依达拉奉软膏的处方筛选及体外透皮性能研究

目的 考察依达拉奉软膏体外皮肤渗透性,筛选软膏剂最佳处方。方法 以大鼠离体皮肤作为渗透屏障,采用Valin-Chien双室渗透扩散池,以HPLC测定依达拉奉的浓度,考察依达拉奉含量、环糊精的型号和含量以及月桂氮卓酮用量对依达拉奉软膏剂经皮渗透性的影响。结果 软膏剂处方的最佳组合为6.0%依达拉奉,8.0%月桂氮卓酮,3.0%β-环糊精,依达拉奉12 h累积渗透量平均值可达（1 215.88±27.59）μg·cm^-2,平均渗透速率为（103.69±7.39）μg·cm^-2·h^-1,结论 软膏剂具有较好的皮肤渗透特性,有望成为依达拉奉新的给药剂型。     

利拉萘酯喷雾剂的经皮渗透研究

目的 研究利拉萘酯喷雾剂的经皮渗透性。方法 采用改良Franz扩散池,以小型猪皮肤为渗透屏障,高效液相色谱法测定利拉萘酯含量。结果 利拉萘酯喷雾剂和乳膏剂的稳态透皮速率分别为(0.017±0.006),(0.014±0.003)μg·cm^-2·h^-1;利拉萘酯喷雾剂和乳膏剂的24 h累积渗透量分别为(0.60±0.23),(0.44±0.15)μg·cm^-2;利拉萘酯喷雾剂和乳膏剂在皮肤中的药物残留量分别为(8.2±1.3),(7.7±1.6)μg·g^-1。结论 利拉萘酯喷雾剂的稳态透皮速率、24 h累积渗透量、在皮肤中的药物残留量均稍大于利拉萘酯乳膏剂,但2种剂型之间没有显著性差异。     

遗传算法在经皮给药微乳载体处方优化中的应用

以萘普生为模型药物，用遗传算法优化经皮给药微乳载体的处方。用伪三元相图法确定由Tween 80、IPM、乙醇和水组成的微乳区域。用3因素3水平的中心设计法制备载药量为1.12%的萘普生模型微乳，并进行离体兔皮的体外渗透实验。以稳态渗透速率的二次回归模型为目标函数，用遗传算法对中心设计结果进行优化，筛选出具有最大透皮速率的萘普生微乳载体处方。所得优化处方的组成为：21.41% Tween 80、15.17%乙醇、4.14% IPM和59.28%水，预计的稳态渗透速率为183.57 μg·cm^-2·h^-1。回代试验表明，以优化处方制备的萘普生微乳，其稳态渗透速率的平均值为189.43 μg·cm^-2·h^-1，高于预测值。结果表明，用遗传算法筛选微乳经皮给药载体处方，方法可行，结果合理、可靠。     

十一酸睾酮二元醇质体凝胶剂体内外透皮特性研究

摘 要 目的：对十一酸睾酮（TU）二元醇质体凝胶进行体内外透皮考察。方法: 采用注入法制备TU二元醇质体,以卡波姆941为凝胶基质,制备TU二元醇质体凝胶剂;以小鼠皮肤为屏障,采用Franz扩散池法对其体外透皮特性进行考察;以大鼠为实验动物,背部给予TU二元醇质体凝胶剂后,于设定的时间点测定血浆中TU浓度,计算药动学参数,并与TU二元醇质体进行比较。结果: TU二元醇质体及其凝胶的体外累积透皮百分率Q与时间t均符合一级动力学模型,线性方程分别为：Q=8.68t+6.78（r=0.998 2）和Q=6.09t+3.09（r=0.999 3）,稳态透皮速率分别为8.68 μg·cm^-2·h^-1和6.09 μg·cm^-2·h^-1,24 h后TU在皮肤中的滞留量分别为（208.80±55.26）μg·g^-1和（225.60±38.90）μg·g^-1;大鼠体内TU二元醇质体及其凝胶的主要药动学参数分别为：Cmax（18.50±2.75）mg·L^-1和（20.80±2.42）mg·L^-1;tmax（6.20±0.14）h和（9.54±0.52）h;AUC0-48h（336.74±2.05）h和（486.30±1.68）h。结论:TU二元醇质体及其凝胶均呈现较好的体内外透皮特性,且在缓释性上凝胶剂表现更优。     

槲-芦美白防晒凝胶的制备及体外透皮行为考察

摘要：目的:以槲皮素和芦荟苷为原料,制备复方美白防晒凝胶并考察其体外透皮吸收行为。方法:以卡波姆940为基质,月桂氮艹卓酮为促渗剂,以丙二醇和甘油为保湿剂,采用单因素试验优选制剂的最佳处方并制备槲-芦美白防晒凝胶,考察复方凝胶的外观、黏稠度、流变性、pH及稳定性。建立芦荟苷、槲皮素的HPLC含量测定方法,采用Franze扩散池法,考察复方凝胶中芦荟苷和槲皮素的体外经皮渗透特性。结果:制备的槲-芦美白防晒凝胶外观透明,黏稠度、流变性适中,稳定性较好。芦荟苷、槲皮素检测浓度分别在8.36～83.60"g·ml-1（r=0.999 9）、7.565～75.650μg·ml-1（r=0.999 9）范围内线性关系良好;平均加样回收率分别为99.54%和100.44%,RSD分别为0.34%和0.93%（n=9）。两者24 h累积渗透量分别为660.139μg·cm-2和520.835μg·cm-2,其24 h累积透过率分别为（88.05±1.63）%和（70.70±1.52）%。结论:用于测定复方凝胶中芦荟苷、槲皮素的含量测定方法操作简单,快速准确;两主药成分透皮吸收特性良好,为后期的药效实验提供依据。     

离子导入对降纤酶经皮渗透的影响

目的研究离子导入对降纤酶经皮渗透的影响。方法利用水平式扩散池，对降纤酶进行离子导入透过大鼠皮肤和人尸表皮的渗透性试验，对电极极性、渗透介质的pH以及离子强度等影响进行考察。结果离子导入阳极转运时，在pH 6.4的磷酸盐缓冲介质中，降纤酶的表观经皮渗透系数为（1.2±0.4）×10^-4 cm·h^-1，明显高于阴极转运［（4.3±1.4）×10^-5 cm·h^-1］；在pH 7.4磷酸盐缓冲介质中，降纤酶阳极离子导入经皮渗透量为（25±5）×10^-14 mol·cm^-2高于pH 6.4介质经皮渗透量［(15±4)×10^-14 mol·cm^-2］。结论离子导入阳极转运能够促进降纤酶的经皮渗透，电渗作用有重要影响。     

甘草酸二铵脂质囊泡的体外经皮渗透研究

目的 考察不同种类的甘草酸二铵(DG)脂质囊泡的体外经皮渗透情况,并制备脂质囊泡凝胶剂。方法 分别采用非质子传递溶剂法制备磷脂复合物,薄膜分散法制备柔性脂质体,注入法制备醇质体,并测定粒径;采用改良的Franz扩散池,以离体人皮进行经皮渗透实验;HPLC测定接收液和皮肤组织中药物含量。最后,将皮肤渗透性较好的囊泡处方制备成凝胶剂,考察凝胶的经皮渗透情况。结果 DG磷脂复合物24 h累计透过量为(8.07±5.42)μg·cm^-2,其余处方透过液中均未检测到药物。24 h药物在皮肤中的累积量大小顺序为磷脂复合物>醇质体>柔性脂质体>水溶液。DG磷脂复合物凝胶透皮效果与卡波姆浓度有关,0.5%卡波姆处方的皮肤中药物滞留量为1%卡波姆处方的2.2倍,降低卡波姆的浓度不但能提高DG在表皮层的含量,而且还能使药物进一步渗透至真皮层。结论 磷脂复合物能显著促进DG在皮肤中的渗透,并增加药物在皮肤中的蓄积。采用0.5%卡波姆制备磷脂复合物凝胶具有较好的经皮渗透性。     

白头翁素凝胶剂的体外经皮渗透及小鼠抗炎试验

目的：设计白头翁素凝胶剂，考察不同浓度羟丙甲基纤维素（HMPC）及月桂氮[艹卓]酮对白头翁素体外经皮渗透的影响，观察优选处方的抗炎作用。方法：制备不同组分的白头翁素含醇凝胶剂，采用TK-6A型透皮扩散仪，用人皮进行体外渗透试验；用HPLC法测定各时间点接受室中药物浓度，求算经皮渗透的相关参数。用二甲苯使小鼠耳壳致肿，测定白头翁素凝胶剂对肿胀的抑制作用。结果：HPMC含醇凝胶剂作为基质时白头翁素经皮渗透速率1％HPMC〉3%HPMC〉5％HPMC；月桂氮[艹卓]酮对其有显著的透皮促进作用；含3％月桂氮[艹卓]酮的白头翁素1％HMPC凝胶剂可明显抑制二甲苯引起的耳壳肿胀。结论：白头翁素凝胶剂有望开发成为一种新型的中药抗炎经皮吸收制剂。     

促渗剂对后交联祖师麻凝胶贴膏体外经皮渗透影响的研究

目的 考察不同促渗剂对后交联祖师麻凝胶贴膏中药效成分祖师麻甲素体外经皮渗透特性的影响,筛选出其最佳的透皮促渗剂。方法 采用Franz扩散池法,以离体小鼠皮肤和Strat-M™膜为渗透屏障进行体外透皮试验,采用单因素及正交试验法,以祖师麻甲素72 h内单位面积的累积透过量为评价指标,考察冰片、薄荷脑、樟脑对祖师麻甲素的促渗效果。结果 以离体小鼠皮肤和Strat-M™人工膜为透皮屏障时,祖师麻甲素72 h内单位面积的累积透过量分别为33.85,15.96 μg·cm^-2,稳态透皮速率分别为4.451 2,2.394 5 μg·cm^-2·h^-1,增渗倍数分别可达4.255 0,1.746 4。结论 后交联祖师麻凝胶贴膏以1%薄荷脑、1%冰片、2%樟脑联用时促渗效果最佳。     

不同浓度的月桂氮(艹卓)酮对双氯芬酸钠凝胶剂透皮吸收的影响

目的通过动物离体透皮吸收试验,选择双氯芬酸钠凝胶剂中最佳浓度的月桂氮(艹卓)酮(氮酮,Azone)作为渗透促进剂.方法采用改良的Franz扩散装置,以离体鼠皮为屏障、生理盐水为接受介质,研究了不同浓度的月桂氮(艹卓)酮(0%、1%、2%、3%、5%Azone)对双氯芬酸钠凝胶剂透皮吸收的影响.结果双氯芬酸钠凝胶剂12h累积透皮释药百分率依次为38.42%、62.35%、72.80%、32.10%、55.36%.结论 Azone促进双氯芬酸钠凝胶剂透皮释药的最大浓度为2%,筛选出2%月桂氮(艹卓)酮作为促进剂,制备了具有良好经皮吸收性能的双氯芬酸钠凝胶剂.     

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.     

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.