盐酸氟桂利嗪胶囊在中国健康志愿者空腹和进食条件下的生物等效性研究

摘要：目的:评价山西振东安特生物制药有限公司生产的盐酸氟桂利嗪胶囊与西安杨森制药有限公司生产的盐酸氟桂利嗪胶囊的生物等效性,为一致性评价提供依据。方法:采用随机、开放、单剂量、两制剂、两周期、两交叉给药试验设计,空腹组和高脂餐后组各入组26名受试者,所有受试者随机分为两组,每周期给药1次,每次口服给药剂量为5 mg（1粒）,清洗期28 d,之后进行交叉给药。采用HPLC-MS/MS法测定健康受试者口服受试制剂（T）或参比制剂（R）后,血浆中不同时间点氟桂利嗪的血药浓度。采用WinNonlin8.2和SAS9.4版本软件,非房室模型计算各受试者的药动学参数,并进行统计分析。对受试者的临床观察指标进行安全性评价。结果:空腹组24例和高脂餐后组25例完成全部试验。空腹条件下,盐酸氟桂利嗪胶囊T和R的血药浓度达峰时间(Tmax)分别为2.50 h （1.50～5.50 h）和2.50 h （1.50～4.50 h）,血药峰浓度(Cmax)分别为（21.09±6.72）ng·ml-1和（20.36±5.69）ng·ml-1,血药浓度-时间曲线下面积(AUC0～72h)分别为（239.05±94.19）h·ng·ml-1和（223.78±77.54）h·ng·ml-1;AUC0～t分别为（324.73±152.96）h·ng·ml-1和（298.97±130.39）h·ng·ml-1;AUC0～∞分别为（457.12±268.55）h·ng·ml-1和（366.15±172.77）h·ng·ml-1;半衰期(t1/2)分别为（180.87±153.04）h和（112.18±70.51）h。进食条件下,盐酸氟桂利嗪胶囊T和R的Tmax分别为4.50 （2.50～6.50） h和4.50 （2.50～6.00） h,Cmax分别为（30.52±10.73）ng·ml-1和（30.65±8.55）ng·ml-1,AUC0～72h分别为（269.16±71.76）h·ng·ml-1和（273.30±74.83）h·ng·ml-1;AUC0～t分别为（360.71±121.08）h·ng·ml-1和（362.30±117.22）h·ng·ml-1;AUC0～∞分别为（449.48±171.08）h·ng·ml-1和（470.51±161.88）h·ng·ml-1;t1/2分别为（131.21±60.38）h和（196.35±132.07）h。空腹和餐后状态下T、R的Cmax、AUC0～72h、AUC0～t和AUC0～∞均值比的90%置信区间均在（80.00%,125.00%）等效区间内。结论:盐酸氟桂利嗪胶囊T和R在中国健康志愿者空腹和进食条件下具有生物等效性。     

ELISA法研究聚乙二醇重组人生长激素注射液单次给药人体药代动力学

目的 建立ELISA方法研究聚乙二醇重组人生长激素(PEG-rhGH)注射液单次给药人体药代动力学.方法 将30名健康受试者随机分成4组(其中两组为自身对照),分别单次皮下注射PEG-rhGH注射液(0.1 mg·kg-1、0.2 mg·kg-1、0.4 mg·kg-1)、注射用重组人生长激素(rhGH)(0.067mg· kg-1).ELISA法测定不同时间点PEG-rhGH、rhGH的血药浓度,并计算药代动力学参数.结果 PEG-rhGH、rhGH血药浓度分别在0.312 5～40.0000 ng·ml-1、0.312 5～10.0000 ng· ml-1范围内线性关系良好,最低检测性均为0.312 5ng· ml-1,批间、批内RSD均＜15％. PEG-rhGH(0.1、0.2、0.4 mg·kg-1)、rhGH(0.067mg· kg-1)的t1/2分别为:(31.70±4.70)h、(32.19±4.58)h、(30.39±5.93)h、(1.95±0.44)h,Tmax为:(22.20±9.82)h、(29.40±10.75)h、(40.80±8.39)h、(3.20±1.10)h,Cmax:(105.24±45.37)ng·ml-1、(379.09±109.61)ng·m1-1、(920.69±293.21)ng·ml-1、(30.17±3.20)ng·m1-1,CL/F:(26.97±13.86) ml· kg-1· h-1、(9.21±4.05) ml· kg-1· h-1、(6.29±2.87) ml· kg-1· h-1、(284.26±43.47)ml· kg-1· h-1,AUC0→∞:(4657.70±2337.30) ng· m1-1·h、(25279.58±9407.63) ng· ml-1·h、(74438.89±29 007.81) ng·ml-1·h、(240.97±39.40) ng·ml-1·h.结论 PEG-rhGH体内过程符合线性动力学特征,与rhGH相比,明显推迟达峰时间、延长半衰期、减慢清除率,具有长效特征.     

复方烟酸缓释片与烟酸普通片在犬体内药代动力学的比较研究

目的比较复方烟酸缓释片与烟酸普通片中烟酸及其代谢物烟尿酸在Beagle犬体内的药代动力学。方法6只Beagle犬采用随机交叉给药方案,单剂量口服500mg复方烟酸缓释片或烟酸普通片后,用RP-HPLC法同时测定Beagle犬血浆中烟酸及其主要代谢物烟尿酸的药物浓度,计算药动学参数和相对生物利用度。结果Beagle犬单剂量口服500mg复方烟酸缓释片和烟酸普通片后,烟酸主要药代动力学参数tmax分别为(2.17±0.61)h和(1.04±0.49)h,Cmax分别为(30.85±4.50)mg·mL-1和(68.05±20.48)mg·mL-1,t1/2分别为(0.69±0.43)h和(0.43±0.10)h,MRT分别为(2.12±0.62)h和(1.72±0.40)h,AUC0-12h分别为(62.17±21.13)mg·h·L-1和(138.67±44.86)mg·h·L-1;烟尿酸主要药代动力学参数tmax分别为(2.42±0.49)h和(1.50±0.45)h,Cmax分别为(0.76±0.34)mg·mL-1和(1.66±0.63)mg·mL-1,t1/2分别为(1.74±1.24)h和(1.64±1.03)h,MRT分别为(2.42±0.62)h和(1.79±0.38)h,AUC0-12h分别为(1.55±0.76)mg·h·L-1和(3.25±1.16)mg·h·L-1。结论单剂量口服复方烟酸缓释片,测得的Cmax、tmax和AUC与烟酸普通片均有显著性差异,受试缓释片的tmax长于参比普通片,Cmax低于参比普通片,说明受试缓释片无突释现象,有一定缓释效果。     

双嘧达莫缓释微丸的药动学及相对生物利用度研究

目的以市售双嘧达莫普通片为参比制剂,评价自制双嘧达莫缓释微丸的相对生物利用度和生物等效性.方法采用随机交叉分组实验设计,给4条Beagle犬分别口服单剂量50mg的自制双嘧达莫缓释徽丸和普通片,按设计采集12h内动态血标本;以经改进的HPLC法测定血浆药物浓度,以二室模型计算两种制剂在动物体内的药动学参数和相对生物利用度.结果参比制剂和测试制剂的tmax分别为(0.92±0.09)h和(1.57±0.12)h,Cmax分别为(434.4±36.93)ng·ml-1和(279.52±24.8)ng·ml-1,AUCo-12分别为(922.56±52.73)ng·h·ml-1和(1152.87±55.18)ng·h·ml-1,t1/2α分别为(0.69±0.05)h和(0.89±0.12)h,t1/2β分别为(4.71±0.71)h和(17.6±5.53)h,MRT分别为(2.91±0.14)h和(3.54±0.06)h,统计分析显示,各主要药动学参数均有显著性差异.自制双嘧达莫缓释微丸相对于普通片的平均生物利用度为(125.06±4.38)%.结论自制双嘧达莫缓释微丸具有明显的缓释特征,其生物利用度和药物吸收程度显著优于双嘧达莫普通片.     

高效液相色谱串联质谱法测人血浆中氯雷他定浓度及其药代动力学研究

目的建立灵敏的氯雷他定血浓度测定方法,评价氯雷他定的药代动力学特点.方法固定相ORBAX Eclipse XDB-C8(5μm,150 mm×4.6 mm),HP1100LC-MSD质谱检测器;流动相乙腈 -0.1%醋酸和0.2%醋酸铵水溶液,流速 1.0 ml·min-1.离子源AP-ESI,正离子模式,雾化电压30 psi,保护气10 L·min-1N2,毛细管电压4000 V,碎片电压为170V.SIM离子采集方式,采集离子(m/z)氯雷他定383.2(M+H),内标罗哌卡因275.1(M+H).结果氯雷他定线性范围0.5～50 ng·ml-1,最低定量限为0.5 ng·ml-1.氯雷他定片(T1)、胶囊(T2)、开瑞坦(R)主要药代动力学参数t1/2为13.52±1.35,13.14±0.98,14.00±1.25 h;Tmax为1.24±0.06,1.18±0.12,1.18±0.12h;Cmax为21.72±7.70,21.49±8.34,20.50±8.65 ng·ml-1;AUC0-48为137.24±47.87,139.65±45.69,134.19±49.03ng·h·ml-1,AUC0-∞为146.61±51.03,148.04±48.10,143.70±52.08 ng·h·ml-1.试验制剂氯雷他定片/胶囊相对生物利用度分别为(105.49±8.08)%和(102.90±10.02)%.结论HPLC-MS法测定氯雷他定血浓度实用、可行,适用于常规治疗药物监测和氯雷他定药代动力学研究.试验制剂和参比制剂为生物等效制剂.     

HPLC法测定头孢硫脒在家犬体内的浓度及其药代动力学

目的:建立犬体内头孢硫脒的血药浓度测定方法,研究静脉注射头孢硫脒不同剂量(31.5、63.0、126.0mg·kg-1)在犬体内的药代动力学。方法:采用RT-HPLC法测定犬静脉注射给药后不同时间血浆中头孢硫脒的浓度。C18反相色谱柱(Hypersil,250mm×4.0mm,5μm),流动相为乙睛∶磷酸盐缓冲液(80∶20)。结果:测定方法的最低检测浓度为0.2μg·ml-1,线性范围为0.2~50.0μg·ml-1,回收率在93.27%~102.18%。犬静注头孢硫脒后符合开放二房室模型处置特征,3个剂量组主要药代动力学参数如下:T1/2α为0.11±0.05,0.13±0.03,0.10±0.03h;T1/2β为1.01±0.29,0.84±0.17,1.08±0.31h;AUC为14.3±1.2,27.3±7.7,74.4±21.2mg·L-1·h。结论:本方法适合头孢硫脒的药动学研究,测定结果为临床合理用药提供依据。     

国产罗格列酮胶囊在健康人体的相对生物利用度

目的研究健康受试者口服罗格列酮胶囊的药代动力学。方法20名健康受试者随机服用罗格列酮受试和参比制剂各4mg,用HPLC-MS法测定血浆中罗格列酮的浓度。结果经3P97程序处理,主要药代动力学参数如下。罗格列酮胶囊剂:t1/2为(5.18±0.84)h,AUC0-24h为(2.13±0.21)μg·h·mL-1,Cmax为(305.31±38.21)ng·mL-1,tmax为(1.1±0.4)h;罗格列酮片剂:t1/2为(5.10±0.64)h,AUC0-24h为(2.20±0.20)μg·h·mL-1,Cmax为(318.84±38.38)ng·mL-1,tmax为(1.2±0.3)h。罗格列酮受试和参比制剂的相对生物利用度为(97.6±12.7)%。结论2制剂具有生物等效性。     

单剂口服盐酸托烷司琼颗粒剂在健康人体的生物等效性

目的研究盐酸托烷司琼颗粒剂的药代动力学特征及生物等效性。方法用随机交叉给药方法,20名健康男性志愿者分别单剂量口服盐酸托烷司琼颗粒剂试验药及胶囊对照药20mg,用LC-MS/MS法测定血药浓度。计算2者的药代动力学参数及相对生物利用度。结果口服托烷司琼颗粒剂试验药及胶囊对照药20mg的主要药代动力学参数AUC0-t分别是:(523.82±432.96)和(547.04±455.59)ng·h·mL-1;AUC0-∞分别为(568.07±491.48)和(591.77±513.15)ng·h·mL-1;Cmax分别为(36.67±12.30)和(37.44±14.30)ng·mL-1;tmax分别为(1.85±1.66)和(1.85±0.79)h;t1/2分别为(9.76±6.33)和(9.77±5.51)h。相对生物利用度为(98.03±17.11)%。结论2种制剂具有生物等效性。     

雷贝拉唑钠肠溶胶囊Beagle犬体内药动学及生物等效性研究

目的：建立HPLC-MS测定方法分析Beagle犬血浆中雷贝拉唑的含量,并作不同厂家两种雷贝拉唑钠肠溶胶囊的药动学及生物等效性研究。方法：6只Beagle犬随机分为两组,采用单剂量双周期交叉试验,分别口服给予60 mg雷贝拉唑钠肠溶胶囊受试制剂或参比制剂,给药后不同时间点采血,测定血药浓度,利用DAS3.0软件计算药动学参数,并比较两个厂家生产的制剂的生物等效性。结果：Beagle犬单次给予雷贝拉唑钠肠溶胶囊受试制剂和参比制剂后的tmax分别为（3.57±0.91）h和（3.43±0.87）h,Cmax分别为（539.03±129.13）ng·mL-1和（554.90±135.75）ng·mL-1,t1/2分别为（2.20±0.90）h和（2.09±0.78）h,药时曲线下面积AUC（0→24 h）分别为（1341.40±442.03）ng·h·mL-1和（1319.41±402.29）ng·h·mL-1。结论：结果表明不同厂家的两种雷贝拉唑钠肠溶胶囊具有生物等效性。     

富含铁元素食物对非洛地平片在Beagle犬体内药动学的影响

目的 研究高铁饮食对非洛地平在Beagle犬体内药动学影响。方法 采用随机、开放、单剂量给药、双交叉试验设计。12条健康Beagle犬采用随机数字表法分为两组,每组6条,分别空腹和餐后服用5 mg非洛地平片,给药前后按不同采血时间点采集血样,采用液相色谱-质谱联用(HPLC-MS/MS)法测定血浆中非洛地平浓度,用DAS3.2.8软件计算药动学参数。结果 空腹与餐后主要药动学参数如下:Cmax(12.59±2.17)、(7.13±2.96)ng/mL,tmax(1.25±0.24)、(1.32±0.35)h,t1/2(1.1±0.69)、(1.2±0.72)h,AUC0-12(19.46±5.23)、(11.87±3.85)ng·h-1·mL-1,AUC0-∞(20.69±5.75)、(12.76±4.18)ng·h-1·mL-1。以AUC0-12计算,实验组的相对生物利用度F为(61.0±12.7)%。与对照组相比,实验组Beagle犬的生物利用度偏低,而且达峰浓度也降低,说明食物中Fe3+抑制了非洛地平药物的吸收。结论 高铁饮食可显著降低非洛地平片在Beagle犬体内的吸收程度,但不影响其吸收速度。     

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.

     

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.     

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.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

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.