地洛他定胶囊人体药动学和生物等效性评价

目的研究地洛他定胶囊和地洛他定片在人体的药动学和生物等效性.方法 20名健康受试者随机交叉单剂量口服地洛他定胶囊或地洛他定片20 mg后,采用高效液相色谱-质谱联用(HPLC-MS)测定血浆中地洛他定的经时血药浓度,计算其药动学参数和相对生物利用度,评价两种制剂的生物等效性.结果经3P97拟合,两者的体内过程皆符合口服给药一室模型,采用梯形法计算的两者AUC 0-72分别为(238.22±57.18) μg·h·L-1和( 247.66±73.34) μg·h·L-1,Cmax均值分别为(13.70±4.27) μg·L-1和(14.31±4.53) μg·L-1,tmax均值分别为(2.2±0.7)h和(2.3±0.9)h,地洛他定胶囊对地洛他定参比片的相对生物利用度为(96.4±6.3)%.结论两种制剂具有生物等效性.     

左羟丙哌嗪口崩片在健康志愿者的生物等效性

目的:建立HPLC-荧光法测定人血浆中左羟丙哌嗪浓度,研究左羟丙哌嗪口崩片的人体生物利用度和生物等效性.方法:健康男性志愿者20名,随机交叉单剂量17服左羟丙哌嗪17崩片和参比制剂左羟丙哌嗪胶囊,以HPLC法测定血药浓度,DAS软件计算药动学参数与生物等效性.结果:单剂量口服受试制剂和参比制剂后的主要药动学参数Gmax分别为(326.5±106.4)μg·L-1和(289.5±101.0)μg·L-1;tmax分别为(0.48±0.17)h和(0.57±0.19)h;t1/2分别为(3.6±1.3)h和(3.5±1.3)h;AUCo-t分别为(1 089.3±274.7)/μg·h·L-1和(1 164.9±310.2)μg·h·L-1;AUCo-∞分别为(1 158.3±300.5)μg·h·L-1和(1 241.6±297.5)μg·h·L-1;受试制剂的相对生物利用度为(95.6±7.3)%.结论:左羟丙哌嗪口崩片和参比制剂具有生物等效性.     

西洛他唑片在健康志愿者体内的药动学及生物等效性

目的:研究国产西洛他唑片在人体的药动学和生物等效性.方法:20名男性健康志愿者随机交叉单剂量口服西洛他唑受试和参比制剂(Pletaal)100mg,采用反相高效液相色谱法测定其血药浓度,计算其药动学参数和相对生物利用度,评价两种制剂的生物等效性.结果:西洛他唑受试和参比制剂的主要药动学参数:t1/2分别为(11.9±4.6)h和(11.2±3.0)h,Tmax分别为(3.7±1.2)h和(4.0±1.2)h,Cmax分别为(749.2±348.7)μg·L-1和(655.2±222.1)μg·L-1,AUC0-48分别为(10 088.5±4 606.1)μg·L-1·h和(9 259.0±3 511.8)μg·L-1·h,AUC0-∞分别为(10 926.3±4 713.6)μg·L-1·h和(10 183.4±3 540.7)μg·L-1·h,西洛他唑受试制剂的相时生物利用度为(107.5±14.9)%.结论:经统计学分析,两种制剂具有生物等效性.     

枸橼酸他莫昔芬胶囊的人体生物等效性

目的:研究枸橼酸他莫昔芬胶囊在人体的相时生物利用度和生物等效性.方法:20名健康男性受试者,采用双周期交叉、自身对照试验设计,分别单剂量口服枸橼酸他莫昔芬受试和参比制剂各40 mg,采用液相色谱-串联质谱法测定其血药浓度,应用DAS软件计算药动学参数和相对生物利用度,评价2种制剂的生物等效性.结果:枸橼酸他莫昔芬受试和参比制剂的主要药动学参数:t1/2分别为(53.5±14.4)h和(51.7±8.9)h;tmax分别为(3.9±0.9)h和(4.0±1.1)h;Cmax分别为(108.1±19.8)μg·L-1和(101.3±16.5)μg·L-1;AUC0-72分别为(3 073.7±439.1)μg·h·L-1和(3148.8±373.7)μg·h·L-1;AUC0-∞分别为(5 074.8±1 082.2)μg·h·L-1和(5 121.2±902.0)μg·h-1.方差分析结果表明,2种制剂的主要药动学参数之间差异无显著性.枸橼酸他莫昔芬受试制剂的相对生物利用度为(97.9±10.8)%.结论:经统计学分析,两种制刑具有生物等效性.     

奥昔布宁缓释胶囊与普通片的药动学及生物等效性

目的 研究健康志愿者单剂量和多剂量口服奥昔布宁缓释胶囊后的药动学特征,并评价奥昔布宁缓释胶囊与奥昔布宁普通片是否生物等效,为临床合理用药提供参考依据.方法 20名健康志愿者分别单剂量、多剂量口服试验缓释胶囊和参比普通片剂,于规定时间点取血,以LC-MS联用法测定奥昔布宁血药浓度,采用3P97软件计算各制剂单剂量和多剂量给药后的药动学参数.结果 单剂量给药,奥昔布宁缓释胶囊和普通片的ρmax分别为(8.27±7.28)μg·L-1和(17.16±12.17)μg·L-1;tmax分别为(2.55±0.85)h和(0.82±0.35)h;t1/2分别为(6.23±2.78)h和(5.54±2.18)h;AUC0→t分别为(51.94±40.27)μg·h·L-1和(49.8±434.33)μg·h·L-1;AUC0→∞.分别为(57.25±40.78)μg·h·L-1和(54.68±36.44)μg·h·L-1.奥昔布宁缓释胶囊相对于普通片生物利用度F0→1为(104.15±15.47)%.多剂量给药,奥昔布宁缓释胶囊和普通片的ρss max分别为(24.00±10.41)μg·L-1和(15.37±8.00)μg·L-1;ρss min分别为(1.59±0.80)μg·L-1和(1.33±0.80)μg‘L-1;ρss av分别为(5.01±2.22)μg·L-1和(2.49±1.17)μg·L-1;AUCss分别为(120.19±53.24)μg·h·L-1和(59.85±28.01)μg·h·L-1;DF分别为(446.23±135.27)%和(579.75±148.10)%;奥昔布宁缓释胶囊波动度明显小于普通片.结论 试验制剂具有缓释作用.试验制剂与参比制剂的ρmax生物不等效,但AUC0→t生物等效.     

美洛昔康片、胶囊人体药动学及相对生物利用度

目的:研究健康人口服美洛昔康片、胶囊的人体药动学及相对生物利用度.方法:18例健康志愿者按照三制剂,三周期随机交叉试验设计,分别单剂量口服国产美洛昔康(试验片、试验胶囊)及进口美洛昔康(参比片)各15mg,采用RP-HPLC紫外法检测血药浓度.结果:口服试验片、试验胶囊及参比片Cmax分别为(2.28±0.29),(2.01±0.33)和(2.04±0.47)μg·L-1,Tmax分别为(4.67±2.85),(4.78±3.21)和(5.78±2.96)h;t1/2分别为(26.11±12.21),(25.77±11.22)和(28.27±12.99)h;AUC0～∞分别为(87.09±38.76),(82.10±29.56)和(83.60±33.09)μg·h·L-1.试验片、试验胶囊生物利用度分别为(106.2±21.1)%和(102.6±22.8)%.结论:试验片、试验胶囊与参比片的药动学参数均无显著性差异,两制剂具有生物等效性.     

马来酸依那普利片的健康人体生物等效性

目的:研究马来酸依那普利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名,随机双交叉单剂量口服马来酸依那普利片试验制剂和参比制剂,剂量分别为20 mg,用高效液相色谱(HPLC)法测定血浆中依那普利的浓度.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.结果:受试制剂与参比制剂的Cmax分别为(272.6±42.2)μg·L-1和(263.5±42.2)μg·L-1;tmax分别为(0.81±0.11)h和(0.80±0.10)h;AUC(0-∞)分别为(664.7±105.1)μg·h·L-1和(661.2±99.5)μg·h·L-1)AUC(0-inf)分别为(698.0±116.3)μg·h·L-1和(689.0±106.0)μg·h·L-1.试验制剂与参比制剂的人体相对生物利用度为(102.3±19.7)%,结论:试验制剂与参比制剂具有生物学等效性.     

国产与进口替莫唑胺胶囊在Beagle犬体内的生物等效性研究

目的:研究国产与进口替莫唑胺胶囊在Beagle犬体内的药动学及生物等效性。方法:6只Beagle犬随机交叉单剂量口服进口替莫唑胺胶囊(参比制剂)和国产替莫唑胺胶囊(受试制剂),采用HPLC法测定犬血浆中替莫唑胺的浓度,Bapp 3.0软件计算其主要药动学数据,并进行两种制剂的等效性评价。结果:参比制剂与受试制剂的Cmax分别为(11.35±1.35)和(11.70±2.77)μg·m L-1;Tmax分别为(0.97±0.56)和(1.08±0.49)h;t1/2β分别为(1.44±0.37)和(1.43±0.24)h;AUC0~t分别为(27.34±2.30)和(28.34±7.47)μg·h·m L-1,AUC0~∞分别为(29.85±4.49)和(30.85±8.46)μg·h·m L-1。受试制剂对参比制剂的相对生物利用度为(106.1±36.1)%。结论:本实验结果表明,两种替莫唑胺胶囊在Beagle犬体内具有生物等效性。     

扎来普隆片的人体药动学及生物等效性评价

目的:评价扎来普隆片的生物等效性.方法:20例健康志愿者随机交叉自身对照,单剂量口服扎来普隆片剂和胶囊10mg后,血浆样品经液-液萃取后,以液相色谱荧光检测法测定浓度,进行人体相对利用度及生物等效性研究.结果:受试制剂扎来普隆片及参比制剂扎来普隆胶囊的Cmax分别为(35.01±9.01)和(34.63±12.75)μg·L-1,Tmax分别为(0.72±0.40)和(0.73±0.30)h,t1/2分别为(1.04±0.21)和(1.09±0.39)h,AUC0-t分别为(75.31±26.35)和(74.54±37.13)μg·h·L-1,主要药动学参数均无显著性差异(P>0.05 ).受试制剂与参比制剂的相对生物得用度为(105.94±17.69)%.结论:扎来普隆片与扎来普隆胶囊具有生物等效性.     

盐酸曲美他嗪胶囊的人体生物等效性

目的 评价国产盐酸曲美他嗪胶囊和进口盐酸曲美他嗪包衣片的人体生物等效性.方法 20名健康男性受试者按两制剂两周期的交叉试验设计单剂量口服20 mg的参比制剂和受试制剂后,采用LE-MS法测定血浆中盐酸曲美他嗪的浓度,使用DAS 1.0软件计算药动学参数并进行生物等效性统计分析.结果 参比制剂和受试制剂的ρmax分别为(55.9±9.2)和(56.4±12.2)μg·L-1;tmax分别为(2.5±0.8)和(2.7±0.9)h;AUC0→24h分别为(493.8±82.8)和(489.8±108.4)μg·h·L-1;AUC0→∞分别为(513.7±88.6)和(510.1±116.8)μg·h·L-1;t1/2分别为(4.8±0.4)和(4.7±0.4)h.双单侧t检验结果显示受试制剂的ρmax、AUC0→24h的90%置信区间分别为参比制剂相应参数的92.0%～108.4%和91.5%～105.3%,受试制剂的相对生物利用度为(99.6±16.5)%(以AUC0→24h计算).结论 国产盐酸曲美他啶胶囊与其进口包衣片具有生物等效性.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

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.