兰索拉唑片人体药代动力学和生物等效性研究

目的：评价兰索拉唑片（受试制剂）与兰索拉唑胶囊（参比制剂）的人体生物等效性。方法：血浆样品采用液-液萃取处理，HPLC法测定。18名健康受试者随机分组、自身交叉口服单剂量受试制剂和参比制剂进行生物等效性评价。结果：受试制剂的AUC0^1，AUC0^∞，Cmax，tmax，t1／2分别为4．70±0．57mg·h^-1·L^-1，5．10±0．58mg·h·L^-1，1．33±0．10mg·L^-1，2．5±0．1h，2．2±0．4h。参比制剂的AUC0^1，AUC0^∞，Cmat，tmax，t1／2分别为4．62±0．59mg·h·L^-1，4．98±0．63mg·h·L^-1，1．32±0．08mg·L^-1，2．5±0．1h，2．0±0．2h，受试制剂相对参比制剂的人体相对生物利用度F1为（102．2±10．1）％，R为（103.1±9．2）％。受试制剂相对参比制剂的主要药动学参数经交叉试验方差分析示无统计学差异（P均〉0．05），两制剂的AUC0^1，AUC0^∞，Cmax，经双单侧t检验示90％置信区间均位于有效置信区间80％-125％范围内。结论：受试制剂和参比制剂具有生物等效性。     

替硝唑片的血浓度测定及相对生物利用度研究

目的：建立HPLC法测定替硝唑血浓度，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名健康受试者口服受试制剂和参比制剂1000mg，用HPLC法测定血浆中的替硝唑浓度。结果：受试制剂和参比制剂的A‰分别为（391．2±74．0）和（394．7±78．1）mg·h·L^-1；AUC0→∞分别为（420．4±80．7）和（426．1±85．8）mg·h·L^-1；Cmax分别为（20．2±4．9）和（20．0±4．5）mg·L^-1；tmax分别为（1．4±0．8）和（1．5±0．8）h；t1／2分别为（15．4±1．5）和（15．9±1．8）h。受试制剂的相对生物利用度为（99．6±8．3）％。经统计学分析，两制剂的AUC0→∞，Cmax,tmax，t1/2无显著性差异（P〉0．05）。结论：两制剂具有生物等效性。     

头孢羟氨苄咀嚼片的人体生物等效性

目的：评价头孢羟氨苄咀嚼片与参比片剂在人体内生物等效性。方法：采用随机交叉试验设计，20名健康男性受试者分别口服单剂量受试制剂与参比制剂500mg，HPLC法测定血浆中头孢羟氨苄的浓度，用DAS1．0统计软件计算药动学参数并进行生物等效性评价。结果：受试制剂与参比制剂的已。分别为（19．2±2．3）mg·L^-1和（18．4±2．7）mg·L^-1,tmax分别为（0．95±0．22）h和（1．3±0．4）h，t1/2分别为（1．78±0．14）h和（1．73±0．09）h，AUC（0→10）分别为（53．3±7．5）mg·h·L^-1和（54．0±7．4）mg·h·L^-1,AUC（0→∞）分别为（54．4±7．9）mg·h·L^-1和（55．1±7．7）mg·h·L^-1。受试制剂相对于参比制剂的生物利用度为（99．0±7．0）％。结论：两制剂具有生物等效性。     

二氟尼柳分散片的人体药动学及生物等效性

目的：研究二氟尼柳分散片的人体药动学及生物等效性。方法：采用随机交叉、自身对照试验设计，18名健康男性志愿者，随机等分成两组，每组9人，志愿者单剂量口服二氟尼柳分散片或普通片后，不同时间点取肘部静脉血4～5mL，血药质量浓度采用高效液相色谱（HPLC）法测定。由血药质量浓度计算药动学参数，主要药动学参数（AUC、Cmax）经对数转换后进行方差分析．以双单侧t检验及90％的可信区间进行生物等效性判定。结果：志愿者单次服用500mg二氟尼柳分散片或普通片后药动学参数AUC0-∞分别为（797．7±301．8）和（824．9±306．3）mg·h·L^-1，AUC0-∞分别为（1125．4±485．5）和（1160．7±501．8）mg·h·L^-1,Cmax分别为（55．5±16．4）和（57．2±17．4）mg·L^-1，tmax分别为（2．5±1．0和（2．6±1．2）h。相对生物利用度为（97．0±13．1）％。双单侧t检验证明分散片与普通片等效。结论：分散片的药动学与普通片的药动学统计学上无差异，且二者具有生物等效性。     

氟康唑口服液人体相对生物利用度和生物等效性

目的：考察氟康唑新制刺氟康唑口服液与参比制刑氟康唑胶囊的人体相对生物利用度，并作出生物等效性评价。方法：按照两制剂两周期随机交叉设计，20名男性健康志愿者单剂量口服试验制剂氟康唑口服液和参比制剂氟康唑胶囊150mg。采用HPLC-紫外法测定血浆氟康唑浓度，并进行统计学分析。结果：单剂量口服150mg的氟康唑试验和参比制剂，测得AUCL（0→120）分别为（150．6±23．6）mg·h·L^-1和（150．6±18．6）mg·h·L^-1,AUC（0→∞）分别为（163．6±27．4）mg·h·L^-1和（162．2±21．4）mg·h·L^-1；Cmax分别为（3．8±0．5）mg·L^-1和（3．6±0．4）mg·L^-1；tmax分别为（1．9±1．4）h和（2．4±1．3）h。用药时曲线下面积AUC（0→120）计算，20名健康志愿者单剂量口服氟康唑口服液（试验制剂）相对生物利用度为（102．0±24．3）％。结论：两种制剂的AUC和Cmax数值经对数转换后均落在置信区间范围内，说明混悬剂与参比片生物等效。     

氢溴酸加兰他敏缓释片人体药物动力学研究

目的：建立HPLC-MS方法分析人血浆中氢溴酸加兰他敏的含量，并研究氢溴酸加兰他敏缓释片在健康人体内的药物动力学特征。方法：12名健康受试者口服单剂量（10mg）或多剂量氢溴酸加兰他敏缓释片（10mg×7d）后，分别在不同时间点收集血样，HPLC—MS法测定，采用DASS2．0软件计算给药后的药物动力学参数。结果：健康受试者单剂量口服氢溴酸加兰他敏缓释片的tmax为（4．0±1．4）h；Cmax为（27．2±3．3）μg·L^-1；t1／2为（10.3±0．9）h；MRT为（15．4±1．3）；AUC0-60h为（483.1±70．4）μg·h·L^-1。多剂量口服氢溴酸加兰他敏的AUC0→∞为（916．0±99．0）μg·h·L^-1，Cmax^ss为（56．8±11．6）μg·L^-1，Cmin^ss为（15．5±4．0）μg·L^-1，Css为（38．2±4．1）μg·L^-1，DF为（1．1±0．3），tmax为（3.6±1．9）h，t1/2为（11．7±1．4）h。结论：氢溴酸加兰他敏缓释片主要药动学参数单剂量和多剂量之间无显著性差异，具有明显的缓释特征，多剂量给药后体内无蓄积。     

复方赖诺普利片人体药动学考察

目的：研究复方赖诺普利片在健康人体内药动学特征。方法：单剂量：空腹口服复方赖诺普利片1片（每片复方赖诺普利片含赖诺普利10mg、氢氯噻嗪12．5mg）。多剂量：多次给药连续9d，每天服药1次．每次1片。采用LC-MS法测定血浆中赖诺普利、氢氯噻嗪的浓度，计算药动学参数．以考察复方赖诺普利片多剂量口服达稳态过程和稳态药动学特征。结果：单剂量口服受试制剂：赖诺普利的tmax为（7．3±1．2）h；Cmax为（42．5±6．8）μg·L^-1；t（1/2）为（8．6±1．8）h；MRT为（20．1±3．0）；AUC（0-72）为（545．1±147．4）ng·h·L^-1。氢氯噻嗪的tmax为（2．8±0．7）h；Cmax为（81．6±22．7）μg·L^-1；t（1/2）为（13．7±2．0）h；MRT为（10．4±2．0）；AUC（0-48）为（679．8±280．7）ng·h·L^-1。多剂量口服受试制剂：赖诺普利的AUCss为（576．9±124．4）ng·h·L^-1，Css-max为（47．7±13．2）μg·L^-1，Css-min为（6．2±1．8）μg·L^-1．Css-av为（24．0±5．2）μg·L^-1，DF为（1．71±0．24）．tmax为（7．3±1．1）h，t（1/2）为（13．1±2．7）h；氢氯噻嗪的AUCss为（731．4±224．9）ng·h·L^-1，Css-max为（101．0±31．6）μg·L^-1，Css-min为（8．4±3．8）μg·L^-1，Css-av为（30．5±9．4）μg·L^-1，DF为（3．1±1．2），tmax为（3．0±0．9）h，t（1/2）为（8．8±1．6）h。结论：复方赖诺普利片主要药动学参数单剂量和多剂量给药差异无显著性，复方赖诺普利片在人体内无蓄积。     

吗替麦考酚酯胶囊在健康人体中的相对生物利用度

目的：评价吗替麦考酚酯胶囊在健康人体的相对生物利用度。方法：采用高效液相色谱-紫外检测法测定。18名健康志愿者采用两制剂双周期交叉试验方法，分别测定口服两种制剂后不同间隔时间的血药浓度，并依次计算药动学参数评价胶囊的生物利用度。结果：受试者口服1g吗替麦考酚酯胶囊参比制剂和受试制剂的Gmax分别为（41．5±11．8）mg·L^-1和（37．2±10．0）mg·L^-1；tmax为（0．53±0．19）h和（0．54±0．18）h；t（1/2）为（13．6±7．6）h和（11．6±6．2）h；AUC（0-24）分别为（62．4±12．0）mg·h·L^-1和（63．7±15．1）mg·h·L^-1。受试制剂的相对生物利用度为（102±12）%。结论：两种制剂的主要药动学参数，经对数转换后进行交叉试验的方差分析与双单侧t检验表明．两种制剂的AUC及有关的药动学参数具有生物等效性。     

氟氯西林钠胶囊在健康人体的生物等效性

目的研究氟氯西林钠胶囊（青霉素类抗生素）的相对生物利用度并评价其生物等效性。方法用随机交叉给药方法，20名男性健康志愿者分别口服单剂量试验制剂和参比制剂的氟氯西林钠500nag；用高效液相色谱法测定血浆中浓度，计算2者的药代动力学参数及相对生物利用度。结果单次口服氟氯西林钠试验制剂和参比制剂500mg后的主要药代动力学参数：AUC01-10分别为（31．06±14．81），（33．13±15．97）nag·h·L^-1；AUC0-∞分别为（31．67±14．76），（33．79±16．01）mg·h·L^-1；Cmax分别为（13．61±9．06），（14．90±8．29）mg·L^-1；tmaz分别为（0．99±0．26），（0．85±0．32）h；t1/2分别为（1．79±0．50）和（1．84±0．33）h。受试制剂的相对生物利用度为（96．8±29．9）％。结论2种制剂具有生物等效性。     

氟罗沙星片的人体生物等效性研究

(1. ［摘要］目的研究氟罗沙星片的人体相对生物利用度和生物等效性。方法健康志愿者20例，随机双交叉单剂量口服氟罗沙星片试验和参比制剂，剂量均为0.4 g，剂间间隔为2周。分别于服药后48 h内多点抽取静脉血；用高效液相色谱（HPLC）法测定血浆中氟罗沙星浓度。用DAS药动学程序计算相对生物利用度并评价两种制剂生物等效性。AUC(0 48)、AUC(0 ∞)和Cmax经方差分析和双单侧t检验，tmax进行秩和检验。结果单剂量口服试验和参比制剂后血浆中氟罗沙星的Cmax分别为（5.30±1.20），（5.58±1.01 ） mg·L 1；tmax分别为（2.10±0.97 ），（1.90±0.79 ） h；AUC(0 48)分别为（91.05±17.76 ），（90.39±14.58 ） mg·h·L 1；AUC(0 ∞)分别为（97.49±19.33），（97.29±17.90） mg·h·L 1。AUC(0 48)、AUC(0 ∞)、Cmax的90%可信区间分别为94.0%～105.9%，92.9%～106.6%和88.6%～100.0%。结论氟罗沙星试验制剂与参比制剂的人体相对生物利用度为（100.82±14.66）%，试验制剂与参比制剂具有生物学等效性。     

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.