左氧氟沙星羧甲基壳聚糖微球结肠靶向释药的实验研究

目的:检测所制备的左氧氟沙星羧甲基壳聚糖(LVFX/CMC)微球在人工消化液中和大鼠体内结肠靶向释药的性能。方法:以分光光度仪测定微球在人工消化液中的累积释放量,电镜观察微球在人工消化液中形态的改变。SD大鼠60只,随机分为两组,分别以LVFX/CMC微球(含40 mg左氧氟沙星)及等量左氧氟沙星溶剂灌胃,以高效液相色谱法对LVFX/CMC微球和左氧氟沙星(LVFX)灌胃后大鼠盲肠、结肠中药物浓度进行定量检测。结果:左氧氟沙星壳聚糖微球在人工胃液介质中溶解缓慢,2 h仅释药8.62%;在人工小肠液介质中溶解速度稍见加快,6 h释药29.39%,但表现为药物缓释曲线,24 h仅释药42.13%;在人工结肠液中,4 h后释药84.56%,24 h内累积释药量为93%。扫描电镜观察人工胃液中的微球明显溶胀,稍见变形;人工结肠液中的微球溶解,粒径明显减小。灌胃后LVFX/CMC微球组5和9 h时段盲肠、结肠药量明显高于LVFX组。结论:左氧氟沙星羧甲基壳聚糖微球在体外、体内实验中的释放符合结肠靶向释药的特点。     

甲硝唑缓释微球结肠溶胶囊的制备及体外释放

目的：研制甲硝唑缓释微球并装于结肠溶胶囊，评价其体外释放特性。方法：用乳化交联法制备甲硝唑羧甲基壳聚糖微球，测定平均粒径、载药量、包封存率等指标；将微球和原料药分别装于结肠溶胶囊，测定微球、原料药及结肠溶胶囊剂型在人工胃液、人工小肠液、人工结肠液中的释放性能。结果：重复制备6批微球，微球平均粒径为（197．1±3．9）μm，载药量为（48．2±1．5）％，包封率为（37．5±1．9）％；体外释放甲硝唑原料药0．75h释放完全，甲硝唑微球7h释放完全；甲硝唑原料药结肠溶胶囊和甲硝唑微球结肠溶胶囊，在人工胃液、人工小肠液5h均无释放，移至人工结肠液后，前者于6．25h释放完全，后者于13h释放完全。结论：甲硝唑羧甲基壳聚糖微球的制备工艺稳定，甲硝唑羧甲基壳聚糖微球结肠囊胶囊具有结肠定位及缓释性能。     

替莫唑胺壳聚糖缓释微球的制备及体外释药特性

目的:制备替莫唑胺壳聚糖缓释微球,并对其体外释药模式进行研究.方法:以替莫唑胺为模型药物,采用乳化交联法制备壳聚糖微球,两步优化法优化处方和制备工艺.通过测定微球的粒径及其分布、载药量、包封率和体外释放速度对微球进行质量评价.结果:优化工艺制得的微球平均粒径为(3.9±1.6)μm,载药量为(7.1±0.5)%(n=3),包封率为(25.0±0.8)%(n=3),体外释药特性研究具有良好的缓释特性,在0～8 h符合Higuchi方程,Q=11.717 26.951t1/2(r=0.980),8～24 h符合一级释放曲线,lnQ=4.37 0.007 5t(r=0.983).结论:通过优化处方和制备工艺,采用乳化交联法可制备出以壳聚糖为载体、替莫唑胺为模型药物的缓释微球,其体外释药具有明显的缓释作用.     

吸附和包埋法制备洛美沙星淀粉微球及其体外释放比较研究

目的制备盐酸洛美沙星淀粉微球,并对其体外释药模式进行研究。方法以盐酸洛美沙星为模型药物,采用吸附载药法和包埋载药法制备了载药淀粉微球,通过测定微球载药量、包封率和在不同的释放介质中的体外释放情况,对上述2种方法制备的载药微球进行质量评价。结果吸附法制备的载药微球的平均载药量为14.54μg·mg^-1,药物包封率为39.72%;而包埋载药法制备的淀粉微球的平均载药量为19.32μg·mg^-1,药物包封率为48.95%。体外释药特性研究表明它们具有缓释特性,其中包埋载药法制备的淀粉微球比吸附载药法制备的淀粉微球有更好的缓释能力,在不同的释放介质中释药曲线也有所不同,在模拟胃液中累计释药量只能得到70%;而在模拟肠液中累计释药量能达到80%以上。结论吸附载药法和包埋载药法制备的载药淀粉微球都具有缓释作用,但后者体外释药具有更明显的缓释效果。     

载环孢素A海藻酸钙-壳聚糖微球的制备及体外释放特性

目的:针对角膜移植术后免疫抑制治疗需求,制备眼部局部给药的小粒径载环孢素A缓释微球,并进行体外释放考察。方法:以海藻酸钠、壳聚糖为载体材料,采用静电液滴工艺,通过向制备体系添加表面活性剂,制备小粒径载环孢素A微球,设计正交试验优化处方工艺,扫描电镜观察微球表面形态,动态透析法考察微球的体外释放特性。结果:所制微球形态良好,粒径分布窄,平均粒径为(12.4±0.8)μm,包封率为(82.8±1.8)%,载药量为(50.1±1.2)%,体外释放行为用Higuchi方程拟合效果最好。结论:采用静电液滴工艺,通过减小制备体系的表面张力,制备了球形度优良、粒径小、包封率和载药量较高的载环孢素A的壳聚糖-海藻酸盐缓释微球,所得制剂的体外释药规律服从扩散机制。     

结肠定位壳聚糖包衣氟尿嘧啶脂质体的制备、形态与体外释放

目的探讨药物结肠定位壳聚糖包衣脂质体的制备、形态及其在体外释药特性。方法用罗丹明B异硫氰酸(RBITC)和Bodipy-PC分别标记壳聚糖和磷脂,用前体脂质体方法制备氟尿嘧啶脂质体,利用激光扫描共聚焦显微镜观察壳聚糖包衣脂质体的形态;考察壳聚糖包衣脂质体在人工胃液、人工肠液和人工结肠液中的释放。结果 脂质体包衣前后粒径分别为2.071和2.750 μm。壳聚糖能较好地包覆脂质体;3种脂质材料不同的包封率分别为99%,61%,72%。未包衣的脂质体在人工胃液中4 h已释放完全,而包衣脂质体在人工胃液4 h释放6.3%,在人工肠液中8 h仅释放6.8%,但在人工结肠液中释药明显加快,t1/2为3.63 h。结论结肠定位壳聚糖包衣脂质体制备可行,在人工结肠液中,体外释放符合Higuchi方程。     

吸附和包埋法制备洛美沙星淀粉微球及其体外释放比较研究

目的 制备盐酸洛美沙星淀粉微球,并对其体外释药模式进行研究。方法 以盐酸洛美沙星为模型药物,采用吸附载药法和包埋载药法制备了载药淀粉微球,通过测定微球载药量、包封率和在不同的释放介质中的体外释放情况,对上述2种方法制备的载药微球进行质量评价。结果 吸附法制备的载药微球的平均载药量为14.54 µg·mg^-1,药物包封率为39.72%;而包埋载药法制备的淀粉微球的平均载药量为19.32 µg·mg^-1,药物包封率为48.95%。体外释药特性研究表明它们具有缓释特性,其中包埋载药法制备的淀粉微球比吸附载药法制备的淀粉微球有更好的缓释能力,在不同的释放介质中释药曲线也有所不同,在模拟胃液中累计释药量只能得到70%;而在模拟肠液中累计释药量能达到80%以上。结论 吸附载药法和包埋载药法制备的载药淀粉微球都具有缓释作用,但后者体外释药具有更明显的缓释效果。     

磁性壳聚糖微球的释药和靶向研究

目的：利用改变pH值法制备磁性壳聚糖微球,并对微球的载药量、缓释特性和磁靶向特性进行测试.方法：采用紫外光谱吸收法测定载药量,渗透袋扩散技术测试微球的释药速度,体外模拟法测定微球的磁靶向性.结果：载药量为37%,包封率62%.微球10h内药物释放约为75%,连续释放78h.外加磁场应在2000～3000Gs左右,施加时间在2h为宜.结论：使用改变pH值法制备的壳聚糖微球,具有较高的载药量和包封率,微球缓释效果明显,并实验测出了适合微球靶向控制的磁场施加方式.     

槲皮素包合物微球的制备及其体外释放研究

目的:制备槲皮素β-环糊精包合物-壳聚糖微球(QT-CD-CM),并考察其理化性质和药物体外释放性能。方法:采用有机溶剂挥发法制备槲皮素β-环糊精包合物,再用乳化分散-离子交联法、以三聚磷酸钠为交联剂制备壳聚糖微球,并考察其形态、粒径、包封率、载药量和体外释放情况。结果:制备的QT-CD-CM形态规则、均质、无粘连,平均粒径(3.327±0.124)μm,包封率为32.4%,载药量为12.3%,在5%乙醇-磷酸盐缓冲液介质中72h可以达到完全释药,释药过程符合一级动力学模型。结论:QT-CD-CM理化性质及体外释药性能良好,制备工艺简单,有望成为理想的槲皮素给药系统。     

卡铂碳包铁纳米壳聚糖微球的制备和特征

目的制备卡铂碳包铁纳米壳聚糖微球,检测其性能,并与卡铂纯铁纳米壳聚糖微球进行比较。方法以吸附药物的碳包铁纳米磁粉为磁性内核,壳聚糖为基质,卡铂为负载药物,采用反相微乳法制备卡铂碳包铁纳米壳聚糖微球。卡铂纯铁纳米壳聚糖微球的制备方法相似,不同的是以无吸附药物能力的纯铁纳米磁粉为磁性内核。检测和比较两种纳米药物微球的形态、粒径、磁响应性、载药量、包封率和体外释药。结果两种药物微球的球形圆整,平均粒径(210±26)nm,粒径分布150~300nm,磁响应性强。碳包铁纳米微球的载药量(11.15±1.03)%,纯铁纳米微球载药量(9.21±1.10)%。碳包铁纳米微球1,2,3,4d的体外释药量分别为60%、74%、84%、92%;纯铁纳米微球1,2d的释药量分别为81%,91%。结论通过活性碳吸附和物理基质包裹双重物理机制载药载药的卡铂碳包铁纳米壳聚糖微球不但载药量高,而且释药速度平稳。多重机制的有机结合是优化纳米微球性能的有效方法。     

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.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.     

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.