目的:探讨葛花总黄酮对2型糖尿病大鼠认知功能障碍及海马中脑源性神经营养因子(BDNF)表达的影响.方法:将Wistar大鼠100只随机分为对照组、模型组、吡拉西坦组(10 mg/kg)、葛花总黄酮低剂量组(20 mg/kg)及葛花总黄酮高剂量组(40 mg/kg),每组20只.模型组、吡拉西坦组、葛花总黄酮低及高剂量组均建立2型糖尿病大鼠模型,并于造模成功后给予相应药物灌胃;对照组和模型组大鼠灌胃等体积0.9％氯化钠溶液;给药体积均为10 ml/kg,1日1次,持续给予140 d.给药结束后,通过Morris水迷宫试验评价大鼠认知功能;采用苏木精-伊红染色观察大鼠海马神经元病理结构变化;检测大鼠海马组织中BDNF mRNA和蛋白,白细胞介素4(IL-4)、白细胞介素8(IL-8)和肿瘤坏死因子α(TNF-α)蛋白水平.结果:(1)对照组大鼠海马区神经元细胞结构正常;模型组大鼠海马区神经元大量坏死,有明显炎症细胞浸润;吡拉西坦组、葛花总黄酮低及高剂量组大鼠海马神经元细胞坏死减少,且神经元细胞结构较为完整.(2)与对照组相比,模型组大鼠逃避潜伏期时间明显延长,IL-4、IL-8及TNF-α蛋白表达水平明显升高,经过原平台位置的次数明显减少,原平台象限停留时间明显缩短,BDNF mRNA和蛋白表达水平明显降低,上述差异均有统计学意义(P<0.05).(3)与模型组相比,吡拉西坦组、葛花总黄酮低及高剂量组大鼠逃避潜伏期时间明显缩短,IL-4、IL-8及TNF-α蛋白表达水平明显降低,经过原平台位置的次数明显增多,原平台象限停留时间明显延长,BDNF mRNA和蛋白表达水平升高,差异均有统计学意义(P<0.05);与葛花总黄酮低剂量组相比,葛花总黄酮高剂量组大鼠逃避潜伏期时间明显缩短,IL-4、IL-8及TNF-α蛋白表达水平明显降低,经过原平台位置的次数明显增多,原平台象限停留时间明显延长,BDNF mRNA和蛋白表达水平明显升高,差异均有统计学意义(P<0.05).(4)与吡拉西坦组相比,葛花总黄酮低剂量组大鼠逃避潜伏期时间明显延长,IL-4、IL-8及TNF-α蛋白表达水平明显升高,经过原平台位置的次数明显减少,原平台象限停留时间明显缩短,BDNF mRNA和蛋白表达水平明显降低,差异均有统计学意义(P<0.05);葛花总黄酮高剂量组大鼠逃避潜伏期时间、原平台象限停留时间,IL-4、IL-8及TNF-α蛋白表达水平,经过原平台位置的次数,BDNF mRNA和蛋白表达水平与吡拉西坦组相比,差异均无统计学意义(P>0.05).结论:葛花总黄酮对2型糖尿病大鼠认知功能障碍的疗效明显,其机制与葛花总黄酮促进BDNF mRNA和蛋白表达,降低IL-4、IL-8及TNF-α表达水平,减轻胰岛素抵抗以及炎症反应有关.

目的 观察丹参酮ⅡA对实验性急性脑梗死(ACI)大鼠的治疗作用及脑组织Cyclin D1、糖原合成酶激酶3β(GSK-3β)和p-GSK-3β的影响.方法 将50只雄性SD大鼠随机分为假手术组,急性脑梗死组,丹参酮ⅡA低、中、高剂量组.采用线栓法制备动物大脑中动脉栓塞模型,造模成功后,丹参酮ⅡA低、中、高剂量组分别给予丹参酮ⅡA 10、20、40 mg/kg腹腔注射,每日1次,连续给药14 d,对大鼠进行神经功能评分,检测血清中丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽过氧化物酶(GSH-Px)的含量,对脑组织进行TTC染色和脑含水量测定,检测脑组织中Cyclin D1、GSK-3β和p-GSK-3β的表达.结果 与假手术组比较,急性脑梗死组大鼠神经功能评分、脑梗死体积和脑含水量显著升高,血清中MDA含量显著升高,SOD、CAT和GSH-Px含量显著降低(P<0.05),脑组织中Cyclin D1含量和p-GSK-3β/GSK-3β比值变化不显著;与急性脑梗死组比较,各丹参酮ⅡA治疗组大鼠神经功能评分、大鼠脑梗死体积和含水量明显降低,血清中MDA含量显著降低,SOD、CAT和GSH-Px含量显著升高(P<0.05),脑组织中Cyclin D1含量和p-GSK-3β/GSK-3β比值显著升高(P<0.05),且随药物剂量增大而增加.结论 丹参酮ⅡA对实验性ACI大鼠具有一定的治疗作用,可抑制氧化应激,上调cyclin D1含量和p-GSK-3β/GSK-3β比值.

We aimed to evaluate the bioequivalence of clopidogrel in healthy Chinese volunteers after administration of a single oral dose. We administered a single oral dose of 75 mg clopidogrel (test and reference) to 32 healthy Chinese volunteers according to an open, randomized, crossover design. The concentration of clopidogrel acid (carboxylic metabolite of clopidogrel) in the plasma was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioequivalence of the test and reference preparations were calculated using analysis of variance and one-sided t-test by using the DAS 2.0 software. The pharmacokinetic parameters of the test and reference preparations were as follows: peak plasma concentration (Cmax), 1351.101 ± 654.955 ng/mL and 1184.652 ± 607.713 ng/mL; area under the curve, 2642.017 ± 1093.848 ng·h/mL and 2780.666 ± 1283.100 ng·h/mL; and time to reach Cmax (Tmax), 0.789 ± 0.318 h and 0.953 ± 0.633 h, respectively. The relative bioavailability of the formulation was 101.7 ± 35.3%, which indicated that the test preparation was bioequivalent to the reference drug.

OBJECTIVETo investigate the pharmacokinetics of Ambroxol and Clenbuterol Tablets in Chinese healthy volunteers after a single or multiple dosages oral administration.METHODSA total of 9 healthy adult subjects were given Ambroxol and Clenbuterol Tablets in a single dosage or multiple dosages respectively. LC/MS/MS were used for the determination of Ambroxol and Clenbuterol of in plasma. The important pharmacokinetic parameters were calculated by DAS 2.0 software (compartment model).RESULTSSingle and multiple dosage groups of Ambroxol and Clenbuterol were all fitted two-compartment model. The pharmacokinetics fitted first order kinetics process. No difference in pharmacokinetics of Ambroxol in single and multiple dosage groups volunteers was observed, Which showed no marked changes, suggesting that multiple dosing did not influence the velocity of drug metabolism. Moreover, parameters of Clenbuterol had significant difference between the single and multiple dosage groups (P<0.05), showing there was accumulation in the body. 9 subjects had completed single or multiple dosages oral administration test, with no adverse drug reactions appeared during the test.CONCLUSIONThere was no obvious accumulation of Ambroxol after repeated dosing. But obvious accumulation of Clenbuterol was noted in multiple-dose administration. The established method is sensitive, accurate, reliable and specific, and it can meet the requirement of clinical pharmacokinetic trial.

目的 研究厄多司坦胶囊在健康人体的药代动力学,评价其生物等效性.方法 20名男性志愿者随机分为2组,按照两制剂两周期的随机交叉试验设计,分别单剂量口服厄多司坦试验或参比制剂各1粒(0.3 g),采用LC-MS/MS法测定血浆中厄多司坦及其代谢产物M1的浓度,用DAS2.0药动学软件分别计算厄多司坦及其代谢产物M1药动学参数并进行生物等效性统计分析.结果 试验及参比片的厄多司坦的主要药动学参数Cmax分别为(1570.7±488.3)和(1447.8 ±449.9) ng ·ml-1;Tmax分别为(1.1±0.5)和(1.2±0.5)h;t1/2分别为(1.3±0.3)和(1.3±0.4)h;AUC(0-10h)分别为(3444.7±1242.4)和(3229.9±1225.6)ng·h ·ml-1;AUC(0-∞)分别为(3485.0±1233.7)和(3279.6±1233.7) ng·h·ml-1;双单侧t检验结果表明,厄多司坦受试制剂Cmax的90％置信区间落在参比制剂的94.1％～124.4％范围内,AUC(0-10h)的90％置信区间落在参比制剂的90.7％ ～ 123.9％范围内;受试制剂对参比制剂厄多司坦的相对生物利用度F为(116.6±36.6)％.试验及参比片的M1的主要药动学参数Cmax分别为(396.5±177.6)和(385.0±192.7) ng·ml-1;Tmax分别为(1.7±0.8)和(1.9±0.7)h;t 1/2分别为(2.6±0.9)和(2.6±1.1)h;AUC(0-10h)分别为(1259.2±609.8)和(1331.3±694.0)ng·h·ml-1;AUC(0-∞)分别为(1372.4 ±607.3)和(1451.7 ±719.0) ng·h·ml-1;双单侧t检验结果表明,M1受试制剂Cmax的90％置信区间落在参比制剂的89.2％ ～ 121.1％范围内,AUC(0-10h)的90％置信区间落在参比制剂的80.9％ ～111.6％范围内;受试制剂对参比制剂M1的相对生物利用度F为(103.2±39.6)％.结论 对厄多司坦及其代谢产物M1的主要药动学参数进行评价,按照生物等效性判定标准,认为2种制剂生物等效.

PPARD encodes peroxisome proliferator-activated re-ceptor delta, which has been shown to play an important role in control-ling lipid metabolism and atherosclerosis. In this case-control study, we explored the relationship between PPARD rs2016520 polymorphism and coronary heart disease (CHD) in a Han Chinese population. A to-tal of 657 CHD cases and 640 controls were included in the associa-tion study. rs2016520 polymorphism genotyping was performed using the melting temperature-shift polymerase chain reaction method. The PPARD rs2016520-G allele reduced CHD risk by 17.9% (χ(2) = 5.061, P = 0.025, OR = 0.821, 95%CI = 0.692-0.975). Furthermore, a signifi-cant difference in CHD risk was observed for the PPARD rs2016520 polymorphism in the dominant model (AG + GG vs AA: χ(2) = 4.751, degrees of freedom (df) = 1, P = 0.029, OR = 0.784, 95%CI = 0.631- 0.976). Analysis by age suggested that the G-allele decreased CHD risk by 14.8% in ages greater than 65 years (χ(2) = 4.446, P = 0.035, OR = 0.852, 95%CI = 0.684-1.060). In contrast, meta-analysis of PPARD rs2016520 among 3732 cases and 5042 controls revealed no associa-tion between PPARD rs2016520 and CHD (P = 0.19). We found that the PPARD rs2016520-GG genotype decreased CHD risk in a Han Chinese population. Moreover, we found an association between serum high-density lipoprotein cholesterol level and PPARD rs2016520 in senior individuals aged ≥ 65 years. The meta-analysis revealed no association between PPARD rs2016520 and CHD, suggesting ethnic differences in the association between the PPARD locus and CHD.

The aim of the present study was to investigate the pharmacokinetic and pharmacodynamic characteristics of febuxostat following the administration of single and multiple oral doses under fasting conditions to healthy individuals. Thirty-six healthy subjects were randomly divided into three groups, each containing 12 subjects (six male and six female) as follows: Group A, treated with a single oral dose of febuxostat (40 mg); group B, treated with a single oral dose of febuxostat (80 mg) followed by multiple oral doses of febuxostat for 7 days; and group C, treated with a single oral dose of febuxostat (120 mg). Blood samples were collected, and the plasma drug levels and serum uric acid (UA) concentrations were determined by clinical laboratory testing. Febuxostat displayed a linear pharmacokinetic profile for oral doses of 40 to 120 mg. Drug accumulation was not detected following multiple oral doses. When febuxostat was administered as single doses of 40, 80 and 120 mg, the 24-h UA concentration (UA24) values displayed a linear correlation with the dosage. The relationship between UA24 and the three single dose levels (40, 80 and 120 mg) was analyzed. The difference in UA24 between every single dose was significant (P<0.05). After 3 and 7 days of dosing, reductions of 46.67 and 52.69%, respectively, were observed in UA24. On day 7 of dosing, the mean reduction in the UA concentration was 51.83±7.00%. This study demonstrates that febuxostat reduces serum UA concentrations in a dose-linear manner.

Objective To investigate the effect of CYP2C9 polymorphism on the pharmacokinetics of meloxicam in Chinese healthy subjects.Methods The CYP2C9 genotypes of twenty-four Chinese healthy male subjects were selected by the pyrosequencing method.The subjects were genotyped with CYP2C9*3 wild-type and mutation.HPLC-MS-MS method was used for the determination of meloxicam in plasma.The important pharmacokinetic parameters were caculated by DAS 2.0 software.The pharmacokinetics of meloxicam based on identification of genotypes(CYP2C9*3 wild-type and mutation) was compared.Results Two kinds of CYP2C9*3 phenotype existed in the subjects.CYP2C9* 3(A/A) was found in twenty-two subjects while CYP2C9*3(A/C) in two subjects.For meloxicam,the A/A of CYP2C9*3 alleles was more active than the A/C.Conclusion CYP2C9 genetic polymorphism has significant influence on the pharmacokinetics of meloxicam.A/A is more active than A/C.Pharmacogenomic studies will help rational and individualized medication.

目的 建立液质联用色谱法(LC-MS-MS)测定人血浆中阿托伐他汀(atorvastatin )浓度。 方法 采用萃取法处理血浆样品进行LC-MS-MS分析。分析柱为美国Thermo公司Thermo BioBasic-C8柱(2.1 mm×100 mm,5 μm) ;流动相为乙腈(含0.1%甲酸):水(含0.1%甲酸)=70:30;流速0.3 ml/min;质谱条件:电喷雾离子化电离源ESI负离子检测,喷雾电压(SP)3 500 KV,鞘气(SGP)流速10 Arb,辅助气(AGP)流速15 Arb,毛细管温度(TEM)314 ℃;选择反应监测(SRM)分别测定阿托伐他汀和甲苯磺丁脲 558→278 m/z(30 EV)和269→106 m/z(22 EV) 。 结果 阿托伐他汀在0.1~20 μg/L检测浓度范围内呈良好线性关系(r>0.99),最低定量限(LLOQ)为0.1 μg/L,绝对回收率在70%以上,高中低3种浓度的日内和日间RSD≤15%。 结论 该方法操作简便、灵敏、准确,适用于临床阿托伐他汀的血药浓度监测及I期临床试验。

Objective To study the relative bioavailability of levofloxacin hydrochloride oral liquid and tablets in healthy volunteers. Methods In a randomized two- way crossover design,a single oral dose of 200mg levofloxacin hydrochloride oral liquid and tablets were given to 24 male healthy volunteers.The plasma levofloxacin concentration within 36 h after administration was determined by HPLC and parameters C_(max),T_(max),T_(1/2),AUC_((0-1)),AUC_((0-∞)) were obtained and analyzed by two- one side test.Results The C_(max) were(2.80±0.59) and(2.64±0.56)μg /ml,respectively;T_(max) were(0.66±0.18 ) and(0.82±0.34) h,respectively;T_(1/2) were (6.60±1.37)and(7.26±1.20) h,respectively;AUC_((0-t)) were(14.97±2.32)μg.h/ml和(15.04±2.32)μg·h/ml,AUC_((0-∞)) were(15.66±2.38 ) and(15.92±2.35 )μg.main pharmacokinetic parameters of levofloxacin hydrochloride oral liquid and tablets were as follows:C_(max) was(2.80±0.59) and(2.64±0.56)μg/ml,respectively;T_(max) was(0.66±0.18) and(0.82±0.34) h,respectively; T_(1/2) was(6.60±1.37) and(7.26±1.20) h,respectively;AUC_((0-t)) was(14.97±2.32)μg·h/ml and(15.04±2.32)μg·h/ml,respectively.AUC_((0-∞)) was(15.66±2.38) and(15.92±2.35)μg·h/ml,respectively.There was no statistically significant difference between these two test groups.The relative bioavailability of the test oral liquid was(100.1±10.6)%.Conclusions The levofloxacin hydrochloride oral liquid and tablets are bioequivalent.

OBJECTIVE To study the pharmacokinetics and pharmacodynamics of amlodipine in healthy subjects and explore the relationship between the blood concentration of amlodipine and the antihypertensive effect. METHODS 24 male volunteers were administered 10 mg amlodipine by single dose.The blood samples of different time points in these subjects were sampled and the drug concentrations of amlodipine were analyzed by LC-MS-MS,and the primary variables measured in this study were systolic and diastolic blood pressure(SBP and SDP) and pulse rate in a sitting position. RESULTS Amlodipine was a two-compartment model with slow elimination(t1/2,36 h) and a large apparent volume of distribution.The Cmax was(6.1±1.5)ng·mL-1.SBP and SDP were depressed after administration,and it was related to the change of drug concentration.The efficacy hysteresis rings were found from the curves of efficacy-concentration. CONCLUSION Amlodipine can depress the SBP and DBP with efficacy hysteresis.The most efficacy Emax(SBP:6.3±3.2 mmHg,DBP:10.1±2.9 mmHg) was appeared after administration 6-10 h.The efficacy hysteresis was better form on the antihypertensive effect in clinical therapy.

他汀类药物可显著降低冠心病事件的发生率和死亡率。对国内外报道的他汀类药物所致不良反应进行分类分析,探讨他汀类药物所致不良反应的一般规律及特点,为临床合理用药提供参考。他汀类药物较严重的不良反应临床表现以肝毒性最常见,其次为肌肉损害(以横纹肌溶解症最为严重)和神经系统疾病,其他不良反应有骨关节痛、阳痿、脱发等。临床应用应严格掌握用药指征,规范用药剂量及联合用药,密切观察患者临床表现及生化指标监测结果,确保其使用安全,减少不良反应的发生。

Objective:To develop a LC-MS-MS assay for the determination of ibuprofen in human serum and to investigate the pharmacokinetics and bioequivalence of two preparation in Chinese healthy volunteers.Methods: A single per rectum dose of 50 mg ibuprofen test suppositories and reference suppositories was given to 20 healthy male volunteers in a randomized double cross-over design.Ibuprofen concentration were determined by LC-MS-MS assay,and pharmacokinetic parameters were calculated with DAS2.0 practical pharmacokinetics program.Results:The calibration curve was linear over the range of 0.05~6.4 mg/L.The main pharmacokinetic parameters of test suppositories and reference suppositories were as follow: t1/2(2.77±0.65) and(3.02±0.99) h,ρmax(2.148±0.643) and(2.013±0.844) mg/L,tmax(3.2±0.7) and(3.1±0.5) h,AUC0-12(11.37±3.56) and(11.30±4.62)mg·h/L.Conclusion:The method applied was convenient,accurate and specific,and the statistical analysis showed that the test and reference preparation bioequivalent.

Aim To investigate the pharmacokinetics of prulifloxacin tablets in Chinese healthy volunteers after a single oral administration of prulifloxacin tablets.Methods A total of 12 healthy adult subjects were randomly grouped by 3×3 Latin square and assigned to receive a single oral dose of 100,200 and 400mg of prulifloxacin tablets.LC/MS/MS were used for the determination of NM394,the metabolite of prulifloxacin,in plasma after a single oral dose of prulifloxacin tablets.Important pharmacokinetic parameters were caculated by DAS 2.0 software(compartment model).Results No prulifloxacin but its metabolite-NM394 was identified in the blood sample of subjects.All the three dosage groups(100,200,400mg) conformed to the two-compartment model.The pharmacokinetics fitted first-order kinetic process.No difference in pharmacokinetics of NM394 in male and female volunteers was observed.12 subjects completed the single oral administration test,with no adverse drug reactions during the test.Conclusion The Cmax 、AUC of NM394 are highly correlated with given prulifloxacin doses.The established method is sensitive,accurate,reliable and specific,and it can meet the requirement of clinical pharmacokinetic trials.

Aim To study the pharmacokinetics of Adefovir Dipivoxil Capsules in healthy volunteers and to provide the reference for clinical dosage regimen and dosage interval by calculating the major parameters of pharmacokinetics. Methods A single dose and multiple doses of adefovir were given orally to 8 healthy volunteers in a randomized study. The concentrations of Adefovie in plasma after administration were determined by the LC/MS/MS. Results The main pharmacokinetic parameters of the test were as follows:Cmax was(27.560±10.836)and(27.271±6.695)μg·L-1;Tmax was(1.75±0.267)and(1.688±0.259)h;AUC(0-24) was(161.798±51.324) and(173.486±38.359)μg·h·L-1;AUC0-∞ was(170.582±57.067) and(185.713±45.058)μg·h·L-1;Ka was(1.019±0.252) and(1.081±0.377)h-1;K10 was(0.324±0.105) and(0.307±0.127)h-1;t1/2β was(7.117±1.345) and (8.044±2.489)h;CL/F was (61.994±18.628) and (55.854±11.794)L·h-1;V/F was (218.998±122.07) and ( 203.457±76.736 )L, respectively. The pharmacokinetic parameters were statistically analyzed by t-test. There was no safety problem observed in the process of testing. Conclusion There is no significant difference between the two kinds of pharmacokinetic parameters after a single oral and multiple doses of administration,suggesting no accumulation by the administration of multiple doses.The dosage regimen and the dosage interval are to be in line with clinical medication.

Objective:To establish LC/MS/MS method for determination of Simvastatin in plasma and to study the pharmacokinetics and relative bioavailability following oral administration of trail Simvastatin tablets and reference simvastatin tablets in Chinese healthy volunteers.Methods:Eighteen volunteers were randomly divided into 2 groups.A LC-MS-MS method was used for the determination of Simvastatin in plasma after a single oral dose of 40 mg Simvastatin trail or reference samples in a crossover design.The pharmacokinetic parameters as well as relative bioavailability were analyzed based on a non-compartment model of DAS2.0 statistical software,variation analysis and a two-sided t-test.Results:The main pharmacokinetic parameters of Simvastatin test and reference tablets were as follows:cmax:(9.70±6.62),(10.06±6.29) μg/L;tmax:(1.64±1.01),(1.64±0.68)h;t1/2:(3.48±1.16),(4.15±1.90) h;AUC0～14 h:(29.96±16.28),(32.78±18.53) μg·h·L-1;AUC0～∞ :(31.49±16.65),(36.39±21.71) μg·h·L-1respectively.The relative bioavailability of the test to reference tablets was(97.79±26.63)%.Conclusion:The two preparations are bioequivalent.

OBJECTIVE To study the pharmacokinetics and relative bioavailability of domestic etodolac capsules and tablets in healthy volunteers.METHODS A reversed-phase high performance liquid chromatography was used for the determination of etodolac in plasma after a single oral dose of 200 mg domestic etodolac capsules and tablets in a crossover design.RESULTS The important pharmacokinetic parameters of domestic etodolac capsules were similar to those of etodolac tablets.The relative bioavailability of the test capsules was(99.1±14.4)%.CONCLUSION The domestic etodolac capsules and tablets were bioequivalent.

Aim To investigate the pharmacokinetics and relative bioavailability of amoxycillin and sulbactam pivoxil test and reference tablets in Chinese healthy volunteers.Methods The study was conducted in a two-treatment,two-period,two-sequence randomized cross-over trial.HPLC and LC/MS/MS were used for the determination of Amoxycillin and Sulbactam in plasma respectively after a single oral dose of Amoxycillin and Sulbactam Pivoxil tablets.The important pharmacokinetic parameters and relative bioavailability were caculated.Results The main pharmacokinetic parameters of test and reference tablets were as follows respectively:Amoxycillin:Cmax was(9.61±2.00)and(10.40±2.87)mg·L-1;Tmax was(1.20±0.28)and(1.21±0.36)h;T1/2 was(1.46±0.86)and(1.13±0.48)h;AUC0-∞ was(23.38±4.04)and(23.04±6.04)mg·h·L-1;AUC0-∞ was(25.28±4.37)and(24.48±5.98)mg·h·L-1;The relative bioavailability of Amoxycillin was(109.3±19.4)%.Sulbactam:Cmax was(7.72±1.43)and(7.85±1.93)mg·L-1;Tmax was(1.71±0.61)and(1.65±0.52)h;T1/2 was(1.93±0.80)and(2.08±0.71)h;AUC0-8 was(26.29±6.62)and(27.54±7.83)mg·h·L-1;AUC0-∞ was(28.51±7.25)and(29.85±8.32)mg·h·L-1;The relative bioavailability of Sulbactam was(98.0±4.6)%.Conclusion The Amoxycillin and Sulbactam Pivoxil test and reference tablets were bioequivalent.