Gender differences in pharmacokinetics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances in rats

The aim of this study was to confirm and investigate the gender differences in pharmacokinetic (PK) characteristics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances (PFASs) consisted of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) in both male and female rats. For this study, a simultaneous determination method of the 3 PFASs in rat plasma and tissues was developed and validated using a UPLC-MS/MS system. The PK parameters after a single oral or intravenous administration of the 3 PFASs in both rats were calculated using WinNonlin^® software. The mean half-life of the 3 PFASs in female and male rats was in the range of 0.15–0.19 and 1.6–1.8 days for PFOA, 23.5–24.8 and 26.4–28.7 days for PFOS, and 0.9–1.7 and 20.7–26.9 days for PFHxS, respectively. The 3 PFASs were highly distributed in the liver and kidney. These results suggest that there are gender differences in the PKs for PFOA and PFHxS in rats, whereas the PFOS represented no significant gender differences except the Kp value of liver. The validated simultaneous determination method of the 3 PFASs was also within the accepted criteria of the international guidance.     

基于离散型地理信息的H7N9流感病毒动态时空传播模式

目的 基于离散型的地理信息构建了H7N9病毒时空动态传播模式图，探索H7N9病毒的空间传播路径。方法 选取全球共享禽流感数据倡议组织（GISAID）中中国以人类为宿主的H7N9流感病毒血凝素（HA）和神经酰胺酶（NA）基因序列，利用BioEdit 7.0软件进行多序列比对。在贝叶斯理论框架下，运用BEAST 1.8.2软件构建H7N9时空传播模型，采用symmetric substitution model和贝叶斯随机搜索变量选择（BBSVS）方法，对H7N9的历史传播轨迹进行推断和检验。以Google Earth软件展现H7N9病毒的时空传播动态图。结果 感染人类的H7N9病毒起源于上海或杭州，最早可追溯到2012年10月。并在2013年3、4月份开始传向邻近省份，同年8、9月份传播加剧，3个月内传向10余处地区。结论 基于基因核苷酸序列和空间地理信息，追踪了H7N9病毒历史传播轨迹，为早期流感疫情的防控及病毒的溯源提供线索。     

Bayesian leveraging of historical control data for a clinical trial with time-to-event endpoint

The recent 21st Century Cures Act propagates innovations to accelerate the discovery, development, and delivery of 21st century cures. It includes the broader application of Bayesian statistics and the use of evidence from clinical expertise. An example of the latter is the use of trial-external (or historical) data, which promises more efficient or ethical trial designs. We propose a Bayesian meta-analytic approach to leverage historical data for time-to-event endpoints, which are common in oncology and cardiovascular diseases. The approach is based on a robust hierarchical model for piecewise exponential data. It allows for various degrees of between trial-heterogeneity and for leveraging individual as well as aggregate data. An ovarian carcinoma trial and a non-small cell cancer trial illustrate methodological and practical aspects of leveraging historical data for the analysis and design of time-to-event trials.     

腺样体肥大或伴扁桃体肥大的睡眠呼吸障碍儿童平均血小板体积和血小板分布宽度变化的临床意义

目的 探讨腺样体肥大或伴扁桃体肥大的睡眠呼吸障碍(SDB)儿童的平均血小板体积(MPV)和血小板分布宽度(PDW)变化的临床意义。方法 选择2018年1月至2019年1月安徽医科大学附属巢湖医院耳鼻咽喉-头颈外科住院患儿99例,均诊断为SDB(腺样体肥大或伴扁桃体肥大),设为病例组。另选取同时期因SDB以外原因(包括先天性耳前瘘管,鼻骨骨折,先天性鳃裂瘘管,颈部良性肿瘤,外耳道异物)而收住入院的51例患儿为对照组,并经过仔细询问病史,否认有SDB,体格检查均无腺样体肥大或伴有扁桃体肥大。记录病例组与对照组的血常规各项指标数值,比较两组血常规相关指标的差异。结果 病例组平均血小板体积(MPV)为(10.89±1.30)fL,对照组为(11.38±1.28)fL,差异有统计学意义(P<0.05)。对照组血小板分布宽度(PDW)为[13.60(12.00,15.90)]fL,病例组为[12.70(10.85,15.35)]fL,差异有统计学意义(P<0.05)。其余血常规指标在病例组与对照组间差异均无统计学意义(P>0.05)。Pearson积差相关分析显示,病例组的MPV和PDW均与年龄呈正相关,Spearman秩相关显示,MPV和PDW均与腺样体肥大等级呈负相关。结论 MPV和PDW可能作为判断腺样体肥大或伴有扁桃体肥大SDB患儿病情严重程度的潜在指标。     

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.