7-[3-氨甲基-4-(脲亚氨基)吡咯烷-1-基]喹诺酮衍生物的合成与抗菌作用研究

目的 寻找新的喹诺酮类抗菌药.方法 设计合成7-位具有较强亲水性取代基的7个氟喹诺酮衍生物,测定其体外抗菌活性.结果 化合物10对金葡菌(包括MRSA)和表葡菌(包括MRSE)的活性(MIC:0.06～4μg/mL)与左氧氟沙星和吉米沙星基本相当.化合物11对肺炎链球菌08-2的活性(MIC:0.25μg/mL)分别是左氧氟沙星和吉米沙星的128倍和32倍,化合物12对肺炎克雷伯菌09-22和09-23的活性(MIC:1μg/mL)分别是左氧氟沙星和吉米沙星的16倍和4倍,但目标物对革兰阴性菌的活性普遍弱于对照药.结论 7-位取代基的水溶性并非决定喹诺酮抗菌活性的主要因素.     

帕珠沙星对临床分离致病菌的体外抗菌活性研究

目的评价帕珠沙星的体外抗菌活性。方法采用琼脂二倍稀释法，测定帕珠沙星与左氧氟沙星对342株临床分离菌株的最低抑菌浓度（MIC）。结果帕珠沙星对革兰阴性菌和革兰阳性菌的MIC90分别为0．06～4和1～16μg／ml。对大肠埃希菌、阴沟肠杆菌、变形菌、铜绿假单胞菌、不动杆菌和链球菌的MIC90为0．06～4μg／ml，是左氧氟沙星的1／2～1／8;对肺炎克雷伯菌、金葡菌和表葡菌与左氧氟沙星抗菌作用相当，MIC90分别为0．5、1、1μg／ml；对流感嗜血杆菌、黏膜炎莫拉菌和粪肠球菌的MIC90为0．5、1、16μg／ml，高于左氧氟沙星（0．25、0．5、8μg／ml）。结论帕珠沙星对革兰阴性菌和革兰阳性菌均具有广谱的抗菌作用，对革兰阴性菌的抗菌活性优于革兰阳性菌。     

复方盐酸莫西沙星滴鼻液的制备及质量控制

莫西沙星（moxifloxacin）是德国拜尔公司开发的一种第四代新型超广谱喹诺酮类抗菌药，它在保持传统喹诺酮类药物良好抗革兰阴性菌活性的基础上抗革兰阳性菌活性得到了增强，革兰阳性菌对本品很少产生耐药性或耐药产生很慢。莫西沙星对链球菌最低抑制浓度（MIC90）是环丙沙星、左氧氟沙星的4—64倍，对喹诺酮类敏感的金黄色葡萄球菌和表皮葡萄球菌MIC如是环丙沙星、左氧氟沙星的4．16倍。     

新喹诺酮左氟沙星的体外抗结核杆菌活性

新喹诺酮类抗菌药左氟沙星(Levofloxa-cin,DR3355)是消旋体氧氟沙星的光学异构体[S-(-)-氧氟沙星].它对一般细菌的抗菌谱与氧氟沙星相同.而抗菌活性为氧氟沙星的2倍.以氧氟沙星为首的一部分新喹诺酮类抗菌药具有优良的体外抗结核杆菌活性,而且在临床上也是有效的.因此研究了左氟沙星的体外抗结核杆菌活性.在进行左氟沙星的药物敏感性试验时,同时以氧氟沙星和司帕沙星作为对照药.首先将各药物100mg用0.1mol/L NaOH溶解,再以灭菌的精制水稀释后,加到1%小川培养基,制备成含有5、2.5、1.25和0.63ug/ml药物浓度的小川培养基.另将由患者痰中分离得到的结核杆菌菌株置于小川培养基上培养2～3周后制成2mg/ml的菌悬液,吸取0.025ml(菌量0.05mg)接种到含有药物的小川培养基上.进行培养和评价抗结核杆菌活性.氧氟沙星在2.5μg/ml浓度时20株中有20株(100%),在1.25μg/ml时,20株中有10株(50%)的生长被完全抑制.左氟沙星在1.25μg/ml浓度时20株中有20株(100%),0.63μg/ml时20株有5株(25%)的生长被完全抑制.左氟沙星的体外抗结核杆菌活性约为氧氟沙星的2倍.然而司帕沙星在0.63μg/ml时20株中17株(85%)的生长被完全抑制.左氟沙星的抗结核杆菌活性没有超过司帕沙星.对于氧氟沙星耐药菌株,左氟沙星在5μg/ml浓度时14株     

差示紫外分光光度法测定左氧氟沙星制剂的含量

左氧氟沙星(levofloxacin,LVFX)是第三代氟喹诺酮类抗菌药物氧氟沙星的左旋体,其抗菌活性约为氧氟沙星的二倍.对革兰阴性和革兰阳性细菌的MIC90值比氧氟沙星低50%;对甲氧西林敏感和耐药的金葡球菌的平均MIC90是环丙沙星的25%～50%[1].左氧氟沙星主要作用机制为抑制细菌DNA转移酶(细菌拓扑异构酶)的活性,阻碍细菌DNA复制.适用于敏感细菌所引起的呼吸系统、泌尿生殖系统及软组织感染.左氧氟沙星的含量测定方法有紫外分光光度法[2]、高效液相色谱法[3]等、差示紫外分光光度法尚未见报道.本文用差示紫外分光光度法测定甲磺酸左氧氟沙星片及盐酸左氧氟沙星葡萄糖注射液的含量,为该药提供了又一含量测定方法,方法简便、快速,结果满意.……     

差示紫外分光光度法测定左氧氟沙星制剂的含量

左氧氟沙星(levofloxacin,LVFX)是第三代氟喹诺酮类抗菌药物氧氟沙星的左旋体,其抗菌活性约为氧氟沙星的二倍.对革兰阴性和革兰阳性细菌的MIC90值比氧氟沙星低50%;对甲氧西林敏感和耐药的金葡球菌的平均MIC90是环丙沙星的25%～50%[1].左氧氟沙星主要作用机制为抑制细菌DNA转移酶(细菌拓扑异构酶)的活性,阻碍细菌DNA复制.适用于敏感细菌所引起的呼吸系统、泌尿生殖系统及软组织感染.左氧氟沙星的含量测定方法有紫外分光光度法[2]、高效液相色谱法[3]等、差示紫外分光光度法尚未见报道.本文用差示紫外分光光度法测定甲磺酸左氧氟沙星片及盐酸左氧氟沙星葡萄糖注射液的含量,为该药提供了又一含量测定方法,方法简便、快速,结果满意.     

复方左氧氟沙星滴鼻液的制备

左氧氟沙星（Levofloxacin）是新一代全合成氟喹诺酮类抗菌药，是氧氟沙星的左旋异构体，对革兰阳性菌及包括绿脓杆菌在内的革兰阴性菌，有广谱和高效的抗菌活性，其抗菌活性是氧氟沙星的2倍，是诺氟沙星的8倍。为了增加局部用药的药物浓度，减少全身用药的不良反应，制备了复方左氧氟沙星滴鼻液用于治疗急慢性鼻炎、鼻窦炎、副鼻窦炎、过敏性鼻炎等疾病。     

国内左氧氟沙星制剂的开发与临床应用

左氧氟沙星是第3代喹诺酮类抗菌药，是氧氟沙星的左旋体，其抗菌活性是氧氟沙星的2倍，具有抗菌谱广，抗菌作用强的特点，临床应用广泛。左氧氟沙星的制剂日渐增多，笔者查阅近年相关文献，将国内左氧氟沙星制剂的开发与临床应用作一概述。[第一段]     

左氟沙星、氯霉素、红霉素的体外抗菌效应比较

目的　为研制开发更好的外用抗感染制剂提供科学的参考依据。方法　检测了 6种 186株常见临床感染菌对左氟沙星、氯霉素、红霉素的敏感性。结果　左氟沙星、氯霉素、红霉素对 6种临床分离细菌MIC范围为 0 .0 6 2 5～ 8.0 μg/ml,0 .12 5～ 12 8μg/ml,0 .12 5～ 2 5 6 μg/ml;MIC50 为 0 .5 2 μg/ml,2 6 μg/ml,98μg/ml,MIC90 为 5 .6 μg/ml,10 8μg/ml,2 0 8μg/ml。 结论　左氟沙星的体外抗菌活性较氯霉素、红霉素强 ,氯霉素的体外抗菌活性较红霉素强     

左旋氧氟沙星类似物的合成及其构效关系

目的：发现新型高效的喹诺酮类抗菌药。方法和结果：设计合成了23个左旋氧氟沙星类似物,其中化合物5～23为新化合物,测定了它们对5株革兰阳性菌和5株革兰阴性菌的体外抗菌活性(MIC),并讨论了构效关系。结论：8-位氨基有利于提高喹诺酮抗阳性菌活性,化合物13,14的抗菌活性优于对照样品左旋氧氟沙星及环丙沙星。     

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.     

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.     

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.