α－羧乙基锗倍半氧化物胶囊在健康人中的药物动力学参数测定

采用苯基荧光酮分光光度法测定了６例健康人单剂口服２０ｍｇ／ｋｇα－羧乙基锗倍半氧化物后血清药浓度，人体内药物动力学过程符合单室模型，主要参数Ｋ０．３２１ｈ－１，Ｋａ１．２２１ｈ－１，Ｔ１／２２．１６１ｈ，Ｔｍａｘ１．８８５ｈ，Ｃｍａｘ１２．７６１μｇ／ｍｌ。     

对乙酰氨基酚凝胶在人体的药动学和生物利用度

８名健康男性志愿者交叉服用５００ｍｇ剂量的对乙酰氨基酚凝胶剂和片剂。血药浓度采用ＨＰＬＣ测定。对乙酰氨基酚凝胶剂的药动学参数：Ｔ１／２（Ｋａ）０．３０±０．２２ｈ，Ｔ１／２（Ｋｅ）２．１±０．４ｈ，Ｔｍａｘ１．０±０．４ｈ，Ｃｍａｘ５．１±１．５μｇ／ｍｌ，ＡＵＣ２１±５（μｇ／ｍｌ）·ｈ。这些参数与片剂的相似，凝胶剂相当于片剂的生物利用度为１０５．１％     

α—羧乙基锗倍半氧化物胶囊在健康人中的药物动力学参数测定

采用苯基荧光酮分光光度法测定了６例健康人单剂口服２０ｍｇ／ｋｇα－羧乙基锗倍半氧化物后，血清药浓度，人体内药物动力学过程单室模型，主要参数Ｋ０．３２１ｈ＾－１，Ｋ１．２２１ｈ＾－１，Ｔ１／２２．１６１ｈ，Ｔｍａｘ１．８８５ｈ，Ｃｍａｘ１２．７６１μｇ／ｍｌ。     

吡罗昔康凝胶的兔透皮吸收及药物动力学

作者采用高效液相色谱法研究了吡罗昔康（Ｐｉｒ）凝胶剂２０、３０ｍｇ／ｋｇ在１０只家兔的透皮吸收过程及药物动力学。药－时曲线符合一房室模型特征，两组的吸收和消除参数无明显差异（Ｐ＞０．０５），平均值（ｎ＝１０）Ｋａ为０．４３５ｈ￣（－１），Ｋｅ为０．１０９ｈ￣（－１），Ｔ＿（１／２）Ｋａ为２．０５ｈ，Ｔ＿（１／２）Ｋｅ为６．７４ｈ，Ｔ＿（ｍａｘ）为５．５７ｈ。Ｃ＿（ｍａｘ）和ＡＵＣ随给药剂量增加呈比例增高。两组的Ｃ＿（ｍａｘ）分别为５．４２和８．９５μｇ／ｍｌ，ＡＵＣ为８３．７５和１３４．４０（μｇ·ｈ）／ｍｌ，表明该Ｈｒ凝胶剂透皮性能较好。     

盐酸特拉唑嗪胶囊人体生物利用度及药物动力学研究

目的：对盐酸特拉唑嗪胶囊的人体内生物利用度进行研究。方法：单剂量口服盐酸特拉唑嗪胶囊和片剂２ｍｇ。血药浓度采用ＨＰＬＣ测定，数据用３Ｐ８７计算药动学参数。结果：盐酸特拉唑嗪胶囊剂的药动学参数：Ｋａ为８．２±４．０ｈ－１，Ｔ１／２为８．２±２．５ｈ，Ｔｍａｘ为０．６１±０．１１ｈ，Ｃｍａｘ为４３．５±８．５ｎｇ·ｍｌ－１，ＡＵＣ为３６７．４±３４．６ｎｇ·ｈ·ｍｌ－１；盐酸特拉唑嗪片剂的药动学参数：Ｋａ为６．４±７．４ｈ－１，Ｔ１／２为７．４±２．１ｈ，Ｔｍａｘ为０．９±０．４ｈ，Ｃｍａｘ为４３．１±４．８ｎｇ·ｍｌ－１，ＡＵＣ为３７１．３±４４．４ｎｇ·ｈ·ｍｌ－１。结论：两种剂型的药物动力学参数之间差异均无显著性（Ｐ＞０．０５），胶囊剂的相对生物利用度为９９．８８％。     

吲哚美辛锌胶囊在兔血浆中药代动力学研究

用ＨＰＬＣ测定了兔口服吲哚美辛锌及吲哚美辛胶囊后血浆中吲哚美辛的浓度，其药－时曲线均符合一室开放模型，数据经３Ｐ８７计算机程序处理拟合得吲哚美辛锌及吲哚美辛药动学参数分别为：Ｃｍａｘ２．０８８ｍｇ／Ｌ，２．６６１ｍｇ／Ｌ；Ｔｍａｘ５．２２７ｈ，３．７０４ｈ；Ｋｅ０．１２３ｈ－１，０．１７２ｈ－１；Ｋａ０．２８９ｈ－１，０．４５９ｈ－１；Ｔ２／２（ａ）２．４０１ｈ，１．５０８ｈ；Ｔ１／２（ｅ）５．６１７ｈ，４．０４０ｈ；ＡＵＣ３１．９０５ｍｇ·ｈ／Ｌ，２７．９０３ｍｇ·ｈ／Ｌ。相对生物利用度为１１４％。     

枢复宁在肺癌患者体内的药物动力学和生物利用度

９名接受顺铂化疗的原发性肺癌患者单次口服和静脉注射枢复宁８ｍｇ后，用反相高效液相色谱法测定血浆药物浓度。经用ＰＫＢＰ－Ｎ１程序在计算机上拟合计算表明，枢复宁在人体内表现为二房室模型。口服后主要药动学参数：Ｔ１／２Ｋａ＝０．４１±０．３０ｈ，Ｔ１／２α＝０．９±０．４３ｈ，Ｔ１／２β＝３．３±１．２ｈ，Ｃｍａｘ＝２８．６±９．５ｎｇ／ｍｌ，Ｔｍａｘ＝１．７±０．９ｈ，ＡＵＣ＝１５８±７３ｎｇ·ｈ／ｍｌ，绝对生物利用度为５５％。     

反相高效液相色谱法测定人血浆中萘普生含量

目的：建立ＲＰ－ＨＰＬＣ测定人血浆中萘普生含量的方法，研究该药在人体内药物动力学。方法：血浆在酸性介质中以氯仿提取，Ｃ１８色谱柱，２３０ｎｍ波长紫外检测，以甲基炔诺酮为内标，流动相为甲醇∶水（６５∶３５，预先用磷酸调至ｐＨ３．０～３．１）；所得药时数据采用ｍｉｎｉｍ３．０８程序拟合计算药动学参数。结果：萘普生血药浓度在０．１～２００μｇ·ｍｌ－１范围内与色谱峰高比呈线性关系，ｒ＝０．９９９９（ｎ＝８）。４名健康受试者单剂量口服５００ｍｇ萘普生片后，药时曲线呈一室模型。Ｃｍａｘ＝７３．６±８．３μｇ·ｍｌ－１，Ｔｍａｘ＝２．３±０．５ｈ，Ｔ１／２Ｋｅ＝９．７±３．５ｈ，Ｋｅ＝０．０８±０．０４ｈ－１，ＡＵＣ０→２４＝８２０．０±８５．７μｇ·ｈ·ｍｌ－１。结论：本法简单、快捷、灵敏，能满足药动学研究的需要     

莫雷西嗪及其代谢产物莫雷西嗪亚砜在健康愿者的药物动力学

建立测定莫雷西嗪（Ｍｏｒ）及其代谢产物Ｍｏｒ－ＳＯ２，Ｍｏｒ－ＳＯ血浆和尿液浓度的ＨＰＬＣ法。健康志愿６人ｐｏＭｏｒ６００ｍｇ后，Ｍｏｒ血浓达峰时间（Ｔｍａｘ）为１．６±０．６ｈ，峰浓度（Ｃｍａｘ）为２．１±０．４μｇ·ｍｌ＾－１，清除率（Ｃｌ）为１．８±０．５Ｌ·ｋｇ＾－１·ｈ＾－１。Ｍｏｒ－ＳＯ的Ｃｍａｘ为０．１９±０．０６μｇ·ｍｌ＾－１，消除半衰期（Ｔ１／２）为２．３±１．０ｈ。４８ｈ…     

甲巯咪唑乳膏透皮吸收和的体内动力学

目的：研究甲巯咪唑乳膏经皮给药体内动力学及血清药物含量测定。方法：兔颈前甲状腺局部经皮给药,以高效液相色谱法测定血清中甲巯咪唑浓度,以３Ｐ８７药动学软件计算药物体内动力学参数。结果：药－时曲线符合一室模型,药物吸收速率常数（Ｋａ）为２．５９０ｈ＾－１;消除半衰期（Ｔ１／２β）为２．２５８ｈ;峰浓度（Ｃｍａｘ）为１．４８０μｇ．ｍｌ＾－１;达峰时间（Ｔｍａｘ）为０．９３４ｈ;曲线下积分面积（ＡＵＣ）     

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.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.