应用Bayesian反馈法预测阿替洛尔药物动力学参数及血药浓度

应用Ｂａｙｅｓｉａｎ反馈法预测２１例高血压病人，口服阿替洛尔的个体药动学参数及稳态血药浓度（Ｃｐｓｓ）并与经典药动学方法估算结果作比较，结果表明本法的Ｔ１／２为６．０±１．７ｈ，Ｖｄ为１．４３±０．１３Ｌ／ｋｇ，ＣＬ为１７２±３４ｍｌ／（ｈ·ｋｇ）；经典法的Ｔ１／２为６．８±２．４ｈ，Ｖｄ为１．４５±０．５６Ｌ／ｋｇ，ＣＬ为１６４±８５ｍｌ／（ｈ·ｋｇ）。两者无显著性差异（Ｐ＞０．０５）。两法所测得Ｃｐｓｓ有较好相关性（ｒ＝０．９９３）。     

血肌酐值法预测地高辛个体化给药方案

在地高辛常规监测中，用血肌酐值法预测个体化药动学参数和给药方案。结果表明，８４例病人的地高辛药物动力学参数预测值为，ＣＬ７６±２１ｍｌ／（ｋｇ·ｈ），Ｖｄ７．０５±１．２０Ｌ／ｋｇ，Ｔ１／２６６±７ｈ。预测的个体化剂量为３．１±０．９μｇ／（ｋｇ·ｄ），预测的稳态血药浓度（Ｃ＿（ｓｓ））为１．２４±０．３８μｇ／Ｌ，与实测Ｃ＿（ｓｓ）１．２±０．４μｇ／Ｌ比较，差异无显著性（Ｐ＞０．０５）。     

环丙沙星3种剂型在62名健康志愿者的药物动力学研究

用微生物测定法对环丙沙星３种剂型在６２名男性健康志愿者身上进行药物动力学研究。在１６名受试者静滴环丙沙星注射液（２００ｍｇ／１００ｍｌ）后，０、１、４、１２ｈ的血药浓度分别为３．６８±０．６３、≤１、０．３３～０．４３及０．１μｇ／ｍｌ，药动学参数Ｔ１／２为３．２４ｈ，总清除率３９３．５ｍｌ／ｍｉｎ，ＡＵＣ０～２４６．２１ｈ·μｇ／ｍｌ，Ｖｓｓ１５５．０±３４．２Ｌ。单次口服环丙沙星１００及５００ｍｇ，体内平均药动学参数Ｃｍａｘ分别为２．３１±０．２８及２．４９±０．２４μｇ／ｍｌ，Ｔｍａｘ分别为１．２６±０．１８及１．４７±０．２１ｈ，Ｔ１／２为２．６９±０．４８及３．８７±０．５３ｈ，ＡＵＣ０～２４为１２．８１±０．８５及１５．０２±２．１１ｈ·μｇ／ｍｌ，结果与文献报道相同。此外，对静滴及口服两种给药途径的血药浓度与临床疗效关系以及统计矩法与房室模型在药物动力学研究中的选用进行了讨论。     

肾移植术后受者环孢素的血药浓度监测

目的 观察环孢素血药浓度与肾移植效果间关系。方法 对９７例接受同种异体肾脏移植术受者术后８周内２０６例次环孢素血药浓度监测结果进行回顾性分析，按照受者术后的临床表现、生化指标将其分为术后正常组、急性排斥组、急性毒性组，采用荧光偏振免疫测定法，以单克隆抗体试剂测定环孢素血药浓度。结果 术后正常组６２例移植肾功能良好，环孢素的给药剂量为５２±１．９ ｍｇ／ｋｇ·ｄ，１７１例次环孢素血药浓度的平均值为３０９．８５±１３１．６９μｇ／Ｌ；术后急性排斥组 ２６例，距发生排斥反应最近一次的环孢素血药浓度平均为１６５．８０±１２３．１３μｇ／Ｌ，环孢素的给药剂量为 ４．８±１．６ｍｇ／ｋｇ·ｄ；术后急性毒性组９例，距发生毒性反应最近一次的环孢素血药浓度平均为５５６．５１±１０２．５０μｇ／Ｌ，环孢素的给药剂量为６．２±１．０ｍｇ／ｋｇ·ｄ。三组之间环孢素的给药剂量无显著性差异（Ｐ＞０．０５），但环孢素血药浓度却相差很大，两两之间有显著性差异（正常组与排斥组 Ｐ＜ ０．０５；正常组与毒性组Ｐ＜ ０．０５；排斥组与毒性组Ｐ＜ ０．０１）。结论 环孢素浓度较低时，出现排斥反应的可能性较大；而环孢素浓度较高时，发生毒性反应的机会较多。     

小剂量亚胺培南／西司他丁在肺部感染患者中的药动学及疗效观察

用小剂量亚胺培南／西司他丁治疗１８例肺部感染患者，通过细菌培养、检测血药浓度动态变化及支气管肺泡灌洗液（ＢＡＬ）的药物浓度测定，以探讨小剂量亚胺培南／西司他丁治疗肺部感染的适用价值。结果显示：致病菌阴转率为８９％，治疗的有效率为８９％；静滴后１．５ｈＢＡＬ中药物浓度为１．３１２±０．１６１μｇ／ｍｌ；血药峰浓度为３７．３２±９．５７μｇ／ｍｌ，用药８ｈ后降为０．９１±０．１１μｇ／ｍｌ，半衰期约为１ｈ。     

羟乙桂胺在肌肉挛缩患者及健康志愿者体内的药物动力学

９名肌肉挛缩患者和６名健康志愿者口服羟乙桂胺片１５ｍｇ／ｋｇ，用ＨＰＬＣ测定血药浓度并计算动力学参数。９名肌肉挛缩患者口服后的达峰时间Ｔｍａｘ（约１ｈ），峰浓度Ｃｍａｘ（５．５±０．８μｇ／ｍｌ）；ｋａ（１．１９±０．１４ｈ－１），ｔ１／２α（１．０８±０．３１ｈ），ｔ１／２β（３．３７±１．０５ｈ），与健康志愿者无显著差异（ｐ＞０．０５）。     

大鼠口服怡康的生物利用度研究

采用ＨＰＬＣ法对怡康（甘露醇烟酸酯）在体内的生物利用度进行了研究。通过口服及静中途经给药证实。静注２５ｍｇ／ｋｇ后，血浓峰值约为５．８１ｕｇ／ｍｌ，同齐量口服后，血浓峰值较低，为１．２μｇ／ｍｌ。口服混县液７５ｍｇ／ｋｇ后为１．０３μｇ／ｍｌ，３００ｍｇ／ｋｇ为１．４５μｇ／ｍｌ。达峰时间在０．５～１小时之间，代谢半衰期约为１小时。     

诺氟沙星滴入兔眼与注入球结膜下其组织分布及药动学比较

用高效液相色谱法对诺氟沙星点眼与球结膜下注射后眼各组织药物浓度进行测定，比较两种给药途径的眼各组织浓度及其药物动力学参数。结果表明，诺氟沙星点眼与球结膜下注射后４ｈ，泪液诺氟沙星浓度分别为２．０８±０．１９与１６．０７±３．１４μｇ／ｍｌ（Ｐ＜０．０１）；角膜分别为０．７１±０．０７与１．６５±０．２４μｇ／ｇ（Ｐ＜０．０１）。泪液ＡＵＣ分别为９８．３３±７．３１与２７９．８２±３１．７ｈ·μｇ／ｍｌ；角膜ＡＵＣ、Ｃｍａｘ、Ｔｍａｘ、Ｔ１／２Ｋｃ分别为１７．４２±１．２１ｈ·μｇ／ｇ、８．９４±０．８μｇ／ｇ、０．５７±０．０６ｈ、０．９１７±０．１６ｈ与２０．０１±１．０１ｈ·μｇ／ｇ、１０．０５±０．０７μｇ／ｇ、０．４５±０．０５ｈ、１．１５±０．２０ｈ；房水ＡＵＣ、Ｃｍａｘ、Ｔｍａｘ分别为１．１３±０．２１ｈ·μｇ／ｍｌ、０．３９±０．０５μｇ／ｍｌ、０．６２±０．０９ｈ与１．７９±０．０７ｈ·μｇ／ｍｌ、１．００±０．１５μｇ／ｍｌ、０．４７±０．１０ｈ。诺氟沙星点眼与球结膜下注射两种给药途径的上述药动学参数有明显差异（Ｐ＜０．０５或０．０１）。     

16888个中药汤剂处方分析与讨论

本文利用微生物法，对６例慢性肾衰尿毒症期血透病人庆大霉素的血药浓度进行了监测，并对其药动学参数进行了研究，结果显示：６例患者的药一时数据均符合单室开放模型，庆大霉素的平均半衰期及消除速率常数分别为１．５５±０．７５ｈ和０．５６±０．２９ｈ－１，表现分布容积与清除率的总平均值分别为：３．９２±１．１５Ｌ、２．１５±１．１３Ｌ·ｈ－１。透析毕庆大霉素的平均透析下降率为８３．４３±７．８８％，这表明庆霉素能被透析器清除。实验还显示：患者透析前以８万ｕ庆大霉素静滴，透析结果时（４．５ｈ）的血浓度为３．１２±１．２４μｇ／ｍｌ，在有效治疗范围内，而１例以１６万ｕ静滴给药的患者于透析结速时（５．０ｈ）的血药浓度为１３．５２μｇ／ｍｌ，仍高于中度血药浓度值。在以后的临床应用中透析前均以８万ｕ庆大霉素静滴，５例中，１例原感染患者得到治愈，其余４例均未发生感染，也未发生中毒现象，从而为肾衰血透患者使用庆大霉素提供了依据。     

头孢唑林临床药物动力学研究及其血药浓度高效液相色谱测定法

本文报告头孢唑林正常人药物动力学研究结果及其体液浓度高效液相色谱测定法的建立。结果表明，头孢唑林１ｇ静滴和肌注后的平均高峰血药浓度分别达１５９．８±１７．ｌｍｇ／Ｌ和７４．１±１４．２ｍｇ／Ｌ，８ｈ时仍可分别测得５．６±３．５ｍｇ／Ｌ和１０．０±４．２ｍｇ／Ｌ。静滴和肌注后的消除半衰期分别为１．９４±０．２６和２．１１±０．５９ｈ。头孢唑林肌注后吸收完全，绝对生物利用度为９２．０±５．６％。静滴和肌注头孢唑林１ｇ后尿药平均峰浓度分别为４１９０±２２９４ｍｇ／Ｌ和２３２０±１７００ｍｇ／Ｌ２４ｈ累积排出率分别为８６．３±４．２％和８７．５±９．６％。以ＨＰＬＣ法测定头孢唑林血药浓度方法准确，其重复性、特异性高，且方法简单易行，适用于特殊生理或病理情况下头孢唑林血药浓度监测。     

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.