液相色谱/质谱联用法测定国产辛伐他汀胶囊人体相对生物利用度

目的:建立辛伐他汀血浆中药物浓度的液质联用测定方法,研究其在人体的药代动力学及生物等效性。方法:18名健康男性受试者随机自身交叉给药,分别口服单剂量国产辛伐他汀胶囊剂和进口片剂20mg。用液相色谱/质谱联用测定血浆中辛伐他汀在人体内的浓度。结果;国产辛伐他汀胶囊剂和进口片剂主要药代动力学参数为:t_(max)分别为2.09±0.41h和2.13±0.47h,C_(max)分别为4.66±2.23μg·L~(-1)和4.71±2.45μg·L~(-1),AUC_(0-t)分别为19.42±3.99μg·h·~(-1)和19.76±4.13μg·h·L~(-1)。国产辛伐他汀胶囊剂的相对生物利用度为(98.3±10.8)％。结论:经统计学分析,国产辛伐他订胶囊剂和进口片剂具有生物等效性。     

国产托瑞米芬片剂人体药代动力学及生物等效性评价

目的 评价国产和进口托瑞米芬片剂在人体生物等效性。方法 用高效液相色谱法测定20名健康受试者po 20 mg托瑞米芬后血浆中托瑞米芬的浓度。结果 国产托瑞米芬片剂和进口片剂的t_(max)分别为3.15±0.37和3.00±0.65 h,C_(max)分别为1.73±0.32和1.74±0.25 mg·L~(-1),AUC_(0-504)分别为114.41±20.04和112.73±19.92mg·h·L~(-1),t_(1/2)分别为114.12±9.16和114.32±7.38 h,国产托瑞米芬片剂相对生物利用度为(102.4±14.0)％。结论 经统计学分析,国产托瑞米芬片剂和进口片剂具有生物等效性。     

格列美脲片人体药代动力学及相对生物利用度研究

目的研究国产格列美脲片剂的药代动力学和相对生物利用度.方法18名健康志愿者随机交叉单剂量口服国产与进口格列美脲4mg,采用柱前衍生化HPLC-紫外法测定其血药浓度.结果国产片与进口片的主要药代动力学参数tmax分别为3.44±0.92和2.97±0.88h,Cmax分别为296.1±108.4和331.8±103.3μg·L-1,t1/2ke分别8.03±3.01和7.73±2.79h,AUC0-t分别为2307.9±800.9和2302.8±794.8μg·h·L-1,AUC0-∞分别为2672.7±990.5和2589.1±752.5μg·h·L-1.国产片的相对生物利用度为102.4%±19.7%.结论统计学结果显示,两种片剂具有生物等效性.     

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20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:AUC_0-t分别为(52±21)μg·h·L^-1和(51±20)μg·h·L^-1,T_max分别为(2.9±0.9)h和(2.6±0.7)h,C_max分别为(6.0±2.6)μg·L^-1和(6.2±2.9)μg·L^-1。特布他林:AUC_0-t分别为(191±30)μg·h·L^-1和(197±37)μg·h·L^-1,T_max分别为(4.2±1.0)h和(4.2±1.0)h,C_max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102%±8%(班布特罗),100%±12%(特布他林)。结论经统计学证明两制剂有生物等效性。     

液质联用研究5—单硝酸异山梨醇酯缓释胶囊人体生物等效性

目的评价国产和进口5-单硝酸异山梨醇酯缓释胶囊在人体生物等效性研究.方法18名健康受试者随机交叉给药,分别单次(40mg)及多次口服进行人体生物等效性研究,用液相色谱/质谱联用测定血浆中5-单硝酸异山梨醇酯的浓度.结果经数据处理,单次口服国产和进口5-单硝酸异山梨醇酯缓释胶囊的AU0-36分别为7490±1144μg·h·L和7355±1007μg·h·L-1,tpeak分别为4.92±1,31h和4.67±0.79h,Cmax分别为519.15±60.53μg·L-1和523.67±68.99μg·L-1;多次口服达稳态时AUC0-36分别为8514±1318μg·h·L-1和8586±836μg·h·L-1,tpeak分别为4.83±0.94h和4.75±1.14h,Cmax分别为570.44±78.89μg·L-1和580.43±64.04 μ g·L-1,波动系数FI分别为135.10±15.53%和134.82±9.71%.国产5-单硝酸异山梨醇酯缓释胶囊单次给药及多次给药稳态时的相对生物利用度分别为101.9±7.3%和99.1±11.9%.结论单次及多次给药所得梯形法计算的两者的AUC0-36、Cmax、tpeak进行方差分析和双单侧检验结果表明两者具有生物等效性.     

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.     

克拉霉素分散片的相对生物利用度

目的 :比较国产克拉霉素分散片与进口克拉霉素片 (克拉仙 )的相对生物利用度。方法 :采用微生物法测定8名健康男性志愿者随机单剂量口服两种片剂500mg后 ,药物在体内的经时过程。结果 :药 -时曲线符合一级吸收二室模型 ,国产分散片与进口片AUC分别为 (18 58±5 46) μg/(h·ml)和 (19 05±5 75) μg/(h·ml) ;Cmax 分别为 (2 88±0 74) μg/ml和 (2 74±0 65) μg/ml;Tmax 分别为 (1 28±0 41)h和 (1 47±0 51)h ,分散片的相对生物利用度为 (98 49±16 00) %。结论 :国产克拉霉素分散片与进口克拉霉素普通片生物等效。     

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     

环酯红霉素干混悬剂、胶囊与片剂的生物等效性研究

目的:评价环酯红霉素干混悬剂、胶囊与片剂的生物等效性。方法:18名健康志愿者采用开放、随机、三周期交叉的单中心试验。采用HPLC-MS法测定口服给药后不同时间环酯红霉素的血药浓度。利用DAS 2．0计算药动学参数和进行统计分析。结果:受试者口服750 mg参比制剂环酯红霉素片,受试制剂环酯红霉素干混悬剂和胶囊的C_(max)分别为(1375±s 261)Ixg·L~(-1),(1303土356)μg·L~(-1)和(1307±305)μg·L~(-1);t_(max)分别是(2．4±0．8)h,(2．4±1．0)h和(2．9±0．9)h;4UC_(0～48)分别是(13302±4 369)μg·h·L~(-1),(13596±5519)μg·h·L~(-1)和(13564±4 825)μg·h·L~(-1)。受试制剂的相对生物利用度分别为(102±17)％,(102±15)％。结论:环酯红霉素干混悬剂和胶囊与剂量相同的环酯红霉素片参比制剂具有生物等效性。     

舒马普坦胶囊和片剂人体药物动力学及相对生物利用度研究

目的 研究国产舒马普坦胶囊、片剂在人体内的药物动力学及相对生物利用度。方法 采用随机、开放、3×3拉丁方设计,18名男性健康受试者分别单剂量口服试验制剂或参比制剂100 mg。采用HPLC-MS法测定给药后不同时间的血药浓度,采用双单侧t检验进行生物等效性判断。结果 进口参比制剂中舒马普坦的主要药物动力学参数Cmax为(41.68±18.38)μg·L-1;tmax为(2.08±0.65)h;AUC0→12为(152.14±61.63)μg·h·L-1;t1/2为(2.7±0.8)h。国产舒马普坦胶囊的主要药物动力学参数Cmax为(38.01±17.01)μg·L-1;tmax为(1.83±0.45)h;AUC0→12为(136.68±60.71)μg·h·L-1;t1/2为(2.7±1.0)h。国产舒马普坦片剂的主要药物动力学参数Cmax为(38.78±17.67)μg·L-1;tmax为(1.83±0.45)h;AUC0→12为(136.68±60.71)μg·h·L-1;t1/2为(2.7±1.0)h。国产胶囊剂和国产片剂对进口片剂的相对生物利用度分别为91.0％±14.8％和92.0％±11.6％。结论 经统计学分析,国产舒马普坦片剂和胶囊剂与进口制剂具有生物等效性,制剂间药物动力学参数无显著差异。     

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.