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.     

Influence of granulation temperature on particle size distribution of granules in twin-screw granulation (TSG)

This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30?°C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90?°C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG.     

2013-2017年ICU感染病原菌分布及耐药趋势分析

目的 分析重症监护病房(ICU)感染病原菌分布及其耐药趋势，为ICU有效预防与控制医院感染提供依据。方法 采用回顾性研究方法，收集我院2013-2017年综合ICU送检的25057份临床标本分离的病原菌进行细菌种类鉴定和药敏试验。结果 分离病原菌6938株，其中革兰阴性菌5513株(79.46%)，革兰阳性菌710株(10.23%)，真菌715株(10.31%)，排名前4位分别为鲍曼不动杆菌(31.65%)、肺炎克雷伯菌(15.90%)、铜绿假单胞菌(11.46%)和大肠埃希菌(6.31%)。真菌随着时间变化呈现下降后升高趋势，鲍曼不动杆菌、铜绿假单胞菌和大肠埃希菌呈现升高后下降趋势，而肺炎克雷伯菌呈现下降后升高趋势。分离出多重耐药菌1387株，前3位分别为鲍曼不动杆菌(84.21%)、肺炎克雷伯菌(8.22%)和铜绿假单胞菌(4.83%)。5年间多重耐药鲍曼不动杆菌分布率均显著高于肺炎克雷伯菌和铜绿假单胞菌(P=0)，且在2016年检出率达最高，2013和2017年检出率最低；多重耐药肺炎克雷伯菌在2017年检出率达最高，2013年检出率最低；多重耐药铜绿假单胞菌5年间差异无统计学意义(P>0.05)。结论 我院病原菌以革兰阴性菌为主，不同年份病原菌及其耐药性变化有所不同，应定期监测病原菌及其耐药性变迁，正确合理使用抗菌药物。     

Demonstrating effectiveness or demonstrating not ineffectiveness – A potential solution for rare disease drug product development?

ABSTRACT

For review and approval of new drug products, substantial evidence regarding safety and effectiveness of the drug products under investigation are necessarily provided. A traditional approach is to test a null hypothesis of ineffectiveness against an alternative hypothesis of effectiveness at the 5% level of significance. The rejection of the null hypothesis of ineffectiveness is in favor of the alternative hypothesis of effectiveness. This approach, however, is somewhat misleading because the rejection of the null hypothesis of ineffectiveness leads to the conclusion of not ineffectiveness, which consists of the proportion of inconclusiveness and the proportion of effectiveness. In this article, we explore the potential use of the concept of demonstrating not ineffectiveness and then effectiveness for regulatory approval of new drug products, especially for rare disease drug products. For rare disease drug product development, one of the major obstacles and challenges is how to use small patient population available for achieving the same standards for regulatory approval. To address this problem, a two-stage approach by first demonstrating not ineffectiveness and then ruling out (or controlling) the probability of inconclusiveness for demonstrating effectiveness is proposed. The proposed two-stage approach is useful with small patient population available for achieving the same standards for regulatory approval of rare disease drug products.     

Effect of sinapic acid on aripiprazole pharmacokinetics in rats: Possible food drug interaction

Dietary supplements and foods can interact with various drugs, leading to possible clinical concerns. This study aimed to investigate the effect of orally administered sinapic acid (SA) on the pharmacokinetics of aripiprazole (APZ) in rats and its possible modulatory effects on hepatic cytochrome P450 (CYP3A2 and CYP2D6) expression in the liver tissues. Single dose and multiple dose parallel groups of wistar rats were categorized into six groups (n = 6 each) which abstained from food for 12 h prior to the experiment, while water was allowed ad libitum. The investigation was carried out for single dose: Group I was treated with normal saline orally for 15 days (normal control). Group II was administered normal saline orally for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group III received SA (20 mg/kg p.o.) for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group IV was treated with SA (20 mg/kg p.o.) for 15 days. For the multiple dose study, Group I was treated with normal saline orally for 15 days (normal control); Group II received APZ (3 mg/kg p.o.) daily for 15 days; Group III was administered with SA (20 mg/kg p.o.) and APZ (3 mg/kg p.o.) for 15 days and Group IV received SA (20 mg/kg p.o.) for 15 days. The group I and IV were kept common in single and multiple dose groups. After last APZ dose, plasma samples were collected and APZ concentrations were determined using an UPLC-MS/MS technique. The pharmacokinetic parameters were calculated using a non-compartmental analysis. The concomitant administration of APZ with SA (as single or multiple dose) resulted in an increase in APZ absorption and a decrease on its systemic clearance. This was associated with a reduction in CYP3A2 and CYP2D6 protein expressions by 33–43% and -71–68% after the single and multiple co-administration, which are two enzymes responsible of the metabolism of APZ. Therefore, a reduction in the metabolic clearance appears to be the mechanism underlying the drug interaction of dietary supplement containing SA with APZ. Therefore, the concomitant administration of SA and APZ should be carefully viewed. Further investigations are required to assess the clinical significance of such observations in humans.     

玳玳果黄酮降脂提取物体内组织分布规律及特征研究

目的：建立UPLC-MS/MS分析方法同时测定玳玳果黄酮降脂提取物效应组分新橙皮苷和柚皮苷在大鼠10种脏器组织中含量，分布规律及特征。方法：采用UPLC-MS/MS技术建立提取物效应组分新橙皮苷及柚皮苷在大鼠心、肝、脾、肺、肾、脑、胃、小肠、脂质、肌肉组织中的定量分析方法；大鼠给药后分别于0.33，0.67，1，4，8 h的5个时间点，分别摘取以上10种脏器组织，测定脏器组织及血液中效应组分的质量浓度，采用DAS（V 2.0）药动学软件对各样本的药物浓度-时间数据进行房室拟合，并计算不同组织效应组分的药-时曲线下面积（AUC）及平均滞留时间（MRT）。结果：所建立的UPLC-MS/MS定量分析方法具备良好的专属性、标准曲线及线性范围良好、方法准确度与精密度、定量下限均符合有关规定；玳玳果黄酮降脂提取物效应组分在血液中的分布符合一室模型，除肾脏及脑组织外，其余脏器中提取物效应组分的房室特征多为静脉注射的二室模型，柚皮苷在肾脏中的拟合结果为非静脉注射的二室模型，新橙皮苷在脑组织拟合结果为静脉注射的三室模型，给药后8 h各组织中效应组分新橙皮苷及柚皮苷AUC值大小顺序均为小肠 > 胃 > 肾 > 脂质 ≈ 脾脏 > 肺 > 肌肉 > 肝 > 心 > 脑，效应组分在各脏器中均无明显蓄积；效应组分在血液、肾脏、肝脏中的滞留时间较长，MRT均大于2 h，脂质最短，MRT不足1 h；各脏器中新橙皮苷的药-时曲线下面积约是柚皮苷的3倍，而心、肝、肾中则是3.5，2.1和3.4倍。结论：玳玳果黄酮降脂提取物效应组分在大鼠组织中分布迅速，达峰时间早于血液；效应组分在肠道内消除缓慢，给药8 h后在各脏器中的含量均显著下降且无特异的蓄积部位。研究结果揭示玳玳果黄酮降脂提取物效应组分在大鼠体内的分布特征及规律，为进一步理解玳玳果黄酮降脂提取物在体内的作用靶点及机制奠定了基础。     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.