氟西汀及其活性代谢产物在汉族健康人体的药动学

目的:探讨氟西汀及其活性代谢产物去甲氟西汀在汉族健康人体的药动学。方法:24名健康男性志愿者单剂量口服盐酸氟西汀分散片20 mg后,采用液相色谱-串联质谱法测定血浆中氟西汀和去甲氟西汀浓度,应用DAS2.0软件计算药动学参数。结果:氟西汀和去甲氟西汀在人体内药-时曲线呈一室模型。除1例慢代谢型受试者外,23名受试者主要药动学参数如下:t1/2分别为(30.8±7.6)和(130.9±42.0)h;tmax分别为(5.5±2.1)和(58.5±31.7)h;Cmax分别为(11.8±3.5)和(14.2±5.0)ng.mL-1;AUC0-t分别为(487.4±190.2)和(3370.9±1175.8)ng.h.mL-1;AUC0-∞分别为(506.5±208.8)和(3537.8±1424.1)ng.h.mL-1。结论:盐酸氟西汀分散片在人体吸收迅速,消除较慢,而其活性代谢产物去甲氟西汀消除更慢;其中1例受试者呈明显慢代谢型。     

LC/MS联用法测定人血浆中氟西汀的浓度

目的:建立测定人血浆中氟西汀浓度的液/质联用方法。方法:以氯氮平为内标,血浆样品用饱和碳酸钠溶液碱化,经乙酸乙酯振荡萃取后,进样分析。其中色谱柱为C18,流动相为5mmol.L-1乙酸铵溶液(0.5%乙酸)-甲醇-乙腈(42∶22∶36),流速为0.24mL.min-1,柱温40℃;通过电喷雾离子化(ESI)质谱以扫描方式检测,选择性正离子监测质荷比(m/z)为310(氟西汀,M+H)和327(内标,氯氮平,M+H)。结果:氟西汀血浆药物浓度在0.5~100ng.mL-1范围内线性关系良好(r=0.998 6),最低定量浓度为0.5ng.mL-1;方法回收率在96.0%~98.0%之间,日内、日间RSD均小于13%。结论:本方法简便、准确、灵敏度高,可用于临床氟西汀血药浓度的监测和药动学研究。     

健康受试者单次口服盐酸氟西汀肠溶片的药代动力学

目的研究盐酸氟西汀肠溶片(抗抑郁症药)在健康中国人体的药代动力学特征。方法16名健康受试者单剂量口服盐酸氟西汀肠溶片90 mg (以氟西汀计),用高效液相色谱-荧光检测法测定血药浓度,用DAS 2.1.1软件计算药代动力学参数。结果健康人体单剂量口服盐酸氟西汀肠溶片90 mg,体内氟西汀及其主要代谢产物去甲氟西汀的药代动力学参数:t_(max)分别为(8.50±2.03)、(80.25±41.27)h,C_(max)分别为(68.28±16.83)、(53.25±17.12)ng·mL~(-1),t_(1/2)分别为(58.86±2.86)、(133.51±96.20) h,AUC_(0～t)分别为(4.32±1.03)、(13.60±3.65)μg·h·mL~(-1),AUC_(0～∞)分别为(4.32±1.03)、(15.12±5.06)μg·h·mL~(-1);在信噪比=3时,最低检测浓度氟西汀为4 ng·mL~(-1),去甲氟西汀为8 ng·mL~(-1)。结论氟西汀和去甲氟西汀在人体内的药-时曲线呈二室模型,该方法为液相单次提取,简便、准确、可靠。     

盐酸氟西汀胶囊人体生物等效性研究

目的:评价国产盐酸氟西汀胶囊与进口上市的盐酸氟西汀胶囊的人体生物等效性。方法:22例健康男性志愿者,随机分成2个序列,交叉单剂量口服40 mg 盐酸氟西汀胶囊,以液相色谱-质谱联用法测定血清样本中氟西汀的浓度,并计算相关药动学参数判定2种制剂是否生物等效。结果:测得盐酸氟西汀胶囊参比制剂和受试制剂中氟西汀的主要药代动力学数据t_(max)分别为(7.41±1.74)h和(7.36±1.87)h,C_(max)分别为(43.64±11.10)ng·mL~(-1)和(44.90±11.39)ng·mL~(-1),AUC_(0-)分别为(2817.7±927.5)ng·h·mL~(-1)和(2870.5±989.8)ng·h·mL~(-1),AUC_(0～∞)分别为(2847.4±952.9)ng·h·mL~(-1)和(2892.0±1012.0)ng·h·mL~(-1),t_(1/2(k_e))分别为(73.63±16.89)h 和(69.37±13.05)h,K_e 分别为(0.0099±0.0025)h~(-1)和(0.0104±0.0023)h~(-1)。国产盐酸氟西汀胶囊的相对生物利用度(101.74±12.44)%。结论:方差分析和双单侧 t 检验表明2种制剂生物等效。     

LC-MS/MS法同时测定人血浆中氟西汀、去甲氟西汀、帕罗西汀和氟伏沙明的质量浓度

目的建立一种简单、快速的能同时测定血浆中氟西汀、去甲氟西汀、帕罗西汀和氟伏沙明质量浓度的LC-MS/MS方法。方法血浆经乙腈沉淀后,上清液直接进样分析。色谱柱为Hypersil GOLD aQ,流动相为乙腈-1 mL·L~(-1)甲酸溶液,梯度洗脱。正离子检测,扫描方式为选择性反应监测,氟西汀、去甲氟西汀、帕罗西汀、氟伏沙明和内标罗红霉素的检测离子对分别为m/z 310.2→44.4,296.1→134.1,330.2→192.1,319.2→259.1和837.7→679.3。结果血浆中氟西汀、去甲氟西汀、帕罗西汀和氟伏沙明的质量浓度在1～1 000 ng·mL~(-1)范围内线性关系良好,最低定量下限为1 ng·mL~(-1)。氟西汀、去甲氟西汀、帕罗西汀和氟伏沙明的日内和日间精密度RSD值均小于15%,日内和日间相对误差在-15%～15%之间,药物的提取回收率均大于90%,无显著基质效应。药物在反复冻融3次、室温下保存12 h和-80℃保存1个月的条件下稳定。该方法成功应用于抑郁症患者的氟西汀、去甲氟西汀、帕罗西汀和氟伏沙明血药质量浓度监测。结论建立的LC-MS/MS分析方法简便、灵敏、准确,可用于临床血药质量浓度的监测。     

利培酮在健康人体的生物等效性

目的　评价单剂口服试验与参比制剂利培酮片的生物等效性。方法　用随机交叉试验设计,20名健康志愿者单剂口服利培酮试验与参比制剂6mg,RP-HPLC测定利培酮血浆浓度。结果　利培酮试验和参比制剂消除半衰期t1/2β为(4.28±0.46)和(4.36±0.41) h,达峰时间tmax为(0.94±0.14)和(0.98±0.11) h,达峰浓度Cmax 为(49.37±14.41)和(47.05±11.64) ng.mL-1,药-时曲线下面积AUC0-12为(239.26±56.28)和(239.59.83±53.49) ng.h.mL-1,AUC0-∞为(281.31±58.68)和(282.89±56.49) ng.h.mL-1。利培酮片相对生物利用度为(99.28±6.54)%。结论　试验与参比制剂利培酮片具有生物等效性。利培酮人体代谢有较大个体差异。     

进口与国产利培酮薄膜衣片在健康志愿者的生物等效性

目的 研究利培酮薄膜衣片(抗精神分裂症药)在健康志愿者的药代动力学和生物等效性.方法 23名健康男性志愿者随机交叉、单剂量口服受试制剂(进口)和参比制剂(国产)2 mg后,用HPLC-MS/MS测定血浆中利培酮及9-羟基利培酮浓度,计算主要药代动力学参数,评价2种制剂的生物等效性.结果 受试制剂和参比制剂的主要药代动力学参数,利培酮:AUC0～t分别为(94.76±82.93)和(103.05±117.71)ng·h·mL-1;AUC0～1分别为(96.72±84.52)和(105.19±119.36)ng·h·mL0-1;Cmax分别为(15.91±5.63)和(16.21±11.56)ng·mL-1;tmax分别为(1.14±0.73)和(1.15±0.54)h;t1/2分别为(7.32±5.94)和(7.44±6.50)h,受试制剂的相对生物利用度为(106.68±40.21)%.9-羟基利培酮:AUC0-96h分别为(268.56±85.20)和(279.64 ±117.86)ng·h·mL-1;AUC0-∞分别为(282.74±87.46)和(294.28±120.32)ng·h·mL-1;Cmax分别为(10.84±4.69)和(11.11±4.80)ng·mL-1;tmax分别为(3.35±2.32)和(4.48±2.76)h;t1/2分别为(23.18±3.26)和(23.12±4.31)h,受试制剂的相对生物利用度为(101.37±27.23)%.结论 2种制剂具有生物等效性.     

奥美拉唑对利培酮和9-羟利培酮血药浓度影响的研究

目的：观察奥美拉唑对利培酮和9-羟利培酮血药浓度的影响。方法20例精神分裂症合并胃溃疡患者,给予利培酮联合奥美拉唑治疗1周。检测奥美拉唑治疗后利培酮以及9-羟利培酮血药浓度。结果未使用奥美拉唑前,利培酮与9-羟利培酮血药浓度为（29.25±7.82）μg/L;使用奥美拉唑后,利培酮与9-羟利培酮血药浓度为（37.15±11.68）μg/L,差异有统计学意义（P〈0.05）。结论奥美拉唑能够提高利培酮与9-羟利培酮血药浓度,因此,临床上治疗精神分裂症合并胃溃疡患者,给予奥美拉唑联合利培酮治疗时,应该监测患者利培酮与9-羟利培酮血药浓度,及时对药物剂量进行调整。     

瑞波西汀在中国男性健康志愿者体内的药动学研究

目的:考察瑞波西汀在中国男性健康志愿者体内的药动学特点.方法:14例男性健康志愿者单次口服每片含4 mg(R*,R*)-(±)瑞波西汀的甲磺酸瑞波西汀1片,服药前及服药后0.5,1,1.5,2,2.5,3,6,12,24,36,48,60和72 h采取静脉血5 mL,肝素抗凝.给药后各时间点血浆中瑞波西汀的浓度采用高效液相色谱紫外检测法,以210nm波长测定.采用DAS药动学程序求算药动学参数.结果:单次口服甲磺酸瑞波西汀片后,瑞波西汀的血药浓度-时间曲线符合一室模型,主要药动学参数Cmax为(116.91±25.08)ng·mL-1,Tmax为(1.57±0.62)h,t1/2为(12.91±3.32)h,AUC0～72 h为(2 137.27±1 085.93)ng·h·mL-1,AUC0～∞为(2 145.37±1 087.65)ng·h·mL-1,表观分布容积Vd为(36.00±7.16)L,清除率CL/F为(2.12±0.85)L·h-1.受试者服药后的心率和血压有轻度增加,但无心悸的主诉.出现的其他不良反应有恶心、出汗、头晕、排尿不畅、困倦等.这些不良反应均为轻度,无须治疗,可自行缓解.结论:瑞波西汀在中国男性健康志愿者体内的药动学过程与国外文献报道相当.健康志愿者单次口服瑞波西汀4 mg的不良反应轻,耐受性良好.     

液相色谱-串联质谱法测定人血浆中盐酸度洛西汀的浓度及其药代动力学研究

目的建立高效液相色谱-串联质谱联法测定人血浆中度洛西汀(抗抑郁药)并研究其在健康人体的药代动力学。方法5名男性与5名女性健康志愿者口服盐酸度洛西汀肠溶片60mg,色谱柱为phenomenex C18,流动相为水相(5mmol.L-1醋酸胺,含0.02%的甲酸)-乙腈=55∶45;电喷雾电离源正离子模式(ESI+),以氟西汀为内标。用高效液相色谱-串联质谱法测定盐酸度洛西汀血药浓度,并计算药代动力学参数。结果度洛西汀血浆浓度在0.89～106.80ng·mL-1内与峰面积积分值线性关系良好(γ=0.9977)。方法回收率在93.19%～107.27%,萃取回收率在72.81%～89.96%。日内、日间标准偏差均小于11%。主要药代动力学参数:Cmax为(44.40±17.78)ng·mL-1,tmax为(6.10±1.29)h,t1/2为(12.81±2.31)h;AUC0-60和AUC0-∞分别为(696.04±337.82),(733.82±343.40)ng.h.mL-1。结论本方法操作简单,结果准确可靠,适于度洛西汀的血药浓度监测和药代动力学研究。     

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.     

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.