马来酸替加色罗分散片的人体生物等效性研究

目的:研究马来酸替加色罗分散片的人体生物等效性。方法:22名健康男性志愿者随机交叉单剂量口服马来酸替加色罗分散片(受试制剂)和马来酸替加色罗片(参比制剂)6mg,采用LC/MS/MS法测定人血浆中药物浓度。结果:受试制剂和参比制剂的tmax分别为(0.86±0.22)、(1.01±0.24)h,Cmax分别为(2.21±0.69)、(2.05±0.64)ng.mL-1,AUC0~17分别为(6.35±2.48)和(6.47±1.99)ng.h.mL-1,AUC0~∞分别为(6.69±2.59)、(6.70±2.03)ng.h.mL-1。受试制剂相对于参比制剂的生物利用度为(98.2±22.1)%。结论:两种制剂具有生物等效性。     

高效液相色谱-串联质谱法测定人血浆中替加色罗的浓度

目的:建立人血浆中替加色罗浓度的高效液相色谱-串联质谱测定方法。方法:血浆样本经固相萃取(solid-phase extraction,SPE)小柱提取处理后进行色谱分离,质谱条件为电喷雾电离源,采用多反应监测(multiplereaction monitoring,MRM)方式进行定量分析,用于监测的离子为m/z302.1→172.8(替加色罗)和m/z466→183.8(内标,西沙必利)。结果:血浆中替加色罗检测方法的线性范围为0.1~50 ng.mL-1,最低定量限为0.1 ng.mL-1。血浆中替加色罗的绝对回收率为99.4%~104.2%,日内及日间精密度分别低于5%和6%,符合生物样品分析要求。结论:本法灵敏,准确,可用于替加色罗的药动学及生物等效性的研究。     

马来酸替加色罗胶囊与其片剂的人体生物等效性

目的研究马来酸替加色罗胶囊与其片剂的生物等效性。方法20名健康男性受试者随机交叉给药,分别单次口服受试药马来酸替加色罗胶囊和参比药马来酸替加色罗和片剂12 mg,采用LC-MS法测定替加色罗的血浓度。结果替加色罗胶囊与其片剂AUC0→24 h分别为(21.46±2.659)(、21.013±2.842)μg.h.L-1;AUC0→∞为(23.968±2.997)(、23.804±3.404)μg.h.L-1;ρmax为(4.835±1.103)(、4.863±1.164)μg.L-1;tmax为(1.288±0.383)(、1.250±0.292)h;t1/2为(8.373±1.133)(、8.867±1.052)h。马来酸替加色罗胶囊相对生物利用度为(102.183±2.338)%。方差分析显示制剂间、周期间各参数差异无统计学意义(P>0.05),但个体间存在差异。双单侧t检验和(1-2α)置信区间分析示2制剂符合生物等效的假设。结论马来酸替加色罗胶囊与其片剂为生物等效制剂。     

恩替卡韦分散片的健康人体相对生物利用度及生物等效性研究

目的:以中美上海施贵宝制药有限公司生产的恩替卡韦片(博路定)为参比制剂,研究江苏正大天晴药业股份有限公司研制的恩替卡韦分散片受试制剂的相对生物利用度,以判断两种制剂是否具有生物等效性。方法:采用随机双交叉试验设计,20例男性健康受试者禁食过夜后空腹单剂量口服恩替卡韦0.5mg,液相色谱-串联质谱法(LC-MS/MS)测定血浆中恩替卡韦的浓度,应用药物与统计(DrugAndStatistics,DAS)程序计算有关药动学参数并评价两种制剂的生物等效性。结果:单剂量口服受试制剂和参比制剂的主要药动学参数Cmax分别为(5.15±1.35)和(4.55±2.46)ng.mL-1;Tmax分别为(0.44±0.20)和(0.75±0.31)h;t1/2分别为(147±127)和(127±48)h;AUC0～96分别为(13.7±2.6)和(13.0±1.9)ng.h.mL-1;AUC0～∞分别为(27.2±13.8)和(23.3±4.5)ng.h.mL-1;相对生物利用度为(107.5±24.7)%。两制剂的AUC0～96无显著性差异,Cmax和Tmax有显著性差异。结论:两制剂吸收程度等效;与参比制剂比较,受试制剂...     

替吉奥胶囊(S-1)在中国癌症患者体内的药代动力学和生物等效性

目的 研究替吉奥胶囊(S-1,抗肿瘤药)在中国癌症患者体内的药代动力学特性并评价其生物等效性.方法 21名癌症患者随机交叉单剂量口服替吉奥胶囊(受试制剂)和爱斯万(参比制剂)各50 mg后,采用液相色谱-串联质谱法测定血浆中替加氟、5-氟尿嘧啶、吉美嘧啶和奥替拉西的浓度,并进行药代动力学和生物等效性研究.结果 受试者口服受试制剂和参比制剂后,血浆中替加氟的Cmax分别为(1887.0±491.0)和(1876.0±522.0)ng·mL-1;t1/2分别为(11.5±5.3)和(11.6±5.0)h;AUC0-t分别为(20.8±9.6)和(19.8±10.0)μg·h·mL-1.5-氟尿嘧啶的Cmax分别为(121.8±44.3)和(119.7±45.1)ng·mL-1;t1/2分别为(2.2±1.8)和(2.1±1.6)h;AUC0-t分别为(591.2±176.2)和(580.1±186.9)ng·h·mL-1.吉美嘧啶的Cmax分别为(304.6±107.3)和(297.2±103.6)ng·mL-1;t1/2分别为(4.1±1.8)和(4.0±2.5)h;AUC0-t分别为(1458.0±1094.0)和(1410.0±1043.0)ng·h·mL-1.奥替拉西Cmax分别为(77.4±77.3)和(79.9±73.4)ng·mL-1;t1/2分别为(4.7±2.7)和(4.3±2.0)h;AUC0-t分别为(403.7±333.2)和(427.8±377.3)ng·h·mL-1.受试制剂中替加氟、5-氟尿嘧啶、吉美嘧啶和奥替拉西的相对生物利用度分别为(108.1±23.6)%,(104.9±24.2)%,(107.2±23.9)%和(103.4±39.0)%.结论 AUC0-t、AUC0-∞和Cmax经对数转换后,应用方差分析法、双单侧t检验及90%信区间判断,2制剂具有生物等效性.     

尼美舒利分散片在健康人体内的药代动力学及生物等效性的LC-MS/MS研究

目的:建立人血浆中尼美舒利浓度的LC-MS/MS测定法,并用于尼美舒利分散片的药代动力学和生物等效性研究。方法:采用自身双交叉试验设计,20名男性受试者随机分成2组,分别单剂量口服100 mg受试制剂或参比制剂,0～24 h间隔采集血样。以LC-MS/MS内标法测定尼美舒利血药浓度,使用Agilent TC-C18色谱柱(250 mm×4.6 mm,5μm),流动相为甲醇-0.1%甲酸溶液(82∶18,v/v);多反应监测[M+H]+离子通道分别为m/z 309.1→m/z 153.9(尼美舒利)和m/z 237.1→m/z 194.0(内标卡马西平),DAS 2.1计算药动学参数。结果:建立的LC-MS/MS法在0.075～12μg·mL-1范围内色谱响应与浓度相关性良好,最低定量限为0.075μg·mL-1,批内及批间精密度RSD均小于15%。受试制剂与参比制剂的Tmax分别为(3.0±0.7)h和(3.5±1.0)h,Cmax分别为(4.863±1.194)μg·mL-1和(4.657±1.038)μg·mL-1,t1/2分别为(3.2±1.0)h和(3.3±1.1)h,AUC0-24 h分别为(32.35±12.50)h·μg·mL-1和(32.32±11.69)h·μg·mL-1,相对生物利用度F为(105.2%±35.0)%。结论:建立的LC-MS/MS法准确、灵敏,结果可靠,测得尼美舒利受试制剂和参比制剂生物等效。     

液相色谱-串联质谱法测定人血浆氯吡格雷浓度及其生物等效性评价

目的:建立液相色谱-串联质谱法(LC-MS/MS)测定人血浆中氯吡格雷的浓度,研究2种硫酸氢氯吡格雷片的人体药动学及相对生物利用度。方法:血浆样品中加入内标美利曲辛,经乙腈沉淀蛋白提取,采用液相色谱-串联质谱法。用建立的方法测定20例健康男性受试者单剂量口服硫酸氢氯吡格雷受试制剂或参比制剂后的血药浓度,求得药动学参数,并对2种制剂的生物等效性进行评价。结果:在0.02～20 ng·mL-1内呈良好的线性关系,方法回收率98.4%～103.2%,日内、日间RSD均小于15%。单次口服75 mg硫酸氢氯吡格雷受试制剂或参比制剂后的Cmax分别为(1.9±1.5)ng·mL-1和(1.8±1.1)ng·mL-1;tmax分别为(0.8±0.5)h和(1.0±0.8)h;t1/2分别为(3.4±1.6)h和(3.5±1.5)h;AUC(0-48)分别为(4.4±4.3)h·ng·mL-1和(4.4±4.6)h·ng·mL-1;AUC(0-∞)分别为(4.7±4.4)h·ng·mL-1和(4.7±4.7)h·ng·mL-1。受试制剂对参比制剂的相对生物利用度为(98.2±32.8)%。结论:该方法灵敏,无杂质干扰。测得的受试制剂与参比制剂的主要药动学参数之间无明显差异,表明2种制剂在人体内生物等效。     

克拉霉素分散片的健康人体生物等效性研究

目的:研究克拉霉素分散片在健康人体的药动学及生物等效性.方法:采用两制剂双周期双交叉前后自身对照试验设计.20名健康志愿者分别口服克拉霉素分散片受试制剂或参比制剂500 mg,采用高效液相色谱-质谱法(LC-MS)测定血浆中克拉霉素的浓度,经DAS 2.1软件处理后得药动学数据,并进行等效性检验.结果:受试制剂的t1/2为(3.72±0.42)h,Cmax为(2 350.7±604.2)ng·mL-1,Tmax为(1.48±0.36)h,AUC0-t为(12 425±1 975)ng·h·mL-1;参比制剂的t1/2为(4.22±1.15)h,Cmax为(2 045.0±379.5)ng·mL-1,Tmax为(1.76±0.52)h,AUC0-t为(11 954±2 152)ng·h·mL-1.以AUC0-t计算,与参比制剂比较,受试制剂平均相对生物利用度为(101.7±7.3)%,AUC0-t,AUC-∞和Cmax均拒绝生物不等效假设.结论:测定结果经方差分析及双单侧t检验,表明两种制剂具有生物等效性.     

进口与国产利培酮薄膜衣片在健康志愿者的生物等效性

目的 研究利培酮薄膜衣片(抗精神分裂症药)在健康志愿者的药代动力学和生物等效性.方法 23名健康男性志愿者随机交叉、单剂量口服受试制剂(进口)和参比制剂(国产)2 mg后,用HPLC-MS/MS测定血浆中利培酮及9-羟基利培酮浓度,计算主要药代动力学参数,评价2种制剂的生物等效性.结果 受试制剂和参比制剂的主要药代动力学参数,利培酮:AUC0～t分别为(94.76±82.93)和(103.05±117.71)ng·h·mL-1;AUC0～1分别为(96.72±84.52)和(105.19±119.36)ng·h·mL0-1;Cmax分别为(15.91±5.63)和(16.21±11.56)ng·mL-1;tmax分别为(1.14±0.73)和(1.15±0.54)h;t1/2分别为(7.32±5.94)和(7.44±6.50)h,受试制剂的相对生物利用度为(106.68±40.21)%.9-羟基利培酮:AUC0-96h分别为(268.56±85.20)和(279.64 ±117.86)ng·h·mL-1;AUC0-∞分别为(282.74±87.46)和(294.28±120.32)ng·h·mL-1;Cmax分别为(10.84±4.69)和(11.11±4.80)ng·mL-1;tmax分别为(3.35±2.32)和(4.48±2.76)h;t1/2分别为(23.18±3.26)和(23.12±4.31)h,受试制剂的相对生物利用度为(101.37±27.23)%.结论 2种制剂具有生物等效性.     

盐酸罗匹尼罗渗透泵型控释片的药代动力学研究

目的建立一种测定动物血浆中盐酸罗匹尼罗的方法,并进行盐酸罗匹尼罗渗透泵型控释片的药物动力学研究,并计算与参比制剂(Requip XL)的相对生物利用度。方法 6只Beagle犬分别单次口服盐酸罗匹尼罗渗透泵片(受试制剂)和Requip XL(参比制剂)1片,用LC-MS法测定血浆中的药物浓度,计算药物动力学参数和相对生物利用度。结果参比制剂和受试制剂的主要药代动力学参数tmax分别为(2.92±0.49)和(3.58±0.49)h,Cmax分别为(2.60±0.41)和(2.35±0.39)ng·mL-1,MRT分别为(7.76±0.89)和(8.48±0.59)h,t1/2(Ke)分别为(4.70±0.67)和(5.94±1.19)h,AUC(0~t)分别为(16.06±5.55)和(17.90±2.75)ng·mL-1·h,AUC(0~∞)分别为(16.71±5.87)和(19.03±3.08)ng·mL-1·h,受试制剂相对于参比制剂的相对生物利用度Fr为111.48%。结论统计结果显示,各主要药动学参数均无显著性差异。本方法能测定口服盐酸罗匹尼罗渗透泵的血药浓度,进行动物药物动力学和相对生物利用度研究。     

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.