富马酸替诺福韦酯胶囊与片剂的人体生物等效性研究

目的:评价口服富马酸替诺福韦酯胶囊和片剂在健康人体的生物等效性。方法:采用标准双周期交叉设计自身对照试验方法,18例男性健康志愿者单剂量口服2种富马酸替诺福韦酯制剂300 mg,用HPLC/MS/MS法测定替诺福韦酯血药浓度。结果:富马酸替诺福韦酯胶囊与片剂的主要药动学参数t1/2Ke分别为(15.32±2.74)和(15.67±2.12)h;Cm ax分别为(262.28±61.05)和(336.35±77.18)ng.mL-1,Tm ax分别为(2.81±0.89)和(1.14±0.29)h,AUC0~48 h分别为(2547.46±394.77)和(2940.65±568.79)ng.h.mL-1,AUC0-∞分别为(2851.56±466.34)和(3285.25±602.52)ng.h.mL-1。受试制剂的相对生物利用度为(88.10±13.62)%。经方差分析和双单侧t检验结果显示,富马酸替诺福韦酯的2种制剂具有生物等效性。结论:两种富马酸替诺福韦酯制剂生物等效。     

中国西部健康人群口服替诺福韦富马酸酯片的药动学研究

目的:研究口服替诺福韦富马酸酯片在中国西部健康人群的药动学特征。方法:24名健康志愿者随机分为3组,每组8人,分别给予替诺福韦富马酸酯片300mg、恩曲他滨胶囊200mg+替诺福韦富马酸酯片300mg、脂肪食物(食物中脂肪比例50%)+替诺福韦富马酸酯片300mg,分别在服药前0h及服药后0.5、0.75、1、1.5、2、3、4、6、8、12、24、36、48、72h时取静脉血2mL,分离血浆,采用固相萃取,以高效液相色谱-紫外(HPLC-UV)法测定替诺福韦血药浓度,以DAS(Ver2.1.1)软件计算药动学参数。结果:3组药动学参数分别为:t1/(218.78±3.28)、(12.72±2.83)、(13.08±1.47)h,tma(x1.05±0.16)、(1.28±0.30)、(1.55±0.37)h,cma(x290.71±63.21)、(420.84±96.71)、(429.06±174.81)ng·mL-1,AUC0～7(21871.60±377.00)、(3869.42±962.85)、(3569.47±633.47)μg·h·L-1,AUC0～∞(2284.16±373.54)、(4107.09±974.82)、(3856.00±618.39)μg·h·L-1,CL/F(2.25±0.39)、(1.28±0.28)、(1.33±0.20)L·h-1·kg-1。与替诺福韦富马酸酯组比较,恩曲他滨+替诺福韦富马酸酯组、脂肪食物+替诺福韦富马酸酯组的t1/2降低,cmax、AUC0～72、AUC0～∞、tmax均明显增加。结论:中国西部人群单独给予替诺福韦富马酸酯的药动学特征与国外人群相似,高脂肪饮食以及合用恩曲他滨可改变替诺福韦的药动学特征。     

吗替麦考酚酯分散片的相对生物利用度及生物等效性

目的:研究吗替麦考酚酯分散片和吗替麦考酚酯胶囊在健康志愿者中的药动学及生物等效性。方法:根据交叉试验方案口服单剂量(1 000mg)两种吗替麦考酚酯制剂,采用高效液相色谱法测定血浆中霉酚酸的浓度。结果:吗替麦考酚酯分散片和吗替麦考酚酯胶囊(对照药)的tmax分别为(0.51±0.29)h和(0.54±0.26)h;Cmax分别为(53.6±22.2)mg.L-1和(52.4±18.3)mg.L-1;AUC0→48分别为(133.7±43.6)mg.h.L-1和(142.8±46.2)mg.h.L-1;分散片相对于胶囊的生物利用度为(96.1±19.7)%。经配对检验,结果表明,两种制剂的主要药动学参数Cmax、AUC0→48的差异无显著性(P>0.05)。结论:吗替麦考酚酯分散片和吗替麦考酚酯胶囊为生物等效制剂。     

国产替米沙坦胶囊在健康人体内的药动学

目的:研究国产替米沙坦胶囊在健康人体内的药动学。方法:10名健康志愿者单剂量口服120mg替米沙坦胶囊,采用高效液相色谱法测定血浆中替米沙坦浓度,并用3P97软件统计处理。结果:替米沙坦胶囊药-时曲线符合二室模型,其Cmax,tmax,t1/2,AUC0-84,AUC0-∞分别为(821.6±271.0)μg.L-1,(0.68±0.17)h,(24.6±2.5)h,(2 132±1 171)μg.L-1.h,(2 208±1 183)μg.L-1.h。结论:替米沙坦胶囊在人体内药动学过程符合二室开放模型,本试验可为临床用药提供药动学参数。     

富马酸替诺福韦二吡呋酯片在健康国人体内的药动学及生物等效性研究

目的:建立人血浆中替诺福韦浓度的LC-MS/MS测定法,并用于富马酸替诺福韦二吡呋酯片的药动学和生物等效性研究。方法:采用自身双交叉试验设计,20例男性健康受试者随机分成2组,分别空腹口服受试制剂或参比制剂300 mg,0～72 h间隔采集血样。以LC-MS/MS法测定血浆替诺福韦浓度,DAS2.1.1计算药动学参数。结果:建立的LC-MS/MS法在2～1 200 ng.mL-1范围内线性关系良好,最低定量限为2 ng·mL-1,批内及批间精密度RSD均小于15%。受试制剂与参比制剂的Tmax均为(0.5±0.2)h,Cmax分别为(604±207)和(573±189)ng.mL-1,t1/2分别为(17.1±2.9)和(17.4±4.0)h,AUC0～72 h分别为(2 490±604)和(2 297±499)h·ng·mL-1。结论:建立的LC-MS/MS法准确可靠,富马酸替诺福韦二吡呋酯片两种制剂生物等效。     

西尼地平的健康人药动学研究

目的:建立西尼地平血药浓度的液相色谱串联质谱(LC-MS/MS)测定法,研究中国健康男性受试者口服西尼地平胶囊后的血浆药动学特点.方法:20名健康男性受试者单剂量口服10 mg西尼地平胶囊,以尼莫地平为内标,采用液相色谱串联质谱(LC-MS/MS)正离子选择性反应检测测定血浆中的西尼地平浓度,使用DAS软件计算药动学参数.结果:西尼地平在0.1～20μg·L-1范围内线性关系良好(r0.996 7),最低定量限为0.10μg·L-1,日内、日间精密度(RSD)均<15%,绝对回收率80%.口服10 mg西尼地平胶囊后的主要药动学参数分别为:Cmax为(14.6±5.0)μg·L-1,Tmax为(4±1.1)h,t1/2为(11.3±5.8)h,AUC0～48 h为(77.5±31.3)h·wg·L-1,AUC0～∞为(82.2±35.8)h·μg·L-1,MRT为(12.3±5.0)h,CL/F为(144.9±64.6)L·h-1,V/F为(2 253±1 592)L.结论:建立的LC-MS/MS测定法专属准确,灵敏度高,可用于西尼地平血药浓度分析及药动学研究.     

注射用盐酸罗沙替丁醋酸酯在健康人体内的药动学研究

目的:研究盐酸罗沙替丁醋酸酯注射剂在人体的药动学特征。方法:20例健康志愿受试者,采用开放、单周期的低剂量和高剂量单次给药设计的试验方法,以液相色谱-质谱-质谱联用法测定服药后24 h内不同时刻罗沙替丁的血药浓度,采用Topfit药动学软件计算给药后的药动学参数。结果:受试者分别静脉推注盐酸罗沙替丁醋酸酯37．5和75 mg后,其活性代谢物罗沙替丁的主要药动学参数t_(1/2)分别为(3．74±0．27)和(3．90±0．19)h; AUC_(0～t)分别为(727±98)和(1566±276)ng·h·mL~(-1),AUC_(0～∞)分别为(733±100)和(1582±281)ng·h·mL~(-1),MRT分别为(4．58±0．24)和(4．61±0．38)h,Cl_(tot)分别为(52．1±8．1)和(48．8±9．0)L·h~(-1),V_z分别为(280±43)和(274±40)L,Vss分别为(238±31)和(222±25)L。结论:当分别以37．5和75 mg单次注射盐酸罗沙替丁醋酸酯时,在人体内表现为线性药动学特征。     

人血浆中氢氯噻嗪的LC-MS／MS测定及药动学

建立了LC-MS/MS法测定人血浆中的氧氯噻嗪,并研究了20名健康受试者口服坎地沙坦酯氢氯噻嗪片后的药动学.血浆中氢氯噻嗪在1～200ng/ml浓度范围内线性关系良好.单剂量口服12.5、25mg坎地沙坦酯氯氯噻嗪片后,氢氯噻嗪的主要动力学参数分别为:cmax(74.14±15.04)、(125.57±23.47)ng/ml,tmax(1.85±0.53)、(2.20±0.59)h,t1/2β(11.57±2.39)、(10.93±1.71)h,AUC0→48h(470.0±90.7)、(794.75±182.6)h·ng·ml-1;稳态时药动学参数分别为:tmax(1.835±0.25)h,cssmax(80.21±17.98)ng/ml,cssmin(3.72±1.79)ng/ml,Cav(19.37±3.20)ng/ml,AUC0→48h(484.90±76.89)h·n·ml-1.     

富马酸卢帕他定的人体药动学

目的:研究健康受试者单剂量和多剂量口服富马酸卢帕他定片的药动学.方法:采用HPLC-MS/MS法测定12名健康受试者单剂量和多剂量口服马酸卢帕他定片血浆药物浓度经时过程,运用DAS2.0程序计算主要的药动学参数.结果:血浆富马酸卢他定的线性范围为0.05～13μg·L-1,定量下限为0.05μg·L-1(S/N≥10).12名健康受试者单次空腹口服10mg富马酸卢帕他定片的主要药动学参数分别为:AUC0-24:(30.3±12.4)μg·L-1·h;AUC0-∞:(31.9±12.5)μg·L-1·h;V1/F:(619.0±202.5) L;CL/F:(368.5±166.4) L·h-1;MRT＜0-24:(5.0±0.6) h;MRT0-∞:(6.7±2.0) h;tmax: (1.0±0.4) h;Cmax:(8.3±2.7)μg·L-1;t1/2:(6.5±4.7)h.12名健康受试者连续7d服用10 mg富马酸卢帕他定片的主要药动学参数分别为 AUC0-24:(34.0±11.4)μg·L-1·h,AUC0-∞:(35.8±12.2)μg·L-1·h;C55_max:(9.4±3.2)μg·L-1;C55_max(0.35±0.14)μg·L-1;tmax: (0.92±0.31)h;V1/F:(702.9±289.2) L;CL/F: (321.3±145.8) L·h-1;MRT0-24:(5. 24±0. 34) h;MRT0-∞:(7.9±1.8)h;t1/2:(7.6±7.2)h.结论:单剂量组、多剂量组中男性和女性受试者药动学参数差异都无统计学意义,同时单剂量和多剂量之间差异也无统计学意义.     

LC-MS/MS法研究阿德福韦酯胶囊的人体药动学

目的建立LC-MS/MS法测定血浆中阿德福韦酯活性代谢物阿德福韦的浓度,并用于健康受试者口服阿德福韦酯(E晶型)胶囊后的药动学研究。方法10名受试者口服阿德福韦酯胶囊后,血浆样品经高氯酸沉淀蛋白,LC-MS/MS法测定阿德福韦的浓度,用3P97程序计算主要药动学参数。结果测定血浆中阿德福韦的最低定量限为0.5μg·L-1,血药浓度为0.50~150μg·L-1时质谱响应线性关系良好(r=0.9996)。测得单剂量和稳态时口服10mg阿德福韦酯(E晶型)胶囊后主要药动学参数:ρmax分别为(23.93±6.86)和(38.93±7.52)μg·L-1,tmax分别为(1.5±0.7)和(1.7±0.5)h,t1/2分别为(8.70±1.56)和(10.57±1.16)h,AUC0→48分别为(292.07±62.75)和(486.78±110.65)μg·h·L-1。结论该方法灵敏,可用于阿德福韦酯人体药动学研究。     

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.