球面对称设计筛选罗沙替丁缓释片的处方及其释放度考察

目的研究球面对称设计法在缓释片处方优化中的应用并考察其释放度。方法采用球面对称设计法,以海藻酸钠、羟丙基甲基纤维素、十八醇用量3因素为考察对象,对罗沙替丁缓释片的处方进行优化并制备缓释片;另测定释放度,并对数据进行评分及统计学分析。结果采用球面对称设计法,可得到影响因素的二项式方程和优化处方,且试验值与预测值非常接近。结论采用球面对称设计法对罗沙替丁缓释片的处方进行优化和预测可行。     

基于星点设计-效应面法优化的曲美他嗪双层渗透泵控释片的制备及评价

目的制备曲美他嗪双层渗透泵控释片并优化其处方。方法以含药层聚氧乙烯用量、助推层氯化钠用量、包衣增重为考察因素,药物的8 h累积释放度和0⁸ h释放曲线的线性相关系数为考察指标,应用星点设计-效应面法对处方进行优化并验证。结果最优处方为含药层聚氧乙烯的用量86 mg,助推层氯化钠用量为25 mg,包衣增重7%。其释放曲线在08 h释放曲线的线性相关系数为考察指标,应用星点设计-效应面法对处方进行优化并验证。结果最优处方为含药层聚氧乙烯的用量86 mg,助推层氯化钠用量为25 mg,包衣增重7%。其释放曲线在0⁸ h零级释放特征显著,8 h累积释放量达到89%以上,实测值与预测值无明显差异。结论采用星点设计-效应面法成功得到曲美他嗪双层渗透泵控释片的处方优化模型,实现了处方优化。     

Box-Behnken设计-效应面法优化盐酸阿夫唑嗪胃漂浮控释骨架片的处方

目的应用Box-Behnken设计-效应面法优化盐酸阿夫唑嗪胃漂浮控释骨架片的处方。方法采用干法压制包衣技术制备盐酸阿夫唑嗪胃漂浮控释骨架片;以骨架片包衣层中药物含量、包衣层中HPMC K100M和碳酸氢钠的用量为考察因素,以体外漂浮性能、2 h药物累积释放度和零级释放动力学模型决定系数R~2为评价指标;采用三因素三水平的Box-Behnken设计效应面法筛选胃漂浮控释片的最优处方,并进行验证。结果最优处方为包衣层中药物含量为40%、包衣层中HPMC K100M和碳酸氢钠的用量分别为53%和12%。按最优处方制备的胃漂浮控释片起漂时间小于5 min,续漂时间大于24 h,2 h药物累积释放度为8.34%,零级释放动力学模型决定系数R~2为0.994 4,预测值与实测值相对误差小于5%。结论 Box-Behnken设计-效应面优化法可用于胃漂浮控释片的处方优化,所建立的数学拟合模型预测性良好。     

定制设计法在盐酸丁咯地尔缓释片处方设计中的应用

目的应用定制设计法优化盐酸丁咯地尔缓释片的处方。方法以片芯中乙基纤维素和氯化钠比例的变化、包衣增重为考察因素,以不同时间点的累积释放量为优化指标,应用定制设计法筛选最佳处方,并对优化处方进行验证。结果最优处方组成为,盐酸丁咯地尔600 mg、乙基纤维素90 mg、氯化钠10 mg、包衣增量为3%,12 h累积释放量为80%以上,体外释放曲线平稳。结论采用定制设计法得到了盐酸丁咯地尔缓释片的处方优化模型,应用优化处方制备缓释片所得的实测值与预测值无明显差异,实现了处方优化。     

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。     

压制包衣法制备盐酸地尔硫缓释片

目的探讨制备盐酸地尔硫缓释片的方法。方法以HPMC为主要包衣材料,采用干包衣法制备缓释片,正交实验优选处方并对最优处方进行体外释放度验证。结果缓释片最优处方为:片芯:盐酸地尔硫0.15 g;包衣层:盐酸地尔硫0.10 g,HPMC K4M 0.25 g。结论制备的缓释片8h内恒速释药,片剂处方设计和工艺方法可行,质量稳定。     

压制包衣法制备二甲双胍脉冲缓释片

目的探讨制备二甲双胍脉冲缓释片的方法。方法以羟丙基甲基纤维素(HPMC)为包衣材料,采用压制包衣法制备二甲双胍脉冲片;正交实验优选处方,对最优处方进行体外释放度验证。结果采用压制包衣法可制备出缓释效果很好的脉冲片,缓释片时滞为5h。结论用压制包衣法制出的二甲双胍缓释片处方设计和工艺可行,质量稳定。     

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。     

扎来普隆脉冲释放微丸的制备及体外释放

目的制备扎来普隆脉冲释放微丸,并对其进行处方筛选与优化。方法以交联羧甲基纤维素钠(CC-Na)为内包衣溶胀层,乙基纤维素水分散体为外包衣控释层制备扎来普隆脉冲释放微丸,考察处方因素及介质pH对药物释放的影响,用Box-Behnken效应面设计法对处方进行优化。结果溶胀层厚度、组成及控释层包衣增重对微丸的时滞和释药速率均有显著影响。结论按Box-Behnken效应面设计法所得最优处方制备的微丸具有良好的延时脉冲释药效果。     

星点设计-效应面法优化依普利酮双层渗透泵片处方

目的:通过星点设计-效应面法优化依普利酮双层渗透泵片处方。方法:以含药层、包衣液组分用量和包衣增重为考察因素,药物释放曲线的相关系数和12h的累积释放度为考察指标,分别用3种数学模型描述考察指标与任意2个考察因素之间的关系,并绘制了二次多项式模型的效应面和等高线图,通过重叠区域确定最优处方,并通过实测值与预测值的比较进行验证。结果:二次多项式为拟合的最佳模型,优化处方考察指标的实测值与预测值非常接近,12h的累积释放度为97.38%,释放曲线相关系数为0.9968。结论:采用星点设计-效应面法得到了基于二次多项式模型的依普利酮渗透泵片处方优化的模型,实现了该渗透泵片的处方优化。     

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.     

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.