高脂饮食对双嘧达莫在中国健康人体内药动学的影响

目的 观察中国健康受试者空腹和高脂高热量饮食情况下口服双嘧达莫片的药动学特征。方法 75名健康受试者分别在空腹或高脂饮食条件下单剂量口服双嘧达莫片25 mg,分别在不同时间点采集静脉血样。采用LC-MS/MS测定人血浆中双嘧达莫的浓度,用PhoenixWinNonlin 8.0软件按非房室模型计算药动学参数。结果 空腹和高脂饮食后双嘧达莫片的主要药动学参数如下：C_max分别为(594.69±172.14),(333.64±167.18) ng·mL^-1,餐后较空腹C_max降低了43.9%(P<0.01);t_1/2分别为(9.87±4.21),(10.57±3.75) h;AUC_0-t分别为(1 733.22±715.49),(1 268.61±571.07) ng·mL^-1·h,AUC_0-∞分别为(1 801.69±707.61),(1 353.64±602.29) ng·mL^-1·h,餐后较空腹AUC_0-t及AUC_0-∞分别降低26.8%,24.9%(P<0.01);T_max中位数(范围)分别为0.75[0.50,5.00] h和1.50[0.49,4.52] h,餐后服药的T_max明显延迟(P<0.01)。结论 高脂饮食后服药较空腹条件下服药,C_max、AUC_0-t及AUC_0-∞均明显降低,T_max明显延迟,说明食物对双嘧达莫片的吸收速度、吸收程度均有显著影响。     

杜鹃素在大鼠体内的药动学研究

目的 研究杜鹃素在正常大鼠体内的药动学特征。方法 杜鹃素单剂量ig给予大鼠后,采用HPLC法测定给药后不同时间点大鼠血浆中的杜鹃素,通过DAS软件程序模拟计算,得出杜鹃素在大鼠体内相应的药动学参数。结果 杜鹃素在大鼠体内的药动学模型符合二室模型,主要药动学参数为：t_1/2α＝（0.33±0.10）h,t_1/2β＝（15.22±8.98）h,CL/F＝（14.89±3.45）L/(h?kg),C_max＝（1.61±0.14）mg/L,T_max＝（0.25±0.01）h,MRT_(0-t)＝（2.35±0.08）h,AUC_(0-t)＝（3.06±0.16）mg?h/L。结论 本研究建立的HPLC方法专属性强,简便、准确,可用于杜鹃素在大鼠体内的药动学研究;大鼠ig给予杜鹃素后,其在血浆中分布较快,半衰期较短。     

注射用重组人成纤维细胞生长因子-21食蟹猴药动学研究

目的 研究注射用重组人成纤维细胞生长因子-21（FGF-21）在食蟹猴体内单次和多次皮下给药后的药代动力学特征。方法 采用随机、平行和剂量递增设计,18只食蟹猴分别单次sc150、300和600 μg/kg的FGF-21或多次sc 300 μg/kg的FGF-21,按设计采集动态血清样本。采用双抗体夹心ELISA法检测血清中药物浓度的动态变化,采用DAS 3.2.4药动程序拟合并计算药动参数。结果 食蟹猴单次sc FGF-21后,各剂量组峰浓度C_max和药时曲线下面积AUC_（0-24h）、AUC_（0-∞）均随给药剂量的增加而增大,C_max、AUC_（0-24h）和AUC_（0-∞）三者均与剂量呈线性相关,各剂量组t_1/2Z、T_max、CL_z和V_z均较为一致。与单次给药相比,食蟹猴多次sc给药后的t_1/2z有所延长但其他主要PK参数（T_max、V_z和CL_z等）均较为一致,多次给药后,体内药物无蓄积倾向。结论 食蟹猴单次sc FGF-21后,在150~600 μg/kg剂量范围内呈现线性动力学特征。单次与多次sc给予FGF-21后,两者的PK行为特征基本一致,无明显药物蓄积。     

氟康唑片在健康人体的药物动力学和生物等效性研究

摘 要 目的:研究氟康唑片在健康人体的药物动力学并评价其生物等效性。方法: 采用双周期自身随机交叉试验设计。20名健康男性志愿者分别单剂量口服受试制剂和参比制剂200 mg,以非那西丁为内标,采用HPLC法测定血药浓度。用DAS软件计算药动学参数和进行统计分析。结果:单次口服受试制剂和参比制剂200 mg后的主要药动学参数：t_max（1.08±0.44）和（1.35±0.76）h,C_max（5.40±0.60）和（5.37±0.72）μg·ml^-1,t_1/2(29.1±3.4)和（29.0±3.5）h,AUC_（0-t）（191.3±13.8）和(190.4±15.7) μg·h·ml^-1,AUC_(0-∞)(204.0±17.5) 和（202. 4±18.1）μg·h·ml^-1,MRT（34.7±1.7）和（34.0±1.9）h,以AUC_（0-t）计算,受试制剂的相对生物利用度为100.9%±6.8%。结论:两种氟康唑片剂具有生物等效性。     

普卢利沙星片的健康人体药动学

目的 健康志愿受试者口服普卢利沙星片后,测定血浆中其活性代谢物(UFX)并作药动学研究。方法 10名受试者分别单剂量和多剂量稳态时服用普卢利沙星片(相当于200 mg UFX),采集血浆和尿液样品,液相色谱分离荧光检测UFX浓度,3P97软件计算药动学参数。结果 单剂量时测得UFX的主要药动学参数分别为c_max(1.64±0.29)μg·ml^-1,t_max(0.7±0.2)h,AUC_0-36(6.87±1.78)h·μg·ml^-1,AUC_0-∞(7.14±1.79)h·μg·ml^-1,t_1/2(7.54±0.59)h,MRT(8.76±0.65)h;0～36 h尿液累积排泄量为(56.85±9.12)%。稳态时测得UFX的主要药动学参数分别为c_max(1.26±0.41)μg·ml^-1,t_max(0.8±0.3)h,AUC_0-36(7.77±2.73)h·μg·ml^-1,AUC_0-∞(8.10±2.70)h·μg·ml^-1,t_1/2(7.71±1.13)h,MRT(9.85±1.40)h。结论 健康志愿受试者口服普卢利沙星片后,在体内转化为活性代谢物(UFX)发挥作用,主要经尿液排泄。每日2次,每次2片(相当于200mg UFX),在体内无积蓄。男女健康受试者的主要药动学参数无显著性差异。     

依托考昔片在中国健康受试者的药动学及安全性研究

目的 研究中国健康受试者空腹、餐后单次口服依托考昔片的药动学及安全性。方法 将68例健康受试者随机分为空腹组和餐后组，采用双周期交叉试验设计进行给药，LC-MS/MS测定人血浆中依托考昔浓度，用WinNonLin软件计算药动学参数，比较国产依托考昔片和原研参比制剂药动学差异以及不同性别和进食对托考昔片药动学的影响。以受试者生命体征及体格检查、实验室检查值以及心电图变化为指标进行依托考昔片安全性评价。结果 空腹组受试制剂和参比制剂的药动学参数T_max为1.25，1.25 h，C_max为（2 767.50±421.89），（2 707.81±674.90） ng·mL^-1，AUC_0-∞为（52 967.87±13 843.25），（53 479.56±16 066.32） h·ng·mL^-1；餐后组受试制剂和参比制剂的药动学参数T_max为2.50，1.75 h，C_max为（2 000.61±314.89），（2 209.06±429.05） ng·mL^-1，AUC_0-∞为（51 450.80±17 241.02），（49 287.23±16 192.87） h·ng·mL^-1；餐后组受试制剂和参比制剂T_max差异具有统计学意义（P<0.05），但不具有临床意义。受试者空腹、餐后口服依托考昔片后，T_max、C_max差异具有统计学意义（P<0.01），但AUC_0-∞差异无统计学意义；不同性别受试者空腹口服依托考昔片后，主要药动学参数T_max、C_max、AUC_0-∞均无统计学意义，但女性受试者餐后口服依托考昔片后t_1/2、AUC_0-∞较男性受试者高（P<0.05）。空腹和餐后给药后不良事件涉及多系统，均为轻度，无严重不良反应。结论 国产依托考昔片和原研参比制剂具有生物等效性；进食影响依托考昔片的吸收速度，但不影响其吸收程度；空腹给药后依托考昔片的药动学参数无性别差异，但餐后给药后t_1/2、AUC_0-∞存在性别差异。依托考昔片在中国健康受试者中具有良好的安全性和耐受性。     

伏立康唑胶囊人体药动学及相对生物利用度研究

目的 研究健康受试者口服伏立康唑胶囊的药动学和相对生物利用度。方法 20名健康受试者随机服用伏立康唑受试胶囊剂和参比片剂各100 mg,用HPLC-MS/MS测定血浆中伏立康唑的浓度。结果 主要药动学参数,伏立康唑受试制剂与参比制剂的T_max分别为(0.75±0.15)和(0.84±0.25)h,C_max分别为(605.4±136.6)和(595.2±134.7)ng·mL^-1;t_1/2分别为(4.91±1.44)和(5.06±2.06)h,AUC_0-15分别为(1737.6±325.1)和(1750.6±352.8)ng·h·mL^-1。受试制剂与参比制剂的AUC_0-15和C_max经双单侧t检验,T_max经非参数检验,差异均无统计学意义。结论 统计学结果表明,2种制剂生物等效。     

伸筋草提取物中玉柏碱在大鼠体内的药动学研究

目的 通过给予大鼠伸筋草提取物,探讨其中主要活性成分玉柏碱的药动学特征。方法 利用RP-HPLC法,以Centurysil C₁₈ EPS为色谱柱,甲醇-水（61∶39）为流动相;紫外检测器测定大鼠ig伸筋草提取物后血浆中玉柏碱的血药浓度,计算药动学参数。结果 玉柏碱在大鼠体内呈二室模型分布,线性范围为0.354～14.16 μg/mL,r＝0.999 8。日内和日间精密度均小于5%。玉柏碱口服给药后在大鼠体内的主要药动学参数为：t_1/2为2.681 h,t_max为0.75 h,C_max为6.309 mg/L,AUC_(0→t) 为16.626 mg/L,AUC_(0→∞) 为18.798 mg/L。结论 本方法适用于大鼠血浆中玉柏碱的检测及其体内药动学研究。     

萘普生胆碱离子液体在大鼠体内的药动学及生物利用度研究

目的 研究萘普生胆碱离子液体灌胃给药后在大鼠体内的药动学和生物利用度。方法 采取灌胃给药的方式给予大鼠萘普生胆碱离子液体,于给药后不同时间点采集血样,血样经甲醇沉淀蛋白后离心,采用Extend-C₁₈色谱柱（4.6 mm×250 mm,5 μm）,甲醇（A）-0.3%磷酸水溶液（B）（74：26）为流动相,流速为0.8 mL·min^–1,检测波长为230 nm,以吲哚美辛为内标液,萘普生为测定对象,分析大鼠体内血浆中萘普生胆碱离子液体的浓度。应用DAS 2.0软件拟合药动学参数。结果 大鼠灌胃给药萘普生混悬剂后t_1/2α为5.12 h,t_1/2β为10.13 h,T_max为2 h,C_max为112.92 mg·L^–1,AUC_（0-t）为1 091.01 mg·L^–1·h;大鼠灌胃给药萘普生胆碱离子液体后t_1/2α为5.64 h,t_1/2β为69.32 h,T_max为1 h,C_max为135.97 mg·L^–1,AUC_（0-t）为1 305.79 mg·L^–1·h,相对生物利用度为119.686%。结论 大鼠灌胃萘普生胆碱离子液体后,萘普生达峰时间提前,达峰浓度和生物利用度均高于萘普生混悬剂。     

高效液相色谱法测定大鼠血浆和子宫中黄体酮及其代谢物的浓度

目的建立高效液相色谱法测定大鼠血浆和子宫样品中的黄体酮及其代谢物20α-羟基黄体酮,并研究大鼠肌肉注射黄体酮后血浆和子宫中的药物代谢动力学。方法样品经液-液萃取后,以乙腈-水(60∶40,pH 4.0)为流动相,用ODS柱进行分离,240 nm检测。以18-甲基炔诺酮为内标。结果血浆中黄体酮C_max为(508±62) μg·L^-1,T_max为(3.2±0.4) h,T_1/2(k_e)为(10±4) h,AUC_0-48h为(5 886±1 573) μg·L^-1·h,子宫中黄体酮T_max为(5.2±1.1) h,C_max(1.7±1.1) μg·g^-1。20α-羟基黄体酮具有与黄体酮相似的T_max。结论该方法简便、准确,可同时测定黄体酮和代谢物,适用于黄体酮及其代谢物20α-羟基黄体酮的药代动力学研究。     

Alcohol-induced locomotor activation in C57BL/6J, A/J, and AXB/BXA recombinant inbred mice: strain distribution patterns and quantitative trait loci analysis

RATIONALE: Quantitative trait loci (QTLs) for initial sensitivity to alcohol have been identified in a number of mouse strains (e.g. BXD); however, confirmation is required. OBJECTIVES: The present paper aimed to characterize the C57BL/6J, A/J, and AXB/BXA recombinant inbred (RI) strains of mice for basal and ethanol-induced locomotor activation as measured in an open field and to provide provisional location of QTLs for these phenotypes. METHODS: A/J and C57BL/6J mice were habituated to handling and then randomly assigned to receive one of four alcohol doses (0, 0.5, 1.0, 2.0 g/kg). Subsequently, all available strains of the AXB/BXA RI were tested with the 2 g/kg dose of ethanol or vehicle control. RESULTS: Simple regression and interval mapping were used initially to identify significant gene markers associated with ethanol-induced activation (calculated as total activity on alcohol day-total activity on saline day). Subsequently, composite interval mapping (CIM) was used to increase the accuracy in mapping individual loci. Genetic markers on chromosomes 2, 3, 8, 13, 16, 18 and 19 were associated with ethanol-induced activation. CONCLUSIONS: Three significant markers identified through CIM accounted for 86% of the genetic variance in the ethanol-induced activation. QTLs on chromosome 16 (45.6 cM) and 19 (24 cM) previously associated with alcohol consumption in the AXB/BXA RI mice were found to overlap with QTLs for ethanol-induced activation identified in the present study.     

浅谈国内BALB／c小鼠及KM小鼠的基本生物学特性

小鼠是在生物医学研究中广泛使用的实验动物。BALB／c小鼠是我国常用的近交系小鼠,KM小鼠是我国常用的封闭群小鼠。本文对我国BALB／c小鼠及KM小鼠的生物学特性作一综述,以利于研究者在生物医学研究中选择适宜的小鼠。     

双苯氟嗪对小鼠记忆障碍的改善作用(英文)

用跳台法和电迷宫法,观察双苯氟嗪(dipfluzine)对亚硝酸钠和戊巴比妥钠造成的小鼠记忆障碍的改善作用,双苯氟嗪可明显改善亚硝酸钠引起的小鼠记忆障碍和戊巴比妥钠造成的小鼠方向辨别的获得障碍,且有剂量关系,20和40mg·kg~(-1)双苯氟嗪使小鼠跳台错误次数和出现跳台错误动物的百分率均显著低于溶剂对照组.20 mg·kg~(-1)双苯氟嗪使小鼠在训练的d1和d2受到电刺激后的正确逃避反应数均显著高于溶剂对照组(P<0.05).双苯氟嗪改善亚硝酸钠引起的小鼠记忆障碍的作用与桂利嗪(cinnarizine)相似,在改善记忆的有效剂量(20mg·kg~(-1))下,双苯氟嗪还有抗小鼠急性脑缺氧作用,使断头后小鼠张口呼吸动作持续时间(32±s7s)显著长于溶剂对照组(20±s4s,P<0.01).     

Studies on the Distribution and Metabolism of 14C-dimethylnitrosamine in Foetal and Young Mice

Abstract In pregnant mice injected with ¹⁴C-dimethylnitrosamine, whole-body autoradiography was performed with hemisections at -80° (to prevent evaporation of the volatile dimethylnitrosamine) and with dry tape sections (to localize the non-volatile metabolites). The results indicated that the non-metabolized substance passed to the foetal tissues with a uniform distribution and without formation or accumulation of non-volatile metabolites. Autoradiography in young (1-10 days old) and adult mice showed a high level of metabolites in the liver already 5 min. after the administration of ¹⁴C-dimethylnitrosamine. No metabolism of the substance could be detected at in vitro incubations of liver tissue obtained from foetuses on the last day of gestation (¹⁴CO²-production and incorporation of radioactivity in acid-insoluble macromolecules were used as metabolic indices). However, in vitro experiments with livers of 1-5 days old mice indicated a rapid increase in enzymatic activity after birth. Studies in vivo showed an increased incorporation of radioactivity in the acid-insoluble macromolecules of the liver and a decreased exhalation of ¹⁴CO₂ in 10 and 14 days old mice as compared with 21 and 60 days old mice. This indicates a difference in the fate of dimethylnitrosamine in vivo between the young and older mice.     

荷癌小鼠与正常小鼠组织中抑癌因子活性观察研究

目的观察癌鼠的实体瘤和肝脏、肌肉以及正常小鼠的肝脏、肌肉组织中抑癌因子的活性。方法(1)制作肝癌、S180肉瘤小鼠实体瘤模型。(2)分别将两癌鼠的实体瘤和肝脏、肌肉组织以及正常小鼠的肝脏、肌肉组织用生理盐水制成匀浆并提取纯化抑癌因子G50制品。用HepA细胞作为鉴定抑癌因子活性的指示细胞。用台酚兰染色法鉴定抑癌因子的活性。结果抑癌因子只存在癌鼠的实体瘤组织且活性高,而两种癌鼠和正常小鼠的肝脏、肌肉几乎未检出抑癌因子的活性。结论抑癌因子具有特异性强、敏感性高、只由肿瘤组织产生、不存在正常组织和非癌组织、能与正常组织相区别等特点。     

Evidence that the selectively bred long- and short-sleep mouse lines display common narcotic reactions to many depressants

This report challenges the notion that the long-sleep and short-sleep selectively bred mouse lines display unique narcotic reactions to alcohols. First, we found that the specific ethanol sensitivity hypothesis is not supported by the relevant literature. Second, we found that much of the ambiguity with respect to this hypothesis concerns just pentobarbital. Consequently, the major intent of this paper was to further explore what effect pentobarbital had on these two mouse lines. Additionally, we examined the effects of barbital and ethanol. Our results for each of these compounds clearly indicate that when these mouse lines can be differentiated by particular doses the long-sleep animals always displayed greater narcotic reactions. In this inquiry only one sex was employed, and testing was always initiated at the same time of day. It is our contention that many of the equivocal findings that have been reported concerning pentobarbital are due to combining data from both sexes, circadian rhythmicity, and similar procedural variables.     

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Titanium dioxide nanoparticles (TiO₂ NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO₂ NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO₂ NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO₂ NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO₂ NPs per day. The TiO₂ NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO₂ NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO₂ NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen‐activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO₂ NPs.     

孕鼠铅暴露对仔鼠血铅水平影响的研究

目的探讨孕鼠铅暴露对仔鼠血铅水平的影响。方法wistar大鼠42只,雌雄各半,按雌雄配对分为五组（A、B、C、D、E）。A组为正常对照组,进食正常饲料B、C、D、E组每公斤饲料分别添加醋酸铅0．3g,0．9g,2．7g,8．1g,产仔后恢复正常饲料。母鼠与仔鼠组a—e1、2于生后1、3周分别进行血铅测定。结果仔鼠血铅水平与母鼠血铅水平呈正相关（r=0．517）。结论胎鼠血铅水平与母鼠孕期铅暴露的程度相关。     

海洛因对小白鼠生育的影响

目的:研究海洛因依赖小白鼠的生育情况。方法:先腹腔注射海洛因,6天后腹腔注射盐酸纳洛酮进行催促实验,海洛因依赖模型建立后,分成二组:一组继续注射海洛因,一组停止注射海洛因,在d14,将已对海洛因产生依赖的♀♂小白鼠各10只,作为海洛因依赖组;已脱毒的♀♂小白鼠各10只,作为海洛因戒断组;已对海洛因产生依赖的♀小白鼠10只与NS组的♂小白鼠10只,作为海洛因♀依赖组;已对海洛因产生依赖的♂小白鼠10只与NS组的♀小白鼠10只,作为海洛因♂依赖组;剩余的NS对照组♀♂小白鼠各10只,作为NS对照组。各组♀♂分别配对,观察不同组别小白鼠生育情况。结果:海洛因依赖组、海洛因戒断组、海洛因♂依赖组、海洛因♀依赖组与NS对照组比较,有极显著差异(P<0.001),海洛因依赖组与海洛因戒断组比较有显著性差异(P<0.05),海洛因♂依赖组与海洛因♀依赖组比较,无显著性差异(P>0.05)。结论:海洛因对♀♂小白鼠的生育能力均有明显影响。