匹多莫德干混悬剂人体药动学及生物等效性研究

目的:研究匹多莫德干混悬剂在健康人体的药动学及生物等效性。方法:健康男性志愿者20名,随机交叉单剂量口服匹多莫德干混悬剂(受试制剂)和颗粒剂(参比制剂)各0.8g,采用液-质联用法测定血浆中匹多莫德的浓度。应用DAS软件计算药动学参数和相对生物利用度,评价其生物等效性。结果:口服受试制剂和参比制剂后的主要药动学参数:t1/2分别为(1.84±0.35)、(1.93±0.51)h;tmax分别为(2.23±0.82)、(2.25±1.01)h;Cmax分别为(4.72±1.75)、(4.72±2.16)μg·mL-1;AUC0～20分别为(22.34±6.97)、(21.07±8.04)μg·h·mL-1;AUC0～∞分别为(23.01±7.10)、(21.74±8.14)μg·h·mL-1。受试制剂相对于参比制剂的生物利用度为(111.2±31.7)%。结论:2种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。     

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　 2 0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 :AUC0 -t分别为 (5 2± 2 1) μg·h·L-1和 (5 1± 2 0 ) μg·h·L-1,Tmax分别为 (2 9± 0 9)h和 (2 6± 0 7)h ,Cmax分别为 (6 0± 2 6 ) μg·L-1和 (6 2± 2 9) μg·L-1。特布他林 :AUC0 -t分别为 (191± 30 ) μg·h·L-1和 (197± 37) μg·h·L-1,Tmax分别为 (4 2± 1 0 )h和 (4 2± 1 0 )h ,Cmax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 10 2 %± 8% (班布特罗 ) ,10 0 %±12 % (特布他林 )。结论　经统计学证明两制剂有生物等效性     

托吡酯片在健康人体的药代动力学及生物等效性

目的 研究托吡酯片剂在健康人体内的药代动力学过程,并比较2种托 吡酯片剂的生物等效性。方法 用随机交叉给药方案,18名健康男性受试者 分别单剂量口服试验和参比托吡酯片剂100 mg,用毛细管气相色谱-氮磷检测 法(GC-NPD)测定血浆中托吡酯浓度,并评价2种制剂的生物等效性。结果 口服试验和参比托吡酯片剂后的Cmax分别为(2．05±0．45)和(1．97±0．43) μg·mL-1;tmax分别为(1．14±0．68)和(1．28±0．60)h;t1／2分别为(30．19± 5．01)和(31．07±4．67)h;AUC0-t分别为(52．00±8．84)和(52．88±9．84)μg· h·mL-1;AUC0-∞分别为(65．74±14．34)和(67．62±14．22)μg·h·mL-1,口 服试验和参比托吡酯片剂后的相对生物利用度F0-t为(99．12±10．50)％,F0-∞ 为(97．65±10．96)％。结论 试验和参比托吡酯片剂具有生物等效性。     

法莫替丁滴丸剂和片剂的人体生物等效性

目的　采用HPLC法测定法莫替丁的血药浓度,评价法莫替丁滴丸剂和片剂的人体生物等效性。方法　2 0名健康志愿者分别单次口服法莫替丁滴丸剂或片剂4 0mg ,采用固相萃取HPLC法测定血药浓度。结果　法莫替丁滴丸剂和片剂的tmax分别为(2 .4 0±0 .6 4 )、(2 .5 5±0 .4 8)h ;cmax为(12 2±30 )、(135±37) μg·L-1;T1/2 为(3.35±0 .4 0 )、(3.2 4±0 .4 1)h ;AUC0→16h为(799±176 )、(84 4±2 2 3) μg·h·L-1;AUC0→∞为(84 5±188)、(885±2 2 9) μg·h·L-1。滴丸剂的相对生物利用度为(96 .98±16 .34) %。结论　2种制剂具有生物等效性     

氯雷他定3种制剂生物等效性研究

目的 :评价受试氯雷他定片 (T1)和颗粒(T2 )与参比氯雷他定片 (R)的生物等效性。方法 :2 4名健康男性受试者按体重配对、随机三交叉单次口服氯雷他定 4 0mg ,RT HPLC法测定血浆中药物浓度。结果 :T1,T2 及R的主要药动学参数Tmax分别为 (1.0±s 0 .5 ) ,(1.0± 0 .4 )和 (0 .9± 0 .3)h ;Cmax分别为 (36± 15 ) ,(37± 16 )和 (36± 15 ) μg·L- 1;T1/ 2 分别为 (3.5± 1.0 ) ,(3.6± 0 .8)和 (3.7±1.0 )h ;AUC0 - 12 分别为 (10 9± 4 6 ) ,(110± 5 1)和(10 8± 4 6 ) μg·h·L- 1,AUC0 ∞ 分别为 (118± 5 0 ) ,(12 0± 5 4)和 (119± 5 1) μg·h·L- 1。T1,T2 相对生物利用度分别为 (10 1± 12 ) %和 (10 1± 14 ) %。结论 :T1,T2 与R具有生物等效性。     

国产格列美脲片的药代动力学及相对生物利用度

目的 :研究健康受试者口服国产格列美脲片的人体相对生物利用度及生物等效性。方法 :2 0例健康志愿者采用随机交叉自身对照试验 ,分别单次口服国产及进口格列美脲片剂各 4mg ,用HPLC法检测血药浓度 ,以内标法定量。结果 :国产片与进口片的Cmax分别为 (462 .3± 1 32 .2 )及 (41 2 .4± 1 1 7.7) μg·L- 1 ;Tmax分别为 (3 .2± 0 .6)及(3 .3± 0 .8)h;t1 / 2 分别为 (7.1± 1 .5)及 (7.5± 1 .7)h ;AUC0 -t分别为 (2 571 .6± 564 .9)及 (2 362 .3± 51 9.6) μg·h·L- 1 ;AUC0～∞ 分别为 (2 769.8± 60 8.2 )及 (2 592 .4± 572 .5) μg·h·L- 1 。国产片与进口片比较生物利用度为 (1 1 1 .3±2 3 .3) %。Cmax,AUC0～t及AUC0～∞ 经生物等效性检验均为等效。结论 :国产格列美脲片相对进口品具生物等效性     

2种匹多莫德制剂在健康人体内的生物等效性研究

目的:以进口匹多莫德糖浆为对照,评价国产匹多莫德颗粒生物等效性。方法:20名健康男性志愿者自身交叉单剂量口服匹多莫德颗粒(受试制剂)或糖浆(参比制剂)800mg后,采用高效液相色谱法测定人血浆中匹多莫德的浓度,计算药动学参数,并用DAS2.0药动学程序评价二者等效性。结果:参比制剂与受试制剂的主要药动学参数:t1/2分别为(2.70±0.80)、(2.62±0.84)h,Cmax分别为(4.04±0.59)、(3.87±0.66)μg.mL-1,tmax分别为(2.28±0.44)、(2.13±0.43)h,AUC0～14分别为(22.11±4.20)、(23.00±4.25)mg.h.L-1,AUC0～∞分别为(22.85±4.42)、(23.83±4.52)mg.h.L-1。匹多莫德受试制剂相对于参比制剂的生物利用度为(106.08±22.05)%。结论:匹多莫德颗粒与匹多莫德糖浆生物等效。     

特拉唑嗪滴丸的人体生物等效性

目的　评价单剂量口服两种特拉唑嗪制剂后的人体药动学和生物等效性。方法　采用高效液相色谱-荧光检测方法测定2 0名健康志愿者自身交叉单剂量口服特拉唑嗪滴丸和片剂2mg后的经时血药浓度。采用3P97程序计算药动学参数及相对生物利用度,评价其生物等效性。结果　2 0名受试者口服特拉唑嗪滴丸和片剂后的药动学参数分别为:tmax(0 . 93±0 . 35 )、(0 .95±0 . 39)h ;cmax(5 0 . 0±15 . 3)、(43 .2±13. 3) μg·L-1;MRT (15 . 8±2 . 0 )、(16 . 2±2 .1)h ;T1/2 (11. 3±1 .3)、(11. 4±1 .3)h ;AUC0→3 6h(433±110 )、(40 .0±10 .4 ) μg·h·L-1;AUC0→∞(479±12 .3)、(44 .3±117) μg·h·L-1。经方差分析,两种制剂的药动学参数除cmax和AUC外均无显著性差异。结论　特拉唑嗪滴丸的平均相对生物利用度为(10 9. 4 3±12 . 39) % ,特拉唑嗪滴丸和片剂生物等效。     

枸橼酸莫沙必利口服液与片剂人体生物等效性评价

目的建立测定枸橼酸莫沙必利血浆浓度的高效液相色谱(HPLC)法,并对枸橼酸莫沙必利的口服液与片剂进行人体相对生物利用度和生物等效性研究.方法20名健康志愿者分别单剂量口服枸橼酸莫沙必利口服液或片剂10 mg,HPLC测定血药浓度,采用DAS 1.0程序进行药动学分析,并评价两制剂的生物等效性.结果单剂量口服10 mg枸橼酸莫沙必利口服液和片剂的药动学参数,AUC0→t分别为(170.2±40.7)μg·h·L-1和(176.6±69.4)μg·h·L-1,AUC0→∞分别为(182.2±43.7)μg·h·L-1和(193.2±73.3)μg·h·L-1;Cmax分别为(61.3±17.0)μg·L-1和(58.6±22.0)μg·L-1;tmax分别为(0.60±0.21)h和(0.8±0.4)h.分别以AUC→t与AUC0→∞计算其相对生物利用度分别为(105.8±36.0)%和(102.9±35.1)%.结论两种制剂具生物等效性.     

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.     

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.