慢性肾衰患者血液透析时司帕沙星的药物动力学

目的 观察司帕沙星在慢性肾衰患者血液透析时的药物动力学特征.方法 用高效液相色谱法测定透析和非透析住院患者单剂量口服司帕沙星后血清和尿药物浓度,并计算药物动力学参数.结果 经PKNP-N_1药代动力学软件摸拟和计算,司帕沙星的药物动力学符合一级吸收二室开放模型,主要药动学参数:透析时T_(1/2(ka))=(1.25±0.57)h,T_(1/2β)=(11.88±4.13)h,T_(peak)=(4.18±0.78)h,C_(max)=(0.80±0.17)mg·L~(-1),AUC_(0~∞)=(6.90±3.25)mg·h·L~(-1)尿中24h原形药物排除率为(8.98±3.92)%;未透析时T_(1/2(ka))=(1.12±0.42)h,T_(1/2β)=(15．93±5．20)h,T_(peak)=(3.88±0.75)h,C_(max)=(0.69±0.37)mg·L~(-1),AUC_(0~∞)=(10.05±4.13)mg·h·L~(-1),尿中24h原形药物排出率为(10.58±5.64)%.结论 司帕沙星在慢性肾衰患者血液透析时消除加快.     

左旋氧氟沙星血药浓度测定及药物动力学

目的:测定国产左旋氯氟沙星胶囊po后在人体内的药物动力学.方法:10例健康志愿受试者,单次po国产左旋氯氟沙星胶囊,用反相高效液相色谱法测定血浆中药物浓度.结果:左旋氧氟沙星药物动力学参数分别为:C_(?)=(2.12±0.21)μg/ml,t_(?)=(1.16±0 18)h,T_(1/2α)=(1.50±0.65)H,T_(1/2β)=(6.16±1.15)h,CL=(16.27±2.15)L/h,V_d=(70.33±10.94)L,AUC_(0→∞)=(13.72±1.03)(Mg/L)·h.结论:国产左旋氧氟沙星胶囊的主要药物动力学参数与国外文献报道基本一致.     

表柔比星在肿瘤患者体内的药物动力学

目的;研究表柔比星(Epi)在肿瘤患者体内的药物动力学.方法:11例肿瘤患者单次iv 60mg/m~2Epi,用HPLC测定Epi血药浓度,数据用3P87药物动力学程序进行模型拟合并计算药物动力学参数.结果:Epi的药-时曲线符合三室模型,其主要药物动力学参数分别为:T_(1/2p)=(0.052±0.018)h,T_(1/2(?))=(1.25±1.18)h,T_(1/2p)=(31.1±13.7)h,Vc=(23.9±11.2)ml,AUC=(2009±429)ng·h/ml,CL=(50.1±12.1)ml/h.结论:Epi在肿瘤患者体内分布迅速,消除缓慢.     

国产四环格列齐特片在健康人体内的药物动力学及相对生物利用度

10名健康志愿者随机自身交叉单次po国产被试格列齐特片80mg和国产标准参比格列齐特片80mg后,应用高效液相色谱法测定血浆格列齐特浓度.格列齐特在健康人体内的血药浓度-时间过程符合二室模型.被试格列齐特片的药物动力学参数分别为:T_(1/2ka)=1.01±0.67h,T_(1/2β)=4.81±1.91h,T_(max)=3.32±0.92h,C_(max)=4.20±1.77μg/ml,AUC=45.89±22.98(μg·h)/ml.参比格列齐特的药物动力学参数分别为:T_(1/2Ka)=0.84±0.42h,T_(1/2β)=6.30±3.22h,T_(max)=3.28±0.79h,C_(max)=3.68±1.89μg/ml,AUC=41.42±19.35(μg·h)/ml.两种格列齐特片剂的各项药物动力学参数经3P87程序及统计学分析处理,被试格列齐特片对标准参比格列齐特片的相对生物利用度为107%.     

盐酸曲普利啶胶囊在中国健康志愿者体内的药物动力学

目的:研究单剂量和多剂量盐酸曲普利啶胶囊在中国健康志愿者体内的药物动力学特征。方法:健康受试者单次(2.5 mg)或多次(2.5 mg,tid,连续服药6d)口服盐酸曲普利啶胶囊,用LC-MS法测定血浆中曲普利啶浓度,用DAS 2.0处理数据。结果:本法线性良好,精密度、准确度、回收率均符合要求。所得药物动力学参数如下,单剂量:t_(1/2)=(5.88±1.62)h,t_(max)=(2.21±0.62)h,C_(max)=(27.50±6.32)ng·ml~(-1),AUC_(0-∞)=(216.74±67.18)h·ng·ml~(-1),MRT_(0-∞)=8.64±1.24 h。多剂量:t_(1/2)=(6.38±2.58)h,t_(max)=(1.71±0.58)h,AUC_(8S)=139.29±47.22 h·ng·ml~(-1),C_(max)=(27.78±6.52)ng·ml~(-1),C_(min)= (10.12±9.26)ng·ml~(-1),C_(av)=(17.41±5.90)ng·ml~(-1),DF=1.13±0.60。结论:该法灵敏度高,操作简便,盐酸曲普利啶胶囊多剂量给药与单剂量给药的药物动力学参数基本一致,无蓄积,给药后安全性良好。     

液相色谱—质谱联用法测定人血浆中多潘立酮及其在健康中国志愿者中的药物动力学

目的:测定人血浆中多潘立酮的浓度,并研究在中国志愿者中单剂量口服20mg后的药物动力学过程.方法:用液-液萃取法提取血浆中药物.采用液相色谱-质谱联用分析手段,建立测定人血浆中多潘立酮浓度的分析方法.结果:多潘正酮在0.52—154.5μg/L浓度范围内线性良好(r=0.9999),其在人血浆中的回收率大于75％,低浓度(0.52μg/L)的日内、日间差异分别为9.4％和7.6％.多潘立酮的血药浓度-经时曲线符合二房室模型,其主要药物动力学参数为:T_(max)=(0.8±0.7)h,C_(max)=(50±32)μg/L,T_(1 2)=(7.8±1.6)h.结论:本方法专属性强,灵敏度高,可准确测定多潘不酮在人血浆中的浓度.     

长效二氢奎尼丁治疗40例心房纤颤患者的疗效与血药浓度的关系

目的:观察长效二氢奎尼丁治疗心房纤颤的疗效与血药浓度的关系.方法:10例心房纤颤病人一次po长效二氢奎尼丁,以TDx测定血药浓度.结果:T_(1/2(Ka))=(2.22±1.25)h,T_(1/2)=(8.22±4.25)h,T_(max)=(6.99±3.03)h,C_(max)=(0.6±0.41)μg/ml,AUC=(9.99±5.96)μg/(h·ml).结论:长效二氢奎尼丁治疗房颤时有效血药浓度为0.82～1.20μg/ml.     

曲马多滴剂的相对生物利用度

采用反相高效液相色谱-荧光检测法检测血清中曲马多的浓度,比较研究了进口和国产曲马多滴剂在9名男性健康志愿者的药物动力学参数和生物利用度,结果:国产滴剂C_(max)=327.7±92.8ng·ml~(-1),T_(max)=1.567±0.781h,T_(1/2)=11.85±5.46h,AUC=2940±750ng·h~(-1)·nl~(-1);进口滴剂C_(max)= 340.9±74.2ng·ml~(-1) ,T_(max)=1.204±0.698h,T_(1/2)=8.857±7.326h,AUC=2938±607ng·h~(-1)·ml~(-1).国产滴剂的生物利用度为进口滴剂的99.85%.两种滴剂AUC、T_(1/2)数据经对数转换后的配对t检验结果均无显著性差异(P>0.05).生物等效性检验合格.     

果胶铋对雷尼替丁在人体内药物动力学的影响

目的:研究果胶铋对雷尼替丁的药物动力学的影响.方法:6名健康男性随机分两组交叉单次po雷尼替了胶囊及雷尼替丁和果胶铋胶囊后.采用HPLC测定雷尼替丁的血药浓度,计算药物动力学参数.结果:单用雷尼替丁胶囊和合用果胶铋组T_(1/2β)分别为(1.79±0.32)和(2.04±0.40)h,t_(max)分别为(2.34±0.46)和(2.70±0.49)h,c_(max)分别为(0.93±0.27)和(0.55±0.26)mg/L.AUC_(0-∞)分别为(4.78±1.55)和(3.11±1.57)[(mg/L)·h].经数理统计学分析.两组c_(max)(P0.05).同服果胶铋时雷尼替丁的生物利用度降低约40%.结论:雷尼替丁应尽量避免与果胶铋同时服用.     

沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度

目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:T_(max)(0.22±0.07)和(1.8±0.6)h,C_(max)(3.4±1.1)和(3.9±1.4)μg·L~(-1),T_(1/2)(4.5±1.5)和(4.6±1.1)h,AUC_(0-20min)(0.9±0.3)和(0.16±0.10)μg·h·L~(-1).两种给药途径的T_(max)和AUC_(0-20 min)之间差异显著(P<0.01).AUC_(0-20min)(nihal)为 AUC_(0-20 min)(po)的 8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为 57％±24％.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.     

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.