乙酰半胱氨酸颗粒在健康人体的生物等效性研究

目的：建立人血浆乙酰半胱氨酸浓度测定方法,研究乙酰半胱氨酸颗粒在健康人体内的相对生物利用度与生物等效性。方法采用二制剂三周期自身对照完全三交叉试验设计,其中每位受试者有一周期不服药,健康男性受试者24例分别单剂量口服乙酰半胱氨酸受试制剂或参比制剂0.6 g。高效液相色谱串联质谱法测定血浆乙酰半胱氨酸浓度,应用DAS 3.0版统计软件计算药动学参数并评价两种制剂生物等效性。结果单剂量口服乙酰半胱氨酸颗粒受试制剂和参比制剂0.6 g的主要药动学参数：AUC0→t分别为(8547.64±2860.04)和(8783.07±4042.10)μg·h·L-1;AUC0→∞分别为(9481.64±3444.76)和(9540.51±4239.30)μg·h·L-1;Cmax分别为(1994.39±726.42)和(2090.27±885.46)μg·L-1;tmax分别为(1.18±0.60)和(1.13±0.53) h;t1/2分别为(8.60±3.76)和(7.75±5.01) h;相对生物利用度以AUC0→t和AUC0→∞计算分别为(107.0±43.3)％和(106.5±40.1)％。结论乙酰半胱氨酸颗粒两种制剂具有生物等效性。     

组蛋白去乙酰化酶抑制剂抗肿瘤作用机制研究进展

组蛋白去乙酰化酶抑制剂可通过阻滞细胞周期、诱导细胞凋亡、抑制血管新生、诱导自我吞噬等多种途径发挥抗肿瘤作用。此外,与其他抗肿瘤化合物联合应用时也表现出良好的抗肿瘤活性,具有极大的临床开发潜力。     

高效液相色谱-质谱联用法快速测定人血浆中丙戊酸钠浓度

目的：建立有效测定人血浆中丙戊酸钠浓度的高效液相色谱-质谱连用（HPLC-MS/MS）的方法。方法：血浆样本经乙腈沉淀蛋白后,以替米沙坦为内标,采用Agilent ZORBAX300SB-C₁₈柱（2.1 mm×150 mm, 5 μm）色谱柱,乙腈-20 mmol·L^-1乙酸胺（55：45）为流动相,流速0.25 mL·min ^-1,以液相色谱分离,电喷雾离子化串联质谱进行检测,采用多反应监测（MRM）测定丙戊酸钠（m/z 143.0→m/z 143.0）和内标替米沙坦（m/z 513.5→ m/z 469.4）的浓度。结果：校准曲线线性浓度范围从0.2~100 μg·mL^-1,最低定量限为0.2 μg·mL^-1。3个不同浓度（低、中、高）丙戊酸钠提取回收率分别为90.46%,93.18%,95.31%。日内和日间精密度均小于10%和8%。结论：此法简单灵敏,重现性好。已成功应用于丙戊酸钠片在中国健康志愿者的药动学研究。     

液-质联用法测定人血浆中卢非酰胺的浓度及其在药动学研究中的应用

目的:建立高效液相色谱-质谱联用(HPLC-MS/MS)测定人血浆中卢非酰胺浓度的方法。方法:40名健康受试者随机分成4组,分别单剂量口服给药卢非酰胺片200,400,800,1200 mg。血浆样品经乙腈沉淀蛋白提取分离,色谱柱为Ultimate^® AQ-C₁₈(100 mm×2.1 mm,5 μm,Welch Material Inc.);流动相为乙腈-5 mmol·L^-1乙酸胺水溶液(含0.1%甲酸)=32:68;流速为0.30 mL·min^-1;内标为埃索美拉唑。采用电喷雾离子源,以多反应监测(MRM)方式进行正离子检测。结果:卢非酰胺的血浆浓度在40~5000 ng·mL^-1范围内线性良好,定量下限为40 ng·mL^-1,日内精密度(RSD)均≤8.20%,日间精密度(RSD)均≤6.35%,提取回收率为91.94%~96.48%。卢非酰胺呈非线性药动学特征,单剂量空腹口服给药卢非酰胺片200,400,800,1200 mg后,C_max分别为1803.50±528.06, 2485.00±562.71, 3710.00±965.50和4158.00±1181.91 μg·L^-1。AUC_0-t分别为34522.13±9525.00, 56138.53±18021.98, 88848.53±23348.14和107058.03±34420.08 μg·h·L^-1。结论:该法操作简单,灵敏,准确,重复性好,适用于卢非酰胺片临床药动学研究。从药动学研究可知,卢非酰胺在中国健康受试者中呈非线性药动学特征。     

基于PK/PD参数优化阿莫西林/克拉维酸钾缓释片给药方案

摘 要 目的：依据PK/PD参数优化阿莫西林/克拉维酸钾缓释片的临床给药方案。方法: 30名健康受试者随机分为3组,分别于空腹、餐前和餐后口服阿莫西林/克拉维酸钾缓释片,通过比较其药动学特征确定最佳给药方式。3组受试者分别单次口服低、中、高3个剂量的阿莫西林/克拉维酸钾缓释片,比较不同给药剂量下的PK/PD参数,确定给药剂量和给药间隔。结果: 阿莫西林的AUC空腹组[（32.2±15.0）μg·h·ml^-1]较餐前组[（41.7±1.92）μg·h·ml^-1]和餐后组[（42.6±17.7）μg·h·ml^-1]有所降低,而克拉维酸的AUC则是餐后组[（1.89±0.54）μg·h·ml^-1]明显低于空腹组[（2.55±0.76）μg·h·ml^-1]和餐前组[（2.58±0.76）μg·h·ml^-1]（P<0.05）。阿莫西林和克拉维酸分别在剂量1 000～4 000 mg、62.5～250 mg剂量范围内呈线性药代动力学特征。以最小抑菌浓度（MIC）为2.0 μg·ml^-1计,单次口服低、中、高剂量的阿莫西林/克拉维酸钾缓释片后,12 h内血药浓度大于MIC的持续时间（T＞MIC）分别为5.5,7,10 h,百分比分别为46%、58%和83%。以MIC为4.0 μg·ml^-1,则12 h内T＞MIC分别为4.5,6,8 h,百分比分别为38%、50%和67%。结论:给予阿莫西林/克拉维酸钾缓释片的最佳时机是在标准餐前服用,每天给药2次,每次2片即可满足T＞MIC时达到40%~50%。     

Pharmacokinetics and Tissue Distribution of Clevidipine and Its Metabolite in Dogs and Rats

The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H 152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/（kg·min）, and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short （16.8 min）, pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/（min·kg）. In comparison, plasma concentra- tion of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the high- est concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small （0.042‰） compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite raoidlv.     

左舒必利注射液在中国健康受试者的药代动力学

目的 研究左舒必利注射液在中国健康受试者单次及多次给药的药代动力学。方法 用开放、随机、平行的试验设计。30名受试者,男女各半,分为3个剂量组,分别接受单次及多次肌内注射不同剂量左舒必利,采集不同时间的血样,用高效液相色谱-串联质谱法(HPLC/MS/MS)测定血浆中左舒必利的浓度。用DAS 3.0软件计算药代动力学参数。结果 单次肌内注射25,50,75 mg左舒必利的主要药代动力学参数:cmax分别为(724.70±248.91),(949.60±234.80),(1619.00±366.80)μg·L-1;t1/2分别为(7.65±1.32),(7.58±0.89),(8.01±0.88)h,AUC0-t分别为(2874.17±1093.71),(4481.75±913.09),(7559.33±1428.87)μg·L-1·h。连续给药组t1/2为(7.41±0.79)h;AUC0-t为(4658.33±909.51)μg·L-1·h。结论 中国健康受试者单次肌内注射给药左舒必利在25~75 mg内呈线性药代动力学特征,多次给药没有蓄积倾向,男、女间比较,差异无统计学意义。     

Development of a liquid chromatography-tandem mass spectrometry method for determination of butoconazole nitrate in human plasma and its application to a pharmacokinetic study

Summary： A liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was developed and validated for the determination of butoconazole in human plasma. Human plasma samples of 0.2 μL were pretreated by a single step protein precipitation procedure and analyzed using a high performance liquid chromatography （HPLC） electrospray tandem mass spectrometer system. The compounds were eluted isocratically on an Inertsil ODS-SP column （100 min×2.1 mm, 3 μm）, ionized using a positive ion atmospheric pressure electrospray ionization source and analyzed using multiple reaction monitoring （MRM） mode. The ion transitions monitored were m/z 412.8→q65.1 for butoconazole and m/z 453.4→230.3 for the internal standard. The chromatographic run time was 3.5 min per injection, with retention time of 2.47 rain and 2.15 min for butoconazole and repaglinide, respectively. The method was validated to be linear over the range of 20 to 8000 pg/mL （r〉0.999） by using a weighted （1/x2） quadratic regression. The mean recovery rate was more than 86.7%, and the intra- and inter-day precision of the quality control samples （QCs） was less than 8.3% and the accuracy ranged from 96.0% to 110.2%, which indicated that the quantitative method was reliable and accurate. The method is simple, rapid, and has been applied successfully to a pharmacokinetics study of butoconazole nitrate suppositories in healthy Chinese females.     

紫花地丁灌洗联合凝胶敷料用于胰瘘合并瘘口感染护理

目的探讨凝胶敷料联合中药水煎剂灌洗在胰瘘合并瘘口感染护理中的效果。方法选取胰腺肿瘤术后发生胰瘘合并瘘口感染的63例患者按入院时间先后分为对照组(使用生理盐水间断灌洗清洁后,瘘口消毒,常规氧化锌涂抹保护皮肤等继续引流),敷料组(使用生理盐水间断灌洗清洁后,瘘口消毒,涂抹普朗特凝胶敷料包扎继续引流),联合组(使用生理盐水间断灌洗清洁后,使用超滤后紫花地丁水煎剂间断灌洗清洁,瘘口消毒,涂抹普朗特凝胶敷料包扎继续引流)。观察比较三组患者瘘口周围皮炎改善情况,瘘口周围皮肤换药疼痛程度及瘘口愈合时间。结果治疗1周、1个月后三组瘘口周围皮炎程度、换药时疼痛评分比较,差异有统计学意义(均P0.01),敷料组与联合组显著优于对照组(均P0.05);疼痛评分联合组显著优于敷料组(P0.05)。三组瘘口周围皮肤炎症愈合时间比较,差异有统计学意义(均P0.01),联合组愈合时间最短。结论紫花地丁水煎剂灌洗联合普朗特凝胶敷料能够控制瘘口感染和加快瘘口周围皮炎皮损的愈合,减轻换药时疼痛。