Z‐ligustilide: A review of its pharmacokinetics and pharmacology

Z‐ligustilide is a natural benzoquinone derivative found in many widely used Chinese herbal medicines such as Angelica sinensis (Oliv.) Diels as well as Ligusticum chuanxiong Hort and so on. It has been used as a part of traditional Chinese medicine and is also present in various Chinese medicine preparations. Pharmacokinetic studies have shown that Z‐ligustilide has poor oral bioavailability in rats due to severe first‐pass metabolic reactions. New evidence suggests that Z‐ligustilide has a wide range of pharmacological properties, including anticancer, antiinflammatory, anti‐oxidant as well as neuroprotective activities and so on. The literature discussed is derived from readily accessible papers spanning the early 1970s to the end of March 2019. Information were collected from journals, books, and online searches (Google Scholar, PubMed, Science Direct, Science Citation Index Finder, Springer link, and CNKI). This review intends to provide a comprehensive overview of the pharmacokinetics and pharmacology of Z‐ligustilide in recent years, with a focus on its biological properties and mechanisms, which is of great significance for Chinese medicine.     

Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro

1. Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significant effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro.

2. Wild-type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10–500?μM substrate for 40?min at 37?°C and terminated at ?80?°C immediately. Then these samples were treated as required and detected with ultra-performance liquid chromatography-tandem mass spectrometry used to analyze its major metabolite desethylamiodarone.

3. Among the 21 CYP3A4 variants, compared with the wild-type, the intrinsic clearance values (V_max/K_m) of two variants were apparently decreased (11.07 and 2.67% relative clearance) while twelve variants revealed markedly increased values (155.20～435.96%), and the remaining of seven variants exhibited no significant changes in enzyme activity.

4. This is the first time report describing all these infrequent alleles for amiodarone metabolism, which can provide fundamental data for further clinical studies on CYP3A4 alleles.     

Two novel genetic variants in the STK38L and RAB27A genes are associated with glioma susceptibility

Glioma is the most common malignant primary brain tumors with poor prognosis. Genome wide association studies (GWAS) of glioma in populations with Western European ancestry were completed in the US and UK. However, our previous results strongly suggest the genetic heterogeneity could be important in glioma risk. To systematically investigate glioma risk–associated variants in Chinese population, we performed a multistage GWAS of glioma in the Han Chinese population, with a total of 3,097 glioma cases and 4,362 controls. In addition to confirming two associations reported in other ancestry groups, this study identified one new risk-associated locus for glioma on chromosome 12p11.23 (rs10842893, p_meta = 2.33x10-12, STK38L) as well as a promising association at 15q15-21.1 (rs4774756, p_meta = 6.12x10-8, RAB27A) in 3,097 glioma cases and 4,362 controls. Our findings demonstrate two novel association between the glioma risk region marked by variant rs10842893 and rs4774756) and glioma risk. These findings may advance the understanding of genetic susceptibility to glioma.     

壮药材滇桂艾纳香及其易混品种东风草和高艾纳香比较研究

目的： 建立壮药材滇桂艾纳香专属性检验方法。方法： 采用基原鉴别、性状鉴别、显微鉴别、薄层鉴别、分子生物学及特征图谱等方法对滇桂艾纳香及其易混品种东风草和高艾纳香进行对比研究。结果： 三者的根、茎、叶性状基本相同，区别点在于滇桂艾纳香头状花序小（直径0.5~0.8 cm），东风草头状花序大（直径1.5~2 cm），高艾纳香头状花序具密集的长绒毛；三者的根、茎横切面，粉末显微特征基本相同，高艾纳香具基部膨大的非腺毛；薄层鉴别（1）中高艾纳香比滇桂艾纳香和东风草少1个斑点；薄层鉴别（2）中滇桂艾纳香比东风草和高艾纳香少1个特征斑点；ITS2序列N-J树聚类分析显示三者具有良好的单系性，三者种间最小遗传距离均大于种内最大遗传距离；与滇桂艾纳香对照图谱相比，东风草平均相似度为0.962，高艾纳香平均相似度仅为0.789。结论： 高艾纳香与滇桂艾纳香区别较大，不宜混用，在日常使用中应注意甄别；东风草与滇桂艾纳香在性状、显微、薄层、分子生物学、特征图谱等方面相似度较高，在对二者进行充分的药理活性以及临床试验等基础上，可考虑作为滇桂艾纳香的替代品使用，以缓解药用资源不足的问题。     

基于虚拟现实技术的放疗CT模拟定位远程培训系统研发

目的 研发一种基于虚拟现实技术的放疗CT模拟定位的远程培训系统,探索一种医学培训的新方法。方法 使用3DMax与Maya进行3D建模,Unity3D引擎开发3D虚拟操作及交互系统;Java的SpringMvc架构作为系统后台服务,MySQL作为后台数据库系统;并将用户分为教师和学员两种角色,模式分为教学与考核模式。结果 系统功能涵盖CT模拟定位全过程,主要包括患者信息管理、CT模拟定位机认知、体位固定技术、CT定位扫描、处理突发事件等模块。自2018年投入使用以来,运行稳定,系统浏览量达14 920人次,培训通过率为86.66%。与传统培训相比,培训效率明显提升,并获得一致好评。结论 远程培训系统能有效提升学员的临床实践能力、人文关怀能力,具有良好的自主性、共享性、创新性。目前系统已上线且推广性较强,应用前景广阔。     

Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report

Patients with non‐small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1‐targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1‐fusion targeted therapy are acquired mutations in ROS1. Along with the use of next‐generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)‐TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74‐ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short‐term disease control for cabozantinib.Key Points

• The D1228N point mutation of MET is an acquired mutation for crizotinib resistance.
• The patient obtained short‐term clinical benefit from cabozantinib therapy after resistance to crizotinib.
• The clinical use of next‐generation sequencing could maximize the benefits of precision medicine in patients with cancer.

     

Association of heart rate and diabetes among 0.5 million adults in the China Kadoorie biobank: Results from observational and Mendelian randomization analyses

Background and aimsObservational studies have associated resting heart rate with incident diabetes. Whether the associations are causal remains unclear. We aimed to examine the shape and strength of the associations and assessed the causal relevance of such associations in Chinese adults.Methods and resultsThe China Kadoorie Biobank enrolled 512,891 adults in China. Cox proportional hazard regression models was conducted to estimate hazard ratios (HRs) for the associations of resting heart rate with type 2 diabetes and total diabetes. Among 92,724 participants, 36 single-nucleotide polymorphisms (SNPs) related to resting heart rate were used to construct genetic risk score. We used Mendelian randomization analyses to make the causal inferences. During a median follow-up of 9 years, 7872 incident type 2 diabetes and 13,349 incident total diabetes were documented. After regression dilution bias adjustment, each 10 bpm higher heart rate was associated with about a 26% higher risk of type 2 diabetes (HR, 1.26 [95% CI, 1.23, 1.29]) and 23% higher risk of total diabetes (HR, 1.23 [95% CI, 1.20, 1.26]). Instrumental variable analyses showed participants at top quintile compared with those at bottom quintile had 30% higher risk for type 2 diabetes (HR, 1.30 [95% CI, 1.17, 1.43]), and 10% higher risk for total diabetes (HR, 1.10 [95% CI, 1.02, 1.20]).ConclusionsThis study provides evidence that resting heart rate is an important risk factor for diabetes risk. The results suggest that novel treatment approaches targeting reduction of high heart rate for incidence of diabetes may be worth further investigation.