单剂口服盐酸托烷司琼颗粒剂在健康人体的生物等效性

目的研究盐酸托烷司琼颗粒剂的药代动力学特征及生物等效性。方法用随机交叉给药方法,20名健康男性志愿者分别单剂量口服盐酸托烷司琼颗粒剂试验药及胶囊对照药20mg,用LC-MS/MS法测定血药浓度。计算2者的药代动力学参数及相对生物利用度。结果口服托烷司琼颗粒剂试验药及胶囊对照药20mg的主要药代动力学参数AUC0-t分别是:(523.82±432.96)和(547.04±455.59)ng·h·mL-1;AUC0-∞分别为(568.07±491.48)和(591.77±513.15)ng·h·mL-1;Cmax分别为(36.67±12.30)和(37.44±14.30)ng·mL-1;tmax分别为(1.85±1.66)和(1.85±0.79)h;t1/2分别为(9.76±6.33)和(9.77±5.51)h。相对生物利用度为(98.03±17.11)%。结论2种制剂具有生物等效性。     

甲磺酸仑伐替尼胶囊在中国健康受试者中的生物等效性研究

摘 要 目的：研究国产甲磺酸仑伐替尼胶囊在中国健康受试者中的药代动力学特征,评价国产受试制剂（T）与原研参比制剂（R,商品名：乐卫玛■）的生物等效性。方法：采用空腹/餐后、随机、开放、两周期、两序列、双交叉试验设计。空腹试验和餐后试验分别入组28例健康受试者,男女兼有。入组的受试者随机分配至T-R或R-T给药序列组,每周期单次空腹或餐后口服甲磺酸仑伐替尼胶囊受试制剂或参比制剂4 mg/粒。采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定0 ~ 120 h不同采集点的血浆中仑伐替尼浓度。采用Phoenix WinNonlin 8.2软件计算药代动力学参数（Cmax、tmax、AUC0 - t、AUC0 - ∞、t1/2）,并对主要参数进行生物等效性评价。结果：健康受试者空腹单次口服给药后,受试制剂及参比制剂的Cmax、AUC0 - t、AUC0 - ∞的算数平均值分别为70.55和69.89 ng·mL-1、801.3和792.6 h·ng·mL-1、823.6和814.6 h·ng·mL-1,几何均值比值及90%CI分别为103.17%（96.52% ~ 110.28%）、101.15%（98.09% ~ 104.30%）和101.10%（98.12% ~ 104.18%）;健康受试者餐后单次口服给药后,受试制剂及参比制剂的Cmax、AUC0 - t、AUC0 - ∞算数平均值分别为44.82和49.21 ng·mL-1、738.1和747.5 h·ng·mL-1、765.1和777.1 h·ng·mL-1,几何均值比值及90%CI分别为90.41%（83.92% ~ 97.42%）、98.81%（96.16% ~ 101.53%）和98.50%（95.94% ~ 101.13%）。不良事件程度轻度,未出现严重不良事件和非预期不良反应。结论：国产甲磺酸仑伐替尼胶囊与参比制剂甲磺酸仑伐替尼胶囊（乐卫玛■）于空腹或餐后状态下给药后,在中国健康受试者体内两制剂生物等效。     

高效液相色谱法测定人血浆中卡托普利和人体药动学的研究

目的　建立简便的测定人血浆中卡托普利血药浓度的高效液相色谱法 ,研究卡托普利在健康人体中的药动学参数。方法　以对溴苯乙酰基溴为紫外衍生化试剂 ,采用高效液相色谱紫外检测法测定 18名健康志愿受试者口服单剂量卡托普利受试制剂和参比制剂 ( 5 0mg)后血药浓度。结果　卡托普利的血药浓度标准曲线的线性范围为 2 5～ 12 0 0ng·mL- 1 ,其最低定量限为 2 5ng·mL- 1 ,日内及日间RSD均小于 8%。应用所建立的血药浓度检测方法测定 18名健康志愿受试者口服单剂量卡托普利受试制剂和参比制剂 ( 5 0mg)后血药浓度 ,并计算药动学参数。结果表明口服受试制剂或参比制剂后的tmax分别为( 0 6 4± 0 18)h和 ( 0 82± 0 4 1)h ;Cmax分别为 ( 6 0 0 2± 194 3)ng·mL- 1 和 ( 5 82 7± 175 3)ng·mL- 1 ;AUC0→ 8h分别为 ( 14 4 8 5± 4 83 7)ng·h·mL- 1 和 ( 1389 9± 392 5 )ng·h·mL- 1 ;AUC0→∞ 分别为 ( 186 9 4± 70 1 6 )ng·h·mL- 1 和 ( 1781 8± 6 15 5 )ng·h·mL- 1 。结论　本方法操作便捷 ,灵敏度高 ,为血药浓度监测及药代动力学研究提供了方法学基础     

酒石酸美托洛尔片在中国健康人体的药代动力学

目的　研究单剂量和多剂量酒石酸美托洛尔片在中国健康人体的药代动力学。方法　22名健康受试者口服酒石酸美托洛尔片50mg,用HPLC-荧光检测法测定血浆中美托洛尔的浓度。结果　所得药代动力学参数如下。单剂量:AUC0-t为(395. 6±298. 95)ng·h·mL-1,AUC0-∞为(433. 83±342. 94)ng·h·mL-1,Cmax为(63. 06±34. 61)ng·mL-1,tmax为(1. 573±0. 52)h,MRT为(7. 40±2. 31 )h;多剂量:AUCss0-t为( 504. 67±322. 35 )ng·h·mL-1,Cmax为(77. 72±45. 69)ng·mL-1,tmax为(1. 7±0. 6)h,Cmin为(4. 12±1. 57)ng·mL-1,平均稳态血药浓度Cav是( 21. 03±13. 43 )ng·mL-1,血药浓度波动度DF为(367. 29±112. 56)%。结论　酒石酸美托洛尔片单剂量和多剂量给药后,安全性良好。     

佐米曲普坦片剂在健康人体的药代动力学和相对生物利用度

目的研究佐米曲普坦片在中国健康志愿者体内的药代动力学及相对生 物利用度。方法用双周期随机交叉自身对照方法,18名健康男性志愿者单 剂量口服试验制剂或参比制剂各5 mg,用高效液相色谱／质谱连用法测定血药 浓度。结果试验及参比的佐米曲普坦片剂Cmax分别(9．92±2．62)和(9．99± 3．22)ng·mL-1;tmax分别为(1．78±1．24)和(2．14±1．74)h;t1／2分别为(3．51 ±0．52)和(3．33±1．17)h;AUC0-tn分别为(53．51±18．25)和(54．24±18．00) ng·h·mL-1;AUC0-∞分别为(56．573±19．738)和(57．549±17．685)ng·h· mL-1;佐米曲普坦片剂的相对生物利用度F0-tn、F0-∞分别为(100．80± 20．40)％,(98．98±17．78)％。结论试验制剂和参比制剂具有生物等效性。     

LC-MS/MS法测定人血浆中米拉贝隆及其 中国健康人体药动学研究

目的：建立人血浆中米拉贝隆浓度的LC-MS/MS测定方法,并评价其在中国健康受试者体内的药动学特征。方法：在冰浴条件下,经蛋白沉淀法进行血浆样品前处理,采用ACE Excel 3 AQ（2.1 mm × 100 mm）色谱柱,流动相为5.00 mmol·L-1醋酸铵水溶液（含0.1%甲酸）及5.00 mmol·L-1醋酸铵-90%乙腈水溶液（含0.1%甲酸）,流速为0.400 mL·min-1;多反应监测正离子模式,米拉贝隆和米拉贝隆-d5的检测反应离子对分别为m/z 397.2→260.0和m/z 402.2→260.0。入选20名中国健康受试者,空腹单次口服米拉贝隆缓释片50 mg,于不同采血时间点将全血采集至含氟化钠的肝素钠采血管中,分离得到血浆样品进行LC-MS/MS检测。结果：血浆中米拉贝隆的线性范围为0.160~85.0 ng·mL-1, 20名受试者单次口服米拉贝隆缓释片50 mg后的药代动力学参数：AUC0-t为(304 ± 136) h·ng·mL-1,AUC0-∞为（342 ± 153）h·ng·mL-1,t1/2为（34.1 ± 6.58）h,tmax为（4.16 ± 1.10）h,Cmax为（35.3 ± 21.7）ng·mL-1。结论：本研究建立了人血浆中米拉贝隆的LC-MS/MS测定方法,该方法快速、灵敏、准确、专属性强,可应用于该药的中国健康受试者人体药代动力学研究。     

马来酸咪达唑仑片在汉族健康人体内的药动学研究

目的:研究马来酸咪达唑仑片在汉族健康人体内的药动学。方法:10名汉族健康受试者口服马来酸咪达唑仑片15mg后,用高效液相色谱法测定咪达唑仑血药浓度,用DAS2.0药动学软件拟合药动学参数。结果:受试者单剂量口服马来酸咪达唑仑片后的主要药动学参数分别为Cma(x103.11±26.37)ng·mL-1、tma(x1.52±0.75)h、t1/(22.96±0.77)h、Vz/F(170.08±50.97)L、CL/F(41.05±12.33)L·h-1、AUC0～1(2368.80±103.37)ng·h·mL-1、AUC0～∞(397.29±124.06)ng·h·mL-1。部分受试者的药-时曲线存在双峰现象。结论:咪达唑仑片的药动学参数个体差异较大,临床应用时应注意个体化给药。     

苯佐那酯软胶囊在中国健康受试者中的药代动力学研究

目的：研究中国健康受试者口服苯佐那酯软胶囊后苯佐那酯及其代谢产物4-N-丁基氨基苯甲酸（BBA）的药代动力学特征。方法：36名健康受试者分为A、B、C 3组,A、C组分别单次口服苯佐那酯软胶囊100 mg（低）、400 mg（高）,B组单次及多次口服苯佐那酯软胶囊200 mg（中）。通过HPLC-MS/MS法检测血浆中BBA的浓度,推算血浆中苯佐那酯的浓度,估算药代动力学参数。结果：A、B、C 3组受试者单次给药苯佐那酯软胶囊后,BBA的Tmax分别为（0.74±0.40）、（0.54±0.24）、（0.61±0.43） h,Cmax分别为（1 603±443）、（2 833±1131）、（6 549±2 009） ng·mL-1,AUC0-10h分别为（2 395±1 062）、（3 403±1 228）、（9 104±4 134） ng·h·mL-1,t1/2分别为（1.42±0.52）、（1.84±0.89）、 （1.70±0.75） h;苯佐那酯的Tmax分别为（0.62±0.25）、（0.62±0.27）、（0.58±0.37） h,Cmax分别为（1 201± 449）、（1 838±700）、（3 554±1 775） ng·mL-1,AUC0-10h分别为（1 314±589）、（1 751±656）、（3 452± 2 111） ng·h·mL-1,t1/2分别为（1.57±1.17）、（1.80±1.05）、（1.68±1.04） h。B组受试者多次给药苯佐那酯软胶囊200 mg后,BBA的Cav为（604±220） ng·mL-1,DF为（5.34±1.26）,RCmax为（1.20±0.45）,RAUC为（1.10±0.13）;苯佐那酯的Cav为（356±126） ng·mL-1,DF为（5.91±1.35）,RCmax为（1.24±0.57）,RAUC为（1.31±0.33）。结论：在100~400 mg的给药剂量范围内,苯佐那酯不具有线性药代动力学特征。多次给药苯佐那酯软胶囊200 mg后,BBA和苯佐那酯在体内会产生蓄积。     

利培酮片人体生物等效性研究

目的：考察2种利培酮片在健康受试者空腹和餐后状态下的药代动力学参数,进行生物等效性评价。方法：采用开放、随机、两周期、交叉试验设计,空腹和餐后各48例受试者交叉服用受试制剂或参比制剂,LC-MS/MS检测血浆中的利培酮和帕利哌酮的浓度。结果：在空腹状态下,受试制剂和参比制剂利培酮的Cmax为（7.06±3.42）和（6.77±2.81）ng·mL-1,AUC0-t为（44.5±46.9）和（41.5±42.1）ng·h·mL-1,AUC0-∞为（45.4±47.9）和（42.4±43.2）ng·h·mL-1;帕利哌酮的Cmax为（4.20±1.59）和（4.13±1.51）ng·mL-1,AUC0-t为（117±29）和（116±30）ng·h·mL-1,AUC0-∞为（125±32）和（124±33）ng·h·mL-1。在餐后状态下,受试制剂和参比制剂利培酮的Cmax为（6.30±3.06）和（6.47±3.03）ng·mL-1,AUC0-t为（44.6±32.6）和（44.3±35.1）ng·h·mL-1,AUC0-∞为（45.5±32.8）和（45.0±35.5）ng·h·mL-1;帕利哌酮的Cmax为（4.24±2.08）和（4.20±2.14）ng·mL-1,AUC0-t为（121±36）和（118±34）ng·h·mL-1,AUC0-∞为（132±38）和（128±38）ng·h·mL-1。结论：空腹和餐后状态下,利培酮和帕利哌酮的90%CI均在80%~125%,2种利培酮片具有生物等效性。     

国产罗格列酮胶囊在健康人体的相对生物利用度

目的研究健康受试者口服罗格列酮胶囊的药代动力学。方法20名健康受试者随机服用罗格列酮受试和参比制剂各4mg,用HPLC-MS法测定血浆中罗格列酮的浓度。结果经3P97程序处理,主要药代动力学参数如下。罗格列酮胶囊剂:t1/2为(5.18±0.84)h,AUC0-24h为(2.13±0.21)μg·h·mL-1,Cmax为(305.31±38.21)ng·mL-1,tmax为(1.1±0.4)h;罗格列酮片剂:t1/2为(5.10±0.64)h,AUC0-24h为(2.20±0.20)μg·h·mL-1,Cmax为(318.84±38.38)ng·mL-1,tmax为(1.2±0.3)h。罗格列酮受试和参比制剂的相对生物利用度为(97.6±12.7)%。结论2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.     

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.     

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.