人工神经网络预测别嘌醇HP MC缓释片药物释放

目的用人工神经网络模型定量的预测HPMC的量和其固有黏度对药物释放的影响。方法以难溶性药物别嘌醇为模型药物,固定其他因素,HPMC的量和HPMC的固有黏度作为自变量,设计了18个处方并进行释放度检查;其中的13个处方作为训练处方,其他5个处方为验证处方,将上述的变量作为人工神经的输入,以药物在各个取样时间点的释放为输出,采用剔除一点交叉验证法建立人工神经网络模型。通过线性回归和相似因子说明人工神经网络的预测能力。结果训练和验证处方人工神经网络预测值与实际测定相符。结论建立BP人工神经网络,根据HPMC的量和其固有黏度可以定量的预测药物在各个时间点的药物释放。     

人工神经网络预测HPMC缓释片中易溶性药物的释放

目的应用BP人工神经网络模型预测水溶性药物从HPMC缓释片中的释放。方法以6种不同溶解性的水溶性药物(对乙酰氨基酚、氧氟沙星、盐酸环丙沙星、乳酸左氧氟沙星、多索茶碱、氯苯那敏、维拉帕米)为模型药物,设计62个处方,其中前面55个处方作为训练处方,另外7个处方作为验证处方,压制HPMC缓释片,进行释放度检查。以溶解度、载药量、HPMC的量、HPMC的固有黏度、MCC的量、PVP的浓度和药物溶出仪的转速作为自变量,药物在各个取样时间点的累积释放量作为输出,建立BP人工神经网络模型,并与响应面法进行对照,通过线性回归法和相似因子法比较人工神经网络和响应面法的预测能力,借助三维图说明各个变量对药物释放的影响。结果线性回归和相似因子法表明人工神经网络较响应面法的预测值与实际测定值更吻合,更能充分地说明单因素对药物释放的影响规律。结论人工神经网络可以代替响应面法处理HPMC缓释片处方设计中的不同溶解度的水溶性药物的多因素多响应的非线性问题而且可以推广到别的制剂设计中。     

人工神经网络预测HPMC缓释片中易溶性药物的释放

目的应用BP人工神经网络模型预测水溶性药物从HPMC缓释片中的释放。方法以6种不同溶解性的水溶性药物(对乙酰氨基酚、氧氟沙星、盐酸环丙沙星、乳酸左氧氟沙星、多索茶碱、氯苯那敏、维拉帕米)为模型药物,设计62个处方,其中前面55个处方作为训练处方,另外7个处方作为验证处方,压制HPMC缓释片,进行释放度检查。以溶解度、载药量、HPMC的量、HPMC的固有黏度、MCC的量、PVP的浓度和药物溶出仪的转速作为自变量,药物在各个取样时间点的累积释放量作为输出,建立BP人工神经网络模型,并与响应面法进行对照,通过线性回归法和相似因子法比较人工神经网络和响应面法的预测能力,借助三维图说明各个变量对药物释放的影响。结果线性回归和相似因子法表明人工神经网络较响应面法的预测值与实际测定值更吻合,更能充分地说明单因素对药物释放的影响规律。结论人工神经网络可以代替响应面法处理HPMC缓释片处方设计中的不同溶解度的水溶性药物的多因素多响应的非线性问题而且可以推广到别的制剂设计中。     

人工神经网络预测盐酸帕罗西汀缓释微丸的药物释放

目的利用人工神经网络对盐酸帕罗西汀缓释微丸的释药行为进行预测。方法设计20个处方,其中16个处方作为训练处方,其余4个处方作为测试处方,制备盐酸帕罗西汀膜控释微丸,进行释放度检查。以致孔剂PVPK30的用量、包衣增重作为自变量,考察药物在各个取样点的累积释放量作为输出,建立盐酸帕罗西汀缓释微丸释药行为的人工神经网络预测模型。通过线性回归法、相似因子法、AIC法评价人工神经网络的预测能力。结果通过实测数据和BP神经网络预测结果比较,验证了人工神经网络的预测精度达0.989 9。结论用人工神经网络对盐酸帕罗西汀缓释微丸的释药行为进行预测,拟合度较高,从而为盐酸帕罗西汀缓释微丸的处方优化和释药行为预测提供了可行的依据。     

人工神经网络辅助设计褪黑素缓释片处方

应用人工神经网络模型辅助设计褪黑素缓释片处方,将HPMC粘度、HPMC、MCC 和乳糖的量作为输入变量,累积释放百分率作为输出变量,选择反向传播网络,隐含层为1层,隐含层神经元个数为6,建立人工神经网络模型,预测和评价褪黑素缓释片体外释放度,研究缓释片的释放机理.结果显示,该人工神经网络模型能很好地预测褪黑素缓释片的释放量,成功优化褪黑素缓释片处方,其释放机理为溶蚀与扩散的结合,辅料的种类和量会对药物的释放机理产生不同影响.     

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。     

人工神经网络应用于骨架型缓释片处方设计

建立了一个设计二氢吡啶类钙拮抗剂骨架片的人工神经网络，该系统由输入层、隐含层、输出层组成，输入层有４个节点（药物的溶解度、骨架材料的水化速率和用量、表面活性剂的用量），隐含层有３个节点，输出层有３个节点（第２、４、６ｈ药物的释放量）。以卡波姆为骨架材料研究了该系统在设计硝苯地平与尼莫地平骨架片的可行性。结果表明：本网络能较好地模拟给定处方的药物释放情况     

星点设计-效应面法优化四逆散渗透泵片处方

 目的：通过星点设计-效应面法优化四逆散双层渗透泵片处方。方法：以含药层N750用量和NaCl用量、包衣液中PEG 4000用量和包衣增重为考察因素,以药物释放曲线的相关系数和12 h的累积释放量为考察指标,分别用多元线性模型、二次多项式模型和三次多项式模型描述考察指标和任意2个考察因素之间的关系,并绘制了三次多项式模型的效应面和等高线图,通过重叠区域确定优化处方,并通过实验值与预测值比较进行验证。结果：三次多项式为拟合的最佳模型,优化处方考察指标的实验值与预测值非常接近。12 h的累积释放量为97.86%,释放曲线相关系数为0.995 6。结论：采用星点设计-效应面法得到了基于三次多项式模型的四逆散渗透泵片处方优化的模型,实现了该渗透泵片的处方优化。     

神经网络用于口服缓释制剂的处方设计

目的　用反向传播(backpropagation ,BP)神经网络,从药物的溶解度设计符合一定释放度要求的缓释制剂处方。方法　选取9种药物(异烟肼、利巴韦林、盐酸地尔硫,盐酸雷尼替丁、盐酸环丙沙星、茶碱、替硝唑、丙基硫氧嘧啶、磺胺甲唑)作为模型药物,按HPMC∶糊精=(5 - 0.2 )∶1配比制成不同释放度的缓释片,测定各个处方的释放度,其释放度数据用于BP神经网络的建模、训练。结果　得到隐含层为一层、结点数为5个和迭代次数为25次的最佳神经网络,并成功拟定了4个制剂处方,按此处方制备的缓释片的实测释放值与神经网络预测值相符。结论由MATLAB 5.1中的BP神经网络和优化工具箱编写的程序可根据药物溶解度设计符合某一释放度要求的缓释制剂处方     

效应面法优化吲哚美辛HPMC／果胶／氯化钙骨架片的双相释放

考察HPMC／果胶／氯化钙骨架片中两个自变量果胶／氯化钙重量比和骨架总重量对吲哚美辛释放的影响。采用二因素五水平星点设计，效应面法优化Peppas方程拟合参数n、K和T0.1（10％释放时间）。自变量对双相释放参数n和K值有显著影响，n、K和T0.1值可用二次多项式拟合，线性拟合效果不佳。数学模型拟合和效应面结果表明果胶／氯化钙重量比和骨架总重量两个因素间有显著交互作用。在具有较大n和T0.1值和较小K值的优化处方中，其果胶／氯化钙的比例约为1．0，骨架总重量处于中间值，约200mg。优化处方只有很好的预测性，n、K和T0.1值的预测偏差介于-7．33％和6．26％之间。星点设计可用于优化和预测药物从HPMC／果胶／氯化钙骨架片的释放。     

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.     

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.     

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.     

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.