吡嗪酰胺片剂的人体生物等效性

目的 :研究吡嗪酰胺片剂的人体生物等效性与药动学。方法 :2 0名健康受试者交叉口服单剂量 10 0 0mg吡嗪酰胺的2种片剂 ,分别在服药前及服药后 0 .2 5 ,0 .5 ,0 .75 ,1,1.5 ,2 ,4 ,6 ,9,12 ,2 4 ,36h取血样 ,以HPLC法测定吡嗪酰胺的血药浓度 ,并评价其生物等效性。结果 :口服受试制剂与参比制剂的药动学参数 :cmax分别为 (2 1.6 6± 3.0 4 ) ,(2 2 .4 5± 2 .97)mg·L-1;tmax分别为 (1.11± 0 .5 3) ,(1.0 6± 0 .39)h ;消除半衰期 (T1/2 β)分别为 (11.6 5± 2 .80 ) ,(10 .4 7± 1.6 7)h ;AUC0→ 13h分别为 (2 80 .89± 4 1.12 ) ,(2 87.4 3± 4 1.79)mg·h·L-1;AUC0→∞ 分别为 (312 .14± 4 6 .17) ,(315 .92± 5 0 .14 )mg·h·L-1;受试制剂相对生物利用度为 (99.0±16 .9) %。对参数cmax,AUC0→ 13h进行方差分析 ,并进行双单侧t检验 ,tmax经非参数检验均无统计学差异。结论 :2种制剂具有生物等效性     

洛索洛芬钠片在健康志愿者体内的生物等效性

目的　研究洛索洛芬钠片的人体生物等效性。方法　健康志愿者2 0名,用随机双交叉试验方法,单剂量(6 0mg)口服洛索洛芬钠的试验或参比制剂,洗净期为2wk ;分别于服药后10h内不同时间点抽取静脉血。用HPLC法测定血浆中洛索洛芬浓度。用3P97程序进行生物等效性评价。结果　单剂口服试验或参比制剂的cmax分别为(3.6 72±1.0 4 1)、(3.35 4±0 .6 93)mg·L-1;tmax分别为(0 .6 6 7±0 .16 7)、(0 .75 0±0 .183)h ;T1/2 分别为(1.4 4 3±0 .2 0 4 )、(1.5 82±0 .30 5 )h ;AUC0→10 分别为(8.5 15±1.84 5 )、(8.0 2 4±1.36 9)mg·h·L-1;AUC0→∞分别为(8.6 19±1.85 1)、(8.14 9±1.4 4 0 )mg·h·L-1。AUC0→∞、AUC0→10 、cmax的90 %置信区间分别为93.3%～115 .8%、99.2 %～114 .8%、10 2 .4 %～12 3.3% ;相对生物利用度为(10 6 .5±16 .9) %。结论　试验制剂和参比制剂具有生物等效性     

氢溴酸右美沙芬片健康人体生物等效性

目的 :研究氢溴酸右美沙芬片在健康人体的药动学及相对生物利用度。方法 :8名健康受试者单剂量随机交叉口服氢溴酸右美沙芬片参比制剂和被试制剂 6 0mg ,采用HPLC法测定用药后不同时间的血药浓度。结果 :2种制剂的体内过程均符合一房室开放模型 ,参比制剂和被试制剂的tmax分别为 (2 72± 0 2 1)h和 (2 74± 0 19)h ,cmax分别为 (5 5 1± 0 4 4) μg·L-1和(5 5 8± 0 2 7) μg·L-1,AUC分别为 (4 5 3± 2 9) μg·h·L-1和 (4 5 7± 3 0 ) μg·h·L-1,被试制剂的相对生物利用度为 (10 1±5 9) %。结论 :2种制剂具有生物等效性。     

西那普利片在人体的相对生物利用度

目的 :研究国产西那普利片在人体的药动学和相对生物利用度。方法 :采用随机交叉试验设计 ,12名健康男性志愿者单剂量西那普利片试验品与参比品各 2 5mg,po ,以放射酶学分析法对血浆中活性代谢产物西那普利拉进行定量测定。结果 :试验品与参比品的tmax分别为 (2 1± 0 4 ) ,(2 0± 0 5 )h ;cmax分别为 (10 2 7± 6 8) ,(10 4 6± 9 1)ng·mL-1;AUC0→t分别为(95 5 6± 2 73 7) ,(10 2 2 0± 42 8 7)ng·mL-1·h ;MRT0→t分别为 (18 8± 6 5 ) ,(19 5± 7 3)h。经交叉试验方差分析 ,上述药动学参数均无统计学差异 (P >0 0 5 )。试验品与参比品的cmax与AUC0→t经双单侧t检验分析 ,P >0 0 5。试验品的相对生物利用度为 (98 92± 17 87) %。结论 :试验品与参比品具有生物等效性。     

复方布洛芬软胶囊的人体药动学和生物等效性

目的:研究复方布洛芬软胶囊的人体药动学和生物等效性。方法:采用随机交叉试验设计,20名健康男性受试者分别单剂量口服布洛芬软胶囊(布洛芬400 mg,参比制剂)和对乙酰氨基酚片(对乙酰氨基酚500 mg,参比制剂)与复方布洛芬软胶囊(布洛芬400 mg和对乙酰氨基酚325 mg,受试制剂), LC-MS／MS法和HPLC-UV法测定血浆中布洛芬和对乙酰氨基酚的浓度。结果:参比制剂和受试制剂布洛芬的cmax分别为(42±s 9)和(41±10)mg·L-1;tmax分别为(0．6±0．2)和(0．5±0．3)h;t1／2分别为(2．0±0．3)和(2．1±0．3)h;AUC0～12分别为(126±24)和(131±25)mg·h·L-1。对乙酰氨基酚的cmax分别为(7．5±1．2)和(4．6±0．9)mg·L-1;tmax分别为(0．8±0．5)和(0．8±0．4)h;t1/2分别为(2．8±0．6)和(3.0±0．7)h;AUC0～12分别为(27±6)和(17±4)mg·h·L-1。受试制剂布洛芬的相对生物利用度为(105±12)％,经剂量校正后,受试制剂对乙酰氨基酚的相对生物利用度为(96±12)％。结论:受试制剂与参比制剂具有生物等效性。     

多西环素肠溶微粒胶囊与片剂的人体生物等效性

目的 :研究多西环素肠溶微粒胶囊和多西环素片的人体生物等效性与药动学。方法 :2 0名男性健康志愿者随机分 2组 ,按双周期交叉口服单剂量 2 0 0mg多西环素的 2种制剂 ,分别于服药前及服药后 0 5 ,1,1 5 ,2 ,2 5 ,3,4,6 ,8,12 ,2 4,48,72h取血样 ,以HPLC法测定血浆中多西环素浓度 ,计算 2种制剂相对生物利用度参数 ,并评价其生物等效性。结果 :口服受试制剂多西环素肠溶微粒胶囊和参比制剂多西环素片的药动学参数 :cmax分别为 (3 6 5± 0 81) μg·mL-1和 (3 6 5± 0 73) μg·mL-1,tmax分别为 (2 5± 0 3)h和 (2 2± 0 7)h ,T1/ 2 (消除半衰期 )分别为 (2 1 4 8± 3 2 0 )h和 (2 1 85± 3 11)h ,AUC0→ 72 分别为 (72 18±2 2 6 8) μg·h·mL-1和 (72 0 6± 2 1 0 8) μg·h·mL-1,AUC0→∞ 分别为 (81 4 4± 2 4 94) μg·h·mL-1和 (81 82± 2 3 19) μg·h·mL-1,多西环素肠溶微粒胶囊相对生物利用度为 (10 1 9± 2 5 2 ) %,对参数cmax,AUC0→ 72 先进行方差分析 ,再进行双单侧t检验 ,表明 2种制剂的参数生物等效 ,tmax经非参数检验表明无统计学差异。结论 :多西环素肠溶微胶囊和多西环素片具有生物等效性。     

奥硝唑片、奥硝唑胶囊人体生物等效性研究

目的 :比较试验制剂国产奥硝唑片及国产奥硝唑胶囊与参比制剂进口奥硝唑片的生物等效性。方法 :18名健康志愿者 ,单剂三交叉口服试验制剂奥硝唑片、奥硝唑胶囊和参比制剂 1.5 g ,于药前和药后0 .5 ,1,1.5 ,2 ,3,4 ,6 ,8,12 ,2 4 ,36 ,4 8,72h取肘静脉血 ,用高效液相色谱法测定奥硝唑经时血药浓度 ,数据经 3P97处理得药代动力学参数 ,根据试验制剂和参比制剂AUC计算相对生物利用度。同时对主要药代动力学参数进行方差分析、双单侧t检验和 (1- 2α)置信区间分析 ,评价试验制剂和参比制剂的生物等效性。结果 :试验制剂奥硝唑片、奥硝唑胶囊和参比制剂主要药代动力学参数t1/ 2 ( β) 分别为 (16 .2 9± 2 .199) ,(16 .0 8± 2 .317)和 (15 .84 9± 2 .2 6 4 ) ,tpeak分别为 (1.75± 0 .4 93) ,(1.75± 0 .4 93)和 (1.75± 0 .4 79)h ,Cmax分别为(2 1.5 34± 3.5 3) ,(2 1.936± 3.314 ) ,(2 0 .85± 5 .939) μg·ml-1,AUC0～ 72 分别为 (44 4 .5 6± 5 5 .872 ) ,(44 6 .4 98± 5 5 .138)、(433.30 9± 5 8.5 2 1) μg·ml-1·h-1,AUC0～∞ 分别为 (46 2 .94 9± 5 5 .35 4 ) ,(46 5 .2 2 1± 5 6 .73) ,(45 1.6 6 8± 5 7.971) μg·ml-1·h-1,奥硝唑片、奥硝唑胶囊相对生物利用度分别为 10 2 .91± 8.93%     

3种头孢克洛制剂在健康人体内的药动学及生物等效性研究

目的:比较3种头孢克洛制剂在健康志愿者体内的药动学,并评价3种制剂的生物等效性。方法:18名男性健康志愿者,单剂量三交叉分别口服干混悬剂(受试制剂1)、头孢克洛分散片(受试制剂2)和头孢克洛片(参比制剂)500mg后,用高效液相色谱(HPLC)法测定血浆药物浓度,数据经DAS软件处理,计算药动学参数并评价生物等效性。结果:头孢克洛受试制剂1、2与参比制剂的cmax分别为(13.94±3.76)、(13.54±2.27)、(13.86±3.13)μg·mL-1,tmax分别为(0.56±0.13)、(0.55±0.14)、(0.51±0.13)h,t1/2分别为(0.67±0.09)、(0.68±0.15)、(0.80±0.26)h,AUC0～4分别为(15.16±2.58)、(14.56±1.70)、(14.74±2.07)μg·h·mL-1。受试制剂1、2的F0～4分别为(103.80±17.80)%、(100.50±18.40)%。统计分析表明,2种头孢克洛受试制剂的cmax、tmax、AUC0～4、AUC0～∞与参比制剂相比均无显著性差异。结论:头孢克洛干混悬剂和分散片与参比制剂生物等效。     

人血浆中氧氟沙星的HPLC测定及其相对生物利用度

目的　建立人血浆中氧氟沙星测定含量的HPLC法,评价氧氟沙星片在健康人体内的药动学及生物等效性。方法　采用改进的HPLC法,测定2 0名健康受试者单剂量交叉口服4 0 0mg氧氟沙星供试片或参比片后不同时间点的血药浓度,计算其药动学参数和相对生物利用度,评价2制剂的生物等效性。结果　氧氟沙星供试片与参比片的主要药动学参数分别为:AUC0→2 4(2 7. 16 1±4 . 0 86 )、(2 5 . 32 2±3 2. 96 )mg·h·L-1;cmax(3 4.12±0 . 6 4 2 )、(3 331±0 . 6 17)mg·L-1;tmax(1 2 .93±0 . 4 6 4 )、(1 .14 3±0 . 5 72 )h;T1/ 2ke(7 .12 0±0 . 4 86 )、(7 .184±0 . 5 16 )h。2制剂主要药动学参数AUC0→2 4、cmax经对数转换后进行等效性分析,其90 %置信区间分别为10 2 . 1%～112 . 0 %、93 2 %～112. 2 %。结论　2制剂具有生物等效性。     

HPLC-MS法测定人血浆中阿奇霉素浓度及其药动学

目的　建立人血浆中阿奇霉素的HPLC MS测定法,用其测定了志愿者口服阿奇霉素片剂(5 0 0mg)后的血药浓度,并对受试制剂与参比制剂的生物等效性进行评价。方法　血浆样品经直接沉淀酸化后进行HPLC MS分析。2 0名健康志愿者交叉口服受试制剂或参比制剂5 0 0mg。计算主要药动学参数及相对生物利用度,以判断生物等效性。结果　在1 0～16 2 7 2 μg·L-1范围内阿奇霉素峰面积与内标峰面积的比值与阿奇霉素的浓度之间呈良好线性关系,最低定量限为1 0 μg·L-1。受试制剂和参比制剂的T1/ 2 分别为(38 .5±3 .8)、(39. 0±4 . 5 )h ,tmax分别为(2 . 5±1. 0 )、(2 . 6±0 . 9)h ,cmax分别为(5. 18 8±2. 39 9)、(5 13. 6±2 31. 9) μg·L-1。以AUC0 . 14 4 计算的受试片剂的相对生物利用度为(99 .7±12. 6 ) %。两制剂的药动学主要参数无显著性差异。结论　2种制剂具有生物等效性。     

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.     

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.