星点设计-效应面法优化尼美舒利双层渗透泵片处方

目的制备大剂量难溶性药物尼美舒利双层渗透泵片,并考察其处方因素和体外释放行为,优化尼美舒利双层渗透泵的处方。方法以12 h药物累积释放量、释放曲线的线性为考察指标,以含药层聚氧乙烯量、包衣膜中致孔剂量、包衣增质量,为考察的主要因素,采用星点设计-效应面法对尼美舒利渗透泵片处方进行优化,并对优化处方进行验证。结果成功找到了最优释药区域,优化处方为:含药层聚氧乙烯220.27 mg,致孔剂用量质量分数为19.27%,包衣增质量6.81%。自制渗透泵与预测值基本一致,2~12 h内药物呈零级释放特征。结论星点设计-效应面法成功建立了处方优化模型,实现了尼美舒利双层渗透泵的处方筛选。     

星点设计-效应面法优化苯扎贝特渗透泵片处方

目的:制备苯扎贝特渗透泵片,运用星点设计-效应面法优化处方。方法:选择渗透泵片辅料聚氧乙烯(PEO)N80处方用量(A)、Na2CO3用量(B)和包衣增重(C)为考察因素,以该片在1h、6h的累积释药量以及累积释放量对时间进行线性拟合的相关系数为考察指标,采用星点设计-效应面法优化处方,并进行优化处方验证。结果:优化处方为A40mg、B20mg、C29mg,以该优化处方制备的渗透泵片具有较好的释药行为,各指标偏差的绝对值均小于5%。结论:星点设计-效应面法可用于苯扎贝特渗透泵片的处方优化,所建模型具有良好的预测能力。     

星点设计-效应面法对帕利哌酮渗透泵控释片处方的优化

目的： 制备一种帕利哌酮渗透泵控释片,通过在由含药层和助推层压制的双层片芯外包裹一层控释衣,达到理想、稳定的控释效果。方法： 应用星点设计-效应面法对处方进行优化,以含药层中HPMC E5用量、助推层中氯化钠用量和PEO WSR Coagulant用量、半透膜包衣增重为自变量,以2,8,14,24 h的累积释放百分率为考察指标,绘制优化模型的效应面图,得到了最优处方。结果： 得到一个最优处方,并对优化处方进行验证,释放结果与预测值基本一致,24 h内药物呈零级释放特征。自制片与国外市售片体外释药行为一致。结论： 采用星点设计-效应面法得到了帕利哌酮渗透泵控释片的优化模型,实现了处方优化。     

星点设计-效应面法优化硝苯地平缓释微丸的包衣处方

目的以星点设计-效应面法筛选并优化硝苯地平缓释微丸包衣处方,量化Eudragit RL/RS用量及比例与释放度之间的关系,为硝苯地平缓释微丸胶囊的研究提供参考。方法采用层积上药法制备含药丸芯,流化床包衣制备缓释微丸。以释放度作为考察指标,将Eudragit RL/RS比例和包衣增重为自变量,采用星点设计-效应面法优化包衣处方,并对模型进行验证。结果包衣液中Eudragit RL/RS的配比、包衣增重量对释放度影响显著。二次方模型是描述指标与因素之间的最佳模型。当Eudragit RL/RS的包衣增重量为15%,Eudragit RL/RS的配比为4:6时,制备的硝苯地平缓释微丸能维持12 h持续释药,释药速率实测值与预测值的偏差<10%。结论星点设计-效应面法可用于硝苯地平缓释微丸包衣处方的优化,所建模型具有较好的预测能力和实用性。     

秋水仙碱双层片体外释放研究

目的建立秋水仙碱双层片体外释放方法,并考察工艺、体外释放条件与缓速释比例对秋水仙碱双层片释药的影响。方法采用相似因子（f2）法评价释药曲线的相似性,并分别用零级、一级、Higuchi、Peppas方程拟合优化处方。结果工艺对秋水仙碱双层片影响较小,浆速对秋水仙碱双层片影响较大。依据最优处方制备的控释片在1～12h呈良好的缓释释放特征,12h累积释药率90％以上。结论建立了较为准确、可靠的秋水仙碱双层片体外释放度测定方法,体外释放度结果符合要求。     

盐酸二甲双胍1000mg缓释片的制备及其体外释药机制考察

目的:制备1000mg规格的盐酸二甲双胍缓释片,考察其体外释药行为并与吡格列酮二甲双胍缓释片(Actoplus MetXR)中的二甲双胍缓释部分比较。方法:用亲水骨架结合缓释膜包衣技术制备盐酸二甲双胍缓释片,以羟丙甲纤维素(HPMC)K100M为片芯缓释材料,以丙烯酸树脂(尤特奇)NE30D为缓释包衣膜,以ActoplusMetXR中的二甲双胍缓释部分(规格:1000mg)为对照药,以两者体外释放曲线比较的相似因子(f2)为考察指标,采用星点设计-效应面法优化处方,同时考察最佳处方的体外释药机制。结果:最佳处方为片芯HPMCK100M/盐酸二甲双胍为0.15(m/m)、缓释膜HPMCE6/尤特奇NE30D为0.18(m/m)、包衣增质量控制在4%～6%;缓释片体外释放行为符合Higuchi方程(r=0.9954),以扩散机制为主,类似骨架系统释药。结论:盐酸二甲双胍1000mg缓释片可以达到与对照药相似的体外释药行为。     

四乙酰基葛根素固体自微乳化双层片的研究

目的:探索固体自微乳化释药系统,制备四乙酰基葛根素固体自微乳化双层片。方法:考察各吸附材料对自微乳化液的吸附能力;以片剂外观、硬度、崩解时限等为指标筛选速释层处方;采用相似因子(f2)法评价双层片释药曲线的相似性,通过单因素考察,确定影响药物释放的主要因素;利用中心复合设计法对双层片处方进行优化,以HPMC K100LV和PEO400用量的各水平分别进行多元线性回归和二项式方程拟合,用效应面法预测最佳处方。结果:速释层的最佳处方为10%四乙酰基葛根素,30%自微乳化液,15%微粉硅胶,15%微晶纤维素,30%交联聚维酮,粘合剂为20%淀粉浆。缓释层中HPMC K100LV用量是影响药物释放的主要因素。中心复合设计优化处方的体外释放度预测值与实验值很接近。结论:中心复合设计法优化的固体自乳化双层片处方良好,双层片体外释放度达到了设计要求。     

阿魏酸钠胃内漂浮片的制备及体外释放机制考察

目的优化阿魏酸钠胃内漂浮片的制备工艺,并对其体外释药机理进行研究。方法以HPMC K4M为亲水性凝胶骨架,十六醇为助漂剂,NaHCO3为产气剂,采用星点设计-效应面法对处方进行优化,并通过方程拟合探讨释药机制。结果优化得到最优处方,所制得胃内漂浮片均能在1 min内起漂,持续漂浮10 h。结论采用星点设计-效应面法优化的处方预测性良好,并且所制得的胃内漂浮片具有良好的漂浮和控释能力。     

星点设计-效应面法优化单硝酸异山梨酯微孔渗透泵片处方

目的:应用星点设计-效应面法优化单硝酸异山梨酯微孔渗透泵片处方.方法:以渗透压活性物质用量、致孔剂用量、包衣增重量为影响片剂释放的主要因素,2、4、7、9、12 h的药物累积释药量为效应值,应用Design Expert进行处方优化,并对优化处方进行验证.结果:成功找到了最优释药区域;优化处方呈零级释放特性.结论:通过星点设计-效应面法成功建立了处方优化模型,实现了单硝酸异山梨酯微孔渗透泵片的处方筛选.     

星点设计-效应面法优化盐酸苯环壬酯控释片的处方

目的：采用星点设计-效应面法优化盐酸苯环壬酯控释片处方,制备盐酸苯环壬酯控释片并考察其稳定性。方法：根据单因素实验结果,选择含药层氯化钠含量、助推层高取代聚氧乙烯（WSR-HM）含量和包衣增重为自变量,以12 h累积释放度和药物释放曲线拟合度为因变量,应用星点设计-效应面法筛选最佳处方并验证。结果：Quadratic多项式模型为最佳拟合模型,盐酸苯环壬酯控释片的最优处方为：含药层氯化钠含量为5 mg/片,助推层高取代聚氧乙烯含量为47.5 mg/片,包衣增重为14%。优化制得的3批样品12 h平均累积释放度分别为99.89%、98.66%、99.36%,释药曲线线性拟合度R²分别为0.897 1、0.921 0、0.931 9,实测值与预测值无显著差异。稳定性试验表明,该制剂稳定性良好。结论：采用星点设计-效应面法筛选得到的优化处方合理,制得的盐酸苯环壬酯控释片具有显著缓释作用。     

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.     

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.