蝙蝠葛苏林碱和蝙蝠葛碱在犬体内的药动学-药效学模型

目的：研究蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的药动学-药效学结合模型,并比较两种药物对其心电、血压和血流动力学的作用。方法：利用反相高效液相色谱法测定其血药浓度,生理记录仪观察药理效应,并计算药动学和药动学-药效学结合模型参数．结果：血药浓度-时间数据符合二房室开放模型．药效与效应室药物浓度之间的关系符合sigmoid-Emax模型．主要药动学和药动学-药效学结合模型参数在两种药物间差异无显著性．结论：蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的处置规律和对心血管系统的抑制作用基本-致。     

蝙蝠葛碱在Beagle犬体内的药动学与其对心电图的影响

目的:建立药动学-药效学结合模型分析蝙蝠葛碱在犬体内药动学与其对心电图影响之间的关系。方法:蝙蝠葛碱6 mg·kg-1静脉注射后,8 h内定时取血,同时观察并记录心电图变化。采用反相高效液相-紫外法测定血浆中蝙蝠葛碱的浓度。应用3P97程序药动-药效参数估算程序对血药浓度和效应时间数据进行估算。结果:蝙蝠葛碱在犬体内动力学行为符合二房室开放模型,t1/2α=0.049±0.016 h;t1/2β=2.7±0.6 h。蝙蝠葛碱对HR的最大抑制率为(26.4±6.1)％,对PR,QRS,和Q-Tc间期的最大延长率分别为(33.7±10.0)％、(35.6±12.0)％和(25.5±9.4)％。效应滞后于血药浓度10~15 min。药理效应与效应室浓度之间的关系符合sigmoid-Emax模型。结论:以上模型很好地描述了蝙蝠葛碱在犬体内的血药浓度与其对心电图的药理效应之间的关系。     

蝙蝠葛碱在犬体内的药代动力学和药效动力学研究

目的　应用药动学药效学结合模型方法研究蝙蝠葛碱在犬体内的药代动力学和药效动力学之间的关系。方法　4只beagle犬给蝙蝠葛碱6mg·kg-1静脉注射后,分时取血及行心电、血压及血流动力学变化观察。采用反相高效液相紫外法测定血浆中蝙蝠葛碱的浓度。结果　蝙蝠葛碱主要药动学参数T1 /2α,T1 /2β,Vd,AUC分别为(0 049±0 016)h,(2 .7±0. 6)h, (15. 8±3 5)L·kg-1和(1. 48±0. 17)mg·h·L-1。对Q Tc的最大延长率为( 25 5±9 4 )%;SBP,DBP,±(dp/dt)max的最大抑制率分别为( 23 .0±4. 9 )%,(21 .9±5. 9)%, ( 42. 8±6 .6 )%和( 39 .0±17 .1 )%。药理效应滞后于血药浓度10 ~15min。药理效应与效应室浓度之间的关系符合sigmoid Emax模型。结论　建立了蝙蝠葛碱在犬体内血药浓度、时间、药物效应三者之间的关系。     

蝙蝠葛苏林碱在兔血浆浓度监测及药代动力学蝙蝠葛苏林碱在兔血浆浓度监测及药代动力学

目的建立测定血浆中蝙蝠葛苏林碱浓度的方法,并研究蝙蝠葛苏林碱在家兔体内的药代动力学。方法 以蝙蝠葛碱作为内标。血浆样品经乙腈去蛋白,再用二氯甲烷两次萃取,采用RP-HPLC方法检测。结果血浆药物浓度在0.05～20.00 mg·L^-1线性关系良好(r=0.999 6),最低定量浓度为0.05 mg·L^-1,绝对回收率均大于80%,相对回收率为(101±5)%,精密度试验的日内及日间RSD%分别为1.9%～5.6%和3.5%～6.5%。药代动力学研究表明,家兔蝙蝠葛苏林碱单剂量iv后,其体内血药浓度时间数据符合二房室开放模型。结论本方法专属性强、灵敏度高、回收率高、重现性好,可用于蝙蝠葛苏林碱血药浓度测定及药代动力学研究。     

应用薄层荧光扫描法测定血清蝙蝠葛碱浓度

<正> 蝙蝠葛碱(Dauricime)系从防己科植物蝙蝠葛(Menispermum DauricumDC.)根茎中提出的一种双苄基异喹啉类生物碱。实验研究和临床试验均证明本品具有良好的抗心律失常作用。为进一步了解该药的体内过程,提供合理用药的药代动力学依据,测定蝙蝠葛碱血药浓度至为重要。目前,蝙蝠葛碱血浓测定方法学尚未见报道,本工作建立蝙蝠葛碱血清浓度测定法,实验证明采用薄层荧     

蝙蝠葛碱大鼠体内药物代谢动力学研究

目的研究不同给药途径后蝙蝠葛碱在大鼠体内的药代动力学特征。方法以大鼠为实验对象,经灌胃及静脉注射两种途径给药,采用ＲＰ－ＨＰＬＣ法测定各组织及体液中药物浓度。结果静注蝙蝠葛碱在大鼠体内药代动力学为二室开放模型,符合一级动力学线性消除过程。灌胃给药后大鼠血药浓度低,峰浓度小于１ｍｇ·Ｌ－１,且血药浓度－时间曲线呈明显双峰现象。其绝对生物利用度约为１６．６％。蝙蝠葛碱经两种给药途径后药物在各组织器官中均有分布,且在同一时间内各组织含量明显高于血药浓度。静注后以肺组织含量最高,而灌胃给药后以胃、肠、肝组织含量最高。４８ｈ尿粪累积排泄３１．２２％。给药后不同时间点胃肠道各段药物残余量研究结果提示胃肠循环的存在。结论蝙蝠葛碱口服用药生物利用度较低,血药浓度一时间曲线呈双峰现象,该药在生物体内分布广泛,可由尿液及粪便排泄,也可从胆汁分泌,初步实验结果提示胃肠循环可能是药时曲线双峰现象的主要原因。     

蝙蝠葛苏林碱对小鼠和大鼠脑缺血的保护作用

目的研究蝙蝠葛苏林碱对小鼠缺氧、急性脑缺血和大鼠局灶性脑缺血的保护作用。方法采用小鼠常压密闭缺氧实验，观察了蝙蝠葛苏林碱对小鼠耗氧量和存活时间的影响；结扎小鼠双侧颈总动脉造成急性全脑缺血模型，观察了蝙蝠葛苏林碱对急性脑缺血小鼠死亡率的影响；电凝阻断大鼠一侧大脑中动脉造成大鼠局灶性脑缺血模型，观察了蝙蝠葛苏林碱对局灶性脑缺血大鼠梗塞面积和行为障碍的影响。结果蝙蝠葛苏林碱能明显降低常压密闭缺氧小鼠整体耗氧速度，延长缺氧小鼠的存活时间；明显降低急性脑缺血小鼠２ｈ死亡率；显著降低局灶性脑缺血大鼠梗塞范围，明显改善行为障碍。结论蝙蝠葛苏林碱具有抗缺氧、抗脑缺血作用。     

基于SNAP-tag-EGFR细胞膜色谱的北豆根中潜在抗肿瘤活性组分筛选及验证

目的 从北豆根中筛选与表皮生长因子受体(epidermal growth factor receptor, EGFR)作用的活性成分，为抗肿瘤药物研究提供新的先导化合物。方法 构建SNAP-tag-EGFR细胞膜色谱模型，将其与高效液相色谱-离子阱-飞行时间质谱构成二维联用系统，靶向筛选北豆根中EGFR的潜在抗肿瘤活性组分。用前沿分析和计算机模拟分子对接研究潜在活性组分与EGFR的相互作用。并用细胞增殖抑制实验初步验证潜在抗肿瘤活性组分的药理作用。结果 利用该二维联用系统从北豆根提取物中识别出目标组分蝙蝠葛苏林碱和蝙蝠葛碱。前沿分析测得蝙蝠葛苏林碱、蝙蝠葛碱与EGFR相互作用的平衡解离常数K_D值分别为2.48×10^-6、3.57×10^-6 mol·L^-1,表明蝙蝠葛苏林碱、蝙蝠葛碱与EGFR均存在一定强度的相互作用关系。分子对接实验表明蝙蝠葛碱和蝙蝠葛苏林碱均可结合于EGFR的活性腔，与EGFR的氨基酸残基形成氢键。细胞增殖抑制实验结果显示，蝙蝠葛碱和蝙蝠葛苏林碱在5～100μmol·L^-...     

RP—HPLC法对不同产地蝙蝠葛几种主要生物碱的测定

目的：研究不同产地蝙蝠葛几种主要生物碱在质与量上的区别。方法：采用有机溶剂提取生药,应用ＲＰ－ＨＰＬＣ方法在东北产和咸宁产蝙蝠葛根茎中几种主要脂溶性生物碱定性定量测定。结果：东北生一最高的生物碱前３位依次是蝙蝠葛苏林碱、蝙蝠碱和ｇｕａｔｔｅｇａｕｎｅｒｉｎｅ;而咸宁药材则为蝙蝠葛碱、蝙蝠葛诺林碱及蝙蝠葛新诺林碱,不含蝙蝠葛苏林碱。结论：不同产地蝙蝠葛药材所含生物碱在质和量两方面均有显著差异。     

液质联用测定犬血浆中盐酸西布曲明浓度和药动学

目的建立血浆中盐酸西布曲明浓度的检测方法,评价2种盐酸西布曲明口腔崩解片和盐酸西布曲明胶囊的生物等效性。方法采用LC-MS联用技术检测beagle犬血浆中盐酸西布曲明的浓度。根据血药浓度经时数据使用3P97药动学程序拟合求出6条♂性beagle犬单次给药10 mg试验品(盐酸西布曲明口腔崩解片)和10 mg参比品(盐酸西布曲明胶囊)后的体内药动学参数,研究其药动学特征。结果试验品与参比品的体内过程均符合具有一级吸收的二室药动学模型。试验品和参比品单次给药后的主要药动学参数ρmaxt、max和AUC0→t经交叉试验方差分析,差异均具有统计学意义(P<0.05)。试验品和参比品的ρmax、tmax和AUC0→t经对数转换后的双单侧t检验示:两者不具有生物等效性。试验品的相对生物利用度为(279.51±55.01)%。结论本方法能准确、快速、高效地测定beagle犬血浆中的盐酸西布曲明浓度。试验品给药后能够迅速吸收,符合设计制剂特征。     

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.