洛索洛芬钠片剂的人体相对生物利用度研究

目的 :考察健康受试者口服洛索洛芬钠片的药代动力学 ,判断其与进口洛索洛芬钠 2种制剂是否生物等效。方法 :2 0例健康受试者按体重指数进行分层随机交叉服用洛索洛芬钠被试制剂或参比制剂 6 0mg ,采用高效液相色谱法测定血浆中洛索洛芬钠的浓度。结果 :口服 6 0mg洛索洛芬钠被试制剂和参比制剂的主要药代动力学参数分别为 :t1/ 2ke为 (96 .2± 2 3.1)和 (98.2± 17.1)min ;AUC0～t为 (5 6 3.1± 6 7.5 )和 (5 6 5 .4± 90 .8) μg·min·mL-1,Cmax为 (6 .36± 1.32 )和 (6 .0 9± 1.4 0 ) μg·mL-1,Tmax为 (2 3.5± 14 .2 )和 (2 3.0± 10 .2 )min。被试制剂的相对生物利用度为 (10 1.5± 17.4 ) %。结论 :2种制剂具有生物等效性。     

HPLC法测定国产洛索洛芬钠片人体相对生物利用度

目的 建立人血浆中洛索洛芬钠浓度的HPLC测定方法,研究健康受试者口服国产洛索洛芬钠片的药代动力学,以进口洛索洛芬钠片作为参比制剂,计算两制剂的相对生物利用度,判断两种制剂是否等效。方法 血浆样品加入内标后经三氯乙酸沉淀蛋白、涡旋、离心,吸取上清液进样。色谱柱为Shimadzu VP-ODS(150mm×4.6mm i.d.,5μm C₁₈),流动相为0.05mol·L^-1磷酸二氢钾-甲醇(27∶73)(v/v),紫外检测波长230nm。测定了20名受试者单剂量口服两种洛索洛芬钠片60mg后血药浓度时间过程。结果 最低检测浓度0.2μg·ml^-1,回收率大于80%,日间和日内的变异系数小于10.5%,线性范围为0.2～12.0μg·ml^-1(r=0.9998),符合生物样品分析的要求。主要药动学参数分别为:国产洛索洛芬钠片:t_1/2为1.39±0.15h,AUC_0-6h 10.71±1.45μg·h·ml^-1,C_max7.23±1.02μg·ml^-1,t_max0.4±0.1h；参比制剂t_1/2为1.41±0.15h,AUC_0-6h 10.46±1.32μg·h·ml^-1,C_max7.49±1.26μg·ml^-1,t_max0.4±0.1h。结论 建立的HPLC法简单快速，定量可靠准确，适合于洛索洛芬钠临床研究。洛索洛芬钠受试制剂的相对生物利用度为（103.2±15.1）%。经统计学分析，两制剂生物等效。     

氟康唑片在健康人体内的生物等效性研究

目的:研究氟康唑片的人体生物等效性。方法:20名健康男性受试者,按双交叉设计,随机单剂量口服氟康唑片受试制剂和参比制剂各300 mg,分别于服药后多点采血测定。采用高效液相色谱法测定血药浓度,并计算药动学参数,评价两制剂的生物等效性。结果:受试制剂与参比制剂的t_(1/2)分别为(29 98±4.79)、(30.60±4.66)h,t_(max)分别为(1.9±0.3)、(1.9±0.6)h,C_(max)分别为(7.64±0.98)、(7.93±0.78)μg·mL~(-1),AUC_(0～96)分别为(258.41±36.49)、(267.93±31.24)μg·h·mL~(-1),AUC_(0～∞)分别为(283.17±45.80)、(299.70±38.41)μg·h·mL~(-1),用面积法AUC_(0～96)和AUC_(0～∞)估算氟康唑片受试制荆的相对生物利用度分别为(94.9±11.3)%、(94.8±11.9)%。结论:受试制剂与参比制剂等效。     

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。     

HPLC-MS法快速测定人血浆中洛索洛芬钠的浓度及其药代动力学研究

目的:建立一种快速测定人血浆中洛索洛芬钠含量的方法,并应用于测定洛索洛芬钠的血药浓度,计算其药代动力学参数和相对生物利用度。方法:0.2 ml酸化的血浆样品经正己烷-乙醚(4 1,v/v)提取,色谱柱为Diamonsil 150 mm×2.1 mm,5μm,C18柱,流动相为0.2%醋酸铵-乙腈(25 75,v/v);采用ESI离子源,选择性离子检验法检测血浆中的洛索洛芬。20名健康志愿者随机交叉服用洛索洛芬钠受试和参比制剂后,用LC-MS法测定人血浆中洛索洛芬的药物浓度。结果:洛索洛芬浓度0.10~10.0 g.ml-1线性关系良好(r=0.9997),绝对回收率高于80%;日内、日间RSD均小于15%。用该方法测得受试制剂和参比制剂的Cmax分别为7.17±1.63和6.94±1.33μg.ml-1,Tmax分别为0.46±0.23和0.46±0.28 h,AUC0-10分别为11.65±1.38和11.19±1.83μg.ml-1.h,AUC0-∞分别为12.04±1.42和11.64±1.89μg.ml-1.h。结论:该方法快速灵敏准确,适用于人体生物利用度研究。洛索洛芬钠受试制剂的相对生物利用度为(105.3±11.5)%。受试制剂与参比制剂生物等效。     

液相色谱-串联质谱法测定美托洛尔缓释片的人体药动学及生物等效性

目的建立测定人血浆中美托洛尔浓度的液相色谱-串联质谱(LC—MS/MS)法,研究健康受试者单剂量和多剂量口服美托洛尔受试制剂和参比制剂后的药动学和生物等效性。方法40名男性健康志愿者进行随机双交叉试验,分别单剂量和多剂量口服美托洛尔受试制剂和参比制剂100 mg,采用LC—MS/ MS法测定血药浓度,用DAS软件计算主要药动学参数。结果单剂量时受试制剂和参比制剂的主要药动学参数如下:c_(max)分别为(144±s 43)和(164±40)μg·L~(-1),t_(max)分别为(3.7±1.2)和(3.5±0.8)h,t_(1/2)分别为(6.0±2.5)和(4.9±2.0)h,AUC_(0～24)分别为(1 639±787)和(1 658±636)μg·h·L~(-1),相对生物利用度为(97±21)%。多剂量达稳态时受试制剂和参比制剂的主要药动学参数如下:c_(max)分别为(241±170)和(232±75)μg·L~(-1),c_(min)分别为(115±66)和(121±64)μg·L~(-1),t_(max)分别为(3.7±1.0)和(3.5±1.6)h,AUC_(ss)分别为(1 905±882)和(1 992±834)μg·h·L~(-1),c_(av)分别为(159±73)和(166±69)μg·L~(-1),DF分别为(77±30)%和(75±31)%。受试制剂与参比制剂的AUC_(0～t),AUC_(0～∞)或AUC_(ss),c_(max)和t_(max)均符合生物等效性要求。结论建立的LC—MS/MS法专属、准确、灵敏度适宜。测定的美托洛尔受试制剂和参比制剂生物等效。     

国产阿奇霉素分散片人体生物等效性研究

目的:比较2种阿奇霉素分散片的人体生物等效性。方法:采用双制剂双周期自身交叉对照的方法,将22例健康男性受试音随机分为两组,口服阿奇霉案分散片受试制剂或参比制剂各1g。用HPLC-电化学检测法测定血浆中的阿奇霉素浓度,用DAS软件计算药动学参数,进行生物等效性评价。结果:阿奇霉素分散片受试制剂与参比制剂AUC_(0→132h)分别为(24,25±6．25)和(25．02±6．29)μg·h·mL~(-1);AUC_(0→∞)分别为(29．62±5．91)和(31．35±9．02)μg·h·mL~(-1);C_(max)分别为(1．18±0．17)和(1．18±0．21)μg·mL~(-1);T_(max)分别为(2．27±0．26)和(2．16±0．28)h;t_(1/2)分别为(39,89±9．36)和(42．27±9．62)h。与参比制剂比较,受试制剂相对生物利用度为(97．4±9．8)%。结论:口服阿奇霉素量试制剂和参比制剂生物等效。     

洛美利嗪片剂与胶囊剂的人体生物等效性比较

目的:评价洛美利嗪片与参比制剂(洛美利嗪胶囊)是否生物等效。方法:男性健康受试者20名,随机分成2组,交叉口服受试制剂(洛美利嗪片)和参比制剂各40 mg,用高效液相色谱紫外检测法测定人血清中洛美利嗪浓度,所得数据经BECS软件处理得到主要药动学参数。结果:洛美利嗪片与参比制剂洛美利嗪胶囊的t_(max)分别为:(2．7±s 0．3)h和(2．6±0-3)h,c_(max)分别为:(93±11)μg·L~(-1)和(90±11)μg·L~(-1),用梯形法计算所得的AUC_(0-t)分别为(435±71)μg·h·L~(-1)和(432±77)μg·h·L~(-1)。对经对数转换后的c_(max),AUC_(0-t),进行方差分析和双单侧t检验及90％可信限判断,洛美利嗪片的c_(max)落在参比制剂的963％～11 1．7％范围内,AUC_(0-T)落在参比制剂的91．7％～110．6％范围内,t_(max)经非参数检验法检验无显著差异,洛美利嗪片AUC_(0-t) 的相对生物利用度为(101±12)％。结论:2种制剂具有生物等效性。     

利巴韦林片在健康人体的生物等效性

目的评价利巴韦林2种片剂的生物等效性。方法20例男性健康受试者采用随机双交叉设计试验,用液相色谱-串联质谱法测定单剂量口服利巴韦林片受试制剂和参比制剂各300 mg后利巴韦林的血药浓度,所得数据采用软件BAPP2.0计算主要药动学参数。结果利巴韦林参比制剂与受试制剂主要药动学参数:t_(max)分别为(1.4±s 0.5)h,(1.9±1.0)h;c_(max)分别为(610±183)μg·L~(-1)和(598±194);μg·L~(-1),t(1/2)分别为(38±4)h和(36±5)h,AUC_(0～96)分别为(8 035±1795)μg·h·L~(-1)和(7 868±1 756)μg·h·L~(-1)。以AUC~(0～t)计算,利巴韦林受试制剂的平均相对生物利用度为(98±11)%,统计学结果表明2种制剂主要药动学参数c_(max)、AUC_(0～t)和t_(max)均无显著差异。结论本方法准确、专属、灵敏,2种制剂在人体内具有生物等效性。     

阿伐斯汀胶囊人体药动学和生物等效性

目的:研究国产阿伐斯汀胶囊在正常人体内的药动学和生物等效性。方法:20名健康男性志愿受试者单利量随机交叉口服阿伐斯汀胶囊受试制剂或参比制剂16mg,采用高效液相色谱法测定血药浓度,3P97程序计算药动学参数和相对生物利用度。结果:受试制剂与参比制剂的药-时曲线呈二室模型, t_(max)分别为(1．0±s 0．4)h和(1．1±0．4)h;c_(max)分别为(220±64)μg·L~(-1)和(220±84)μg·L~(-1);AUC_(0～1)分别为(626±276)μg·h·L~(-1)和(650±271)μg·h·L~(-1);t_(1\2β)分别为(1．9±2．3)h和(1．9±1．5)h,2种制剂的主要药动学参数无显著差异(P＞0．05),受试制剂的相对生物利用度为(97±12)％。结论:2种制剂药动学参数与文献报道接近,具有生物等效性。     

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.     

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.