丹参素脂质体的制备及体外释放度研究

摘 要 目的： 制备丹参素脂质体并考察其体外释放度。方法: 采用逆相蒸发法制备丹参素脂质体,以包封率为指标,通过正交试验考察大豆卵磷脂浓度、大豆卵磷脂与丹参素药脂比和水相pH值。透射电镜观察所制备脂质体的形态和粒径,利用HPLC测定丹参素含量,透析法比较丹参素脂质体和游离丹参素的体外释放度。结果: 最佳制备工艺：磷脂浓度为40 mg·mL^-1,药脂比为1∶10,水相pH为6.6。制备的丹参素脂质体为圆整球形,平均粒径(174±36) nm,平均包封率38.9%。丹参素浓度范围在2.0～20.0 mg·L^-1的线性关系良好（r=0.998 4）,丹参素脂质体的体外释放度比游离丹参素慢,能达到24 h缓释。结论:采用逆相蒸发法制备的丹参素脂质体粒径大小均匀,具有一定的缓释效果。～     

达托霉素脂质体的制备和体外释放度考察

摘 要 目的：制备达托霉素脂质体,并考察其体外释放度。方法: 采用主动载药法制备达托霉素脂质体,激光粒度测定仪测定脂质体的粒度及其分布、Zeta电位,高效液相色谱仪测定包封率和体外释放度。结果: 达托霉素脂质体粒径为109.5 nm,多相分散系数为0.042,Zeta电位为-6.48 mV,凝胶柱法和离心法测得的包封率分别为50.8%和50.3%。体外释放度显示：相比于注射用达托霉素,达托霉素脂质体具有良好的缓释效果。结论:本方法制备的达托霉素脂质体,粒径均匀,能够实现药物的缓慢释放,减少给药次数。     

伏立康唑长循环脂质体的制备及在大鼠体内药动学研究

摘 要 目的：制备伏立康唑长循环脂质体,并考察其在大鼠体内药动学特性。方法: 采用薄膜分散 挤压法制备伏立康唑长循环脂质体,并分别考察长循环脂质体在磷酸盐缓冲液和大鼠血浆中的释放情况,评价长循环脂质体在冻干前后的粒径分布、形态等理化性质;测定伏立康唑长循环脂质体在大鼠体内的药动学行为。结果: 所制备的伏立康唑长循环脂质体的平均粒径为（192.1±49.3）nm,呈球形或类球形分布;在磷酸盐缓冲液(PBS)中释放缓慢,而在大鼠血浆中释放较快;大鼠体内药动学表明,伏立康唑长循环脂质体的t1/2及AUC0 t分别为伏立康唑注射剂的2.17和2.31倍。结论:伏立康唑长循环脂质体延长了药物在血浆中的滞留时间,能达到长循环目的。     

叶酸介导的多西他赛脂质体制备、质量控制及稳定性研究

摘 要 目的： 采用几种不同工艺制备叶酸介导的多西他赛脂质体,建立其质量控制方法并考察其稳定性。方法: 将氢化大豆磷脂酰胆碱 (HSPC)、叶酸 聚乙二醇2000 磷脂酰乙醇胺 (FA PEG2000 DSPE)及多西他赛以100∶5∶8的比例分别采用3种不同工艺制备脂质体。采用低速离心法测定包封率,动态光散射法测定粒度分布,GC法测定有机溶剂残留。结果: 脂质体平均粒径为(155 ± 10) nm,多项分散系数 (PdI)均小于0.20;脂质体包封率均大于95.0%;所制得样品于(25±2)℃条件下放置6个月,各项考察指标均未发生明显变化。结论:采用制备工艺3所制得的样品具有较高的药脂比,该制备工艺可行,质量可控,稳定性良好。体外释放曲线表明脂质体有缓释、靶向及长效作用。     

Box-Behnken效应面法优化盐酸美金刚缓释微丸处方工艺

摘 要 目的：对盐酸美金刚缓释微丸进行处方优化,并考察其体外释放。方法: 采用流化床技术制备盐酸美金刚缓释微丸,以进风温度、雾化压力和喷液流速为考察因素,以上药百分率为评价指标,采用正交试验优选微丸上药工艺参数。采用Box-Behnken效应面法优化缓释包衣处方及包衣增重。以乙基纤维素水分散体的含量、聚乙二醇6000（PEG 6000）含量及包衣增重为因素,以盐酸美金刚2,6,12 h的累计释放度为响应值,采用Box Behnken效应面法优化盐酸美金刚缓释微丸的包衣处方及包衣增重,对盐酸美金刚缓释微丸进行释放度考察。结果: 最佳的微丸上药工艺参数为：进风温度45℃,雾化压力1.0 bar,喷液流速1.5 r·min^-1。最佳缓释包衣处方为：乙基纤维素水分散体含量为8.4%,PEG 6000含量为2.3%,缓释层包衣增重16.7%。盐酸美金刚缓释微丸具有良好的缓释效果。结论:正交试验和Box Behnken效应面法可用于盐酸美金刚缓释微丸处方工艺的优化,所建立的拟合模型具有较好的预测性。     

非布司他纳米缓释微丸的制备与体外释放度研究

摘 要 目的：制备非布司他纳米混悬剂,并进一步制备成缓释微丸,考察其体外释放度。方法: 采用高压均质法制备非布司他纳米混悬剂,通过流化床底喷包衣技术制备非布司他载药微丸,使用丙烯酸树脂 RL30D和丙烯酸树脂 RS30D包缓释层衣,制备成非布司他纳米缓释微丸,并评价其释药机制。结果:制备的非布司他纳米混悬剂的平均粒径为（212.5±36.3）nm,多相分散系统（PdI）为（0.193±0.018）,Zeta电位为（-12.4±0.3）mV,扫描电镜显示非布司他纳米混悬剂大小分布较均一;制备的非布司他纳米缓释微丸体外释药较为平缓,符合一级释放模型。结论:本研究制备非布司他纳米混悬缓释微丸体外释药平缓,为非布司他临床应用提供全新给药方案。     

叶酸受体靶向伊马替尼pH敏感脂质体的制备工艺及质量评价研究

摘 要 目的：运用改良的硫酸铵梯度法制备叶酸受体靶向伊马替尼pH敏感脂质体（FSLI）,并评价其质量。方法: 采用改良的硫酸铵梯度法制备FSLI,以包封率为指标进行制备工艺的优化;采用琼脂糖凝胶CL 4B柱分离脂质体和游离药,HPLC法测定FSLI的包封率;运用Zeta PALS粒径电位分析仪测定脂质体的平均粒径及Zeta电位,透射电镜观察脂质体的形态;运用动态透析法考察FSLI在不同pH环境中的药物释放情况,并考察FSLI在不同pH、37℃水浴中的粒径随时间的变化情况。结果: 制得的FSLI为圆形或类圆形的大单室脂质体,平均粒径为（155.2±1.92）nm,Zeta电位为 （29.36±3.21）mV,平均包封率为（90.7±1.70）%。FSLI在pH 7.4的中性环境中,药物释放缓慢,24 h累积释放度为2.76%,而在pH 5.5的酸性环境中,药物释放显著加快,24 h累计释放度均达到93.2%,表现出非常强的pH敏感性能。FSLI在pH 7.4的中性环境中不具有融合性能,而在pH 5.5的酸性环境中,粒径迅速增大,脂质体发生融合。结论:采用改良硫酸铵梯度法制备的FSLI,能获得较高的包封率,并具有良好的pH敏感性能。     

灯盏花素软胶囊的制备和体外溶出度研究

摘 要 目的: 制备灯盏花素软胶囊并考察其体外溶出行为。 方法: 单因素试验确定灯盏花素软胶囊处方与制备工艺,紫外分光光度法测定体外溶出度。结果:灯盏花素软胶囊内容物的沉降体积比为0.95,所制备的3批样品45 min内平均溶出度为99.7%,溶出均一性、溶出重复性合格。结论:研制的灯盏花素软胶囊制备方法可靠,质量可控,值得推广。     

伏立康唑白蛋白纳米粒大鼠体内药动学与组织分布

摘 要 目的：制备伏立康唑白蛋白纳米粒,并考察其在大鼠体内药动学与及组织分布。 方法: 采用超高压微射流技术制备伏立康唑白蛋白纳米粒,并评价了白蛋白纳米粒的粒径分布、Zeta电位、外观形态以及体外释药行为;考察了伏立康唑白蛋白纳米粒在大鼠体内的药动学与组织分布特征。 结果: 本研究制备的伏立康唑白蛋白纳米粒平均粒径为（121.9±41.6）nm,PdI为0.197,Zeta电位为（-42.1±0.9）mV,呈球形或类球形分布;伏立康唑白蛋白纳米粒在0.5%吐温80磷酸盐缓冲液（pH 7.4）中24 h累积释放67.5%;大鼠体内药动学研究表明,伏立康唑白蛋白纳米粒和伏立康唑注射剂的AUC0-24分别为（98.27±1.42）和（105.32±1.45）g?h?L^-1,MRT0-24分别为（4.48±0.38）和（4.86±0.51）h;伏立康唑白蛋白纳米粒能增加药物在大鼠肝、脾、脑中的靶向性。 结论:伏立康唑白蛋白纳米粒在大鼠体内具有良好的肝、脾、脑中靶向性,可以提高药物治疗疗效。     

阿魏酸川芎嗪长循环固体脂质纳米粒的制备及体外巨噬细胞摄取研究

摘 要 目的：研究阿魏酸川芎嗪长循环固体脂质纳米粒( PEG-FATM-SLN) 的制备方法,并考察其体外释放及细胞摄取性能。 方法: 采用乳化超声分散法,以包封率及粒径为考察指标,通过正交试验优化处方及工艺。以小鼠腹腔巨噬细胞( MPM) 为模型做体外细胞摄取试验。 结果:制备PEG-FATM-SLN最优处方为阿魏酸川芎嗪10 mg,单硬脂酸甘油酯0.3 g,乙酸丁酯1.5 ml,蛋黄卵磷脂0.4 g,泊洛沙姆1 880.6 g,硬脂酸钠0.02 g,水20 ml,二硬脂酰基磷脂酰乙醇胺 聚乙二醇2000（DSPE PEG2000） 0.02 g。制备的样品粒径为(107.1±1.1) nm,包封率为(53.3±3.0)%。体外释放试验和巨噬细胞摄取试验结果表明,该制剂具有明显的缓释性能和抗巨噬细胞吞噬作用。 结论:本研究制备了粒径小,包封率高的阿魏酸川芎嗪长循环固体脂质纳米粒,为其新剂型的研究提供了理论依据和试验基础。     

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.