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。     

辛伐他汀固体脂质纳米粒的制备及在大鼠体内的药动学研究

摘 要 目的： 制备辛伐他汀固体脂质纳米粒,并研究其经灌胃给药后在大鼠体内的药动学特征。方法: 采用热熔乳化超声 低温固化法制备辛伐他汀固体脂质纳米粒,考察辛伐他汀固体脂质纳米粒的粒径分布、Zeta电位、包封率、微观形态及体外药物释放特性。研究辛伐他汀固体脂质纳米粒经灌胃给药后在大鼠体内的药动学特征。结果: 辛伐他汀固体脂质纳米粒平均粒径为(242.5±62.1) nm,多聚分散系数为0.225±0.031,Zeta电位为(-32.1±4.2) mV,包封率为(95.7±2.6) %,在24 h内平稳缓慢释药。辛伐他汀固体脂质纳米粒在大鼠体内的Cmax和AUC0 t分别为辛伐他汀混悬液的2.89倍和1.83倍。结论:辛伐他汀固体脂质纳米粒在大鼠体内能快速吸收,显著提高了药物在大鼠体内的生物利用度。     

去甲斑蝥素白蛋白纳米粒的制备及质量评价

摘 要 目的：制备去甲斑蝥素白蛋白纳米粒,并考察其理化性质。方法: 采用超高压微射流技术制备去甲斑蝥素白蛋白纳米粒,以白蛋白纳米粒的平均粒径和药物包封率作为评价指标,首先应用Plackett Burman试验设计法筛选出对白蛋白纳米粒性质影响显著的处方和工艺变量,再通过Box Behnken试验设计法对筛选的变量进一步优化。考察了去甲斑蝥素白蛋白纳米粒的外观形态、粒径分布和Zeta电位及体外释药行为。结果:通过优化制备的去甲斑蝥素白蛋白纳米粒呈类球形分布,平均粒径为（105.2±30.1）nm,PdI为0.127,Zeta电位为（-24.7±1.9）mV,在0.5%吐温80磷酸盐缓冲液（pH 7.4）中24 h的累积释放度为81.4%。结论:采用超高压微射流技术制备去甲斑蝥素白蛋白纳米粒,工艺简便可行,重复性好,有望工业化生产。     

依托泊苷固体脂质纳米粒的制备与抗癌活性研究

摘 要 目的：制备依托泊苷固体脂质纳米粒,并评价其对小鼠接种Lewis肺癌细胞的抑瘤率。方法: 采用热熔乳化 高压均质法制备依托泊苷固体脂质纳米粒,考察依托泊苷固体脂质纳米粒的外观、微观结构、粒径分布、Zeta电位等理化性质,评价依托泊苷固体脂质纳米粒体外释药行为,比较依托泊苷固体脂质纳米粒与依托泊苷注射液对小鼠接种Lewis肺癌细胞的抑制效果。结果:本研究制备的依托泊苷固体脂质纳米粒外观呈淡蓝色透明状液体,在透射电镜观察呈圆整球状或类球状分布,大小较为均匀;平均粒径为（153.2±32.8）nm,PdI为（0.185±0.031）,Zeta电位为（-17.4±1.1）mV;依托泊苷固体脂质纳米粒可延缓药物释放,在24 h内药物累积释放52.4%;依托泊苷固体脂质纳米粒的抑瘤率显著高于依托泊苷注射液（P<0.05）,说明依托泊苷固体脂质纳米粒能够显著抑制Lewis肺癌细胞在小鼠体内生长。结论:本研究通过热熔乳化 高压均质法制备的依托泊苷固体脂质纳米粒对Lewis肺癌细胞具有良好的抑瘤效果,可以作为依托泊苷的新型给药系统,对肺癌治疗具有一定的应用前景。     

美洛昔康固体脂质纳米粒的制备及体外透皮研究

摘 要 目的： 制备美洛昔康固体脂质纳米粒,并考察其透皮吸收行为。方法: 采用热熔乳化超声 低温固化法制备美洛昔康固体脂质纳米粒,并考察其包封率、粒径分布、Zeta电位、微观形态及体外药物释放特性,采用Franz扩散池考察其透皮吸收行为。结果: 美洛昔康固体脂质纳米粒的包封率为（85.6±2.7）%,平均粒径为（213.5±52.6）nm,Zeta电位为（-32.2±3.9）mV,透射电镜显示美洛昔康固体脂质纳米粒粒径均一,成球状分布。其12 h药物累积透皮量显著高于美洛昔康溶液。结论: 美洛昔康固体脂质纳米粒可以显著提高药物累积透皮量,有望成为美洛昔康的新型局部给药制剂。     

塞来昔布纳米混悬剂的制备及大鼠体内药动学研究

摘 要 目的： 制备塞来昔布纳米混悬剂（CXB NSs）,并考察大鼠灌胃给药后体内药动学特征。方法: 采用反溶剂沉淀 高压均质法制备CXB-NSs,并考察其粒度分布,多聚分散系数和Zeta电位。将12只Wistar大鼠随机分为CXB NSs组和CXB混悬液组,灌胃给药剂量均为100 mg·kg^-1,采用高效液相色谱法测定大鼠血浆中的CXB浓度,用3P97软件计算相应的药动学参数。结果: CXB NSs平均粒径为(442.5±61.9) nm,多聚分散系数为0.312±0.057,Zeta电位为(-31.6±3.9) mV。CXB NSs和CXB混悬液在大鼠体内的AUC(0-t)分别为(5.13±0.77)和(13.51±3.18) mg·L^-1·h;t1/2分别为(12.31±1.91)和(12.73±1.83) h;Tmax 分别为(2.48±0.37)和(1.41±0.27) h;Cmax分别为(0.94±0.31)和(2.38±0.25) mg·L^-1。结论:CXB NSs能显著提高药物在大鼠体内的生物利用度。     

多西他赛长循环脂质体的制备与大鼠体内药动学评价

摘 要 目的：制备多西他赛长循环脂质体,并评价大鼠尾静脉给药的药动学特性。方法: 采用薄膜分散 挤出法制备多西他赛长循环脂质体,并对其粒径分布、Zeta电位和微观形态进行表征。将12只Wistar大鼠随机分为多西他赛注射液组和多西他赛长循环脂质体组,尾静脉给药剂量均为7.5 mg·kg^-1,采用HPLC法测定大鼠血中多西他赛的药物浓度,采用3P97程序计算多西他赛大鼠体内药动学参数。结果: 多西他赛长循环脂质体平均粒径为（109.2±28.6）nm,Zeta电位为（-15.8±2.7）mV。多西他赛注射液和多西他赛长循环脂质体在大鼠体内的t_1/2(α)分别为（0.19±0.05）h和（0.36±0.07）h;t_1/2(β)分别为（1.82±0.33）h和（17.93±1.37）h;AUC_0-t分别为（4.42±0.76）μg·mL^-1·h^-1和（33.73±3.52）μg·mL^-1·h^-1。结论:多西他赛长循环脂质体与市售多西他赛注射液相比,延长了药物在血浆中的滞留时间,能达到长循环目的。     

重楼总皂苷固体脂质纳米粒的制备及药剂学性质研究

摘 要 目的：基于质量源于设计（QbD）理念设计和开发重楼总皂苷固体脂质纳米粒。方法: 根据重楼总皂苷固体脂质纳米粒剂型及给药特点确立了目标产品概况,并根据理论知识和实际经验,通过风险评估工具确定影响固体脂质纳米粒制剂学性质的关键性变量。首先应用Plackett Burman试验筛选出对重楼总皂苷固体脂质纳米粒制剂学性质影响显著的关键变量,然后对筛选出的变量应用Box-Behnken效应面法进一步优化。评价重楼总皂苷固体脂质纳米粒的粒径分布、多聚分散系数（PdI）、Zeta电位、微观形态等理化性质,考察固体脂质纳米粒体外释药情况。结果: 最佳处方和制备工艺为：单硬脂酸甘油酯浓度为5.5%,大豆磷脂浓度为8.0%,均质次数为6次,固定药物浓度为5.0%,表面活性剂种类为吐温80,均质压力为600 bar,均质温度为65 ℃。采用优化后处方工艺制得的重楼总皂苷固体脂质纳米粒平均粒径为（116.5±32.1）nm, PdI为0.198±0.018,Zeta电位为（-23.6.5±0.9）mV,透射电镜显示固体脂质纳米粒呈球状分布,体外释放结果表明具有缓释效果,24 h累积释药为63.5%。结论: 运用QbD理念设计和开发重楼总皂苷固体脂质纳米粒切实可行,能确保产品质量符合要求。     

酮洛芬固体脂质纳米粒的制备与评价

摘 要 目的：制备酮洛芬固体脂质纳米粒的处方并对其进行质量评价。方法: 以包封率为评价指标,通过正交试验优化制剂处方并对其从形态、粒径、Zeta电位、药物存在状态进行表征,采用透析法进行体外释放并对释放过程进行拟合。结果: 酮洛芬固体脂质纳米粒的最优处方为酮洛芬50 mg、泊洛沙姆0.1 g、吐温 80 0.2 g、卵磷脂0.15 g、单硬脂酸甘油酯0.05 g,其包封率为61.95%,粒径151.7 nm,Zeta电位为-30.2 mv,形态圆整,差示扫描量热（DSC）分析表明药物以非结晶形式分散于纳米粒骨架中;体外释药曲线显示纳米粒体外释药先快后慢,12 h累积释放药物（85.11±7.62）%,包封于降解材料骨架内的药物通过骨架溶蚀缓慢释放,药物的体外释放符合Higuchi方程。结论: 酮洛芬固体脂质纳米粒制备方法简便、可行,质量评价较好,值得进一步研究。     

塞来昔布纳米结构脂质载体的制备及大鼠组织分布研究

摘 要 目的： 制备塞来昔布纳米结构脂质载体,并考察其在大鼠体内的组织分布特性。方法: 采用热熔乳化超声 低温固化法制备塞来昔布纳米结构脂质载体,并考察其粒径分布、Zeta电位和形态学性质。研究塞来昔布纳米结构脂质载体在大鼠体内各组织的分布特征。结果: 塞来昔布纳米结构脂质载体的平均粒径为（103.5±32.6）nm,Zeta电位为（-37.3±5.1）mV,透射电镜显示塞来昔布纳米结构脂质载体粒径均一,成球状分布。大鼠体内各组织分布结果表明,塞来昔布纳米结构脂质载体在大鼠肝、脾、脑、肌肉组织内的re值分别为塞来昔布注射液的3.43,2.99,2.38和2.93倍。结论:将塞来昔布制备成纳米结构脂质载体,能够改变其在大鼠组织的分布情况,有望提高药物疗效。     

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.