辐状肋柱花2种主要活性成分在大鼠血浆中的药代动力学研究

目的 探究大鼠灌胃辐状肋柱花后体内当药黄素和1,3,5,8-四羟基-5,6,7,8-4H-口山酮的药代动力学(PK)特征。方法 将SD大鼠随机分为高、中、低剂量组，分别灌胃0.60、0.30和0.15 g·kg^-1的辐状肋柱花L-50浸膏粉的蒸馏水溶混悬液，于给药后不同时间点眼底静脉丛取血，用高效液相质谱联用(LC-MS/MS)测定大鼠血浆中当药黄素和1,3,5,8-四羟基-5,6,7,8-4H-口山酮的血药浓度，计算PK参数。结果 低、中、高剂量组中当药黄素的主要PK参数：C_max分别为(57.31±4.12)、(134.81±25.73)和(183.43±28.38)ng·mL^-1;AUC_0-t分别为(209.12±15.07)、(3 051.51±232.73)和(2 544.67±341.10)μg·L^-1·h;t_1/2 分别为(1.42±0.11)、(11.57±1.52)和(12.96±4.63)h。中、高剂量组与低剂量组比较，AUC_...     

磷酸奥司他韦干混悬剂的人体药动学与生物等效性

目的:研究磷酸奥司他韦干混悬剂在健康受试者的人体药动学和生物等效性。方法:78例受试者分别空腹和餐后口服75 mg受试制剂或参比制剂。采用高效液相色谱-串联质谱(HPLC-MS/MS)检测奥司他韦和奥司他韦酸的全血浓度,用WinNonlin 8.2软件计算药动学参数,评价两制剂生物等效性。结果:空腹试验受试制剂和参比制剂的奥司他韦C_max、AUC_0-t、AUC_0-∞分别为(52.07±23.44)和(50.54±16.09)ng·mL^-1、(150.8±32.0)和(153.6±29.3)h·ng·mL^-1、(154.2±32.2)和(157.8±30.9)h·ng·mL^-1;奥司他韦羧酸盐C_max、AUC_0-t、AUC_0-∞分别为(259.66±42.65)和(267.10±44.06)ng·mL^-1、(3 235.1±549.9)和(3 321.6±567.5)h·...     

阿德福韦酯片在中国健康受试者中的药代动力学和生物等效性研究

目的 研究阿德福韦酯片受试制剂(10mg)和参比制剂(10 mg)在健康人空腹及餐后状态下的药代动力学特征,并对两种制剂的生物等效性进行评价。方法 空腹试验24例健康受试者,餐后试验26例健康受试者,按双周期、自身交叉设计、单剂量口服阿德福韦酯片受试制剂或参比制剂10 mg,使用高效液相色谱-串联质谱(HPLC-MS/MS)法测定给药后不同时间点的血药浓度,采用Phoenix WinNonlin软件(7.0版本)进行非房室模型药代动力学参数的估算分析,评价两种制剂的生物等效性。结果 单次空腹口服药物后,参比制剂和受试制剂的C_max分别为(24.92±6.01)和(24.04±3.58) ng·mL^-1,AUC_0-t为(284.85±45.04)和(299.69±49.31) ng·h·mL^-1,AUC_0-∞为(304.44±47.58)和(317.27±50.04) ng·h·mL^-1,t_max为0.75和1 h,t_1/2<...     

丁苯酞注射液在中国健康人体内的生物等效性研究

目的:研究空腹条件下静脉滴注受试制剂丁苯酞注射液(规格:5 mL:25 mg,南京优科制药有限公司生产)与参比制剂丁苯酞氯化钠注射液(商品名:恩必普)在健康受试者体内的生物等效性及安全性。方法:采用随机、开放、两周期、双交叉给药试验设计,选择24名健康受试者分别交叉单次静脉注射丁苯酞注射液受试制剂和参比制剂100 mL,输液量(100±5) mL(输液泵允许有5%以内的误差),时间55 min。采用液相色谱-串联质谱(LC-MS/MS)法测定血浆中丁苯酞浓度,使用WinNonlin 6.4软件计算主要药动学参数,并进行生物等效性评价。结果:24名健康受试者输注受试制剂和参比制剂后,丁苯酞的主要药动学参数:AUC_0-t:(541.0±78.6)ng·mL^-1·h和(525.0±76.1)ng·mL^-1·h;AUC_0-∞:(571.0±82.1) ng·mL^-1·h和(555.0±88.1) ng·mL^-1·h;C_max:(295.0±62.7) ng/mL和(291.0±56.5) ng/mL;T_max分别为0.92(0.33, 0.92)h和0.92(0.33, 0.93)h。t_1/2分别为(16.60±6.85) h和(15.80±5.88)h。受试制剂和参比制剂的AUC_0-t,AUC_0-∞,C_max的几何均数比值(GMR)的90%置信区间均在80.0%-125.0%的范围内。结论:受试制剂丁苯酞注射液与原研丁苯酞注射液具有生物等效性。     

依折麦布片在中国健康受试者中的药代动力学和生物等效性研究

目的研究空腹及餐后条件下单剂量依折麦布片的药代动力学特征,评价其生物等效性和安全性。方法空腹组和餐后组各入组48例健康受试者,采用单中心、单剂量、空腹/餐后、随机、开放、两制剂、两周期、双交叉的试验设计,每周期受试者单次空腹或餐后口服受试药物或参比药物依折麦布片10 mg,用HPLC-MS/MS法测定给药后不同时间点受试者血浆中依折麦布和总依折麦布(依折麦布+依折麦布-葡萄糖醛酸结合物)的浓度。采用非房室模型计算药代动力学参数,评价2种依折麦布的生物等效性。结果单次空腹给药受试药物与参比药物血浆中总依折麦布的主要药代动力学参数:C_max分别为(70.74±30.08)和(72.32±25.46)ng·mL^-1;t_max分别为1.12和1.25 h;t_1/2分别为(14.02±7.40)和(13.75±6.88)h;AUC_0-t分别为(530.93±221.48)和(514.81±215.49)h·ng·mL^-1;AUC_0-∞分别为(565.54±227.79)和(550.86±239.24)h·ng·mL^-1。单次餐后给药受试药物与参比药物血浆中总依折麦布的主要药代动力学参数:C_max分别为(109.78±49.31)和(112.33±40.73)ng·mL^-1;t_max分别为2.00和1.50 h;t1/2分别为(15.50±8.76)和(13.36±6.61)h;AUC_0-t分别为(627.51±267.46)和(565.57±188.63)h·ng·mL^-1;AUC_0-∞分别为(683.91±316.10)和(616.88±218.22)h·ng·mL^-1。受试药物和参比药物的主要药代动力学参数C_max、AUC_0-t、AUC_0-∞经对数转换后进行方差分析,在90%置信区间范围内,空腹状态下总依折麦布分别为88.90%~103.31%,97.84%~109.29%,96.66%~109.94%;餐后状态下总依折麦布分别为84.79%~103.87%,102.71%~112.92%,103.35%~115.71%。结论空腹和餐后状态下,健康受试者口服两种依折麦布的主要药代动力学参数相近,且安全性良好,具有生物等效性。     

硫唑嘌呤片在中国健康受试者空腹状态下的生物等效性

目的 评价国产硫唑嘌呤片与原研片剂在中国健康受试者中空腹条件下的生物等效性及安全性。方法 采用单中心、随机、开放、单剂量、两序列、四周期、完全重复交叉给药设计,入组36例健康男性和女性受试者,随机分为2组。每周期单次空腹口服硫唑嘌呤受试制剂或参比制剂50 mg。用HPLC-MS/MS法测定血浆中硫唑嘌呤及6-巯基嘌呤的浓度。用Phoenix WinNonlin 8.2软件进行药代动力学参数的估算和生物等效性评价。结果 空腹状态下口服硫唑嘌呤片受试制剂和参比制剂后,硫唑嘌呤的C_max分别为(17.81±7.36)和(17.76±6.94)ng·mL^-1,AUC_0-t分别为(17.41±3.65)和(17.03±3.94)h·ng·mL^-1,AUC_0-∞分别为(17.58±3.69)和(17.72±3.82)h·ng·mL^-1;受试制剂和参比制剂的6-巯基嘌呤C_max分别为(29.23±16.91)和(28.18±16.80)ng·mL<...     

盐酸特拉唑嗪片在中国健康受试者中的生物等效性研究

目的 研究盐酸特拉唑嗪片仿制药与原研药在中国健康受试者中单剂量空腹条件下给药的生物等效性。方法 用单中心、随机、开放、单次给药、两制剂、两周期、双交叉试验设计，共纳入24例成年男性和女性受试者随机交叉给药。分别单次口服盐酸特拉唑嗪片受试制剂和参比制剂2 mg,用液相色谱串联质谱法测定血浆中特拉唑嗪的浓度。用Phoenix WinNonlin 8.0软件计算主要药代动力学(PK)参数。结果 空腹组的盐酸特拉唑嗪片受试制剂和参比制剂主要PK参数：C_max分别为(53.79±9.77)和(57.62±14.18)ng·mL^-1,AUC_0-t分别为(519.90±179.49)和(551.99±143.15)ng·mL^-1·h, AUC_0-∞分别为(565.59±161.15)和(576.91±149.43)ng·mL^-1·h,t_max分别为1.00 (0.28, 2.02)和0.75 (0.50, 1.67) h,t_1/2     

利丙双卡因乳膏在中国健康受试者中的生物等效性研究

目的评价利丙双卡因乳膏受试制剂和参比制剂在中国健康受试者中的生物等效性。方法用单剂量、开放性、双周期、双序列、交叉、随机设计。本次研究共40例健康受试者入组(空腹),每周期于受试者双腿正面均匀涂抹受试制剂或参比制剂60 g/400 cm²,清洗期为14 d。用液相色谱-串联质谱法测定人血浆中利多卡因和丙胺卡因的浓度,用WinNonlin 6.4版软件计算主要药代动力学参数,并评估2种制剂的生物等效性。结果在受试者双腿涂抹等量受试制剂和参比制剂后,血浆中利多卡因的主要药代动力学参数:C_max分别为(179.78±93.10)和(182.89±92.68)ng·mL^-1,AUC_0-t分别为(1676.05±726.76)和(1657.15±673.00)ng·mL^-1·h,AUC_0-∝分别为(1691.72±724.67)和(1671.50±671.65)ng·mL^-1·h;丙胺卡因的主要药代动力学参数:C_max分别为(97.75±47.74)和(105.89±51.29)ng·mL^-1,AUC_0-t分别为(793.40±327.87)和(825.63±324.61)ng·mL^-1·h,AUC_0-∞分别为(810.64±329.11)和(843.79±326.57)ng·mL^-1·h。2种制剂的C_max、AUC_0-t及AUC_0-∞经对数转换后的90%置信区间:利多卡因分别为93.10%~107.25%,97.03%~107.59%和97.20%~107.56%;丙胺卡因分别为87.70%~101.24%,92.02%~102.85%和92.08%~102.68%。结论在空腹条件下,单次使用利丙双卡因乳膏受试制剂和参比制剂均具有生物等效性。     

富马酸喹硫平缓释片在中国健康受试者中的生物等效性研究

目的研究富马酸喹硫平缓释片仿制药与原研药在中国健康受试者中单剂量空腹和餐后条件下给药的生物等效性。方法用单中心、开放、随机、单次给药、两制剂、两周期交叉设计,共纳入68例(空腹试验36例,餐后试验32例)成年男性和女性受试者随机交叉给药。分别单次口服受试制剂和参比制剂200 mg,用液相色谱-串联质谱(LC-MS/MS)法测定血浆中喹硫平的浓度。用SAS V9.4软件计算主要药代动力学参数。结果空腹组的富马酸喹硫平缓释片受试制剂和参比制剂主要药代动力学参数如下:AUC_0-t分别为(2432.45±859.54)和(2368.00±792.38)ng·mL^-1·h,AUC_0-∞分别为(2516.56±864.19)和(2461.20±803.72)ng·mL^-1·h,C_max分别为(206.88±92.00)和(207.16±109.88)ng·mL^-1,t_max分别为5.25和4.50 h,t1/2分别为(6.97±2.43)和(7.26±2.13)h。餐后组的富马酸喹硫平缓释片受试制剂和参比制剂主要药代动力学参数如下:AUC_0-t分别为(2774.99±1077.62)和(2856.20±1180.25)ng·mL^-1·h,AUC_0-∞分别为(2840.63±1076.46)和(2916.44±1174.10)ng·mL^-1·h,C_max分别为(398.78±142.90)和(373.15±142.99)ng·mL^-1,t_max分别为5.50和5.00 h,t1/2分别为(4.41±0.63)和(4.68±0.96)h。在空腹及餐后条件下,受试制剂与参比制剂主要药代动力学参数的90%置信区间均在80.00%~125.00%。结论在空腹及餐后条件下,中国健康成年受试者单次口服富马酸喹硫平缓释片仿制药与原研药具有生物等效性。     

盐酸二甲双胍片在中国健康受试者中的生物等效性研究

目的研究盐酸二甲双胍片在中国健康受试者中的药代动力学特征,并评价其生物等效性。方法空腹和餐后分别入组24例健康受试者,采用随机、开放、单次给药、两周期、两制剂、两序列交叉试验设计,受试者单次口服盐酸二甲双胍片受试药物或参比药物0.25 g,采用液质联用法(LC-MS/MS)测定血浆中二甲双胍浓度,计算主要药代动力学参数,评价受试药物与参比药物的生物等效性。结果单次空腹给药受试药物与参比药物盐酸二甲双胍片的主要药代动力学参数:C_max分别为(766.00±280.00)和(784.00±249.00)ng·mL^-1;t_max分别为2.50(1.00,4.00)h和2.50(1.00,4.00)h;t_1/2分别为(3.67±0.92)和(3.39±0.92)h;AUC_0-t分别为(4910.00±1770.00)和(4980.00±1610.00)h·ng·mL^-1;AUC_0-∞分别为(5000.00±1750.00)和(5090.00±1610.00)h·ng·mL^-1。单次餐后给药受试药物与参比药物盐酸二甲双胍片的主要药代动力学参数:C_max分别为(496.00±91.50)和(482.00±56.60)ng·mL^-1;t_max分别为3.50(1.50,4.00)h和4.00(1.00,4.00)h;t_1/2分别为(3.46±0.82)和(3.50±0.77)h;AUC_0-t分别为(3710.00±623.00)和(3660.00±611.00)h·ng·mL^-1;AUC_0-∞分别为(3840.00±624.00)和(3760.00±582.00)h·ng mL^-1。两药物的主要药代动力学参数C_max、AUC_0-t、AUC_0-∞几何均值的比值及其90%置信区间空腹状态下分别为93.90%(85.30%~103.37%),95.05%(87.61%~102.98%)和93.90%(88.24%~102.40%);餐后状态下分别为102.39%(97.67%~107.33%),101.79%(96.22%~107.69%)和102.37%(97.30%~107.70%)。结论在空腹和餐后状态下,两种盐酸二甲双胍片的主要药代动力学参数相近,吸收速度和程度均一致,两制剂生物等效,同时两制剂在中国健康受试人群中具有相似的安全性和耐受性。     

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.