头孢泊肟酯干混悬剂人体生物等效性研究

目的 在健康受试者中观察头孢泊肟酯干混悬剂的药动学特性及其与片剂的生物等效性.方法 按标签开放性随机自身交叉设计,20例健康男性受试者分别口服单剂量头孢泊肟酯干混悬剂和片剂,头孢泊肟酯剂量均为100 mg,血浆头孢泊肟的浓度采用高效液相色谱法(HPLC)检测.结果 头孢泊肟酯干混悬剂和片剂对应tmax分别为(2.55±0.67)和(2.75±0.66)h,Cmax分别为(1.958±0.380)和(1.847±0.506)μg/mL,AUC0→t分别为(10.68+2.18)和(10.06±2.63)h·μg/mL.头孢泊肟酯干混悬剂相对于片剂的平均相对生物利用度为(109.18±18.44)%.两种制剂的AUC0→t和Cmax均无显著差异(P>0.05).结论 头孢泊肟酯干混悬剂与头孢泊肟酯片剂具有生物等效性,结果 可供临床参考.     

马来酸曲美布汀干混悬剂的生物等效性研究

目的研究马来酸曲美布汀干混悬剂在健康人体的药物动力学,并评价其与同剂量片剂间的生物等效性。方法用双交叉试验设计,18名健康志愿者口服马来酸曲美布汀干混悬剂和马来酸曲美布汀片剂,服药后0~8 h内间隔取血,用HPLC法测定血药浓度。计算主要药物动力学参数,并以马来酸曲美布汀片剂为参比制剂,计算马来酸曲美布汀干混悬剂的相对生物利用度,判断其生物等效性。结果马来酸曲美布汀干混悬剂和片剂的体内药物动力学参数分别为Cmax(239.84±97.88)、(235.58±98.02)ng.mL-1、tmax(0.71±0.15)、(0.72±0.17)h、t1/2(2.24±0.48)、(2.18±0.5)h、Vd/F(2.18±0.95)、(2.13±0.96)L、Cl/F(0.65±0.17)、(0.65±0.17)L.h-1、AUC0→8(439.85±125.44)、(443.75±130.69)ng.h.mL-1;受试马来酸曲美布汀干混悬剂的相对生物利用度F=9 9.65%±7.74%。结论两种制剂具有生物等效性。     

国产与进口头孢泊肟酯在健康人体的药代动力学和生物等效性

目的研究国产与进口头孢泊肟酯在健康人体内的药代动力学与生物等效性。方法24名健康受试者按拉丁方分成3组,用自身交叉对照单次空腹口服进口和国产头孢泊肟酯片和头孢泊肟酯干混悬剂200mg,用微生物法测定人体血药浓度。结果进口头孢泊肟酯片(参比)和国产头孢泊肟酯片剂、干混悬剂(受试)的Cmax分别为(3.52±0.76),(3.62±0.90)和(3.67±0.58)mg·L-1;tmax分别为(2.8±0.4),(2.8±0.5)和(2.5±0.5)h;t1/2分别为(2.3±0.3),(2.4±0.3)和(2.4±0.3)h;AUC0-t分别为(19.12±5.08),(19.42±4.59)和(20.15±3.56)mg·h·L-1。3种制剂的Cmax、AUC0-t均无显著性差异(P>0.05)。国产头孢泊肟酯片、干混悬剂相对于进口头孢泊肟酯片的生物利用度分别为(104.2±21.4)%和(108.3±16.8)%。结论国产头孢泊肟酯片剂、干混悬剂与进口头孢泊肟酯片剂具有生物等效性。     

吗替麦考酚酯干混悬剂的人体药动学及生物等效性研究

目的:研究国产吗替麦考酚酯(MMF)干混悬剂和进口片剂在健康人体的药动学及生物等效性。方法:采用随机自身对照双周期交叉试验设计,20名健康男性志愿者口服MMF干混悬剂或进口片剂0.75mg,用高效液相色谱法测定MMF的活性代谢产物麦考酚酸(MPA)的血药浓度,用非房室模型法计算MPA的药动学参数,用方差分析和双单侧t检验评价2种制剂的生物等效性。结果:MMF干混悬剂和进口片剂的药动学参数:t1/2β分别为(16.80±4.10)、(16.77±4.50)h,tmax分别为(0.4±0.1)、(0.7±0.4)h,Cmax分别为(19.29±6.78)、(18.22±7.19)μg.mL-1,AUC0～72分别为(39.22±10.43)、(39.38±10.46)μg.h.mL-1,AUC0～∞分别为(40.58±10.49)、(41.00±10.88)μg.h.mL-1。受试制剂的相对生物利用度为(100.9±10.6)%。结论:2种MMF制剂在人体内生物等效。     

夫西地酸干混悬剂在健康人体的相对生物利用度研究

目的研究由香港澳美制药有限公司生产的夫西地酸干混悬剂的相对生物利用度。方法采用双周期随机交叉试验设计。分别给予20名男性健康受试者试验制剂或参比制剂夫西地酸干混悬剂750 mg,采用HPLC法测定给药后不同时间的血药浓度。结果参比制剂与试验制剂的主要药物动力学参数Cmax、tmax、AUC0→48和AUC0→∞(均数±标准差)分别为:(30.91±5.24)、(30.25±5.82)μg.mL-1;(2.00±0.74)、(1.88±0.60)h;(443.0±136.3)、(435.6±105.2)μg.h.mL-1;(460.4±139.6)、(450.9±108.2)μg.h.mL-1。试验制剂对参比制剂的相对生物利用度F(以AUC0→48作为评价依据)为100%±13%(71%~125%)。结论经统计学分析,香港澳美制药有限公司生产的夫西地酸干混悬剂与丹麦利奥制药有限公司生产的夫西地酸干混悬剂参比制剂具有生物等效性。     

反相高效液相色谱法检测阿莫西林-克拉维酸钾（8∶1）干混悬剂血药浓度及生物等效性研究

目的采用反相高效液相色谱法测定阿莫西林-克拉维酸钾（8∶1）干混悬剂在健康志愿者体内的血药浓度,并研究其相对生物利用度。方法20名男性健康受试者采用双周期自身对照交叉试验,分别服用阿莫西林-克拉维酸钾（8∶1）干混悬剂和阿莫西林-克拉维酸钾（8∶1）片剂。采用RP-HPLC法分别测定血浆中克拉维酸钾和阿莫西林的浓度,使用DAS软件计算克拉维酸钾和阿莫西林的药物动力学参数与干混悬剂的相对生物利用度。结果阿莫西林和克拉维酸的线性范围分别为0.5-40、0.05-5μg.mL-1,提取回收率均〉75%。单剂量口服参比制剂和受试制剂后,阿莫西林和克拉维酸钾的药动学参数如下：t1/2分别为（1.64±0.72）、（1.80±1.05）h和（1.90±0.84）、（2.12±1.35）h;Cmax分别为（13.19±4.61）、（14.95±6.02）μg.mL-1和（1.56±0.48）、（1.51±0.47）μg.mL-1;tmax分别为（1.78±0.26）、（1.80±0.68）h和（1.20±0.33）、（1.06±0.29）h;AUC0→7分别为（28.86±5.56）、（29.15±5.82）μg.h.mL-1和（2.88±0.95）、（2.70±0.95）μg.h.mL-1;AUC0→∞分别为（31.12±6.03）、（31.65±5.79）μg.h.mL-1和（3.08±0.92）、（2.94±0.94）μg.h.mL-1。以实测值AUC0→t计算,受试制剂中阿莫西林与克拉维酸钾的相对生物利用度分别为（101.8±14.2）%和（98.0±27.4）%。结论本法专一性好,操作简便快捷,成功应用于阿莫西林-克拉维酸钾（8∶1）干混悬剂的生物等效性研究,阿莫西林-克拉维酸钾（8∶1）干混悬剂试验制剂相对参比制剂生物等效。     

HPLC法测定头孢特仑酯片中主药的含量

目的:建立以高效液相色谱法测定头孢特仑酯片中主药含量的方法。方法:色谱柱为C18,流动相为乙腈-水(40:60),流速为1.2mL.min-1,柱温为40℃,检测波长为235nm,进样量为10μL。结果:头孢特仑酯检测浓度的线性范围为25～125μg.mL-1(r=0.9999,n=7);平均回收率为104.98%,RSD=0.86%。结论:本方法简便、快速、准确,可用于该制剂的质量控制。     

高效毛细管电泳法测定头孢克洛干混悬剂中头孢克洛的含量

目的:测定头孢克洛干混悬剂中头孢克洛的含量.方法:采用高效毛细管电泳法.毛细管柱(60cm×75μm),运行缓冲液30mmol·L-1硼砂(pH 9.2),高压进样5s,分离电压12kV,温度为25℃,检测波长为254nm,地塞米松磷酸钠为内标.结果:头孢克洛在8～40μg·mL-1浓度范围内线性关系良好(r=0.999 8),平均回收率为 99.18% (n=5,RSD=1.69%).结论:本法简单、快捷、灵敏.     

高效液相色谱法测定头孢特仑酯胶囊的含量和有关物质

目的建立高效液相色谱法测定头孢特仑酯胶囊含量和有关物质的方法。方法色谱柱为依利特HypersilODS2柱,流动相为乙腈-0.01mol·L-1醋酸-醋酸钠缓冲液-水(380∶100∶520),检测波长为254nm,流速1.0mL·min-1。结果头孢特仑酯在0.1038-1.038mg·mL-1浓度范围内呈良好的线性关系,回归方程:Y=38831X 35.94,r=0.9999;平均回收率为100.3%(n=9)。结论该方法简便、快速、准确、灵敏度高,适用于头孢特仑酯胶囊的含量和有关物质测定。     

那格列奈胶囊和片剂的人体药物动力学及生物等效性研究

目的建立高效液相色谱法测定人血浆中那格列奈浓度的方法,研究那格列奈胶囊和片剂的药物动力学及生物等效性。方法以迪马C18(250 mm×1.5 mm,5μm)为分析柱,乙腈-0.02 mol.L-1乙酸胺缓冲液(40∶60)为流动相,流速为1.0 mL.min-1,紫外检测波长为214 nm,柱温为40℃,瑞格列奈为内标,测定人血浆中那格列奈的浓度。结果在浓度0.187 5~12μg.mL-1,那格列奈和内标峰面积比值与浓度呈良好的线性关系(r2=0.995 47),最小检出浓度为0.093 75μg.mL-1。那格列奈的平均回收率为103%±7%,日内、日间RSD均≤6.8%,那格列奈体内过程符合二室模型,tmax、Cmax、t1/2β、AUC0~∞h分别为(1.36±0.40)h、(6.42±0.30)μg.mL-1、(1.36±2.26)h、(16.10±1.54)μg.h.mL-1。结论本方法简便、灵敏、准确,可用于那格列奈血药浓度检测和药物动力学研究。经统计学分析,试验制剂(胶囊剂)和参比制剂(片剂)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.