血浆普卢利沙星活性代谢物的测定及其人体药动学研究

目的:建立人血浆普卢利沙星活性代谢物(UFX)浓度的高效液相色谱测定法,研究普卢利沙星片在健康人体内的药动学。方法:10例健康志愿受试者分别服用普卢利沙星片(相当于UFX为200 mg)单剂量和连续多次给药达稳态时进行药动学研究。血浆样品经甲醇沉淀蛋白,以Zorbax ODS柱、甲醇-0．015 mol·L~(-1)磷酸二氢钾缓冲溶液(pH 3．0)为流动相(35:65),进行HPLC荧光检测分析,测定血浆普卢利沙星活性代谢物浓度经时过程,并计算药动学参数。结果:HPLC测定血浆UFX的色谱峰面积与浓度在0．025～3．00μg·mL~(-1)范围线性关系良好,最低定量限浓度为0．025μg·mL~(-1)。血浆样品分析的回收率、精密度和准确度均良好。受试者单剂量口服普卢利沙星片后与UFX相应的主要药动学参数为C_(max)(1．48±0．44)μg·mL~(-1),T_(max)(0．9±0．8)h,AUC_(0-36h)(6．74±0．96) h·μg·mL~(-1),AUC_(0-∞)(6．97±1．06)h·μg·mL~(-1),t_(1/2)(7．21±1．60)h,MRT(8．44±1．94)h;口服普卢利沙星片达稳态后,C_(max)(1．34±0．41)μg·mL~(-1),T_(max)(0．9±0．4)h,AUC_(0-36h)(8．46±1．43)h·μg·mL~(-1),AUC_(0-∞)(8．61±1．43)h·μg·mL~(-1),t_(1/2)(6．27±0．86)h,MRT(8．38±0．94)h。结论:建立的HPLC荧光测定法专属准确,灵敏度适宜,测得的药动学参数可为普卢利沙星临床用药提供了参考依据。     

三黄汤煎剂中黄芩苷在大鼠体内药动学研究

目的:研究三黄汤煎剂中黄苓苷在大鼠体内的药动学规律。方法:大鼠ig三黄汤煎剂后,在规定时间取血,用高效液相色谱法测定血浆中黄芩苷浓度,并计算主要药动学参数结果:大鼠体内黄芩苷的主要药动学参数分别为t_(max1)=(15±4.23)min, t_(max2)=(6.8±0.54)h,C_(max1)=(4.49±1.56)μg·mL~(-1),C_(max2)=(3.25±1.23)μg·mL~(-1),AUC(0-18)=(35.52±12.35)μg·h·mL~(-1),t_(1-2)=(5.12±0.23)h,CL=(3.86±0.91)L·h~(-1)结论:该方法样品处理简单,快速准确,专属性好,灵敏度较高,可作为含黄芩苷中成药的血药浓度监测手段。     

母乳中甲硝唑、替硝唑药动学及产妇合理哺乳时间

目的确定产后静滴甲硝唑及替硝唑乳妇合理的哺乳时间,避免乳汁中药物对婴儿的不良反应.方法采用高效液相色谱法测定乳汁药物浓度,并计算其药动学参数.结果哺乳妇女单剂量静滴甲硝唑(20mg·kg-1,n=8)﹑、替硝唑(13mg·kg-1,n=7)乳汁中药动学参数达峰时(Tmax)、峰浓度(Cmax)、消除半衰期(T1/2ke)分别是(1.7±1.0)h,(20.1±5.0)μg·ml-1,(6.4±3.3)h和(1.3±0.6)h,(17.2±3.1)μg·ml-1,(11.0±3.5)h.结论静滴甲硝唑(20mg·kg-1)的乳妇宜于给药后3～4h哺乳;静滴替硝唑(13mg·     

西罗莫司滴眼液在兔眼房水内的药动学

目的探讨西罗莫司滴眼液单次滴兔眼后在房水中的药动学特征。方法 40只新西兰大白兔,局部滴入西罗莫司滴眼液50μL,采用高效液相色谱法测定兔眼房水中西罗莫司的药物浓度,用DAS1.0软件计算药动学参数。结果给药后0～120 h,西罗莫司在兔眼房水中的ρ_(max)为(84.92±37.04)μg·mL~(-1)(-1),t_(1/2)为(43.28±18.11)h,AUC_(0-6)为(1 747.44±571.36)μg·h·mL~(-1),AUC_(0-∞)为(2 335.25±702.42)μg·h·mL~(-1)。空白房水不干扰西罗莫司的含量测定。结论单次滴眼后西罗莫司可以快速穿透眼组织到达前房,并在房水中达到较高的药物浓度。     

健康志愿者体内食物对盐酸二甲双胍片药代动力学的影响

目的 研究食物对盐酸二甲双胍片药代动力学的影响。方法 16名健康男性受试者随机分成两组,一组禁食12h后空腹口服格华止片1000 mg,另一组进统一餐后口服格华止片1000 mg,反相高效液相色谱法测定血浆中二甲双胍的浓度。结果 受试者空腹和餐后口服单剂量格华止片后,血浆中二甲双胍的C_(max)分别为2.19±0.50和2.10±0.49μg·mL~(-1),t_(max)分別为3.00±1.07和2.75±1.00h,t_(1/2)分别为3.58±0.40和3.12±0.40h,AUC_(0-16h)分别为14.53±3.74和14.33±3.04μg·h·mL~(-1),AUC_(0-∞)分别为15.32±4.02和14.95±3.24μg·mL~(-1)。结论 食物对格华止片的药代动力学无明显影响。     

氟康唑胶囊的人体生物等效性评价

目的:评价2种氟康唑胶囊的人体生物等效性。方法:血浆样品采用液液萃取处理,HPLC内标法测定。22名健康受试者随机分组、自身交叉口服单剂量试验品和参比品进行生物等效性评价。结果:试验品的AUC_(0→96),AUC_(0→∞),c_(max),t_(max)和T_(1/2)分别为(124.89±26.39)h·μg·mL~(-1),(148.51±39.59)h·μg·mL~(-1),(2.94±0.57)μg·mL~(-1),(2.45±1.63)h和(35.25±9.78)h;参比品的AUC_(0→96),AUC_(0→∞),c_(max),t_(max)和T_(1/2)分别为(123.06±24.94)h·μg·mL~(-3),(150.75±40.85)h·μg·mL~(-1),(2.79±0.42)μg·mL~(-1),(3.31±2.28)h和(38.06±10.77)h。试验品相对参比品的人体相对生物利用度是(102.41±14.91)％(n=22)。2种氟康唑胶囊的主要药动学参数经交叉试验方差分析示无统计学差异(P均>0.05)。2制剂的AUC_(0→96),AUC_(0→∞)和c_(max)经双单侧t检验示90％置信区间位于有效置信区间80％～125％范围内。结论:试验品和对照品具有生物等效性。     

梯度洗脱HPLC同时测定鼻腔洗剂Ⅱ号中3种有效成分含量

目的建立高效液相色谱法同时测定鼻腔洗剂Ⅱ号中甲硝唑、氯霉素和氢化可的松含量.方法采用高效液相色谱法.Intersil C18分析色谱柱(4.6mm×250mm,5μm),流动相为8%乙腈-乙腈梯度洗脱,流速1.6mL·min-1,检测波长245nm.结果甲硝唑、氯霉素和氢化可的松的理论板数分别为16000,12000,5000;回归方程分别为Y=-7.769+3.734×10-6×(r=0.9995),Y=13.97+4.111×10-6×(r=0.9999),Y=8.433+1.046×10-6×(r=0.9999);线性范围分别为52.00～416.0μg·ml-1,131.8～659.0μg·ml-1,21.40～107.0μg·ml-1;平均回收率(±RSD)分别为99.2%(±2.6%),100.4(±1.1%),100.3%(±0.85%);最低检出浓度分别约为0.6,0.6,0.3μg·ml-1.结论用高效液相色谱法同时测定鼻腔洗剂Ⅱ号中甲硝唑、氯霉素和氢化可的松含量,操作简便,结果准确.     

国产洛索洛芬钠片剂的人体相对生物利用度

目的:研究健康受试者口服洛索洛芬钠片(loxoprofen sodium)的药代动力学,以进口洛索洛芬钠(loxonin,日本三共株式会社生产)作为参比制剂计算相对生物利用度,判断两种制剂是否生物等效。方法:20名健康受试者按体重指数进行分层随机服用洛索洛芬钠被试制剂或参比制剂60mg,用高效液相色谱法测定血浆中洛索洛芬钠的浓度。结果:经3P97程序拟合,口服国产和进口洛索洛芬钠60mg的主要药代动力学参数分别为:t_(1/2ke)为93.9±19.8min和92.4±16.3min;AUC_(0-t)为596.97±104.12μg·min·mL~(-1)和598.78±109.62μg·min·mL~(-1),C_(max)为6.40±2.12μg·mL~(-1)和6.60±2.04μg·mL~(-1),t_(max)为25.0±14.3min和23.5±10.3min。结论:国产洛索洛芬钠片的相对生物利用度为(101.2±17.4)％。经统计学分析,两制剂具有生物等效性。     

莫昔沙星滴眼剂兔眼内组织分布及其药动学研究

目的:探讨莫昔沙星滴眼剂兔眼内组织分布及药动学。方法:将27只兔均分为9组,双眼滴0.2%莫昔沙星滴眼液100μL,分别于给药后0.125、0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0 h取样,采用高效液相色谱法测定泪液、角膜、房水、虹膜-睫状体、晶体和玻璃体组织中药物浓度,以3p97程序计算药动学参数。结果:泪液、角膜、房水、虹膜睫状体、晶体和玻璃体组织中最高药物浓度分别为(76.90±28.11)、(7.68±4.18)、(1.56±0.46)、(1.00±0.42)、(0.065±0.020)、(0.030±0.014)μg·g~(-1)或μg·mL~(-1);各组织中t_(1/2β)分别为(3.59±1.81)、(4.83±3.41)、(1.80±0.56)、(4.57±3.68)、(2.36±0.65)、(2.98±2.52)h; AUC_(0(?))分别为(75.95±17.57)、(10.68±1.57)、(2.30±0.44)、(2.86±0.42)、(0.74±0.38)、(0.086±0.042)μg·h·g(-1)或μg·h·mL~(-1)。结论:莫昔沙星易于渗透到眼内各组织,且有较高浓度。     

大鼠口服茯苓素后血浆中的去氢土莫酸药代动力学研究

目的:建立测定大鼠血浆中去氢土奠酸浓度的高效液相色谱方法,并以去氢土莫酸为指标,研究大鼠灌胃给予茯苓素混合提取物后的药代动力学行为。方法:采用HPLC方法测定大鼠灌胃给予茯苓素混合提取物后,血浆中去氢土莫酸的浓度。色谱柱为ODS枉(200mm×4.6 mm,5μm),流动相为甲醇乙腈-2％冰醋酸水溶液(13:12:10),流速为1.0mL·min~(-1),检测波长为242nm,进样量20μL,室温下操作,内标物为丙酸睾丸素。结果:在0.20～20.0μg·mL~(-1)范围内具有良好线性关系(r=0.9981),方法回收率为85.2％～93.6％,日内、日间RSD均小于6.0％,达峰时间约为2h,峰浓度为(10.4±1.4)μg·mL~(-1),药时曲线下面积为32.6μg·mL~(-1)·h~(-1)。结论:此方法稳定、可靠,适用于茯苓素的药代动力学研究。     

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.