格列剂特片在健康人体内的相对生物利用度

目的 研究格列齐特片在健康人体内的相对生物利用度，评价两种格列齐特片剂的生物等效性。方法 10名健康受试口服格列齐特受试片和参比片后，采用高效液相色谱法测定血药浓度，SCEENTIS程序拟合药代动力学参数，t检验比较组间差异，双单侧检验评价生物等效性。结果 格列齐特血药浓度-时间曲线符合单室开放模型，受试片和参比片的达峰时间Tmax分别为（4.272±0.631)h和（4.031±0.574)h，达峰浓度Cmax为（7.497±0.935)μg·ml^-1和（7.408±1.171)μg·ml^-1，曲线下面积AUC为（104.986±27.523）μg·h·ml^-1和（108.232±22.437)μg·h·ml^-1，两组间均无显性差异（P>0.05)。结论 格列齐特受试片的相对生物利用度为96.679%，格列齐特受试片与参比片具有生物等效性。     

阿奇霉素胶囊及片剂的人体相对生物利用度研究

目的研究阿奇霉素胶囊及片剂在正常人体内的药动学及相对生物利用度。方法采用3×3拉丁方试验设计,将24名男性健康志愿受试者随机分为3组,分别单次口服阿奇霉素供试制剂与参比制剂。采用HPLC法测定经时血药浓度。用DAS药动学程序处理试验数据,并对试验结果进行方差分析和双单侧t检验。结果阿奇霉素胶囊及片剂的相对生物利用度为:104.1%±10.2%和99.9%±9.8%;阿奇霉素胶囊及片剂供试品和参比品的药时曲线下面积(AUC0→T)分别为:23.27±4.52μg·h·ml-1、23.33±5.76μg·h·ml-1、23.31±7.70μg·h·ml-1;AUC0→∞分别是31.25±5.13μg·h·ml-1、30.59±6.54μg·h·ml-1、29.78±8.15μg·h·ml-1;达峰时间(Tmax)分别为:2.17±0.38h、2.03±0.55h、2.21±0.48h;达峰浓度(Cmax)分别是:1.260±0.109μg·ml-1、1.310±0.138μg·ml-1、1.298±0.087μg·ml-1。结论经统计学分析,制剂间药动学参数差异无显著性意义,阿奇霉素胶囊及片剂与参比制剂具有生物等效性。     

苦参素片、苦参素胶囊人体生物等效性研究

目的: 比较苦参素片剂与胶囊剂的生物等效性.方法: 20名男性健康志愿者,双交叉于试验当日晨空腹一次口服试验制剂苦参素片、参比制剂苦参素胶囊 600 mg,于药前和药后0.25,0.5,1.0,1.25,1.5,2.0,2.5,3.0,3.5,4.0,5.0,6.0,8.0 h取肘静脉血,高效液相色谱法测定主要成分氧化苦参碱血药浓度.氧化苦参碱血药浓度-时间数据经3P97处理,得药动学参数,参数进行方差分析、双单侧t检验和(1-2α)置信区间分析,并计算相对生物利用度评价两种制剂的生物等效性.结果: 苦参素片和苦参素胶囊氧化苦参碱主要药代动力学参数t1/2分别为(2.144±0.453)h 和(2.066±0.439)h,tmax 分别为(2.275±0.716)h和(2.175±0.654)h,Cmax 分别为(0.384±0.144)μg·ml-1 和(0.370±0.132)μg·ml-1,AUC0-8h分别为(1.098±0.278)μg·ml-1·h和(1.094±0.280)μg·ml-1·h,AUC0-∞分别为(1.216±0.292)μg·ml-1·h和(1.200±0.271)μg·ml-1·h.试验制剂苦参素片相对生物利用度F(以氧化苦参碱计)为100.403%±6.281%,两制剂具有生物等效性.结论: 苦参素片和苦参素胶囊为生物等效制剂.     

布洛芬颗粒剂的人体生物等效性研究

目的:研究布洛芬颗粒剂的人体生物等效性.方法:HPLC法测定18名男性健康志愿者单剂量口服400 mg布洛芬颗粒剂后的血药浓度,拟合药动学参数并进行统计学评价.结果:单剂量口服布洛芬颗粒剂试验制剂和参比制剂后,血浆中布洛芬的Cmax别为(39.35±5.42)μg·ml-1和(40.10±6.33)μg·ml-1;tmax分别为(1.64±0.41)h和(1.58±0.19)h;AUC(0-10)分别为(142.70±25.02)μg·ml-1·h和(150.29±18.24)μg·ml-1·h;AUC(0-in分别为(152.93±28.14)μg·ml-1·h和(161.18±19.59)μg·ml-1·h.相对生物利用度为(95.97±18.91)%.结论:经方差分析与双单侧t检验,试验制剂与参比制剂具有生物等效性.     

烟酸缓释片的人体药代动力学及相对生物利用度

目的:研究烟酸缓释片的人体药代动力学及相对生物利用度.方法:30名男性健康志愿者采用随机交叉给药方案,单剂量口服1 500 mg国产烟酸缓释受试片或进口烟酸缓释参比片,反相离子对高效液相色谱法测定血药浓度,计算两者的药代动力学参数及相对生物利用度,并进行生物等效性评价.结果:单次口服1 500 mg烟酸缓释受试片和参比片的主要药代动力学参数AUC0～10h分别为(11.317±10.058)μg·ml-1·h和(12.030±11.081)μg·ml-1·h,AUC0～∞分别为(11.494±10.052)μg·ml-1·h和(12.334±11.110)μg·ml-1·h,Cmax分别为(6.58±5.28)μg·ml-1和(6.41±5.09)μg·ml-1,tmax分别为(4.90±0.67)h和(4.57±1.06)h,t1/2ke分别为(1.312±0.870)h和(1.467±0.907)h.结论:两种制剂具有生物等效性.     

国产格列齐特片相对生物利用度的比较研究

目的:比较18名志愿受试者单剂量口服(80mg)国内不同厂家生产的格列齐特片后的相对生物利用度。方法:采用反相高效液相色谱法测定了志愿受试者单剂量口服格列齐特片后,其血药浓度变化情况。结果:经3P87药动学程序处理,两厂家的格列齐特药时曲线下面积分别为(81.57±30.26)μg.h·ml-1与(80.31±29.42)μg.h·ml-1,达峰时间分别为(4.64±0.29)h与(4.58±0.26)h,峰浓度分别为(5.77±1.77)μg·ml-1与(5.73±1.91)μg·ml-1。结论:配对t检验结果表明:两厂家的格列齐特药时曲线下面积、峰浓度及达峰时间均无显著性差异(P>0.05),相对生物利用度为101.54%±9.33%。双单侧t检验表明两厂家生产的格列齐特片为生物等效制剂(P<0.05)     

酒石酸双氢可待因/对乙酰氨基酚片在健康人体内的生物等效性

目的:研究对乙酰氨基酚/酒石酸双氢可待因片在健康志愿者中的生物利用度和生物等效性。方法:22例健康志愿者随机单盲、单剂量、双周期两制剂交叉口服国产制剂(试验制剂)与进口制剂(参比制剂),剂量为酒石酸双氢可待因20 mg,对乙酰氨基酚1000 mg,用高效液相色谱法测定10个时间点的血药浓度,采用3P97程序计算主要药代动力学参数和相对生物利用度,并评价两种制剂生物等效性。结果:单剂量口服试验制剂与进口标准参比制剂后,血浆中双氢可待因的AUC0-12分别为399.51 ng·h·ml-1±67.94 ng·h·ml-1和415.10 ng·h·ml-1±68.31 ng·h·ml-1,Cmax分别为78.08 ng·ml-1±28.18 ng·ml-1和79.73 ng·ml-1±24.35 ng·ml-1,Tmax分别为0.98 h±0.61 h和1.20 h±0.64 h。对乙酰氨基酚的AUC0-12分别为59.41μg·h·ml-1±16.78μg·h·ml-1和58.21μg·h·ml-1±17.07μg·h·ml-1,Cmax分别为15.98μg·ml-1±5.25μg·ml-1和15.89μg·ml-1±6.30μg·ml-1,Tmax分别为0.93 h±0.65 h和1.15 h±0.81 h。相对生物利用度分别为97.2%±14.4%和102.7%±8.3%。试验药双氢可待因和对乙酰氨基酚的AUC0-t90%可信限分别为91.5%-101.2%和99.8%-105.1%,Cmax90%可信限分别为85.6%-109.8%和93.8%-111.4%。结论:两种制剂生物等效。     

盐酸二甲双胍缓释片的药代动力学及相对生物利用度研究

目的:研究盐酸二甲双胍缓释片的药代动力学和通过与普通片的药代参数的比较得出相对于普通片的相对生物利用度.方法:采用HPLC法测定20名健康男性志愿者,随机自身交叉单剂量和多剂量口服盐酸二甲双胍缓释片和普通片500rmg后的血药浓度,得出两种剂型的药时曲线,计算各药代参数和相对生物利用度.结果:20名健康志愿者单次口服盐酸二甲双胍缓释片和普通片500 mg的主要药代动力学参数分别为:t1/2(4.64±0.95)h和(4.44±0.91)h;Cmax(0.89±0.25)μg·ml-1和(1.51±0.42)μg·ml-1;tmax(4.2±0.9)h和(1.8±0.5)h;MRT(9.10±1.04)h和(6.07±0.63)h;AUC0-24h(8.76±2.59)μg·h·ml-1和(9.00±2.23)μg·h·ml-1;AUC0-∞(9.21±2.51)μg·h·ml-1和(9.34±2.28)μg·h·ml-1.多次口服盐酸二甲双胍缓释片和普通片(500 mg×5 d)的主要药代动力学参数分别为:Cmax(0.88±0.22)μg·ml-1和(1.39±0.39)μg·ml-1;Cmin(0.05±0.01)μg·ml-1和(0.03±0.01)μg·ml-1;tmax(4.1±1.0)h和(2.1±0.4)h;AUCss(8.34±2.67)μg·h·ml-1和(8.55±2.08)μg·h·ml-1;DF(2.24±0.47)%和(3.87±0.66)%(DF为血药浓度的波动度).盐酸二甲双胍缓释片相对于普通片的相对生物利用度(F)为(96.8±11.5)%.结论:lnAUC经方差分析和双单侧t经检验,无显著性差异,因此两种制剂具有生物等效性.lnCmax经两种方法分析有显著性差异(P＜0.05),Tmax经非参数检验(Wilcoxon符号秩序法)有显著性差异(P＜0.05),且受试缓释片较参比普通片的Gmax小、Tmax有所延长,表明受试制剂具有缓释特性.     

盐酸甲氯芬酯胶囊在健康受试者体内血药浓度测定及生物等效性研究

目的:建立对氯苯氧乙酸血药浓度的HPLC测定法,用于人体生物等效性研究.方法:采用随机双交叉实验设计,20名男性健康受试者分别单次口服受试制剂和参比制剂 200 mg,用HPLC法测定对氯苯氧乙酸的血药浓度.结果:受试制剂和参比制剂的AUC0-τ分别为(33.28±8.16) 和(33.08±7.87)μg·h·ml-1;AUC0-∞分别为(34.92±7.80)和(34.08±7.85)μg·h·ml-1;Cmax分别为(12.62±2.79)和(12.55±2.83)μg·ml-1;tmax分别为(2.11±0.37)和(2.07±0.32)h;t1/2分别为(6.01±2.86)和(6.12±2.74)h.受试制剂的相对生物利用度为(101.2±12.7)%.经统计学检验,两制剂的AUC0~∞、Cmax、tmax、t1/2差异无统计学意义(P>0.05).结论:受试制剂和参比制剂具有生物等效性.     

异福胶囊的人体相对生物利用度研究

目的研究异福胶囊与参比片卫非宁的药物动力学,评价两者的生物等效性.方法采用反相高效液相色谱法测定24名志愿受试者单剂量口服异福胶囊供试品与卫非宁片标准参比制剂后,利福平和异烟肼血药浓度变化情况,用3P97药动学程序和SAS 统计学软件包进行数据处理.结果异福胶囊与参比片卫非宁两种制剂利福平药时曲线下面积AUCn→t分别是(62.28±18.22)μg·h·mL-1与(59.53± 18.75)μg·h·mL-1,Tmax分别为:(2.02 ± 0.38)h与(2.02 ± 0.35)h,Cmax分别是:(13.20±2.77)μg·mL-1与(13.23 ± 3.55)μg·mL-1.两种制剂异烟肼药时曲线下面积AUCn→t分别是:(12.73±4.53)μg·h·mL-1与(15.85±4.97)μg·h·mL-1,Tmax分别为: (1.71 ± 0.25)h与(1.85± 0.35)h,Cmax分别是:(4.39 ±1.47)μg·mL-1与(5.36 ± 1.55)μg·mL-1.结论经剂量校正,两种制剂中两种组份的AUCn→∞,AUCn→t,Cmax及Tmax经方差分析均无显著性差异(P>0.05);经双单侧t检验进行生物等效性评价,表明异福胶囊分别与参比片卫非宁为生物等效制剂(P<0.05).异福胶囊供试品中利福平和异烟肼的相对生物利用度分别为:(105.85± 11.67)%和(102.81±15.42)%.     

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.

---

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.