格列吡嗪片在健康志愿者体内的生物等效性评价

目的比较两种格列吡嗪片剂在健康志愿者体内的药动学及生物等效性.方法12例男性健康志愿受试者,采用标准两周期交叉设计自身对照试验法,单剂量口服进口和国产格列吡嗪片10mg,以高效液相色谱法测定血浆中格列吡嗪的经时浓度,以双单侧t检验统计法比较两种格列吡嗪片之间的差异.结果两种格列吡嗪片在健康志愿者体内的药-时曲线均符合一级吸收的单室模型,国产格列吡嗪片主要的药动学参数Tmax、Cmax和AUC(0-17)分别为(2.6±0.5)h,(609.7±112.9)ng·ml-1和(4499.8±969.0)ng·h-1·ml-1;进口格列吡嗪片主要的药动学参数Tmax、Cmax和AUC(0-17)分别为(2.6±0.5)h,(568.8±101.9)ng·ml-1和(4108.3±724.9)ng·h·     

地红霉素片的人体药代动力学及生物利用度研究

目的　考察国产与进口地红霉素片的药代动力学及生物等效性。方法　采用随机单剂二交叉试验设计,18名健康男性志愿者单剂口服国产与进口地红霉素片 75 0mg,微生物法测定地红霉素血浓度。对二种制剂的主要药代动力学参数进行方差分析、双向单侧t检验,评价试验制剂与参比制剂的生物等效性。结果　国产和进口地红霉素片主要药代动力学参数t1/2ke分别为 19 77± 4 5 1h和 18 5 7± 3 39h,Tpeak分别为 3 89± 0 76h和 3 83± 0 5 1h,Cmax分别为 1 6 12± 0 176 μg·ml-1和1 6 85± 0 10 8μg·ml-1,AUC0～ 96h分别为 11 4 0± 1 88μg·ml-1·h和 11 0 5± 1 84 μg·ml-1·h,AUC0～∞ 分别为 12 14± 2 11μg·ml-1·h和 11 6 6± 1 88μg·ml-1·h,国产地红霉素片相对生物利用度F为 10 3 79%± 10 5 2 %。结论　国产与进口地红霉素片为生物等效制剂。     

国产左甲状腺素钠片剂生物利用度研究

目的采用开放随机原则对国产的两种规格(50μg和100μg)的左甲状腺素钠片与进口左甲状腺素钠片进行相对生物利用度及等效性检验研究,旨在观察片剂质量,为临床应用提供依据.方法21名健康男性受试者参加了单剂量(600μg)三周期交叉试验并用放免分析法测定给药后不同时间点血清药物浓度.结果试验药AUC0-t分别为10.13±1.84μmo1·h-1.L-1和10.30±1.42μmo1·h-1·L-1,参比药AUC0-t为9.37±1.27μmo1·h-1·L-1;试验药Cmax分别为197.57±27.40 nmol.L-1和191.10±27.35nmo1·L-1,参比药Cmax为169.48±22.83 nmo1·     

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%     

胆道手术病人中头孢曲松钠的药动学

目的研究头孢曲松钠(CTRX)在6例施各类胆道手术附胆总管引流患者的药动学.方法采用微生物学的方法测定血清及胆汁中头孢曲松钠浓度.结果静滴头孢曲松钠3g或2g即刻血药浓度分别可达到(470.9±23.4)μg·ml-1和(288.1±14.3)μg·ml-1,8h后仍保持(91.7±5.1)μg·ml-1和(54.6±4.2)μg·ml-1;T型管胆汁药物峰浓度可达到(1645.81±201.3)μg·ml-1和(1123.8±140.4)μg·     

盐酸黄连素对肾移植受者环孢素A增效作用的临床药代动力学研究

目的研究盐酸黄连素对肾移植受者使用环孢素A增效作用的体内动力学过程.方法选择肾移植术后1个月以内、连续服用环孢素A 2周、肝肾功能稳定的患者6名,环孢素A剂量6mg.kg-1·d-1,用FPIA方法(单抗)检测合用黄连素前后各时间点环孢素A全血浓度.结果单服环孢素A的主要药代动力学参数分别为tmax(h)1.33±0.52,Cmax(μg·L-1)1224.75±296 20,Cmin(μg·L-1)173.95±78.71,t1/2(h)2.62±1.00,AUC μg·h·L-14681.34±1300.45,CL/F(L·h-1)35±15;与黄连素合用的主要药代动力学参数为tmax(h)3.00±1.26,Cmax(μg·L-1)1050.10±290.86,Cmin(μg·L-1)321.31±161.29,t1/2(h)5.33±2.60,AUCμg·h·L-16265.71±1 871.33,CL/F(L·     

母乳中甲硝唑、替硝唑药动学及产妇合理哺乳时间

目的确定产后静滴甲硝唑及替硝唑乳妇合理的哺乳时间,避免乳汁中药物对婴儿的不良反应.方法采用高效液相色谱法测定乳汁药物浓度,并计算其药动学参数.结果哺乳妇女单剂量静滴甲硝唑(20mg·kg-1,n=8)﹑、替硝唑(13mg·kg-1,n=7)乳汁中药动学参数达峰时(Tmax)、峰浓度(Cmax)、消除半衰期(T1/2ke)分别是(1.7±1.0)h,(20.1±5.0)μg·ml-1,(6.4±3.3)h和(1.3±0.6)h,(17.2±3.1)μg·ml-1,(11.0±3.5)h.结论静滴甲硝唑(20mg·kg-1)的乳妇宜于给药后3～4h哺乳;静滴替硝唑(13mg·     

替米沙坦片在健康人体的药代动力学和相对生物利用度

目的研究国产和进口替米沙坦片在健康人体的药代动力学并评价2制剂的生物等效性。方法20名健康志愿者单次、交叉口服替米沙坦片80mg后,用高效液相色谱-荧光检测法测定血浆替米沙坦浓度。用3P97药代动力学软件计算药代动力学参数。结果2种替米沙坦片在健康志愿者体内的药-时曲线均符合二室模型,2种制剂的主要药代动力学参数:Cmax分别为(944.71±376.08),(852.72±333.78)ng·mL-1;tmax分别为(0.98±0.60),(1.28±0.65)h;t1/2β分别为(28.78±13.88),(25.83±9.25)h;AUC0-t分别为(4.14±2.44),(3.83±1.97)mg·h·L-1;AUC0-∞分别为(4.64±2.84),(4.17±2.22)mg·h·L-1。国产对进口制剂的平均相对生物利用度F0-t为(99.64±23.93)%,F0-∞为(97.97±26.20)%。结论国产和进口替米沙坦片剂为生物等效制剂。     

国产与进口托烷司琼胶囊的人体生物等效性

目的:评价国产和进口托烷司琼胶囊的生物等效性。方法:采用双周期两制剂交叉试验设计,用LC-MS/MS法对国产和进口托烷司琼胶囊在20名中国健康男性受试者中的血药浓度进行测定。药动学参数用ANOVA处理。结果:国产与进口托烷司琼胶囊的AUC0-→t分别为:(543.61±415.55),(547.04±455.59)μg·h·L-1;AUC0→∞分别为(573.30±439.11),(591.77±513.15)μg·h·L-1;cmax为分别(39.13±14.45),(37.44±14.30)μg·L-1;tmax分别为(1.61±0.71),(1.85±0.79)h;T1／2分别为(9.69±4.81),(9.77±5.51)h。国产托烷司琼胶囊的相对生物利用度为(106.47±24.07)％(n=20)。2组参数cmax,AUC0→t经对数转换后,行方差分析和双单侧t检验,均未见统计学意义。结论:托烷司琼国产的制剂与进口制剂具有生物等效性。     

国产醋氯芬酸胶囊剂与片剂人体相对生物利用度研究

目的评价国产醋氯芬酸胶囊剂、片剂和进口醋氯芬酸片剂3种制剂的生物等效性.方法18名健康男性志愿者按3个周期拉丁方交叉口服单剂量(100mg) 醋氯芬酸制剂,用HPLC法测定血清中醋氯芬酸的浓度,并对试验数据进行统计处理及对3种制剂进行生物等效性评价.结果口服国产待测胶囊剂、片剂及进口醋氯芬酸片剂的Cmax分别为(9.85±3.21),(10.11±3.50)及(8.68±2.65)μg@mL-1;Tmax分别为(1.83±1.00),(2.31±1.25)及(2.42±1.29)h;AUC0～12h分别为(27.09±5.90),(28.16±6.47)及(26.00±4.87)μg@h@mL-1;AUC0～∞分别为(28.29±6.03 ),(29.39±6.66)及(27.11±5.15)μg@h@mL-1;国产醋氯芬酸胶囊、片剂的相对生物利用度为(104.83±15.54)%和(108.97±17.35)%.结论国产胶囊剂、片剂均与进口参比醋氯芬酸片剂具有生物等效性.     

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.