盐酸氟桂利嗪两种制剂的生物等效性

目的评价2种盐酸氟桂利嗪制剂人体生物等效性。方法用双周期交叉实验设计,采用液相色谱-质谱-质谱联用法测定了20名健康男性受试者口服盐酸氟桂利嗪口腔崩解片和盐酸氟桂利嗪胶囊后血浆中氟桂利嗪的浓度,绘制了血药质量浓度-时间曲线并计算药动学参数。结果20名受试者口服含盐酸氟桂利嗪20 mg的受试制剂和参比制剂后血浆中氟桂利嗪的tmax分别为(2.7±0.6)和(2.5±0.6)h,ρmax分别为(55.85±20.66)和(56.74±21.40)μg.L-1,t1/2分别为(6.70±2.46)和(6.89±1.98)h,用梯形法计算,AUC0-t分别为(419.0±126.7)和(428.1±175.2)μg.h.L-1,AUC0-∞分别为(465.3±147.8)和(477.0±202.3)μg.h.L-1。以AUC0-t计算,盐酸氟桂利嗪口腔崩解片的相对生物利用度平均为(104.6±22.0)%。结论盐酸氟桂利嗪两制剂生物等效。     

盐酸氟桂利嗪胶囊人体生物等效性研究

目的研究2种盐酸氟桂利嗪胶囊的生物等效性.方法采用两制剂双周期自身对照交叉试验设计,18例健康男性志愿者分别口服单剂量2种盐酸氟桂利嗪胶囊各20 mg(参比制剂和受试制剂),用高效液相色谱(HPLC)紫外检测法测定血浆中氟桂利嗪的浓度,采用DASl.0程序对药动学参数进行方差分析和双单侧t检验.结果参比制剂和受试制剂在受试者体内的药动学参数分别为Cmax(74.76±16.14)和(70.50±14.96)μg·L-1;Tmax(2.61±0.53)和(2.53±0.36)h;t1/2(6.45±1.13)和(6.48±1.19)h;AUC0～24 h(693.7±170.7)和(686.7±187.4)μg·h·L-1,AUC0～∞分别为(753.4±178.5)和(746.1±189.8)μg·h·L-1,受试制剂对参比制剂的平均相对生物利用度F0～∞为(99.7±16.2)%.AUC0～24 h 90%置信区间为0.921～1.049,Cmax 90%置信区间为0.893～1.000,Tmax经非参数法检验,差异无统计学意义.结论2种盐酸氟桂利嗪胶囊生物等效.     

盐酸氟桂利嗪分散片和胶囊的生物等效性研究

目的:研究盐酸氟桂利嗪分散片药代动力学及生物等效性。方法:20名健康受试者按体重指数进行分层随机交叉服用盐酸氟桂利嗪试验制剂和参比试剂20 mg,采用高效液相色谱法测定盐酸氟桂利嗪的血药浓度。结果:口服20 mg被试制剂与参比制剂后,盐酸氟桂利嗪AUC0-t分别为424.27±74.01和410.25±72.56μg·h-1·L-1;Cmax分别为67.02±14.89和67.45±15.68μg·L-1;Tmax分别为2.90±0.42和2.98±0.47 h;t1/2ke分别为9.73±3.15和8.89±3.08 h。试验制剂的相对生物利用度为(104.12±12.23)％。结论:盐酸氟桂利嗪分散片和胶囊具有生物等效性。     

盐酸氟桂利嗪胶囊在中国健康志愿者空腹和进食条件下的生物等效性研究

摘要：目的:评价山西振东安特生物制药有限公司生产的盐酸氟桂利嗪胶囊与西安杨森制药有限公司生产的盐酸氟桂利嗪胶囊的生物等效性,为一致性评价提供依据。方法:采用随机、开放、单剂量、两制剂、两周期、两交叉给药试验设计,空腹组和高脂餐后组各入组26名受试者,所有受试者随机分为两组,每周期给药1次,每次口服给药剂量为5 mg（1粒）,清洗期28 d,之后进行交叉给药。采用HPLC-MS/MS法测定健康受试者口服受试制剂（T）或参比制剂（R）后,血浆中不同时间点氟桂利嗪的血药浓度。采用WinNonlin8.2和SAS9.4版本软件,非房室模型计算各受试者的药动学参数,并进行统计分析。对受试者的临床观察指标进行安全性评价。结果:空腹组24例和高脂餐后组25例完成全部试验。空腹条件下,盐酸氟桂利嗪胶囊T和R的血药浓度达峰时间(Tmax)分别为2.50 h （1.50～5.50 h）和2.50 h （1.50～4.50 h）,血药峰浓度(Cmax)分别为（21.09±6.72）ng·ml-1和（20.36±5.69）ng·ml-1,血药浓度-时间曲线下面积(AUC0～72h)分别为（239.05±94.19）h·ng·ml-1和（223.78±77.54）h·ng·ml-1;AUC0～t分别为（324.73±152.96）h·ng·ml-1和（298.97±130.39）h·ng·ml-1;AUC0～∞分别为（457.12±268.55）h·ng·ml-1和（366.15±172.77）h·ng·ml-1;半衰期(t1/2)分别为（180.87±153.04）h和（112.18±70.51）h。进食条件下,盐酸氟桂利嗪胶囊T和R的Tmax分别为4.50 （2.50～6.50） h和4.50 （2.50～6.00） h,Cmax分别为（30.52±10.73）ng·ml-1和（30.65±8.55）ng·ml-1,AUC0～72h分别为（269.16±71.76）h·ng·ml-1和（273.30±74.83）h·ng·ml-1;AUC0～t分别为（360.71±121.08）h·ng·ml-1和（362.30±117.22）h·ng·ml-1;AUC0～∞分别为（449.48±171.08）h·ng·ml-1和（470.51±161.88）h·ng·ml-1;t1/2分别为（131.21±60.38）h和（196.35±132.07）h。空腹和餐后状态下T、R的Cmax、AUC0～72h、AUC0～t和AUC0～∞均值比的90%置信区间均在（80.00%,125.00%）等效区间内。结论:盐酸氟桂利嗪胶囊T和R在中国健康志愿者空腹和进食条件下具有生物等效性。     

氟桂利嗪胶囊剂的人体生物等效性研究

20名健康男性志愿者按双周期交叉口服单剂量20mg国产待测氟桂利嗪胶囊剂和对照氟桂利嗪胶囊剂两种制剂,分别于服药前及服药后0.5,1,1.5,2.5,3,4,6,8,12,24h采集血样.用HPLC-荧光法测定血清中氟桂利嗪的浓度,并对试验数据进行统计处理.试验结果表明,单剂量口服国产待测及参比氟桂利嗪胶囊剂的Cmax分别为54.75±14.52μg.L1和52.20±13.04 μg.L-1;tmax分别为2.40±0.45 h和2.33±0.44h;AUC0-24分别为256.56±42.32μg.h.L1和248.81±37.43μg.h.L-1;AUC0-∞分别为275.87±45.62μg.h.L1和267.48±40.10 μg.h.     

盐酸氟桂利嗪片人体生物等效性研究

目的 :12名健康受试者随机自身交叉口服20mg盐酸氟桂利嗪片和孚瑞尔进行药代动力学和生物等效性研究。方法 :采用高效液相色谱荧光检测法 ,测定血浆中盐酸氟桂利嗪的浓度。结果 :经3p97生物利用度计算程序处理拟合 ,得盐酸氟桂利嗪片和孚瑞尔AUC0～∞ 分别为 (328 15±24 52) μg/ (h·L)和 (351 93±35 86) μg/ (h·L) ,Cmax 分别为 (39 41±5 67) μg/L和 (39 89±3 39) μg/L ,Tmax 分别为 (2 56±0 57)h和 (2 64±0 52)h ,经配对t检验 ,两者的主要药动学参数均无显著性差异 (P>0 05)。采用梯形法计算的盐酸氟桂利嗪片和孚瑞尔的AUC0～t 分别为 (360 40±23 50) μg/(h·L)和 (377 81±28 59) μg/(h·L)。结论 :经方差分析和双单侧检验 ,结果表明 ,两者具有生物等效性 ,盐酸氟桂利嗪片剂的相对生物利用度为 (95 7±6 6) %。     

盐酸氟桂利嗪注射液人体药动学研究

目的:建立测定人血清中盐酸氟桂利嗪浓度的液相和串联质谱(LC-MS-MS)定量方法,考察健康志愿者单剂量和多剂量静脉滴注盐酸氟桂利嗪的药动学特征。方法:血清样品经正己烷-异丙醇萃取后,以水(0．01 mol·L-1醋酸铵,醋酸调pH值3．5)-甲醇(25:75)为流动相,经C18柱分离,采用离子源为ESI源的LC-MS-MS测定样品。用上述方法研究了32例健康志愿者单剂量以及多剂量静脉滴注盐酸氟桂利嗪的血药浓度-时间过程,并用DAS 2．0软件计算药动学参数。结果:血浆中样品线性关系较好(r=0．999 9),氟桂利嗪的提取回收率均>90％,定量下限为0．5μg·L-1,批内及批间精密度<10％。单剂量静滴盐酸氟桂利嗪2．5,10,15 mg后估算的Tmax分别为(1．16±0．19),(1．22±0．09)和(1．18±0．12)h,t1/2分别为(7．37±3．26),(7．53±4．32)和(6．78±1．23)h,Cmax分别为(19．04±5．13),(95．62±20．27)和(142．08±37．57)μg·L-1,AUC0-t分别为(63．87±14．09),(320．46±77．50)和(518．48±129．13)μg·h·L-1。多剂量静滴盐酸氟桂利嗪10 mg后估算的t1／2为(7．81±1．68)h,Cav为(16．42±4.44)μg·L-1,DF为(5．36±0．98),AUCss,0-t为(418．81±113．16)μg·h·L-1。结论:盐酸氟桂利嗪注射液人体单剂量给药后呈线性药动学特征,多剂量给药后体内无蓄积。     

盐酸雷尼替丁微丸胶囊在健康志愿者的生物等效性研究

目的:研究盐酸雷尼替丁微丸胶囊和善胃得(盐酸雷尼替丁片,葛兰素史克)的人体药代动力学和生物等效性。方法:20名健康志愿者按双周期随机交叉试验设计口服受试制剂盐酸雷尼替丁微丸胶囊和参比制剂盐酸雷尼替丁片,用高效液相色谱(HPLC)法测定血浆中雷尼替丁的浓度。结果:单剂量口服盐酸雷尼替丁微丸胶囊和盐酸雷尼替丁片后Cmax分别为1.62±0.56和1.78±0.69μg.ml-1,tmax分别为2.8±1.1和2.6±0.8 h,AUC0-τ分别为6.69±1.46和6.67±1.86μg.h.ml-1,AUC0-∞分别为7.06±1.56和7.06±1.86μg.h.ml-1。受试制剂盐酸雷尼替丁微丸胶囊的相对生物利用度为103.8%±19.1%。结论:盐酸雷尼替丁微丸胶囊和善胃得两种制剂生物等效。     

吉非罗齐胶囊的药动学及相对生物利用度

目的:研究吉非罗齐胶囊在人体内的药代动力学及相对生物利用度.方法:采用反相高效液相色谱法测定10名受试者单剂量口服600 mg吉非罗齐供试胶囊与参比胶囊后的血药浓度变化情况.结果:药时曲线下面积分别为(95.71±10.04)μg·h·ml-1与(96.55±10.78)μg·h·ml-1,达峰时间分别为(2.05±0.44)h与(2.10±0.39)h,峰浓度分别为(29.80±2.60)μg.ml-1与(29.35±4.47)μg.ml-1,均无显著性差异(P>0.05),供试胶囊的相对生物利用度为99.72%±10.76%.结论:双单侧t检验表明供试品与参比胶囊为生物等效制剂.     

2种盐酸氟桂利嗪胶囊人体生物等效性比较研究

目的:评价2种盐酸氟桂利嗪胶囊在正常人体内的生物等效性。方法:20名健康志愿受试者分别单剂量交叉口服2种盐酸氟桂利嗪胶囊(FZJ或FZY)20mg,以高效液相色谱法测定血药浓度,3p97计算药动学参数与相对生物利用度。结果:FZJ和FZY在体内药-时曲线呈一室模型,tmax分别为(2·89±0·44)、(2·97±0·47)h,Cmax分别为(62·70±21·67)、(56·15±15·71)μg/ml,AUC(0~t)分别为(391·28±170·77)、(407·18±174·25)(μg·h)/ml,二者比较无显著性差异(P>0·05),FZJ的相对生物利用度为(96·10±14·07)%。结论:2种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.