注射用多西他赛脂质体的制备及其体内外评价

 目的：制备多西他赛脂质体,对其体内外性质进行评价。方法：采用改良薄膜分散法结合冷冻干燥工艺制备多西他赛脂质体冻干粉;用激光粒度仪考察了脂质体的粒径分布和Zeta电位;超滤法测定了包封率;以市售多西他赛注射液为对照,比较体外释放、大鼠骨髓抑制和裸鼠体内肿瘤抑制情况。结果：多西他赛脂质体平均粒径为92 nm,Zeta电位为-52.3 mV,包封率＞95%,24 h累积释放率为84.1%;相同剂量下,多西他赛脂质体比多西他赛注射液的骨髓抑制作用降低,但二者对HT-29移植瘤的抑制作用相同。结论：本实验所制备的多西他赛脂质体包封率较高、稳定性较好;与多西他赛注射液相比,毒性较低,同时具有相同的抗肿瘤效力。      

水溶性壳聚糖包覆多西他赛纳米脂质体的制备及性能研究

目的:制备羧甲基壳聚糖包衣多西他赛纳米脂质体,并考察其体外释放度。方法:采用薄膜分散法制备多西他赛阳离子脂质体,并用不同浓度的羧甲基壳聚糖包覆阳离子脂质体;用超滤法测定其包封率;用激光电位粒径测定仪分别测定其Zeta电位和粒径大小,并用透射电镜观察其形态;用透析法考察其体外释药性质。结果:所制的羧甲基壳聚糖包覆的脂质体包封率达99.98%;Zeta电位为-12.8 mV,平均粒径为(150±17)nm。结论:本实验制备的羧甲基壳聚糖包衣多西他赛纳米脂质体具有高包封率,粒径大小均匀,体外能显著延缓药物释放的性质。     

星点效应面法对多西他赛他莫昔芬复方脂质体处方的优化

摘要：目的:优化多西他赛他莫昔芬复方脂质体处方。方法:采用单因素试验考察脂药比、大豆磷脂/胆固醇比、枸橼酸他莫昔芬/多西他赛比3个因素对脂质体粒径、ζ电位、分散度指数(PdI)、药物包封率和载药量的影响;采用2因素5水平的星点设计-效应面法,以多西他赛包封率和载药率为评价指标进行处方优化。结果:最优处方为脂药比为19∶1,大豆磷脂/胆固醇比为9∶1,多西他赛的包封率为(82.24±1.41)%,他莫昔芬的包封率为(93.14±2.67)%。结论:优化所得处方为多西他赛他莫昔芬复方脂质体的开发提供了基础保证。     

光敏性多西他赛脂质体的制备、处方优化和体外释放度研究

目的：以富勒烯丙二酸衍生物（DMA-C60）-多西他赛为模型药物,构建光敏性脂质体,增强抗肿瘤效果。系统研究脂质体（LP）的制备工艺、理化性质、处方优化和体外释放特性。方法：采用Bingle环加成反应和酯水解反应合成了DMA-C60,采用傅立叶变换红外光谱（FT-IR）对产物表征定性;采用薄膜法制备DMA-C60-DTX脂质体;超滤离心法测量DTX包封率和载药量;采用激光纳米粒度测定仪测定粒径、粒径分布和Zeta电位;透射电镜测定脂质体外观形态;利用差示扫描量热法（DSC）考察LP中原料药DTX及脂质材料的晶形存在状态;采用透析袋法测量体外释放度并拟合释放模型。结果：采用FT-IR表征定性DMA-C60合成成功。最优处方得到的DMA-C60-DTX-LP,平均粒径约为170 nm,Zeta电位约为-30 mV,DTX包封率（85.76±2.60）%,DMA-C60包封率约为89%;透射电镜观察DMA-C60-DTX-LP呈类球形,粒径大小约为170 nm,分布均匀且与所测粒径大小相符;DSC显示DTX原料药几乎以无定型的状态存在于脂质内核中;DMA-C60的加入并不影响DTX的释放,60 h内累计释放百分数为80%,DTX在LP中体外释放行为可用Ritger-Peppas释放动力学方程进行描述。结论：光敏性多西他赛脂质体载药量和包封率较高、脂质体外观呈类球形,粒径较小且分布均匀,体外释放具有一定的缓释作用。     

一种稀释法制备脂质体的方法考察

介绍了一种简单的直接稀释制备脂质体的方法,并考察了工艺因素对空白脂质体平均粒径的影响.结果表明,磷脂在乙醇及水化介质中的浓度越低,得到的脂质体粒径越小;水化介质的离子强度越大,得到的脂质体粒径越大.采用本法以多西他赛为模型药物试制得到的脂质体平均粒径为(110±10)nm,包封率为(99.2±1.4)%.     

多西他赛他莫昔芬脂质体体外释放研究

目的考察多西他赛他莫昔芬复方脂质体体外释放。方法薄膜分散法制备单方和复方脂质体样品,通过透析法进行脂质体体外释放,采用高效液相色谱法测定他莫昔芬和多西他赛药物浓度,并对体外释放曲线进行数学模型拟合。结果单方和复方脂质体中,他莫昔芬和多西他赛均无突释,多西他赛较他莫昔芬释放快,他莫昔芬和多西他赛释放模型符合一级释放方程,他莫昔芬和多西他赛的释放曲线相似。结论他莫昔芬和多西他赛在单方和复方脂质体体外释放并无显著差异。     

不同粒径多西他赛固体脂质纳米粒制剂及其细胞毒活性

目的制备不同粒径的多西他赛(docetaxel,DTX)固体脂质纳米粒,考察多西他赛固体脂质纳米粒理化性质,研究粒径对体外释放行为以及细胞毒作用的影响。方法通过热熔超声法制备不同粒径多西他赛固体脂质纳米粒,观察纳米粒形态,测定其包封率、粒径、Zeta电位。考察粒径因素对固体脂质纳米粒体外释放行为、体外细胞毒性的影响。结果制备的纳米粒均为球形及类球形,3种粒径的多西他赛固体脂质纳米粒平均粒径分别为(83.7±8.4)、(162.7±11.9)、(232.1±26.4)nm;Zeta电位分别为-24.19、-23.67、-23.19 mV;包封率分别为98.03%、97.84%、97.92%。60 h粒径分别为83、16、232 nm的多西他赛固体脂质纳米粒在释放介质中分别累计释放86.34%、76.98%、67.14%。3种不同粒径多西他赛固体脂质纳米粒(DTX-SLN-83,DTX-SLN-162,DTX-SLN-232),多西他赛原料药(DTX solutions)以及空白SLN溶液与多西他赛的混合溶液(physi-calm ixture)对MCF-7细胞作用24 h的IC50值分别为3.36、6.20、9.74、13.15、12.92 mg.L-1;48 h的IC50值分别为0.93、2.01、4.35、9.48、9.21 mg.L-1;72 h的IC50值分别为0.30、0.91、1.67、7.36、7.82 mg.L-1。随着多西他赛固体脂质纳米粒粒径的减小,其肿瘤细胞杀伤力逐渐增强。结论热熔超声法可用于制备不同粒径多西他赛固体脂质纳米粒。降低固体脂质纳米粒粒径有利于药物更完全地释放,同时增强其对肿瘤细胞的杀伤能力。     

多西他赛纳米脂质载体的制备及其性质考察

目的制备多西他赛纳米脂质载体,并考察其剂型性质及体外释药行为。方法采用薄膜超声法制备多西他赛纳米脂质载体,使用透射电镜观察粒子外观形态,光子相关光谱法测定其粒径和分布,微柱离心法测包封率,透析法测体外释药特性。结果在优化条件下制备的纳米级粒子粒径为(124±16)nm,Zeta电位为-19.57 mV,包封率为95.8%。体外释放符合Weibull释放模型。结论制备的多西他赛纳米脂质载体粒径小,药物包封率高,并可实现药物控释。     

共载多西他赛和维拉帕米脂质体逆转肿瘤耐药性的研究

研究共载多西他赛(docetaxel, DTX)和维拉帕米(verapamil, VRP)组成的脂质体(DTX-VRP liposome,DTX-VRP LP)对人乳腺癌化疗多药耐药性的逆转作用。采用薄膜分散法制备DTX-VRP LP;用激光粒度仪考察了其粒径大小和zeta电位;用超滤法测定了载药量和包封率;动态透析法考察脂质体在pH值7.4和6.8的磷酸盐缓冲液(PBS)中体外累积释放率;以DTX诱导的多药耐药人源乳腺癌(MCF-7/DTX)细胞株研究脂质体的体内外药效学。动物实验获得上海交通大学动物伦理委员会批准(批准号:2019-06^-172)。结果表明, DTX-VRP LP平均粒径约为140.9 nm, zeta电位约在-28.7 mV。DTX-VRP LP中DTX及VRP包封率和载药量分别是(81.7±3.9)%、(2.9±0.3)%和(59.6±0.6)%、(1.6±0.5)%;在pH 7.4和6.8 PBS中, 0～4 h内DTX-VRP LP组累积释放率分别约为40%和70%,相较于其他实验组, DTX-VRP LP组累积释放率稍慢些。体外药效学...     

多西他赛混合胶束的制备及其性能评价

目的为提高难溶性药物多西他赛的水溶性,制备多西他赛-聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(soluplus)-聚乙二醇-15-羟基硬脂酸酯(solutol HS15)混合胶束(docetaxel mixed micelles,DTX-MMs),并对其性质进行评价。方法以soluplus和solutol HS15作为两亲性载体材料,采用薄膜分散法制备DTX-MMs;利用马尔文激光粒度仪测定胶束的粒径及分布;采用透射电镜观察混合胶束的形态;采用高效液相色谱法测定混合胶束的包封率和载药量;采用芘荧光探针法测定混合胶束的临界胶束浓度;以自制多西他赛注射液为对照,比较两种制剂的体内外性质差异。结果由薄膜分散法制备的混合胶束的包封率和载药量分别为89.91%和4.658%,平均粒径为(72.54±2.2)nm,多分散系数为0.16±0.036;透射电镜下观察到混合胶束呈球形、分散良好;测得的临界胶束质量浓度值为(6.76×10~(-2))g·L~(-1);与多西他赛注射剂相比,混合胶束具有一定的缓释能力,无溶血现象,药时曲线下面积(AUC_(0-t))提高了2.638倍。结论采用薄膜分散法制备的混合胶束,粒径小,包封率高,稳定性好,可显著提高多西他赛在水中的溶解度,具有良好的体内外性能。     

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.