环丙沙星的临床药物动力学研究

研究健康志愿者口眼和静脉滴注环丙沙星的药物动力学，并比较不同剂量、空腹与进餐、单剂与多剂给药的体内过程。单剂空腹口服环丙沙星５００ｍｇ后，Ｃｍａｘ为３．４８ｍｇ·Ｌ－１、为３．０１ｈ、ＡＵＣ为１４．１４ｈ．ｍｇ·Ｌ－１，静脉滴注环丙沙星２００ｍｇ后Ｃｍａｘ为６．５６ｍｇ·Ｌ－１、为３．７３ｈ，口服环丙沙星绝对生物利用度为６８．８９％。单剂空腹口服２５０、５００和１０００ｍｇ环丙沙星后，Ｃｍａｘ为１．８２～７．７２ｍｇ·Ｌ－１，为２．４７～３．１５ｎ，ＡＵＣ与剂量呈比例增加，进餐与空腹口服环丙沙星５００ｍｇ后的体内过程显示进食可使该药的吸收轻度减少。与单剂口服５００ｍｇ相比，５００ｍｇ日２次×７ｄ多剂给药后的Ｃｍａｘ和ＡＵＣ均较单剂者略增高，草剂口服２５０、５００、１０００和５００ｍｇ多剂量后２４ｈ尿排出率为给药量的４７％～５５％，静滴２００ｍｇ者为７１．０６％，基于上述药动学资料，拟订了环丙沙星对各种感染的治疗方案。     

布洛芬混悬液人体生物利用度和药物动力学研究

用反相高效液相色谱法，血样甲醇沉淀蛋白后直接进样测定。１０名受试者随机分组自身交叉对照试验，单剂量口服布洛芬片或混悬液３００ｍｇ，布洛芬药时数据经３Ｐ８７程序拟合为一房室模型，其主要药动学参数，片剂和混悬液分别为：Ｋａ０．７２±０．１８ｈ－１，２．５０±０．８ｈ－１；Ｔ１／２ｋｅ２．０４±０．３２ｈ，２．２±０．５ｈ；ＡＵＣ０－∞１１１±２５ｍｇ·ｌ·ｈ－１，１１９±２８ｍｇ·ｌ·ｈ；Ｔｍａｘ２．８±０．６ｈ，０．９８±０．２３ｈ；Ｃｍａｘ１９．９±３．４μｇ·ｍｌ－１，２７．３±３．３μｇ·ｍｌ；相对生物利用度１０７．１６±８．１２％。     

奥丹西酮片在8例老年肺癌患者中的药物动力学

目的：观察奥丹西酮在老年人体内的药物动力学特性。方法：８名接受顺铂化疗的老年原发性肺癌患者单次和多次口服奥丹西酮后，用高效液相色谱法测定血浆药物浓度，用ＰＫＢＰ－Ｎ１药动学程序拟合计算。结果：奥丹西酮口服后在老年人体内表现为二房室模型。单剂量和多剂量给药时主要药动学参数为：Ｔ１／２β为４．５±０．５ｈ和５．９±０．７ｈ，Ｃｍａｘ为２０．３±１．８μｇ·Ｌ－１和２４．７±２．２μｇＬ－１，Ｔｍａｘ为１．９±０．２ｈ和１．８±０．１ｈ，ＡＵＣ０～２４为３１６±４０μｇ·ｈ·Ｌ－１和４０７±４５μｇ·ｈ·Ｌ－１，积蓄因子为１．３。结论：老年患者多次口服奥丹西酮后与单次口服相比，体内消除能力明显下降     

盐酸伪麻黄碱在人体中的药物动力学

采用反相高效液相色谱外标法测定人血清中伪麻黄碱浓度，并测定８例志愿受试者伪麻黄碱血药浓度，并计算分析药物动力学参数，结果单剂量口服９０ｍｇ盐酸伪麻黄碱后，药时曲线呈一室模型。Ｔｍａｘ＝１．７±１．１ｈ，Ｃｍａｘ＝３６４±９４ｎｇ·ｍｌ－１，ＡＵＣ（０～∞）＝２６６２±３０３（ｎｇ·ｈ·ｍｌ－１），Ｔ１／２＝４．０±１．０ｈ，Ｋａ＝２．４±１．４ｈ－１，Ｋｅ＝０．１９±０．０４ｈ－１，Ｖｄ＝０．１９±０．０５ｍｇ，Ｃｌ＝０．０３±０．０１ｍｇ·ｈ－１。     

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％。     

两种布洛芬缓释制剂在健康人体内的药物动力学

目的：本文对布洛芬缓释片和胶囊在健康志愿者中的药物动力学进行研究。方法：建立了一个测定人血中布洛芬的高效液相色谱法。结果：口服单剂量６００ｍｇ片剂和胶囊的ＡＵＣ分别为１５０．２±３４．８和１５１．８±３４．５μｇ·ｈ·ｍｌ－１；Ｃｍａｘ分别为２２．７±５．３和２２．２±３．９μｇ·ｍｌ－１；Ｔｍａｘ分别为３．５±０．７和３．８±０．８ｈ。口服多剂量６００ｍｇ达稳态后片剂和胶囊的ＡＵＣ分别为１５６．０±３８．７和１６３．２±４４．７μｇ·ｈ·ｍｌ－１；Ｃｍａｘ分别为２４．６±５．５和２３．８±４．４μｇ·ｍｌ－１；Ｔｍａｘ分别为３．０２±０．２９和３．２±０．５ｈ。达稳态后片剂和胶囊的波动系数分别为１．４±０．３和１．４２±０．２３。经统计学处理，上述各参数间差异均无显著性（Ｐ＞０．０５）。结论：双单侧ｔ检验（ＮＤＳＴ程序）的结果表明，布洛芬两种缓释制剂具有生物等效性。     

氧氟沙星和环丙沙星在老年人中的药物动力学

对氧氟沙星和环丙沙星在老年和年轻健康志愿者中的药物动力学进行同期比较研究。上述两药全部血、尿浓度均以高效液相色谱法测定。老年组单剂口服氧氟沙星３００ｍｇ后的平均血清Ｔ＿（１／２β）为７．０８±０．８１ｈ，Ｃｌ＿ｒ为９５．９±２１．０ｍｌ／ｍｉｎ，ＡＵＣ为３２．６±４．１ｈ·ｍｇ／Ｌ，与年轻组相比，血清Ｔ＿（１／２β）延长，Ｃｌ＿ｒ降低以及ＡＵＣ增大。老年组与年轻组的Ｃ＿（ｍａｘ）则相近，分别为４．６７±０．９８和４．７２±０．５１ｍｇ／Ｌ。老年组每１２ｈ口服氧氟沙星３００ｍｇ连续７天后的Ｃ＿（ｍａｘ）和ＡＵＣ较单剂者明显增高。老年组和年轻组单剂口服环丙沙星５００ｍｇ后的Ｔ＿（１／２ｋｅｌ）分别为３．３２±０．４３和２．７６±０．４３ｈ，Ｃｌ＿ｒ分别为２３１．４±６８．８和２５６．９±６４．０ｍｌ／ｍｉｎ，ＡＵＣ分别为１７．７±４．９和１５．９±３．５ｈ·ｍｇ／Ｌ。根据本研究结果，对上述两药在治疗老年人感染时给药方案的调整提出了建议。     

双氯灭痛在正常人体内的药物动力学研究

采用反相高效液相色谱法测定了１０例健康人单剂量口服７５ｍｇ双氯灭痛片剂后血浆药浓度，研究了该药物在中国人体内药物动力学。经用ＰＫＢＰ－Ｎ＿１程序包在计算机上拟合计算表明，双氯灭痛口服给药多数人表现为二房室模型。其主要药动学参数分别为：Ｔ＿（α１／２）＝０．４０±０．１１ｈ，Ｔ＿（β１／２）＝１．７７±０．５ｈ，Ｔ＿（ｍａｘ）＝１．７８±０．３２ｈ，Ｃ＿（ｍａｘ）＝１．８７±０．９μｇ／ｍｌ，ＡＵＣ＝３．８１±１．７μｇ／（ｍｌ·ｈ）。结果表明，中国人体内的药动学参数与所报道的外国人体内相似。     

进口和国产索他洛尔片剂的相对生物利用度研究

目的：本文对进口和国产索他洛尔片剂在１２名男性健康志愿者中的药物动力学和相对生物利用度进行了研究。方法：建立了一个检测血清中索他洛尔浓度的反相高效液相色谱－荧光检测法。结果：单剂量口服索他洛尔１６０ｍｇ后的血药浓度数据用３Ｐ８７药物动力学程序进行模型拟合，国产片剂ＡＵＣ、Ｃｍａｘ、Ｔｍａｘ、Ｔ１／２分别为１６．２±３．６ｈ·μｇ·ｍｌ－１，１．２±０．２μｇ·ｍｌ－１，２．１±０．７ｈ，１７．０±７．２ｈ；进口片剂ＡＵＣ、Ｃｍａｘ、Ｔｍａｘ、Ｔ１／２分别为１５．９±３．５ｈ·μｇ·ｍｌ－１，１．２±０．４μｇ·ｍｌ－１，２．１±０．６ｈ，１８．６±９．４ｈ。国产片剂的相对生物利用度为１０３．５％。结论：两种片剂的所有药动学参数经统计学（ＳＰＳＳ软件）处理差异均无显著性（Ｐ＞０．０５）。     

头孢克肟在正常人中的药物代谢动力学研究

本文报道头孢克肟在正常人中的药物代谢动力学和测定头孢克肟血浓度的高效液相色谱（ＨＰＬＣ）方法学。８位健康志愿者交叉单次空腹及进食后口胺头孢克厉２００ｍｇ后平均Ｃｍａｘ分别为２．７±０．９和１．７±０．４ｍｇ／Ｌ，平均Ｔ１／２Ｋｅ为３．７±０．４和３．３±０．７ｈ，平均ＡＵＣ为２５．４±８．５和１３．９±４．０ｈ／ｍｇ／Ｌ。２４ｈ内分别排出给药量的２３．７±７．６％和１３，６±４．５％。服药后１２ｈ的平均血药浓度分别为０．８３ｔ０．２６和０．４５±０．１８ｍｇ／Ｌ。经统计学处理（配对Ｔ检验），空腹与进食后口服头孢克肟后的Ｃｍａｘ、ＡＵＣ和２４ｈ内尿排出卒间的差异具极显著意义（Ｐ＜０．０１）。本文建立的高效液相色谱法准确性高、具重复性。以ＨＰＬＣ法测得血药浓度与微生物法测得者相符。     

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.     

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.