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。     

马来酸替加色罗分散片的人体生物等效性研究

目的:研究马来酸替加色罗分散片的人体生物等效性。方法:22名健康男性志愿者随机交叉单剂量口服马来酸替加色罗分散片(受试制剂)和马来酸替加色罗片(参比制剂)6mg,采用LC/MS/MS法测定人血浆中药物浓度。结果:受试制剂和参比制剂的tmax分别为(0.86±0.22)、(1.01±0.24)h,Cmax分别为(2.21±0.69)、(2.05±0.64)ng.mL-1,AUC0~17分别为(6.35±2.48)和(6.47±1.99)ng.h.mL-1,AUC0~∞分别为(6.69±2.59)、(6.70±2.03)ng.h.mL-1。受试制剂相对于参比制剂的生物利用度为(98.2±22.1)%。结论:两种制剂具有生物等效性。     

吗替麦考酚酯胶囊人体生物等效性研究

目的:研究2种吗替麦考酚酯胶囊的人体生物等效性。方法:18名受试者随机、交叉、单剂量分别口服吗替麦考酚酯胶囊受试制剂(国产)和参比制剂(进口)1000mg。血药浓度采用反相高效液相色谱法测定;计算药动学参数并评价生物等效性。结果:受试制剂与参比制剂的主要药动学参数Cmax分别为(26.38±9.55)、(25.84±12.08)μg·mL-1,tmax分别为(0.79±0.40)、(0.94±0.59)h,t1/2分别为(18.01±7.65)、(15.62±8.50)h,AUC0～48分别为(54.69±15.58)、(51.68±12.36)μg.h.mL-1,AUC0～∞分别为(61.10±17.06)、(57.99±17.21)μg.h.mL-1。受试制剂的相对生物利用度为(107.22±25.39)%。结论:国产与进口吗替麦考酚酯胶囊生物等效。     

2种坎地沙坦酯制剂的人体生物等效性研究

目的:研究2种坎地沙坦酯制剂的人体生物等效性。方法:20名健康男性志愿者随机交叉单剂量口服坎地沙坦酯片(受试制剂)和坎地沙坦酯胶囊(参比制剂),以高效液相色谱法测定血药浓度,3p97软件计算药动学参数与相对生物利用度。结果:受试制剂与参比制剂的Cmax分别为(276.785±28.957)、(269.118±30.116)ng.mL-1,tmax分别为(4.12±0.79)、(3.93±0.87)h,t1/2分别为(8.63±1.04)、(9.06±1.14)h,AUC0～48分别为(2589.248±306.674)、(2438.946±313.259)ng.h.mL-1,AUC0～∞分别为(2613.276±309.460)、(2493.636±324.491)ng.h.mL-1,受试制剂的相对生物利用度为(104.80±16.48)%。结论:2种制剂具有生物等效性。     

2种盐酸左氧氟沙星胶囊的人体生物等效性研究

目的:研究2种盐酸左氧氟沙星胶囊的人体生物等效性。方法:22名健康男性志愿者,采用单剂量、随机、自身交叉对照试验设计,分别空腹口服盐酸左氧氟沙星胶囊受试制剂和参比制剂各200mg后,用反相高效液相色谱-荧光检测法检测血清中左氧氟沙星经-时过程的血药浓度,计算其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Cm ax分别为(2 840.7±371.6)、(2 810.5±440.0)ng.mL-1,t1/2β分别为(7.26±1.21)、(7.28±1.58)h,tm ax分别为(1.13±0.44)、(1.09±0.34)h,AUC0~24分别为(20 908.9±3 178.2)、(20 398.0±2 576.4)ng.h.mL-1,AUC0~∞分别为(23 173.6±3 600.4)、(22 492.4±2 649.0)ng.h.mL-1。受试制剂的相对生物利用度为(103.1±14.1)%。结论:2种盐酸左氧氟沙星胶囊具有生物等效性。     

吗替麦考酚酯胶囊人体生物等效性研究

目的:研究吗替麦考酚酯胶囊在健康人体内的生物等效性。方法:24名受试者单剂量、交叉口服吗替麦考酚酯胶囊受试制剂或参比制剂1000mg后,采用高效液相色谱法,二极管阵列检测器和荧光检测器串联检测霉酚酸(MPA)及霉酚酸葡糖醛酸酯(MPAG)的血药浓度,以DAS2.0.1程序计算药动学参数和生物等效性数据。结果:受试制剂与参比制剂的MPA,其Cmax分别为(45.728±16.006)、(49.323±16.098)μg·mL-1,tmax分别为(0.610±0.242)、(0.534±0.260)h,t1/2分别为(14.214±6.308)、(12.707±6.575)h,AUC0～60分别为(84.697±19.917)、(84.312±18.639)μg.h.mL-1,AUC0～∞分别为(89.750±20.728)、(102.995±68.151)μg.h.mL-1;受试制剂与参比制剂的MPAG,其Cmax分别为(54.917±14.715)、(53.916±10.703)μg.mL-1,tmax分别为(1.521±0.454)、(1.396±0.294)h,t1/2分别为(13.542±6.685)、(11.885±3.130)h,AUC0～60分别为(486.686±145.059)、(446.812±100.383)μg.h.mL-1,AUC0～∞分别为(524.357±127.385)、(471.725±101.297)μg.h.mL-1;MPA的相对生物利度为(100.39±16.9)%,MPAG的相对生物利度为(106.89±18.6)%。结论:吗替麦考酚酯胶囊受试制剂与参比制剂具有生物等效性。     

吗替麦考酚酯软胶囊的药动学及生物等效性研究

目的:研究吗替麦考酚酯软胶囊与吗替麦考酚酯胶囊在健康人体内的相对生物利用度及药动学,评价2种制剂的生物等效性。方法:采用双周期随机交叉设计,20名男性健康志愿者单剂量口服试验软胶囊或参比胶囊4粒(每粒0.25g),以高效液相色谱法测定血浆中霉酚酸(MPA)浓度。运用DAS2.0软件处理血药浓度数据和计算药动学参数,对2种制剂做出生物等效性评价。结果:受试者口服1.0g吗替麦考酚酯软胶囊试验药或参比胶囊,其AUC0→t分别为(69.95±14.13)、(66.95±19.05)μg·h·mL-1,AUC0→∞分别为(85.18±20.51)、(77.39±23.78)μg·h·mL-1,Cmax分别为(31.26±13.09)、(31.90±14.45)μg·mL-1,tmax分别为(0.875±0.358)、(0.775±0.291)h,t1/2分别为(20.342±12.546)、(18.837±11.579)h。20名健康志愿者单剂量口服吗替麦考酚酯软胶囊试验药的相对生物利用度为(109.6±26.9)%。结论:试验软胶囊与参比胶囊具有生物等效性。     

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。     

依诺沙星分散片的人体相对生物利用度研究

目的:研究依诺沙星分散片(受试制剂)和依诺沙星片(参比制剂)的生物等效性。方法:采用双周期随机交叉试验设计。分别予20名男性健康志愿者依诺沙星受试制剂或参比制剂各0.4 g单剂量口服。用HPLC法测定给药后血样中依诺沙星的浓度。用DAS软件计算药动学参数。结果:受试制剂与参比制剂的Cm ax分别为(5 320±1 275)和(5 163±1 241)ng.mL-1;Tm ax(0.88±0.37)和(0.89±0.37)h;AUC0→24 h(23 317±7 187)和(22 904±7 098)ng.h.mL-1;AUC0→∞(24 502±7 396)和(24 085±7 377)ng.h.mL-1。受试制剂的相对生物利用度为(102±9)%。结论:依诺沙星分散片与依诺沙星片生物等效。     

2种司帕沙星胶囊人体生物利用度与生物等效性研究

目的:比较2种司帕沙星胶囊的人体药动学参数、生物利用度,评价二者的生物等效性。方法:22名男性健康志愿者随机交叉单剂量口服200mg受试制剂或参比制剂后,应用高效液相色谱法测定血浆中司帕沙星浓度,并利用3p97程序计算药动学参数及评价二者生物等效性。结果:受试制剂与参比制剂体内药-时曲线符合二室模型,Cm ax分别为(0.85±0.23)、(0.90±0.27)μg.mL-1,tm ax分别为(5.59±2.28)、(4.95±1.17)h,AUC0~120分别为(27.92±6.09)、(29.65±8.49)μg.h.mL-1,AUC0~∞分别为(29.95±6.51)、(31.74±9.38)μg.h.mL-1。受试制剂相对生物利用度为(97.47±18.32)%。结论:受试制剂与参比制剂具有生物等效性。     

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.