与帕罗西汀治疗组进行治疗，观察两组的疗效。结果：米氮平能有效治疗老年PCI术后抑郁，与帕罗西汀组比较差异无显著性。但米氮平组不良反应较帕罗西汀组少，两组比较有统计学意义。结论：应用米氮平能有效地控制老年PCI术后的抑郁状态，安全性大，值得推广应用。     

泛素特异性蛋白酶1抑制剂KSQ-4279的合成

目的 合成泛素特异性蛋白酶1(ubiquitin specific protease 1,USP1)抑制剂KSQ-4279。方法 以4-甲酰苯甲酸甲酯为起始原料，经环合、N-烷基化、还原、氯代得到2-[4-(氯甲基)苯基]-1-异丙基-4-(三氟甲基)-1H-咪唑(6);以2,4-二氯嘧啶-5-甲酸甲酯为起始原料，经还原、氧化、卤代、关环得到6-氯-1H-吡唑并[3,4-d]嘧啶(10);中间体10与6发生N-烷基化后经Suzuki偶联反应得到目标化合物KSQ-4279。结果与结论合成的目标化合物经LC-MS和¹H-NMR谱确证，纯度为98.10%(HPLC面积归一化法)。该路线反应条件温和，避免了危险化学试剂的使用，起始原料及催化剂价廉易得，更符合工业化生产要求。     

盐酸替扎尼定的合成改进

目的：改进盐酸替扎尼的合成路线.方法：以4-氯-2-硝基苯胺为起始原料,经还原反应和环合反应得5-氯-2,1,3-苯并噻二唑,再经硝化反应、还原反应得5-氯-4氨基-2,1,3-苯并噻二唑,与N-乙酰基-2-咪唑烷酮发生缩合反应后,再经醇解反应、成盐反应等步骤制得盐酸替扎尼定.结果：目标化合物的结构经红外光谱、核磁共振氢谱、核磁共振碳谱、质谱及元素分析确证.总收率52.4%.结论：本改进合成方法反应条件温和,操作简便.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.