多糖凝胶骨架结肠定位给药缓释系统的体外释放研究

目的: 筛选多糖材料作为水凝胶骨架,以达到结肠定位释药目的.方法: 选用海藻酸钠、果胶、壳聚糖、瓜木耳胶与药物混和制粒,灌装肠溶或结肠溶胶囊,考察其在人工胃液,人工肠液及人工结肠液中的释放情况.结果: 难溶性药物的海藻酸钠骨架结肠溶胶囊在人工胃液和小肠液中均不释放,人工结肠液中3 h释药低于30%;果胶骨架肠溶胶囊在人工胃液亦不释药,人工肠液中5 h释药仅为15%.水溶性药物在人工肠液中5 h释放可达50%.结论: 难溶性药物的海藻酸钠/结肠溶胶囊和果胶/肠溶胶囊体外释放度结果符合结肠定位的要求,可以作为建立酶触发体外释放评价方法和体内评价的制剂形式.水溶性药物的果胶/肠溶胶囊是较理想的缓释剂型.     

肠康宁结肠靶向胶囊体外释放度的评价

目的 对pH依赖型肠康宁结肠靶向胶囊体外释放性能进行评价,探讨制备中药结肠靶向制剂的可行性.方法 以木犀草素为评价指标,采用体外释放度测定法对该制剂的体外释放性能进行评价.结果 体外释放度试验结果表明,木犀草素在人工胃液2h后未见释放,在人工小肠液4h后未见释放,在人工结肠液1h后有一定的释放,2h后释放较高.结论 该制剂能在结肠定位释药.     

布地奈德结肠定位片的体外释放度实验方法及其释药机制研究

建立3步释放度实验法考察布地奈德结肠定位片的体外释药行为，并通过模型拟合阐明其释药机制。分别模拟胃、小肠和结肠部位的pH值、肠道菌群、特异性生物酶、蠕动和转运时间等生理参数，设计定位片体外释放度试验，24 h内定时取样，HPLC法测定布地奈德的累积释放度，采用多种数学模型对定位片的释药曲线进行拟合度分析。结果表明，布地奈德结肠定位片在2 h内无药物释放，6 h累积释放度约为5%，24 h累积释放度达77.5%，其体外释药行为符合First-order模型。本实验建立的3步释放度实验可作为评价布地奈德结肠定位片结肠靶向性的方法，定位片的释药行为遵从以渗透压作为主要释药动力的微孔型渗透泵的释药机制。     

美沙拉嗪结肠靶向微丸的制备和体外评价

目的以结肠溶型丙烯酸树脂为包衣材料制备美沙拉嗪pH控制型结肠靶向微丸,评价其体外释药特性。方法挤出滚圆法制备美沙拉嗪微丸,采用L934正交设计实验优化工艺条件,流化床包衣机包衣,采用U884均匀设计试验优化工艺参数,考察了微丸圆整度、收率及体外释药特性。结果优化条件所得的微丸外观圆整,粒径分布均匀,收率高,在人工胃液中2h、人工小肠液中4h累计释放率<5%,人工结肠液1h累计释放率>95%,具有明显的结肠靶向释药特性。结论美沙拉嗪结肠靶向微丸具有良好的体外结肠靶向释药特性,可进一步进行体内释药行为考察。     

酶控渗透泵型结肠定位微丸的制备及体外释放度考察

目的制备以果胶钙和醋酸纤维素为包衣材料,5-氨基水杨酸（5-ASA）为模型药物的酶触发渗透泵型结肠定位微丸,并考察其体外释药特征及释药机制。方法采用包衣锅法制备含药丸芯,选用L9（3）4正交实验设计,以体外释放度为评价指标优化包衣液处方及丸芯中渗透剂的用量,并进行体外释药模型拟合。结果制备5-ASA渗透泵酶触发微丸最佳工艺参数为：包衣增重25%;药物与NaCl（丸芯）比为3∶1;醋酸纤维素与果胶钙（包衣液）用量比为2∶3。所得微丸在人工胃液中2 h,人工小肠液中4 h累计释放率〈8%,人工结肠液12 h累计释放率〉70%,表明结肠定位性较为突出,且可以在结肠持续释放药物以维持局部药物浓度,进一步研究释药机理表明为零级释放。结论采用果胶钙与醋酸纤维素为包衣材料制备渗透泵酶触发结肠定位微丸可实现结肠定位作用。     

甲硝唑结肠定位缓释片的工艺研究

目的：研制甲硝唑结肠定位缓释片。方法：通过羟丙甲基纤维素（HPMC）骨架缓释材料制备甲硝唑缓释片芯，再采用S100包肠溶衣，制备甲硝唑结肠定位缓释片，并进行体外释放度和药动学研究。结果：所制得的片剂体外释放度符合结肠释放并缓释的特征，犬的药动学研究以及大鼠的消化道药物分布研究表明，药物口服后主要在结肠中释放，胃和小肠中几乎无药物释放。结论：采用本工艺制备的甲硝唑结肠定位缓释片可达到结肠定位和缓释的效果。     

洛伐他汀缓释片的溶出度研究

目的:建立洛伐他汀缓释片的溶出度测定方法,考察其体外性质.方法:通过体外溶出度试验评价不同条件下该剂型的缓释效果.结果:洛伐他汀缓释片在pH 7.0的十二烷基硫酸钠溶液中可持续释药24 h,释放规律符合零级动力学和Higuchi方程,24 h累计释放度95%以上.结论:该方法方便、准确、重复性好,该制剂具有良好的缓释性能.     

复方甲硝唑缓释栓的制备及体外释放度考察

目的:制备适合老年人用的复方甲硝唑缓释栓,并考察其体外释放度。方法:以甲硝唑和硝酸咪康唑为主药,羟丙基甲基纤维素为骨架材料,利用热熔法制备缓释栓剂;同时采用篮法,以0.5%十二烷基硫酸钠溶液为介质,硝酸咪康唑为对象,进行体外释放度评价。结果:所制制剂外观、性状良好,可持续12h释药,体外释放行为符合Higuchi方程。结论:该制剂制备工艺合理、简单易行,并具有良好的体外释药特性,符合缓释制剂的要求。     

吲达帕胺结肠定位释药微球的制备及其体外释放度考察

目的:以羟丙甲基纤维素琥珀酸酯(HAS)为载体材料制备吲达帕胺结肠定位释药微球并考察其体外释放度。方法:根据球晶造粒技术,采用乳化溶剂扩散法制备微球,以收率、载药量、包封率为优化指标,对影响微球制备的因素进行正交试验,通过神经网络遗传算法优选处方及工艺,并对以优化方案制备的微球进行了质量评价。结果:制备的吲达帕胺结肠定位释药微球形态圆整,大小均匀、表面光滑,粒径在50~250μm范围的微球占到92.07%,载药量为15.30%,包封率为95.48%;体外释药试验中,微球在模拟全胃肠不同pH条件下,即先在pH1.2和pH6.8介质中5 h累计释药17.54%,继在pH7.8介质中7 h后累积释药99.75%。结论:本试验筛选的处方及制备工艺可用于制备吲达帕胺结肠微球,且制备的微球能达到结肠定位释药的目的。     

苦参碱壳聚糖微球的制备及体外释药

目的:以壳聚糖为囊材制备苦参碱结肠靶向给药微球及评价其体外释药情况。方法:用乳化化学交联法制备微球,以微球的粒径分布百分数、载药量及包封率为优化指标对影响微球制备的主要因素用正交试验设计优化制备条件;并对最佳制备工艺制得的微球进行3种不同递质(人工胃液、人工肠液及大鼠结肠液)中的体外释放度评价。结果:制得的苦参碱壳聚糖微球在电镜下,球形表面圆整,粒径分布适宜,微球平均粒径为(68.3±2.7)μm,平均载药量为(16.0±0.5)%,平均包封率为(66.3±4.2)%。苦参碱壳聚糖微球在人工胃液中2h不释药;在人工肠液中4h内释放不到1%,96h释药不到10%;在含大鼠结肠内容物的磷酸盐缓冲液(pH6.8)中4h释放10%左右,36h释药近50%,此后释药趋于缓慢,96h释药近80%。结论:苦参碱壳聚糖微球几乎不在上消化道释药,而是在结肠靶向释药。     

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.