Predicting Nonlinear Pharmacokinetics of Omeprazole Enantiomers and Racemic Drug Using Physiologically Based Pharmacokinetic Modeling and Simulation: Application to Predict Drug/Genetic Interactions

Purpose

The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug.

Methods

By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur.

Results

The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively.

Conclusions

PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole.     

外伤性血气胸中心静脉导管置管引流术的护理

目的 探讨中心静脉导管胸腔闭式引流术在外伤性血气胸患者的临床疗效及护理体会.方法 对62例外伤性血气胸的患者采用中心静脉导管胸腔闭式引流法治疗血气胸,护理并观察患者疗效及并发症.结果 本组病例患者疼痛少,引流口创伤小、愈合佳,血气胸吸收满意.结论 中心静脉导管胸腔闭式引流术对外伤性血气胸的治疗有积极的作用,可减轻患者的痛苦,利于血气胸吸收,缩短住院时间,值得临床推广.     

miR-101下调c-met的表达提高宫颈癌干细胞对5-氟尿嘧啶的敏感性

目的 探讨miR-101与宫颈癌干细胞对5-氟尿嘧啶敏感性的关系并研究其机制。方法 流式细胞术分选Hela细胞系的肿瘤干细胞。荧光定量PCR检测Hela肿瘤干细胞中miR-101的表达水平。MTT法检测Hela肿瘤干细胞在5-氟尿嘧啶和miR-101处理下的细胞活力。Western blot试验检测5-氟尿嘧啶和miR-101对Hela肿瘤干细胞c-met表达水平,PI3K、AKT磷酸化水平及caspases 活化水平的影响。流式细胞术检测Hela肿瘤干细胞在5-氟尿嘧啶和miR-101处理下的凋亡率。结果 Hela干细胞中miR-101的表达水平相较Hela非干细胞细胞显著下降。Hela干细胞转染miR-101后,其对5-氟尿嘧啶的敏感性显著上升。Western blot试验显示miR-101能显著降低Hela肿瘤干细胞的c-met蛋白表达水平,表明c-met是miR-101的靶点。western blot流式细胞实验结果表明在Hela肿瘤干细胞中,miR-101通过下调c-met的表达抑制PI3K和AKT的磷酸化,从而提高Hela肿瘤干细胞对5-氟尿嘧啶依赖的凋亡信号的敏感性,促进caspase-9和caspase-3的活化。结论 miR-101通过下调c-met的表达提高宫颈癌干细胞对5-氟尿嘧啶的敏感性。     

松香局部应用对牙本质小管封闭效果的实验研究

目的 观察天然松脂局部应用对牙本质小管的封闭效果以及其浓度效应,为其单独防治牙本质过敏提供实验依据。方法 制备牙本质块80个,采用随机数字表法随为8组,每组10个,酸蚀30 s,分别用无水乙醇,氟涂膜,10%,20%,30%,40%,50%和60%松香乙醇溶液涂布牙本质,场发射扫描电镜观察牙本质表面及剖面的显微形貌,并测量牙本质小管开口面积(ADTO)、牙本质小管开口相对面积(PADTO)和树脂突长度(LTD)。结果 各松香乙醇组ADTO,PADTO均显著低于乙醇组(P＜0.05)。30%,40%,50%和60%松香乙醇组ADTO,PADTO与氟涂膜组差异无统计学意义(P＞0.05),均显著低于10%和20%松香乙醇组(P＜0.05)。扫描电镜见乙醇组牙本质表面牙本质小管完全开放,管壁较疏松;氟保护漆组牙本质小管完全封闭,未见明显树脂突形成;松香乙醇组牙本质小管呈不同程度封闭,剖面可见长度不等的树脂突形成。结论 松香乙醇溶液局部应用可快速封闭开放的牙本质小管,形成树脂突,且50%松香溶液即可达到较好即刻封堵效果。松香可通过封堵开放的牙本质小管防治牙本质过敏。     

祛痰化瘀胶囊治疗痰瘀阻络型脑梗死急性期100例

目的观察祛痰化瘀胶囊治疗痰瘀阻络型脑梗死的疗效,并探讨其作用机制。方法将200例痰瘀阻络型脑梗死患者随机分为祛痰化瘀胶囊治疗组（治疗组）和常规治疗组（对照组）。结果治疗组总有效率93%,对照组总有效率81%,两组比较有统计学意义（P〈0.05）。治疗组治疗后胆固醇、三酰甘油、低密度脂蛋白、高密度脂蛋白均有不同程度改善,与对照组治疗后比较也有统计学意义（P〈0.05）。治疗组治疗后血液流变学指标均较治疗前有明显改善（P〈0.05或P〈0.01）,与对照组治疗后比较也有统计学意义（P〈0.05）。结论祛痰化瘀胶囊能明显改善临床症状,能降低血液黏度,降低血脂,改善高过氧化物脂质及低超氧化物歧化酶血症状态,改善微循环,增加脑血流量。     

资源需求型智慧教育模式在康复评定学教学中的应用

在信息技术不断变革创新的时代,智慧教育模式在逐渐取代传统的教学模式,学习者"学习方式"正在发生深刻的变革,对学习资源的需求也在改变,人们需要学习资源多样化、微型化、切需化,以适应新的学习文化和学习方式.在我校康复评定学课程教学中,我们引入智慧教育模式,开展康复评定学课程"资源需求型"研究,以期探索符合当前信息时代的高等...     

黄芪多糖联合碘-125治疗中晚期非小细胞肺癌的临床研究

目的：探讨黄芪多糖（APS）联合碘-125（I¹²⁵）治疗中晚期非小细胞肺癌（NSCLC）的临床疗效及作用机制。方法：将60例中晚期NSCLC患者随机按住院前后顺序分为观察组和对照组各30例,对照组采用I¹²⁵粒子植入方法,观察组在对照组治疗的基础上加用APS 250 mg,静脉滴注,1次/d。疗程42 d。观察治疗前患者瘤体大小,进行治疗前后KPS评分,检测治疗前后细胞免疫功能（NK,CD₃⁺,CD₄⁺,CD₈⁺）和血清癌胚抗原（CEA）和细胞角蛋白19片段（CYFRA-21-1）水平。结果：治疗后观察组和对照组总有效率分别为83.33%和73.33%,两组比较差异无显著性意义;治疗后观察组卡氏评分提高+稳定率为90.0%,优于对照组的63.3% （P<0.01）;治疗后对照组NK,CD₃⁺,CD₄⁺,CD₈⁺及CD₄⁺/CD₈⁺变化不明显,治疗后观察组NK,CD₃⁺,CD₄⁺及CD₄⁺/CD₈⁺上升并高于对照组,CD₈⁺下降并低于对照组（P<0.01）;两组血清CEA,CYFRA-21-1水平均较治疗前下降,治疗后观察组低于对照组 （P<0.01）。结论：APS联合I¹²⁵治疗中晚期NSCLC,能提高患者生活质量,提高患者免疫功能,并具有一定的抗肿瘤作用,对I¹²⁵起到增效作用,值得进一步研究。     

针灸治疗胎位不正的古代文献分析

目的:对针灸治疗胎位不正的古代文献进行文献计量学分析,分析古代针灸处方的特征。方法:以难产、横生逆产、横产、逆产等为文本词,检索《中华大典.医学分典.针灸推拿总部》中的相关文献并进行文献计量学分析。结果:共44条文献记录,涉及14个穴位和8条经脉,共86频次;采用针刺15条,灸法13条,其余未标明。结论:腧穴经脉的选取体现了胎位不正的病机特点,多选三阴交、至阴、合谷,经脉以脾经、大肠经、膀胱经为多;针刺与灸法并用,至阴多直接灸,其余穴位多针刺。     

麻黄-甘草药对的抗炎、利尿作用研究

目的:观察麻黄-甘草药对的抗炎、利尿作用。方法:采用二甲苯致小鼠耳肿胀实验、醋酸致小鼠腹腔毛细血管通透性增加实验、角叉菜胶致大鼠足肿胀、大鼠棉球肉芽肿实验观察麻黄-甘草药对的抗炎作用;采用麻黄-甘草药对对正常大鼠排尿量及电解质排泄的影响观察其利尿作用。结果:麻黄-甘草药对22.4、11.2、5.6g/kg灌胃,均能抑制二甲苯所致的小鼠耳肿胀;11.2g生药/kg、22.4g生药/kg灌胃,能抑制醋酸所致的小鼠腹腔毛细血管通透性增加;22.4g生药/kg能抑制角叉菜胶注射后3h,5h,7h的大鼠足肿胀和大鼠棉球肉芽肿形成、增加大鼠排尿量及尿液中K+的排泄。结论:麻黄-甘草药对有抗炎、利尿作用。     

A simple high-performance liquid chromatographic method for the determination of brazilin and its application to a pharmacokinetic study in rats

Ethnopharmacological relevance

Caesalpinia sappan is a medicinal plant native to China popularly used to treat chronic pelvic inflammation, dysmenorrhea and hysteromyoma. Its main bioactive component is brazilin which had presented antibacterial, anti-inflammatory and anti-platelet aggregation activities. To establish a sensitive, selective, reproducible, and accurate high performance liquid chromatographic (HPLC) method for the quantitative determination of brazilin in plasma, and study the pharmacokinetics of brazilin in rats after intravenous administration of brazilin.

Materials and methods

Rats received intravenous injection of 25, 50 and 100 mg/kg of brazilin. Concentrations of brazilin in plasma were determined by HPLC method at different time points and all pharmacokinetic parameters were estimated by non-compartmental analysis with WinNonLin 6.2 software.

Results

After single intravenous doses of 25, 50 and 100 mg/kg brazilin in rats, the main PK parameters were as follows: C_max were 18.1±4.1, 46.7±8.7 and 82.2±9.6 µg/mL; AUC_0–24 were 20.4±4.3, 48.7±6.8 and 90.4±10.3 µg h/mL; and t_1/2 were 5.4±1.5, 5.8±0.9 and 6.2±1.2 h, respectively.

Conclusion

It showed that the brazilin was eliminated moderately in rat by intravenous injection route with t_1/2 of 6 h and showed a dose-dependence profile of C_max and AUC_0–24 at the doses of 25~100 mg/kg of brazilin for injection in rats.