甘草次酸修饰多西紫杉醇脂质体的制备和体外抑瘤效果

目的:制备甘草次酸(GA)修饰的多西紫杉醇脂质体,并初步考察其体外抗肿瘤效果.方法:化学合成甘珀酸十八醇酯(18-GA-Suc)作为修饰材料,采用薄膜分散法制备甘草次酸修饰的多西紫杉醇脂质体,考察影响脂质体包封率的因素.采用MTT法评价脂质体对HepG2细胞的体外抑瘤效果.结果:18-GA-Suc修饰的DX脂质体的体外抑瘤效果强于未修饰的DX脂质体,并且抑瘤效果随着载体中18-GA-Suc的增加而增强.结论:甘草次酸修饰的脂质体有望成为新型肝靶向的抗肿瘤载体.     

甘草次酸介导pH敏感主动靶向长循环阿霉素脂质体的制备及其药物动力学

目的制备甘草次酸(glycyrrhetinic acid,GA)介导的pH敏感主动靶向长循环阿霉素(doxorubicin,DOX)脂质体(liposomes,LP)(GA-PEG2000-N=CH-DOXLP)并测定其在大鼠体内药物动力学参数。方法采用薄膜分散法制备甘草次酸介导pH敏感主动靶向长循环阿霉素脂质;采用阳离子交换树脂-微柱离心法测定脂质体的包封率和载药量;动态激光散射法测定脂质体的粒径、粒径分布和Zeta电位;透射电镜观察脂质体形态;透析法测定脂质体在不同pH条件下的体外释放;荧光分光光度法测定阿霉素血浆药物浓度,得到药-时曲线并计算药物动力学参数。结果甘草次酸介导的脂质体(GA-PEG2000-N=CH-DOXLP)和普通脂质体(DOXLP)的粒径分别为(135.5±2.6)nm和(105.6±4.0)nm;包封率分别为(53.8±5.8)%和(52.9±3.5)%,载药量质量分数分别为(2.35±0.16)%和(2.39±0.26)%;Zeta电位分别为-(5.19±0.73)mV和-(1.53±0.57)mV;GAPEG2000-N=CH-DOXLP的AUC(0-72)分别是DOXLP的2.33倍和DOX溶液的5.62倍。结论所制备的甘草次酸修饰的pH敏感主动靶向长循环脂质体制剂学性质稳定并能显著延长其在大鼠体内的循环时间。     

异甘草素脂质体的制备及稳定性考察

目的:制备异甘草素脂质体并考察其包封率及稳定性.方法:采用超声波薄膜分散法制备异甘草素脂质体,正交设计优选制备工艺;透射电镜观察形态;激光粒径仪测定平均粒径;葡聚糖凝胶层析法分离含药脂质体与游离药物并测定包封率;离心加速实验考察脂质体的稳定性.结果:异甘草素脂质体的平均粒径为233.1 nm,跨距为0.74,平均包封率为82.57%,稳定性良好.结论:该法制备异甘草素脂质体工艺可行,质量稳定.     

甘草次酸衍生物修饰去甲斑蝥素脂质体的制备及其小鼠肝靶向性实验研究

目的:制备甘草次酸衍生物修饰去甲斑蝥素(NC)脂质体(GDNL)并考察其肝靶向性。方法:合成甘草次酸硬脂醇酯-3-O-半乳糖苷(Gal-GAOSt)导向分子以修饰NC并制备脂质体,考察其包封率和粒径等指标;取小鼠分别尾静脉注射GDNL和NC水溶液,通过测定给药后各组织中NC的浓度计算GDNL的肝靶向指数(TI)。结果:所制GDNL包封率为56.29%,粒径(210±20)nm,肝组织的TI值为5.213。结论:所制GDNL包封率较高,肝靶向性明显。     

甘草次酸阳离子脂质体的制备及稳定性考察

目的:制备甘草次酸阳离子脂质体,并研究其稳定性。方法:用乙醇注入法制备甘草次酸阳离子脂质体。考察其粒径、包封率、过氧化值、在血浆中的稳定性和放样稳定性等性质。结果:所得脂质体的粒径小而均匀,呈球形和类球形,包封率为(91.6±1.2)%;离心加速试验结果显示脂质体的稳定性参数KE值较小,脂质体在血浆中释放缓慢,在4℃下放置6个月,其外观、包封率、粒径等各项指标无明显改变。结论:制得的甘草次酸脂质体包封率较高,稳定性良好。     

结肠癌细胞及线粒体双级靶向脂质体的处方工艺筛选研究

目的：研究结肠癌细胞及线粒体双级靶向脂质体（HA/TPP-TPGS LP/DOX）的最佳处方工艺。方法：用薄膜分散法结合微孔滤膜法制备;以细胞抑制率为指标,用MTT法筛选最佳聚脂比;以包封率为指标,用正交试验筛选最佳胆脂比、药脂比和超声时间;以粒径为指标,筛选最佳透聚比;以复溶后粒径和包封率为指标,筛选冻干保护剂的品种;用荧光显微镜和流式细胞术考察脂质体的靶向性;用透析法考察体外释药行为。结果：最佳处方是聚脂比1∶7、胆脂比1∶10、药脂比1∶15、超声时间15 min、透聚比2∶1,冻干保护剂为蔗糖。制备的脂质体呈类球形,粒径（142.20±0.54）nm,Zeta电位-（24.06±0.25）mV,包封率（98.20±0.18）%,稳定性高,有双级靶向性和体外药物缓释性。结论：本研究制备的脂质体有包封率高、粒径小、双级靶向性和缓释性等优点,为进一步研究奠定了基础。     

蔗糖八硫酸酯三乙胺梯度法制备重酒石酸长春瑞滨脂质体

 目的：制备重酒石酸长春瑞滨脂质体,并对制备工艺进行考察。方法：以蔗糖八硫酸酯三乙胺（triethylammonium sucrose octasulfate,TEA8SOS）梯度法制备重酒石酸长春瑞滨脂质体,以阳离子交换树脂分离脂质体与游离药物;并以紫外分光光度法和激光粒度仪分别测定重酒石酸长春瑞滨脂质体的包封率和粒径。结果：重酒石酸长春瑞滨脂质体包封率约为95%,粒径为129.5 nm。结论：以蔗糖八硫酸酯三乙胺梯度法制备的重酒石酸长春瑞滨脂质体包封率较高,方法可行。     

复方克林霉素脂质体凝胶的制备及体外透皮释药研究

目的制备复方克林霉素脂质体凝胶并考察其粒径分布、包封率及体外透皮特性。方法采用薄膜分散法制备复方克林霉素脂质体,利用透射电镜观察其形态,用激光纳米粒度仪测定其粒径大小及分布,用HPLC法测定其包封率。将脂质体进一步制成凝胶剂后,考察其体外透皮情况。结果复方克林霉素脂质体的粒径在240nm左右,分布均匀,平均包封率为51.24%;脂质体中的克林霉素能缓慢透过大鼠皮肤,缓释效果明显。结论该制剂制备工艺简单,性质稳定,药物包封率较高,定量测定方法简便、准确;药物透皮速率缓慢,释药稳定。     

甘草次酸固体脂质纳米凝胶的制备及体外透皮效应

目的制备甘草次酸固体脂质纳米凝胶并考察其体外透皮效应。方法采用微乳液法制备甘草次酸固体脂质纳米粒并考察其包封率、粒径与表面电位,以研和法制备固体脂质纳米粒凝胶;采用改良Franz立式扩散池法进行体外透皮实验,HPLC法测定甘草次酸含量,评价甘草次酸固体脂质纳米粒凝胶的经皮渗透结果。结果甘草次酸固体脂质纳米粒外观为圆球形或椭球形;甘草次酸固体脂质纳米粒的包封率为64.75%±1.36%,粒径范围(46.13±20.10)nm,电位分布范围为(-53.4±7.11)mV。24h甘草次酸固体脂质纳米粒凝胶较甘草次酸固体脂质纳米粒的累积透过量提高66%。结论甘草次酸固体脂质纳米粒凝胶能提高甘草次酸的透皮速率,有望成为甘草次酸透皮给药的新型制剂。     

肺靶向吡非尼酮脂质体的制备及体外释药性质研究

目的：研究肺靶向吡非尼酮脂质体的制备方法并考察其体外释药性质。方法：采用薄膜分散法制备吡非尼酮脂质体;用D-甘露糖修饰脂质体并添加适量十八胺调节脂质体表面电荷;用紫外分光光度法测定包封率;用正交实验优化处方,用透析法考察药物体外释放性质。结果：制得的脂质体平均粒径为581.1nm,表面电荷为-20.61mV,包封率为81.1%,稳定性好。药物体外释药符合Weibull方程。结论：采用薄膜分散法,用D-甘露糖修饰并添加十八胺可制得具有较高包封率及稳定性的吡非尼酮脂质体,有助于提高吡非尼酮的肺靶向性。     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.