二甲双胍缓释片人体药代动力学及其相对生物利用度

目的 研究国产盐酸二甲双胍缓释片在人体药代动力学行为并与普通片进行等效性评价比较,并估算其药代动力学参数。方法 20名受试者分两组交叉服用缓释片和普通片,用RP-HPLC法测定血浆中药物浓度,并估算相应的药动学参数。结果 单剂量口服1000mg缓释片和普通片后估算的AUC_0-24分别为11.95±2.62μg·h^-1·ml^-1和10.72±2.23μg·h^-1·ml^-1;C_max分别为1.50±0.22μg·ml^-1和2.34±0.30μg·ml^-1;T_max分别为3.38±0.8h和1.61±0.32h;t_1/2分别为4.94±0.47h和3.20±0.38h;多剂量1000mg·d^-1时AUC_ss分别为15.04±3.01μg·h^-1·ml^-1和14.51±2.69μg·h^-1·ml^-1;C_max分别为1.68±0.25μg·ml^-1和1.60±0.26μg·ml^-1;C_min分别为0.15±0.03μg·ml^-1和0.12±0.04μg·ml^-1;Cav分别为0.62±0.13μg·ml^-1和0.61±0.11μg·ml^-1;T_max分别为3.61±0.60h和1.88±0.38h;AUC_0-24和AUC_ss经对数转换后方差分析和双单侧t检验，显示两制剂吸收程度生物等效。结论受试制剂和参比制剂吸收程度生物等效，但具有缓释特性。盐酸二甲双胍缓释片的相对生物利用度单剂量时为（111.5±8.3）%，多剂量时为（103.6±9.2）%。     

两种国产格列齐特片人体生物利用度的研究

目的 比较两种格列齐特片的生物等效性。方法 用HPLC法测定血浆中格列齐特浓度,研究8名受试者口服两种国产片剂的药动学和生物利用度,并用方差分析和双单侧检验及90%可信限考察生物等效性。结果 8名受试者口服单剂量格列齐特片的药动学参数,试验品的t_max3.38±0.52h,C_max19.91±3.61μg·ml^-1,t_1/26.52±2.40h,AUC 278.86±94.74μg·h·ml^-1;对照品的t_max3.38±0.52h,C_max17.59±3.13μg·ml^-1,t_1/27.77±3.34h,AUC 300.94±87.49μg·h·ml^-1,相对生物利用度为92.46±10.47%。结论 两种片剂经统计分析,C_max的90%可信区间在79.1～99.6%,AUC的可信区间在105.8%～107.4%,这两种片剂完全生物等效。     

普卢利沙星片的健康人体药动学

目的 健康志愿受试者口服普卢利沙星片后,测定血浆中其活性代谢物(UFX)并作药动学研究。方法 10名受试者分别单剂量和多剂量稳态时服用普卢利沙星片(相当于200 mg UFX),采集血浆和尿液样品,液相色谱分离荧光检测UFX浓度,3P97软件计算药动学参数。结果 单剂量时测得UFX的主要药动学参数分别为c_max(1.64±0.29)μg·ml^-1,t_max(0.7±0.2)h,AUC_0-36(6.87±1.78)h·μg·ml^-1,AUC_0-∞(7.14±1.79)h·μg·ml^-1,t_1/2(7.54±0.59)h,MRT(8.76±0.65)h;0～36 h尿液累积排泄量为(56.85±9.12)%。稳态时测得UFX的主要药动学参数分别为c_max(1.26±0.41)μg·ml^-1,t_max(0.8±0.3)h,AUC_0-36(7.77±2.73)h·μg·ml^-1,AUC_0-∞(8.10±2.70)h·μg·ml^-1,t_1/2(7.71±1.13)h,MRT(9.85±1.40)h。结论 健康志愿受试者口服普卢利沙星片后,在体内转化为活性代谢物(UFX)发挥作用,主要经尿液排泄。每日2次,每次2片(相当于200mg UFX),在体内无积蓄。男女健康受试者的主要药动学参数无显著性差异。     

氟康唑片在健康人体的药物动力学和生物等效性研究

摘 要 目的:研究氟康唑片在健康人体的药物动力学并评价其生物等效性。方法: 采用双周期自身随机交叉试验设计。20名健康男性志愿者分别单剂量口服受试制剂和参比制剂200 mg,以非那西丁为内标,采用HPLC法测定血药浓度。用DAS软件计算药动学参数和进行统计分析。结果:单次口服受试制剂和参比制剂200 mg后的主要药动学参数：t_max（1.08±0.44）和（1.35±0.76）h,C_max（5.40±0.60）和（5.37±0.72）μg·ml^-1,t_1/2(29.1±3.4)和（29.0±3.5）h,AUC_（0-t）（191.3±13.8）和(190.4±15.7) μg·h·ml^-1,AUC_(0-∞)(204.0±17.5) 和（202. 4±18.1）μg·h·ml^-1,MRT（34.7±1.7）和（34.0±1.9）h,以AUC_（0-t）计算,受试制剂的相对生物利用度为100.9%±6.8%。结论:两种氟康唑片剂具有生物等效性。     

LC-MS/MS法测定人血浆中辛伐他汀的浓度及相对生物利用度

目的 建立人体血浆中辛伐他汀的LC-MS/MS测定方法,研究辛伐他汀片在男性健康志愿者体内的药代动力学行为,评价其生物利用度和生物等效性。方法 20名健康成年男性志愿者采用随机分组自身交叉对照试验设计,单剂量口服辛伐他汀片40 mg后,用LC-MS/MS联用法测定血浆中药物浓度。结果 试验制剂和参比制剂的主要药代动力学参数:t_max分别为(1.8±1.3)h和(2.10±1.00)h;c_max分别为(7.12±1.61)μg·L^-1和(7.38±1.54)μg·L^-1;AUC_(0-24)分别为(30.50±11.25)μg·L^-1·h^-1和(30.17±10.21)μg·L^-1·h^-1;t_1/2分别为(3.90±0.78)h和(3.76±0.85)h。以AUC_(0-24)计算的试验制剂的相对生物利用度为101.2%±7.8%。结论 建立的分析方法准确灵敏,测得的数据可靠,统计学分析表明两种制剂生物等效。     

大豆苷元对氨茶碱在大鼠体内药动学的影响

摘 要 目的:研究大豆苷元对氨茶碱在大鼠体内药动学的影响。方法: 采用HPLC方法测定大豆苷元和氨茶碱合并给药组与氨茶碱单独给药组茶碱在大鼠体内的血药浓度,比较两者的药动学参数。结果:①茶碱在0.2～20.0 μg·ml^-1浓度范围内线性关系良好,定量下限为0.2μg·ml^-1,低中高3个浓度的绝对回收率分别为（86.7±4.2）%、（90.5±3.4）%和（92.4±4.6）%,相对回收率均大于90%,日间和日内精密度RSD分别小于8.94%、9.01%;②大豆苷元和氨茶碱合并给药组和单独给药组药动学参数分别为：半衰期（t_{1/2）为(123.63±18.23)和(133.94±11.20)min,曲线下面积（AUC(0-∞)）为(1 861.03±511.23)和(2 075.41±720.96) μg·min·ml^-1,AUC(0-8)为（1 749.71±376.68）和（1 963.34±475.84）μg·min·ml^-1,达峰浓度Cmax为(10.35±0.95)和(10.23±0.82)μg·ml^-1;③合并给药组较单独给药组的主要药动学参数峰值Cmax相似,t1/2、AUC有一定降低,但差异无统计学意义。结论:大豆苷元对氨茶碱在大鼠体内的药动学无明显影响。}     

HPLC/MS研究国产盐酸班布特罗片及其代谢物特布他林人体生物等效性

目的研究国产班布特罗片剂和进口片剂进行人体生物等效性研究。方法20名健康受试者随机交叉给药,用液相色谱/质谱联用测定血浆中班布特罗其代谢物特布他林的浓度。结果经数据处理,单次口服国产和进口班布特罗片剂后班布特罗的药代动力学参数:AUC_0-t分别为(52±21)μg·h·L^-1和(51±20)μg·h·L^-1,T_max分别为(2.9±0.9)h和(2.6±0.7)h,C_max分别为(6.0±2.6)μg·L^-1和(6.2±2.9)μg·L^-1。特布他林:AUC_0-t分别为(191±30)μg·h·L^-1和(197±37)μg·h·L^-1,T_max分别为(4.2±1.0)h和(4.2±1.0)h,C_max分别为(10±5)μg·L^-1和(10±4)μg·L^-1。国产班布特罗片剂单次给药后的相对生物利用度为102%±8%(班布特罗),100%±12%(特布他林)。结论经统计学证明两制剂有生物等效性。     

替硝唑胶囊健康人体内的药动学与生物等效性研究

目的 研究替硝唑胶囊在健康人体内的相对生物利用度和生物等效性。方法 20名健康成年男性志愿者,采用随机分组自身交叉对照试验,单剂量口服1.0 g替硝唑胶囊后,用高效液相色谱法测定血浆中药物浓度。结果 替硝唑线性范围为0.208～41.6μg·ml^-1;平均回收率98.64%～99.56%,日内和日间精密度(RSD)均小于10.0%。试验制剂和参比制剂的主要药代动力学参数:T_max:(1.6±0.9)和(1.6±0.9)h;C_max:(18.03±2.35)和(18.45±2.78)μg·ml^-1;AUC_(0-60):(394.39±60.32)和(390.29±53.20)mg·L^-1·h;AUC_(0-∞):(435.20±77.15)和(426.36±66.88)mg·L^-1·h;T_1/2:(17.43±2.47)和(16.73±2.25)h。以AUC_(0-60)计算的受试制剂的相对生物利用度为(101.1±7.7)%。结论 两种制剂生物等效。     

罗红霉素片剂生物利用度的比较研究

为比较不同剂型罗红霉素的生物利用度,用微生物管碟检定法(藤黄微球菌CMCC(B)28001)测定了10名男性健康受试者口服罗红霉素分散片(制剂A)和罗红霉素片(制剂B)后不同时间血浆中活性药物的浓度,绘制了血药浓度—时间曲线。结果表明,受试者交叉口服含罗红霉素150mg的制剂A和制剂B后,血浆T_max分别为1.7±0.9和3.7±1.6h,C_max分别为4.97±1.17和2.04±1.26μg·ml^-1,AUC_0→∞分别为62.2±11.9和35.0±16.9μg·h·ml^-1。以制剂A为参比,制剂B中罗红霉素的相对生物利用度仅为59.8%±32.6%,两种制剂的药物吸收程度有显著差异(P<0.01)。初步分析提示,罗红霉素在胃中的迅速溶出是保证其片剂生物利用度的关键之一。     

乳酸左氧氟沙星分散片健康人体生物等效性研究

目的对乳酸左氧氟沙星分散片和左氧氟沙星片进行生物利用度比较,判定两种制剂是否为等效制剂。方法20名男性健康受试者随机交叉给药,分别口服单剂量乳酸左氧氟沙星分散片(试验制剂)及乳酸左氧氟沙星片(参比制剂)200mg,采用HPLC法测定血药浓度,计算两者的药动学参数及相对生物利用度,并求证两种制剂的生物等效性。结果口服200mg试验制剂或参比制剂的主要药动学参数t_1/2β分别为(5.68±1.79)和(5.38±1.52)h;t_max分别为(0.84±0.79)和(0.95±0.47)h;c_max分别为(2.27±0.47)和(2.26±0.58)μg·mL^-1;AUC_0～t分别为(14.90±2.14)和(15.62±2.49)μg·mL^-1.h;AUC_0～∞分别为(15.17±2.34)和(15.87±2.67)μg·mL^-1.h。试验制剂对于参比制剂的平均相对生物利用度F值:AUC_0～t为(97.23±17.71)%,AUC_0～∞为(97.43±17.76)%。两种制剂的AUC_0～t,AUC_0～∞及c_max经对数转换后双单侧t检验,结果接受两种制剂生物等效的假设。C_max的90%置信区间结果为88.1%～117.3%,AUC_0～t为89.2%～102.5%,AUC_0～∞为89.3%～102.9%,t_max经秩和检验无显著性差异。整个试验期间,受试者均未发生药物不良反应。结论按照生物等效性判定标准,可判定两种制剂生物等效。     

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.