丹参酮亚微乳制剂的制备工艺和质量评价

目的研制丹参酮IIA亚微乳,并对其进行质量评价。方法采用两步高压乳匀法制备丹参酮IIA亚微乳,分别考察了高压均质条件,油相、乳化剂及稳定剂用量,采用正交试验对处方进行优化,制备丹参酮IIA亚微乳。结果自制丹参酮IIA亚微乳的平均粒径为(191.3±0.56)nm,Zeta电位为(41.76±0.31)mV;高速离心和长期试验后,仍保持均一稳定。结论研制的丹参酮IIA亚微乳制剂性质稳定。     

丹参酮ⅡA在大鼠肺脏和肝脏细胞器的分布

目的考察丹参酮ⅡA在大鼠肺脏、肝脏细胞器的分布,以探讨丹参酮ⅡA在大鼠肺脏高浓度储留的机制。方法雄性SD大鼠经颈静脉给予6 mg/kg丹参酮ⅡA,给药后分批处死,取其肝、肺组织,差速离心法分离细胞器,高效液相色谱-串联质谱(LC-MS/MS)法测定丹参酮ⅡA的浓度。结果给药后,丹参酮ⅡA在肺脏的浓度远高于在肝脏的浓度。丹参酮ⅡA在肝脏细胞器中主要以结合型的形式存在,在肺脏中则是原型稍多。丹参酮ⅡA在大鼠肝脏的微粒体和溶酶体部分分布较多,但是无明显的蓄积部位;而在肺脏丹参酮ⅡA主要分布于细胞器的轻线粒体部分。结论丹参酮ⅡA主要蓄积于肺脏细胞器的轻线粒体部分,而在肝脏细胞器无明显蓄积部位。这是TSⅡA在大鼠肺脏细胞器蓄积的可能机制。     

Comparative pharmacokinetics and tissue distribution of cryptotanshinone,tanshinone IIA,dihydrotanshinone I,and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats

Salvia miltiorrhiza is one of the most commonly used traditional Chinese medicines in the treatment of cardiovascular and cerebrovascular diseases. Cryptotanshinone (CTS), tanshinone IIA (Tan IIA), dihydrotanshinone I (diTan I), and tanshinone I (Tan I) are the main active compounds in the liposoluble extract of Salvia miltiorrhiza. The differences in the pharmacokinetic and tissue distribution behaviors of the four tanshinones after oral administration of the liposoluble extract of Salvia miltiorrhiza and pure compounds are not clear. This study aims to compare the pharmacokinetics and tissue distribution of the four tanshinones after oral administration of pure tanshinone monomers and the liposoluble extract of Salvia miltiorrhiza. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) analysis method was developed for the determination of the four tanshinones. The results showed that the AUC and C_max of tanshinones in rats receiving the extract of Salvia miltiorrhiza were significantly increased compared with those receiving the pure tanshinones. In the tissue distribution experiments, the AUC of the four tanshinones in the extract was much greater than the AUC of the monomers in the lung, heart, kidney, liver, and brain, and the coexisting constituents particularly promoted the distribution of tanshinones into tissues that the drug cannot sufficiently penetrate. These findings suggested that the coexisting constituents in the liposoluble extract of Salvia miltiorrhiza play an important role in the alteration of plasma concentration and tissue distribution of the four tanshinones. Understanding these differences could be of significance for the development and application of Salvia miltiorrhiza extract and tanshinone components.     

丹参酮IIA/速释辅料二元固态溶液的玻璃化转变温度研究

目的 探索丹参酮IIA与不同速释辅料的相容性及对辅料玻璃化转变温度的影响。方法 采用溶剂法制备不同种类及比例的丹参酮IIA/速释辅料二元固态溶液,并进行差示扫描量热分析,测定其玻璃化转变温度。结果 丹参酮IIA与3种速释辅料均具有良好的相容性,不同种类辅料及比例的二元固态溶液,受到药物与辅料间的分子作用力、辅料的抗增塑作用等的影响,可对体系的玻璃化转变温度产生不同程度的改变。结论 本研究为以聚合物HPMC K4M、Kollidon VA64或Soluplus为辅料制备具有速释特性的丹参酮IIA无定型态给药体系提供了技术支持。     

Tanshinone ⅡA inhibits endothelin-1 production in TNF-α-induced brain microvascular endothelial cells through suppression of endothelin-converting enzyme-1 synthesis

Aim： To investigate the effects of tanshinone ⅡA （Tan ⅡA） on the regulation of the production of endothelin （ET）- 1 （including large ET- 1）, mRNA levels of ET- 1, endothelin-converting enzyme- 1 （ECE- 1）, endothelin-A receptor （ETA） and endothelin-B receptor （ETB） induced by TNF-α in rat brain microvascular endothelial cells （BMVEC）. Methods： The ET-1 release （including large ET-1） into the culture medium was determined by enzyme immunoassay. The levels of ET-1, ECE- 1, ETA, and ETB mRNA were measured by RT-PCR. Endothelin receptor binding was also tested. Results： The induction of ET- 1 release by TNF-α from cultured BMVEC was dose-dependently reduced by Tan ⅡA, but large ET-1 levels progressively increased in response to Tan ⅡA; the mRNA expression of ET- 1 was unaffected. Tan ⅡA also caused a decrease in ETA receptor mRNA and ECE- 1 expression in a dose-dependent manner. Endothelin receptor binding was unaltered in BMVEC stimulated with TNF-α alone or a combination of TNF-α and Tan ⅡA. Conclusion： These findings suggest that Tan ⅡA may inhibit ET-1 production in TNF-α-induced BMVEC through the suppression of ECE-1 synthesis.     

阿苯达唑聚氰基丙烯酸正丁酯纳米粒的制备、性质及其组织靶向性研究阿苯达唑聚氰基丙烯酸正丁酯纳米粒的制备、性质及其组织靶向性研究

目的制备阿苯达唑聚氰基丙烯酸正丁酯纳米粒（albendazole polybutycyanocrylate nanoparticles，ABZ-PBCA-NP）TDDS给药系统，并考察相关特性及组织分布靶向性。方法种子乳化聚合法制备阿苯达唑纳米粒；等温吸附法考察纳米粒载药特性；动态透析法研究4种制剂的体外释药动力学；同位素标记阿苯达唑纳米粒在小鼠脏器组织分布和生物利用度。结果ABZ-PBCA-NP体外释药遵循Higuchi方程，加入PVP制成的载药纳米粒符合双指数函数。纳米粒的载药方式遵循Langmuir吸附方程。小鼠ig ³H-ABZ-PBCA-NP后, 药物的肝、脾中的靶向指数分别为11.4和3.9，阿苯达唑纳米粒和混悬剂相对生物利用度分别为76.0%和36.9%。结论制备纳米粒加入PVP可使药物具吸附性和分散性，纳米粒载体可降低药物与血浆蛋白结合率，增强药物的肝、脾脏器靶向性和延缓释药。     

Brain pharmacokinetics and tissue distribution of tetrahydropalmatine enantiomers in rats after oral administration of the racemate

Tetrahydropalmatine (THP), a racemic mixture, is a biologically active ingredient isolated from a traditional Chinese herb Rhizoma Corydalis (yanhusuo). The main objective of this study was to determine the brain pharmacokinetics and tissue distribution of THP enantiomers in rats after oral administration of racemic THP (rac-THP). Rats (5 animals/group/per time) were given a single oral dose of rac-THP and killed after different post-treatment times. The concentrations of THP enantiomers in plasma, cortex, cerebellum, diencephalon, brain stem, striatum and hippocampus were measured using a validated chiral high performance liquid chromatographic (HPLC) method coupled with an achiral column. The pharmacokinetic profiles of the two enantiomers in six brain regions were significantly different. The peak concentrations (Cmax) and AUC(0-infinity) values of the (-)-enantiomer were significantly greater than the corresponding values for the (+)-enantiomer while the striatum contained the highest peak concentrations compared with the plasma and other brain regions. The tissue distribution studies also revealed significant differences between the two enantiomers in all tissues except the lung. The highest concentrations of both enantiomers were found in the liver. The (-)/(+)-THP ratios in six brain regions and other tissues were consistent with that observed in plasma indicating that the stereoselective disposition of THP in rat brain and other tissues reflects the situation in plasma.     

川芎嗪硝酮衍生物在大鼠体内的组织分布研究

目的对正常大鼠体内川芎嗪(TMP)硝酮衍生物:(2-N-叔丁基硝酮)-3,5,6-三甲基吡嗪(2-[[(1,1-dimethylethyl)oxidoimino]methyl]-3,5,6-trimethylpyrazine,TBN)的组织分布进行研究。方法用Purospher C18柱(4.6mm×150.0 mm,5μm),以甲醇-0.05 mol.L-1磷酸二氢钾水溶液(45∶55,pH3)为流动相,检测波长为295 nm,建立大鼠血浆及组织内TBN含量分析的HPLC-UV方法,用于组织分布研究。结果静脉(80 mg.kg-1)给药后,TBN在各种组织的AUC0-360在2.48～13.74 mg.min.g-1,从高到低依次为:血浆>肺>肾>肝>脾>脑>心;MRT0-360在129.50～161.95 min,由长到短依次为:肺>脾>肾>脑>肝>心>血浆。结论本研究建立的HPLC方法专属性强、简便、快速、准确;用此法得知,TBN静脉给药后,可快速分布于各组织中,包括脑组织。     

Preparation,characterization, and antimicrobial activity of nanoemulsions incorporating citral essential oil

Citral is a typical essential oil used in the food, cosmetic, and drug industries and has shown antimicrobial activity against microorganisms. Citral is unstable and hydrophobic under normal storage conditions, so it can easily lose its bactericide activity. Nanoemulsion technology is an excellent way to hydrophilize, microencapsulate, and protect this compound. In our studies, we used a mixed surfactant to form citral-in-water nanoemulsions, and attempted to optimize the formula for preparing nanoemulsions. Citral-in-water nanoemulsions formed at S_o 0.4 to 0.6 and ultrasonic power of 18 W for 120 seconds resulted in a droplet size of < 100 nm for nanoemulsions. The observed antimicrobial activities were significantly affected by the formulation of the nanoemulsions. The observed relationship between the formulation and activity can lead to the rational design of nanoemulsion-based delivery systems for essential oils, based on the desired function of antimicrobials in the food, cosmetics, and agrochemical industries.     

The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat

Miglustat (Zavesca?) is a reversible inhibitor of glucosylceramide synthase, which catalyses the first step in the glucosylceramide biosynthetic pathway, and is approved for therapy in patients with type 1 Gaucher disease. The present report describes the pharmacokinetic profile of miglustat in the rat with a focus on tissue distribution. Experiments were performed with radiolabeled miglustat itself and with a perbutyrated prodrug, the latter being readily converted to miglustat during gastrointestinal absorption and first pass metabolism. Miglustat was well absorbed and exhibited an oral bioavailability of 40–60%. Tissue distribution studies indicated the presence of miglustat in a number of organs and tissues that are considered of importance for the long-term therapeutic benefit, in particular the central nervous system, bone and lung. Miglustat was eliminated via renal clearance by a combination of glomerular filtration and active secretion. Hepatic clearance was negligible, as was the role of metabolism in the overall elimination process of miglustat in the rat.     

The importance of tissue distribution in pharmacokinetics

The concentration of a drug at its site of action will be affected by the ability of the drug to distribute to and pass through various membranes and tissues. Mechanisms of drug distribution are summarized in this paper and include the differences between intracellular and extracellular pH,active transport systems for drugs, distribution of drugs between fat and water in adipose tissues, the reversible binding of drugs to phospholipids and to various macromolecules including proteins, nucleic acid, and melanin. These mechanisms usually tend to decrease the concentration of unbound drugs at their sites of action, but usually not to the extent one would predict on the basis of in vitrobinding studies. The effects of drug distribution in altering the biological half-lives of drugs in the body are discussed as well as the interrelationship between the kinetic volumes of distribution for drugs and blood flow rates through the organs that eliminate these drugs. These concepts are illustrated for corticosterone levels following intravenous bolus injections and infusions into rats.This paper was presented at the Conference on Pharmacology and Pharmacokinetics: Problems and Perspectives, October 30–November 1, 1972, at the Fogarty International Center, National institutes of Health, Bethesda, Maryland. This paper, in a slightly different format, will be published in the Proceedings of the Conference by Plenum Press, New York.     

冰片对川芎嗪血药浓度和在脑中分布的影响

目的：探讨冰片对川芎嗪血药浓度和在脑中分布的影响。方法：经股静脉单用或复合冰片给予大鼠川芎嗪10mg／kg，采用高效液相色谱法测定不同时间的血浆和脑组织中川芎嗪药物浓度。结果：川芎嗪复合冰片后，血浆药物浓度发生明显变化，在所观察的时间里，血浆药物浓度比单用川芎嗪低；但川芎嗪复合冰片后能提高川芎嗪在脑组织中的含量。结论：冰片可促进川芎嗪在脑中的分布，川芎嗪复合冰片治疗脑血管疾病时临床显效可能更快。     

紫杉醇纳米混悬剂在大鼠体内的药动学和小鼠的组织分布

目的:考察紫杉醇纳米混悬剂在大鼠体内的药动学及小鼠体内的组织分布情况。方法:将紫杉醇注射液和紫杉醇纳米混悬剂2种制剂静脉给药后,采用HPLC法分别测定给药后5,10,15,30min及1,2,4,6,8,12h时大鼠的血药浓度,给药后5,15,30min及1,2,4,8,12h时紫杉醇在小鼠心、肝、脾、肺、肾、脑组织中的含量,对2种制剂的体内生物分布特征和靶向性进行评价。结果:大鼠血浆中,紫杉醇纳米混悬剂和紫杉醇注射液的消除相半衰期分别为(5.6±0.7)和(3.8±0.4)h;AUC分别为(5.2±0.4)和(20.3±1.1)mg.h.L-1;MRT分别为(3.2±0.4)和(2.8±0.3)h;Cl分别为(2.05±0.22)和(0.56±0.19)L.kg-1.h-1。与紫杉醇注射液相比,紫杉醇纳米混悬剂在肝、脾、脑组织中的药物含量显著增加。结论:相对于市售紫杉醇注射液,紫杉醇纳米混悬剂向靶部位富集,显著降低了非靶器官的药物浓度,可减轻制剂不良反应,使药物在血浆中的循环时间延长。     

Pharmacokinetics,bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats

In order to characterize the pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats, a reliable gradient HPLC‐based method has been developed and validated. After p.o. administration of geniposide, the peak concentration of geniposide in plasma occurred at 1 h and plasma geniposide was eliminated nearly completely within 12 h. The AUC_{0→ ∞} values of geniposide were 6.99 ± 1.27 h · µg/ml and 6.76 ± 1.23 h · µg/ml after i.v. administration of 10 mg/kg and p.o. administration of 100 mg/kg of geniposide, respectively. The absolute oral bioavailability (%F) of geniposide was calculated as 9.67%. After p.o. administration of geniposide, the AUC_0→4h values in tissues were in the order of kidney > spleen > liver > heart > lung > brain. This study improved the understanding of the pharmacokinetics, bioavailability and tissue distribution of geniposide in rats and may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines. Copyright © 2013 John Wiley & Sons, Ltd.     

Tanshinone IIA suppresses lung injury and apoptosis, and modulates protein kinase B and extracellular signal-regulated protein kinase pathways in rats challenged with seawater exposure

1. Tanshinone IIA (TIIA) is one of the main active components of the Chinese herb, Danshen. In the present study, we investigated the role of apoptosis in seawater exposure-induced acute lung injury (ALI), and explored the effects of TIIA on lung injury, apoptosis, and protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK) pathways in seawater-challenged rats. The rats were randomly divided into four groups: (i) naive group, no drug was given; (ii) TIIA control group, TIIA (50 mg/kg) was given intraperitoneally; (iii) seawater (SW) group, seawater (4 mL/kg) was given; and (iv) TIIA/SW group, TIIA (50 mg/kg) was injected intraperitoneally 10 min after seawater instillation. 2. The results showed that TIIA treatment significantly improved seawater exposure-induced lung histopathological changes, alleviated the decrease in PaO(2) , and reduced lung oedema, vascular leakage and cell infiltration. As shown by terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) assay, seawater exposure induced apoptosis in lung tissue cells. Furthermore, seawater exposure also changed apoptosis-related factors Bcl-2 and caspase-3, and caused a reduction in the activation of Akt and ERK1/2 pathways. Furthermore, TIIA treatment decreased the number of apoptotic cells, reversed changes in Bcl-2 and caspase-3, and upregulated the activation of Akt and ERK1/2 in seawater-challenged rats. 3. In conclusion, the data suggest that apoptosis might play an important role in seawater exposure-induced lung injury and that TIIA could significantly attenuate the severity of ALI and apoptosis in seawater-challenged rats, which is possibly through modulation of Akt and ERK1/2 pathways.     

注射用依托泊苷纳米粒临床前的药动学及组织分布

目的比较试验制剂注射用依托泊苷纳米粒与参比制剂依托泊苷注射液的生物等效性及组织分布特征。方法比格犬随机交叉单次静脉注射给予试验制剂与参比制剂各10 mg.kg-1进行药动学试验,评价生物等效性。荷瘤小鼠(雌性)静脉注射给予25 mg.kg-1试验制剂与参比制剂,测定不同时间点各组织器官中的药物含量。药物浓度采用以替尼泊苷为内标的荧光检测法测定。结果试验制剂与参比制剂主要药动学参数分别为tmax:(1.500±0.000)、(1.500±0.000)h;ρmax:(3.033±0.644)、(3.323±0.552)mg.L-1;AUC(0-9.5 h):(5.566±0.592)、(7.173±0.920)h.mg.L-1。给药后5 min,注射用依托泊苷纳米粒在肝、肠、肌肉、脾及实体瘤中分布量较高,给药后3 h在实体瘤的含量显著高于参比制剂。结论试验制剂与参比制剂生物不等效,试验制剂在实体瘤中的含量高于参比制剂,静脉注射后3 h差异显著。     

Preparation, pharmacokinetics and tissue distribution of micelles made of reverse thermo-responsive polymers

New reverse thermo-responsive polymers, poly(ethylene oxide)–poly(propylene oxide) multiblock copolymers (poly(ether-carbonate)s) were synthesized. The micelles made of new reverse thermo-responsive polymers were also prepared loaded with the poorly soluble anticancer drug, hydroxycamptothecin (HCPT). The structure characterization of poly(ether-carbonate)s was determined by ¹H NMR and FT-IR analysis. The critical micelle concentration (CMC), critical micelle temperature (CMT), size distribution and drug release in vitro were determined. The pharmacokinetics and tissue distribution in vivo for novel copolymer micelles were studied. The experimental results showed that the micelles was spherical in appearance and dispersed well. The process of HCPT release from micelles in vitro was composed of two steps, abrupt release and sustained release. After i.v. administration (2 h), the drug concentration of poly(ether-carbonate) micelles group in liver in mice was 3.46 μg/g, while that of HCPT injection group was 0.401 μg/g. Compared with HCPT injection, the elimination half-life of poly(ether-carbonate) micelles group was prolonged remarkably from 1.3 to 12.5 h. The poly(ether-carbonate) micelles showed a combination of liver targeting and sustained drug release in experiments on animals.     

川芎嗪硝酮衍生物在脑缺血模型大鼠脑中浓度

目的 考察脑缺血模型大鼠与正常大鼠脑组织中(2-N-叔丁基硝酮)-3,5,6-三甲基吡嗪(TBN)的浓度差异.方法 用线栓法,建立大脑中动脉栓塞脑缺血大鼠模型,按不同剂量或在不同再灌注时间后给药,用HPLC方法测定脑组织中TBN浓度.结果 以不同剂量、在不同再灌注时间后给药,TBN在模型大鼠脑中的浓度均基本高于正常大鼠.模型鼠脑中TBN浓度随剂量增加而增大,两者呈良好的线性关系.于不同再灌注时问后给药,对脑中TBN浓度影响明显.结论 在脑缺血再灌注后,TBN能更有效地透过大鼠血脑屏障,产生更高的脑药浓度.     

一测多评法测定枣仁安神胶囊中丹参酮ⅡA、五味子醇甲与五味子醇乙的含量

【】目的：建立枣仁安神胶囊中丹参酮ⅡA、五味子醇甲与五味子醇乙含量的一测多评方法。方法：采用高效液相法测定丹参酮ⅡA与五味子醇甲和五味子醇乙间的相对校正因子,考察其重现性,比较计算值与测得值的差异。结果：用一测多评法对6批枣仁安神胶囊中丹参酮ⅡA、五味子醇甲与五味子醇乙进行测定,与外标法实测值基本一致。结论：该方法可靠,结果准确,可用于枣仁安神胶囊的质量控制。