多西他赛长循环脂质体的制备与大鼠体内药动学评价

摘 要 目的：制备多西他赛长循环脂质体,并评价大鼠尾静脉给药的药动学特性。方法: 采用薄膜分散 挤出法制备多西他赛长循环脂质体,并对其粒径分布、Zeta电位和微观形态进行表征。将12只Wistar大鼠随机分为多西他赛注射液组和多西他赛长循环脂质体组,尾静脉给药剂量均为7.5 mg·kg^-1,采用HPLC法测定大鼠血中多西他赛的药物浓度,采用3P97程序计算多西他赛大鼠体内药动学参数。结果: 多西他赛长循环脂质体平均粒径为（109.2±28.6）nm,Zeta电位为（-15.8±2.7）mV。多西他赛注射液和多西他赛长循环脂质体在大鼠体内的t_1/2(α)分别为（0.19±0.05）h和（0.36±0.07）h;t_1/2(β)分别为（1.82±0.33）h和（17.93±1.37）h;AUC_0-t分别为（4.42±0.76）μg·mL^-1·h^-1和（33.73±3.52）μg·mL^-1·h^-1。结论:多西他赛长循环脂质体与市售多西他赛注射液相比,延长了药物在血浆中的滞留时间,能达到长循环目的。     

尼达尼布在家兔体内的药动学研究

摘 要 目的： 建立家兔血浆尼达尼布检测的高效液相色谱方法,研究尼达尼布在家兔体内的药动学。方法: 采用ZORBAX SB-C₁₈色谱柱为分离柱,以乙腈-0.1%三氟乙酸-水（35∶20∶45）为流动相,流速为1.0 ml·min^-1,检测波长为286 nm,柱温为35℃;以卡马西平为内标,血浆在碱性条件下经乙酸乙酯萃取后检测。雄性家兔6只,按20 mg·kg^-1的剂量耳缘静脉注射给予尼达尼布;分别在给药前和给药后不同时间点耳缘静脉采集血液,分离血浆待测。用DAS 3.0计算药动学参数。结果: 尼达尼布浓度在0.05～10.00 μg·mL^-1范围内线性关系良好（r=0.999 8）;低中高三个浓度（0.10,2.50,7.50 μg·mL^-1）的日内精密度RSD分别为5.55％、4.53％和2.74％,日间精密度RSD分别为6.15％、5.45％和3.15％;相对回收率分别为（98.50±5.47）％、（100.25±4.54）％和（99.94±2.74）％。6只家兔血浆尼达尼布浓度经DAS 3.0计算,尼达尼布的主要药动学参数如下：C_max为（3.01±0.35） μg·mL^-1,t_1/2为（4.38±1.53）h,AUC_0-t为（11.67±1.71）μg·h·mL^-1。结论:该方法简便、快速、准确,适用于家兔血浆尼达尼布浓度的测定及其药动学研究。尼达尼布在家兔体内呈一级动力学消除。     

HPLC法测定姜黄素-槲皮素复方自微乳的载药量和包封率

摘 要 目的：建立HPLC法测定姜黄素 槲皮素复方自微乳（CUR-QUE-SMEDDS）的载药量和包封率。方法: 采用离心法分离游离药物,HPLC法测定药物含量。色谱柱：Purospher STAR LP C18 柱（250 mm×4.6 mm,5 μm）,流动相：乙腈 4%冰醋酸（50∶50）,流速：1.0 ml·min^-1,检测波长：370 nm,柱温：30℃,进样量：10 μl。结果: 姜黄素和槲皮素的线性范围分别为10.728~96.552 μg·mL^-1（r=0.999 8）和1.08~9.72 μg·mL^-1（r=0.999 9）,平均回收率分别为99.98%（RSD=1.46%,n=9）和100.34%（RSD=1.06%,n=9）。CUR QUE SMEDDS中姜黄素和槲皮素的包封率分别为（95.97±0.50）% 和（95.91±2.52）%,载药量分别为（25.82±0.15）mg·g^-1和（1.80±0.05）mg·g^-1。结论:该法准确可靠,快速简便,适用于测定CUR-QUE-SMEDDS的载药量和包封率。     

UPLC-MS/MS法同时检测人血浆中卡马西平和苯巴比妥浓度

摘 要 目的：建立同时检测人血浆中卡马西平和苯巴比妥浓度的UPLC-MS/MS方法,应用于临床卡马西平和苯巴比妥血药浓度监测。方法: 以地西泮为内标,血浆样品经乙腈沉淀蛋白,运用Waters XEVO TQD三重四级杆液质联用仪检测, 色谱柱为ACQUITY UPLC BEH C₁₈柱(50 mm×2.1 mm,1.7 μm);流动相为乙腈（10 mmol·L^-1甲酸铵） 水（10 mmol·L^-1甲酸铵,含0.1%甲酸）,梯度洗脱,流速为0.4 ml·min^-1,柱温40℃;采用电喷雾离子化源(ESI),正离子多反应监测模式扫描分析;加入200 μl乙腈沉淀蛋白,12 000×g离心10 min转移至1.5 ml EP管中取2 μl上样。 结果: 卡马西平的保留时间为1.23 min,线性范围为0.25～25 μg·mL^-1(r=0.999 7),最低定量限为0.01 μg·ml^-1;苯巴比妥的保留时间为1.11 min,线性范围为0.5～50 μg·mL^-1 (r=0.999 6),最低定量限为0.05 μg·mL^-1。卡马西平的高、中、低浓度的回收率为(82.1±6.83)%,(82.91±4.3)%和(84.35±3.09)%;苯巴比妥的高、中、低浓度的回收率为(84.27±6.91)%, (84.32±7.74)%和(89.07±6.24)%。卡马西平和苯巴比妥的日内、日间RSD均<10% ,血浆样品体系中的其他内源性物质不干扰测定。结论:该方法准确可靠,操作简便,重复性好,适于检测人血浆中卡马西平和苯巴比妥的血药浓度测定。     

十一酸睾酮二元醇质体凝胶剂体内外透皮特性研究

摘 要 目的：对十一酸睾酮（TU）二元醇质体凝胶进行体内外透皮考察。方法: 采用注入法制备TU二元醇质体,以卡波姆941为凝胶基质,制备TU二元醇质体凝胶剂;以小鼠皮肤为屏障,采用Franz扩散池法对其体外透皮特性进行考察;以大鼠为实验动物,背部给予TU二元醇质体凝胶剂后,于设定的时间点测定血浆中TU浓度,计算药动学参数,并与TU二元醇质体进行比较。结果: TU二元醇质体及其凝胶的体外累积透皮百分率Q与时间t均符合一级动力学模型,线性方程分别为：Q=8.68t+6.78（r=0.998 2）和Q=6.09t+3.09（r=0.999 3）,稳态透皮速率分别为8.68 μg·cm^-2·h^-1和6.09 μg·cm^-2·h^-1,24 h后TU在皮肤中的滞留量分别为（208.80±55.26）μg·g^-1和（225.60±38.90）μg·g^-1;大鼠体内TU二元醇质体及其凝胶的主要药动学参数分别为：Cmax（18.50±2.75）mg·L^-1和（20.80±2.42）mg·L^-1;tmax（6.20±0.14）h和（9.54±0.52）h;AUC0-48h（336.74±2.05）h和（486.30±1.68）h。结论:TU二元醇质体及其凝胶均呈现较好的体内外透皮特性,且在缓释性上凝胶剂表现更优。     

救必应酸在大鼠体内的口服生物利用度研究

摘 要 目的：研究救必应酸在大鼠体内药动学和口服生物利用度。方法: 建立测定大鼠血浆中救必应酸浓度的RP HPLC法。考察大鼠经灌胃和尾静脉给予40 mg·kg^-1的救必应酸后血药浓度变化。采用3p97软件计算分析药动学参数和口服生物利用度。结果: 灌胃组大鼠的C_max为（0.81±0.22）μg·mL^-1,T_max为（45.24±5.13） min,T_1/2为（101.47±8.25） min,AUC为（76.3±13.68）μg·min^-1·mL^-1;静脉注射组的T_1/2为（73.68±11.02） min,AUC为（1 687.4±29.54）μg·min^-1·mL^-1。救必应酸口服利用度为4.52%。结论:救必应酸的口服生物利用度较差。     

LC-MS/MS法测定人血浆中拉莫三嗪浓度的不确定度评定

摘 要 目的：评定液质联用法(LC MS/MS)测定人血浆中拉莫三嗪(LTG)浓度的不确定度。方法: 分析LC-MS/MS法测定人血浆中LTG浓度过程中的不确定度来源,计算其大小并进行合成。结果: 人血浆中LTG低浓度(0.050 4 μg· mL^-1)和高浓度(1.27 μg· mL^-1)的扩展不确定度分别为0.005 18 μg· mL^-1和0.066 4 μg· mL^-1 (P = 95%,k = 2)。结论:LC-MS/MS法测定人血浆中LTG浓度的不确定度在低浓度时主要由蛋白沉淀回收率、基质效应和生物样品配制引入,在高浓度时主要由基质效应、生物样品配制和重复性引入。     

LC-MS/MS法测定氟哌啶醇在大鼠体内的血药浓度及其药动学研究

摘 要 目的：建立液相色谱 串联质谱法测定大鼠血浆中氟哌啶醇浓度,并探索氟哌啶醇在大鼠体内的药动学特征。 方法: 以咪达唑仑为内标,血浆样品经乙腈沉淀蛋白提取分离。前置柱：菲罗门C₁₈柱;色谱柱： Symmetry C₁₈ 柱（50 mm×2.1 mm,3.5 μm）;流动相：10 mmol · L^-1乙酸铵（用甲酸调节pH至3.4） 乙腈;流速：0.3 ml · min^-1,采用梯度洗脱;柱温:40 ℃;进样量为10 μl。离子源：ESI源;检测方式：正离子模式;扫描方式：多反应离子监测（MRM）;喷雾电压：5 500 V;温度：450 ℃;GAS1和GAS2流速：50 ml · min^-1;用于定量分析的离子反应分别为氟哌啶醇（m/z376.2→165.1,碰撞能为32 eV）和咪达唑仑（m/z326.1→291.2,碰撞能为35 eV）。结果: 氟哌啶醇在1.0~200.0 ng · mL^-1浓度范围内线性关系良好（R²=0.997 7）,提取回收率在75.2%~86.3%。主要药动学参数AUC0-t为（175.5±21.3）ng· h· mL^-1,t1/2为（2.12±0.24）h,Cmax为（97.7±21.6）ng · mL^-1。结论:该方法操作简便、快速、准确、重复性好,可应用于氟哌啶醇在大鼠体内的药动学研究。     

液相色谱-串联质谱法同时测定对乙酰氨基酚及其相关代谢产物

摘 要 目的：建立一种检测小鼠血浆中对乙酰氨基酚（APAP）及其5个代谢产物的液相色谱 串联质谱（LC-MS/MS）方法,将之应用于对乙酰氨基酚的代谢研究。方法: 血浆样品经甲醇沉淀蛋白后,以对氨基苯甲酸（PABA）为内标,采用LC-MS/MS法,C18色谱柱,流动相为甲醇 5 mmol·L^-1乙酸铵水溶液（含0.1%甲酸）（55∶45）,流速为0.5 ml·min^-1,柱温为25℃,采用电喷雾离子化（ESI）,正离子多反应监测（MRM）检测方式进行定量分析：APAP,[M-H]^-,m/z 152.0→110.0;APAP cys,[M-H]^-,m/z 271.2→140.1;APAP glut,[M-H]^-,m/z 457.0→328.0;APAP NAC,[M-H]^-,m/z 313.4→208.0;APAP sulf,[M-H]^-,m/z 232.4→152.1;APAP-gluc,[M-H]^-,m/z 328.2→152.1;IS,[M-H]^-,m/z 138.2→120.0。结果: 在0.2~10 μg·mL^-1（APAP）、1.0~20 μg·mL^-1（APAP-gluc）、1.0~20 μg·mL^-1（APAP sulf）、1.0~20 μg·mL^-1（APAP glut）、0.4~15 μg·mL^-1（APAP NAC）和0.2~10 μg·mL^-1（APAP cys）范围内线性良好(r≥0.990 0)。各测定物的日内精确度均在85%~115%间,精密度均小于15%,加样回收率均在85%~115%之间,RSD均低于15%。结论:该方法快速、灵敏、准确,适用于小鼠血浆中对乙酰氨基酚及其5个代谢产物的定量测定。     

HPLC-MS/MS法测定人血浆中卡马西平浓度的不确定度评定

摘 要 目的： 评定HPLC MS/MS测定人血浆中卡马西平(CBZ)浓度的不确定度。方法: 分析HPLC MS/MS法测定人血浆中CBZ浓度的不确定度来源,计算并进行合成和扩展。结果: 人血浆中低浓度(7.46 ng ·mL^-1)和高浓度(745 ng ·mL^-1)CBZ的扩展不确定度分别为0.410 ng ·mL^-1和33.400  ng ·mL^-1 (P=95%,k=2)。结论:HPLC MS/MS法测定人血浆中CBZ浓度的不确定度在低浓度时主要由回收率、生物样品配制和基质效应引入,在高浓度时主要由生物样品配制和重复性引入。     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Polymorphisms in genes involved in neurotransmission in relation to smoking

Smoking behavior is influenced by both genetic and environmental factors. The genetic contribution to smoking behavior is at least as great as its contribution to alcoholism. Much progress has been achieved in genomic research related to cigarette-smoking within recent years. Linkage studies indicate that there are several loci linked to smoking, and candidate genes that are related to neurotransmission have been examined. Possible associated genes include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D₁, D₂, and D₄ receptors, dopamine transporter, and serotonin transporter genes. There are other important candidate genes but studies evaluating the link with smoking have not been reported. These include genes encoding the dopamine D₃ and D₅ receptors, serotonin receptors, tyrosine hydroxylase, trytophan 2,3-dioxygenase, opioid receptors, and cannabinoid receptors. Since smoking-related factors are extremely complex, studies of diverse populations and of many aspects of smoking behavior including initiation, maintenance, cessation, relapse, and influence of environmental factors are needed to identify smoking-associated genes. We now review genetic polymorphisms reported to be involved in neurotransmission in relation to smoking.     

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood–brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.     

Pradigastat disposition in humans: in vivo and in vitro investigations

1.?Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients.

2.?Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans.

3.?In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma.

4.?In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed.

5.?Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.     

Changes in immunoreactive somatostatin in brain following lidocaine-induced kindling in rat

The kindling phenomenon has become a useful model for studying epileptogenesis. The present authors have previously reported increased levels of immunoreactive somatostatin (IR-SRIF) in various regions of the brain of electrically-amygdaloid kindled (EAK) rats. In this study, an examination was made of immunoreactive somatostatin in pharmacologically-kindled (PK) rats. Sixteen male Sprague-Dawley rats were injected intraperitoneally (i.p.) with a subthreshold dose of lidocaine (60 mg/kg), once daily. Once the kindling phenomenon was established, kindled rats (7), non-kindled rats (9) and controls (6) were sacrificed by microwave irradiation. Another group of 5 rats was injected with a single suprathreshold dose of lidocaine (110 mg/kg) and killed 10 min after the resultant seizure. Various brain areas were removed and assayed for immunoreactive somatostatin in kindled rats. Immunoreactive somatostatin was significantly greater than in controls in the amygdala (56%; P less than 0.02), entorhinal + piriform cortex (50%; P less than 0.05) and hypothalamus (29%; P less than 0.02). In non-kindled rats, immunoreactive somatostatin increased only in the amygdala (58%; P less than 0.02). No difference was found in the immunoreactive somatostatin content of rats injected with an suprathreshold dose of lidocaine compared to controls. The alteration of immunoreactive somatostatin, in both lidocaine-kindled and electrically-amygdaloid kindled rats suggests a possible role of this neuropeptide in kindling.