盐酸二甲双胍缓释片人体药代动力学及生物利用度

目的:研究盐酸二甲双胍缓释片单次给药和多次给药的相对生物利用度及生物等效性。方法:采用以阿替洛尔(atenol-ol)为内标的HPLC测定方法,测定健康男性受试者按交叉试验单剂量和多剂量口服(po)盐酸二甲双胍缓释片和常释片后的血中二甲双胍浓度。血浆样品经乙腈沉淀蛋白后,以甲醇-0.02 mmol·L~(-1)磷酸二氢钾水溶液(含10 mmol·L~(-1)十二烷基硫酸钠,pH 3.7)(60:40)为流动相,使用Diamonsil C_(18)柱分离,流速1.0 mL·min~(-1),UV检测波长233 nm。结果:单剂量po盐酸二甲双胍缓释片和常释片后,常释片的C_(max)(2126 ng·mL~(-1))显著高于缓释片(1660 ng·mL~(-1)),缓释片po给药后的T_(max)(4.2h)延迟(常释片T_(max):2.5 h)(P<0.05),相对生物利用度为97.0%。多剂量po给药后,缓释片在稳态时的C_(min)为104 ng·mL~(-1),C_(max)为1674 ng·mL~(-1),而常释片分别为296 ng·mL~(-1),1692 ng·mL~(-1)。结论:经统计学检验表明这两种制剂具有生物等效性,缓释片的达峰时间明显滞后于常释片,该缓释片显示出缓释特征。     

高效液相色谱法测定人体血浆及尿液中多西环素的药物浓度

目的:建市人体血浆及尿液中多西环素药物浓度的高效液相色谱分析方法。方法:美他环素作为内标,待测血浆和尿液分别以高氯酸和甲醇沉淀蛋白,离心后取上清液进行高效液相色谱紫外检测,色谱柱为 Kromasil C_(18)柱(5μm,4.6mm×250mm);流动相为乙腈-水(30:70,含5 mmol·L~(-1)的柠檬酸),流速1.0 mL·min~(-1),检测波长350 nm。结果:本测定方法血浆和尿液的线性范围分别为O.1～6.13 mg·L~(-1)和0.085～13.62 mg·L~(-1),相关系数分别为0.9995和0.9991,血浆及尿液的相对回收率分别为95.2%～101.4%,95.6%～105.5%;日内日间 RSD 均小于10%,最低检测限分别为0.026 mg·L~(-1)及0.034mg·L~(-1)。结论:高效液相色谱法测定血浆与尿液中药物浓度简单、快速、可靠,可用于多西环素的药代动力学及生物利用度研究。     

氯唑西林血药浓度HPLC测定方法的研究

目的:建立氯唑西林血药浓度的高效液相色谱分析方法。方法:以苯唑西林为内标,用乙腈为沉淀剂处理人血浆样品,分析柱为 SinoChrom ODS-BP(5μm,250mm×4.6mm),流动相为0.02mol·L~(-1)磷酸二氢钠缓冲液-乙腈(65:35,用磷酸调pH 为4.6),流速1.10mL·min~(-1),柱温30℃,在225nm 波长处检测。按内标法定量。结果:血药浓度线性范围为0.25～40.0μg·mL~(-1)(r=0.9994),最低检测限0.20μg·mL~(-1)(S/N>3),提取回收率为92.5%～100.5%(n=5),方法回收率为96.2%～100.8%(n=5),日内和日间 RSD(n=5)分别为1.78%～4.05%和1.96%～7.36%。结论:本方法简便、准确、精密度高、重现性好,适用于氯唑西林人体内药代动力学研究及人体生物等效性研究。     

HPLC法测定人血浆中盐酸二甲双胍的浓度

目的:建立HPLC法测定人血浆中的盐酸二甲双胍浓度.方法:血浆在酸性条件下以乙腈沉淀蛋白后,用二氯甲烷萃取纯化,以甲醇-5 mmol·L-1磷酸盐缓冲液(pH 6.6)(51:49,每100ml中含SDS 0.1 g)为流动相,色谱柱为Hypersil ODS C18柱(5 μm,4.6 mm×150 mm),检测波长为234 nm,柱温40℃.结果:线性范围为125～5 000 ng·ml-1,最低检测限为20ng·ml-1.低、中、高3种浓度的方法回收率分别为105.76%,93.60%和91.89%.日内、日间RSD均小于5%.结论:该法简便、准确、灵敏,可用于盐酸二甲双胍生物利用度和药物动力学研究.     

反相离子对色谱法测定替卡西林钠中的有关物质的含量

目的建立反相离子对色谱法测定替卡西林钠中的有关物质的含量。方法色谱柱为Chromegabond TMS C_1(150 mm×4.6 mm,5μm)柱;流动相A为乙腈-磷酸盐缓冲液(含浓度5mmol·L~(-1)四丁基溴化铵的20mmol·L~(-1)的磷酸二氢钠溶液,用磷酸调节pH值至3.0,体积比1∶4),流动相B为乙腈-磷酸盐缓冲液(含5mmol·L~(-1)四丁基溴化铵的20mmol·L~(-1)的磷酸二氢钠溶液,用磷酸调节pH值至3.0,体积比1∶1),梯度洗脱;流速为1.5 mL·min~(-1);检测波长为230nm;柱温为30℃。结果破坏试验结果显示,本方法能够将主峰和杂质峰完全分离;精密度RSD为0.36%;替卡西林杂质A重复性、中间精密度RSD为0.19%、0.33%,替卡西林杂质D重复性、中间精密度RSD为0.94%、1.14%,最大杂质重复性、中间精密度RSD为1.03%、0.95%,总杂质的重复性、中间精密度RSD为0.86%、1.27%;在4℃条件下存放,12h内溶液稳定;替卡西林的质量浓度在10.116~101.16mg·L~(-1)内与峰面积呈良好的线性关系(r>0.999 9,n=5);检测限质量浓度为0.105mg·L~(-1),定量限质量浓度为0.260mg·L~(-1)。结论该方法可用于替卡西林钠的质量控制。     

HPLC法测定盐酸左氧氟沙星血浓度

目的:建立HPLC法测定血清中盐酸左氧氟沙星浓度。方法:采用三氯乙酸提取血样,以盐酸洛美沙星为内标,色谱柱:shim-pack C_(18)柱(250 mm×4．6 mm,5μm),流动相为乙腈:50 mmol·L~(-1)柠檬酸:1 mol·L~(-1)醋酸胺(16:83:1),流速1．0 ml·min~(-1),检测波长295 nm,灵敏度0．01AUFS。结果:本法在0．1～10μg·ml~(-1)之间线性良好(r=0．999 9),日间和日内RSD小于10％,最低检测浓度为0．1μg·ml~(-1)。结论:本法快速、准确、重现性好,可为临床血药浓度监测和药物动力学提供依据。     

复方盐酸二甲双胍片在健康志愿者体内的药物动力学和生物等效性

目的:研究复方盐酸二甲双胍片在健康志愿者体内的药物动力学和生物等效性。方法:18名男性健康志愿者随机交叉单次口服复方盐酸二甲双胍片(含盐酸二甲双胍1000 mg,格列本脲5 mg,受试制剂)或联合服用盐酸二甲双胍片1 000 mg和格列本脲片5 mg(参比制剂)后,采用HPLC法分别测定盐酸二甲双胍和格列本脲的经时血药浓度,用3P97软件计算其药物动力学参数和相对生物利用度,评价两种制剂的生物等效性。结果:单次口服受试制剂和参比制剂后,盐酸二甲双胍主要药物动力学参数C_(max)分别为(1.60±0.55)μg·ml~(-1)和(1.46±0.46)μg·ml~(-1),t_(max)分别为(2.1±0.7)h和(2.5±0.8)h,t_(1/2)分别为(4.9±1.7)h和(4.3±1.6)h,AUC_(0→24)分别为(10.47±2.89)μg·ml~(-1)·h和(9.22±2.56)μg·ml~(-1)·h,AUC_(0→∞)分别为(10.95±3.13)μ·ml~(-1)·h和(9.53±2.73)μg·ml~(-1)·h,受试制剂的相对生物利用度F_(0→24)为114.8%±17.6%。格列本脲主要药物动力学参数C_(max)分别为(117.70±28.38)μg·L~(-1)和(106.92±33.76)μg·L~(-1),t_(max)分别为(4.1±2.7)h和(3.8±1.8) h,t_(1/2)分别为(7.6±4.1)h和(8.8±3.9)h,AUC_(0→30)分别为(899.97±296.76)μg·L~(-1)·h和(902.64±353.82)μg·L~(-1)·h,AUC_(0→∞)分别为(943.00±290.09)μg·L~(-1)·h和(989.82±399.90)μg·L~(-1)·h,受试制剂的相对生物利用度F_(0→30)为104.91%±28.31%。结论:两制剂两组分的AUC、C_(max)对数值,经F分析、双单侧t检验和(1-2α)%置信区间法统计分析。表明两种制剂具有生物等效性。     

高效液相色谱法测定人血浆中法罗培南的浓度

目的:建立测定人血浆中法罗培南浓度的高效液相色谱法。方法:血浆样品用30%的高氯酸沉淀,色谱柱为Ultimate C_(18)柱(250 mm×4.6 mm,5μm),流动相为0.02 mol·L~(-1)NaH_2PO_4(pH 3.8)-乙腈=75:25;流速1.0 ml·min~(-1);检测波长为317nm,采用外标法定量。结果:法罗培南在0.02～12μg·ml~(-1)范围内线性良好,日内和日间差均<15%,绝对回收率>70%,结论:本法灵敏度高,操作简便、快速,适用于法罗培南临床药物动力学和生物等效性的研究。     

固相萃取-高效液相色谱法测定氯雷他定的血药浓度

目的:建立固相萃取-高效液相色谱法测定氯雷他定血药浓度的方法.方法:采用ODS-C18小柱处理样品,Zorbax SB-C18柱(4.6 mm× 250 mm,5μm),流动相:50mmol·L-1磷酸二氢铵缓冲液(磷酸调至pH 4.0)-乙腈(62:38),流速:1.2 mL·min-1,检测波长:275 nm.结果:线性范围1～100 μg·L-1(r=0.999 6),回收率在82.63%～92.41%,日内、日间RSD＜10%,最低定量浓度为1μg·L-1.结论:该法简便、快速、准确,适用于氯雷他定药动学和生物等效性研究.     

HPLC测定比格犬血浆中的盐酸二甲双胍及其药物动力学研究

目的 测定比格犬血浆中低浓度的盐酸二甲双胍,研究盐酸二甲双胍在消化道各部位的吸收情况.方法 采用DikmaDiamonsil C<,18>柱(150 mm×4.6 mm,5 μm),流动相为乙腈-10.0 mmol·L<'-1>磷酸二氢钠水溶液(含7.5 mmol·L<'-1>十二烷基磺酸钠,pH5.5)(32∶68),柱温30℃,检测波长235 nm,流速1.0 ml·min 1,内标法检测.结果 盐酸二甲双胍与内标分离良好,线性范围0.05～4.0 μg·ml<'-1>;在比格犬的胃、小肠和结肠3个部位释药得到的药物动力学参数差异明显.结论 所建方法 灵敏、准确度好,测定快速、简便.     

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.