A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014–2017) and perspectives

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of ‘integrated pharmacokinetics of TCMs’ from 2014 to 2017 and the part of ‘reverse pharmacokinetics in drug discovery from natural medicines’ in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb–drug interactions and herb–herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.     

马来酸罗格列酮的表面增强拉曼光谱研究

目的:研究马来酸罗格列酮在不同激发光波长以及不同酸碱度条件下的表面增强拉曼光谱,对表面增强拉曼光谱中的分子振动模式进行识别。方法:用3种不同的激发光波长对不同pH条件下马来酸罗格列酮的表面增强拉曼散射(SERS)进行考察,推测分子在纳米颗粒上的吸附取向、成键方式,对增强机制作出推断。结果:研究表明,药物分子-银胶体系的pH对马来酸罗格列酮的增强效应有较大的影响,这是pH对药物分子-银胶体系的凝聚状态和马来酸罗格列酮分子存在状态综合影响的结果。另外,激发光波长对马来酸罗格列酮的SERS效应也有很大的影响,这体现了光源对药物分子-银胶体系的选择性激发。结论:本方法简单、快速、可靠,专属性强,可以作为分析马来酸罗格列酮分子在纳米表面吸附情况的方法。     

Suppression of the TNF‐alpha level is mediated by Gan‐Lu‐Yin (traditional Chinese medicine) in human oral cancer cells through the NF‐kappa B,AKT, and ERK‐dependent pathways

Oral cancer is one of the major causes of deaths in the male population of Taiwan. Gan‐Lu‐Yin (GLY) is used for an adjuvant treatment of Traditional Chinese Medicine in clinical patients. In this study, we investigated the molecular mechanisms in oral cancer cell lines after exposure to GLY. The cytometric bead‐based array (CBA) method was used for the examining and analyzing of tumor necrosis factor‐alpha (TNF‐α) secretion level. TNF‐α mRNA expression was determined by real‐time PCR analysis. Nuclear factor kappa B (NF‐κB) activity and other relative proteins were determined by NF‐κB promoter assay, Western blotting, electrophoretic mobility shift assay (EMSA), and immuno‐staining analyses. GLY decreased the secretion of TNF–α from the oral cancer CAL 27 cells. Furthermore, 2000 μg/mL of GLY significantly suppressed TNF‐α mRNA expression of CAL 27 cells in a time‐dependent manner. GLY reduced the levels of proteins, including nuclear NF‐κB (p65 and p50), p‐IKK (ser176), p‐IκB, p‐AKT, p‐ERK, and nuclear Egr‐1 in a time and dose‐dependent manner. GLY also suppressed the NF‐κB activity and translocation in CAL 27 cells. We suggest that GLY might promote the cure of oral cancer through decreasing the level of TNF‐α cytokine, and these actions were mediated partially through the NF‐κB, AKT, and ERK‐dependent pathways in vitro. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1196–1205, 2016.     

中西医结合治疗重症H_1N_1流感40例临床分析

目的:分析甲型H1N1流感重症病例的中西医临床特征,并对其诊治方法进行探讨。方法:对2009年11月13日-12月24日河北医科大学附属哈励逊国际和平医院收治的40例甲型H1N1流感重症病例的临床特征、实验室检查进行回顾分析,并使用中药辩证治疗和奥司他韦抗病毒治疗。结果:40例患者中男14例,女26例,年龄1～68岁,平均26.5岁。仅1例有明确接触史,平均潜伏期平均3.6 d;所有患者均以发热、咳嗽为主要症状。结论:甲型H1N1流感诊疗的关键是早期识别重症病例,并及时给予奥司他韦、中药等综合治疗可迅速缓解症状,改善预后。     

Detection of bioactive peptides including gonadotrophin‐releasing factors (GnRHs) in horse urine using ultra‐high performance liquid chromatography–high resolution mass spectrometry (UHPLC/HRMS)

The use of bioactive peptides as a doping agent in both human and animal sports has become increasingly popular in recent years. As such, methods to control the misuse of bioactive peptides in equine sports have received attention. This paper describes a sensitive accurate mass method for the detection of 40 bioactive peptides and two non‐peptide growth hormone secretagogues (< 2 kDa) at low pg/mL levels in horse urine using ultra‐high performance liquid chromatography‐high resolution mass spectrometry (UHPLC/HRMS). A simple mixed‐mode cation exchange solid‐phase extraction (SPE) cartridge was employed for the extraction of 42 targets and/or their in vitro metabolites from horse urine. The final extract was analyzed using UHPLC/HRMS in positive electrospray ionization (ESI) mode under both full scan and data independent acquisition (DIA, for MS²). The estimated limits of detection (LoD) for most of the targets could reach down to 10 pg/mL in horse urine. This method was validated for qualitative detection purposes. The validation data, including method specificity, method sensitivity, extraction recovery, method precision, and matrix effect were reported. A thorough in vitro study was also performed on four gonadotrophin‐releasing factors (GnRHs), namely leuprorelin, buserelin, goserelin, and nafarelin, using the S9 fraction isolated from horse liver. The identified in vitro metabolites have been incorporated into the method for controlling the misuse of GnRHs. The applicability of this method was demonstrated by the identification of leuprorelin and one of its metabolites, Leu M4, in urine obtained after intramuscular administration of leuprorelin to a thoroughbred gelding (castrated horse).     

Synthesis of N‐(2,5‐dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)[carbonyl‐11C]acetamide ([carbonyl‐11C]DAA1106) and analogues using [11C]carbon monoxide and palladium(0) complex

N‐(2,5‐Dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)acetamide (DAA1106), a potent and selective ligand for peripheral benzodiazepine receptor, and eight structurally related analogues were labelled with ¹¹C at the carbonyl position using a low concentration of [¹¹C]carbon monoxide and the micro‐autoclave technique. A combinatorial approach was applied to synthesize the analogues using similar reaction conditions. Palladium‐mediated carbonylation using tetrakis(triphenylphosphine)palladium, various amines and methyl iodide or iodobenzene was employed in the synthesis. The ¹¹C‐labelled products were obtained with 10–55% decay‐corrected radiochemical yields and the final product was more than 97% pure in all cases. Specific radioactivity was determined for the compound [carbonyl‐¹¹C]DAA1106 using a single experiment and a 10‐µA h bombardment. The specific radioactivity, measured 36 min after end of bombardment, was 455 GBq/µmol. Synthetic routes to the precursors and reference compounds were also developed. The presented approach is a novel method for the synthesis of [carbonyl‐¹¹C]DAA1106 and its analogues, and allows the formation of a library of ¹¹C‐labelled DAA1106 analogues which can be used to optimize the performance as a potential positron emission tomography tracer. Copyright © 2007 John Wiley & Sons, Ltd.     

Effects of decabromodiphenyl ether (BDE‐209) on mRNA transcription of thyroid hormone pathway and spermatogenesis associated genes in Chinese rare minnow (Gobiocypris rarus)

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants, which are ubiquitous environmental contaminant found in both abiotic and biotic environmental samples. Deca‐BDE (BDE‐209) is the principal component, which is currently used worldwide. In this study, the effect of BDE‐209 on the mRNA levels of thyroid hormone (TH) related genes and spermatogenesis associated genes were determined from larvae and adult rare minnow (Gobiocypris rarus) exposed to concentrations 0.01, 0.1, 1, and 10 μg/L for 21 days. The results showed that the type II deiodinase (dio2) and sodium iodide symporter (nis) mRNA levels were significantly up‐regulated in the larvae at 10 μg/L treatment. In adult, histopathological observations showed that liver of female fish were degenerated at 10 μg/L treatment, and inhibition of spermatogenesis were observed in testis of male fish. In addition, the thyroid hormone receptor α (trα), dio2, and nis mRNA levels in the liver of male and female fish were significantly up‐regulated, whereas dio2 and nis mRNA levels were significantly down‐regulated in the brain. These results indicate that exposure to BDE‐209 could result in tissue‐specific alternations of TH‐related genes expression in adults. Moreover, the mRNA levels of the testis‐specific apoptosis genes, the spermatogenesis‐associated 4 (spata4) and spermatogenesis‐associated 17 (spata17), were down‐regulated at 10 μg/L treatment in testis of male fish. Our results suggest that BDE‐209 may pose threat to normal thyroid and reproductive function in fish. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 1–9, 2014.     

Vectorization of Harungana madagascariensis Lam. ex Poir. (Hypericaceae) ethanolic leaf extract by using PLG‐nanoparticles: antibacterial activity assessment

This study was undertaken to compare the in vitro and ex vivo antibacterial activity of an ethanolic Harungana madagascariensis leaf extract (HLE) incorporated into poly (D,L ‐lactide‐co–glycolide) nanoparticles (HLE‐PLG‐NP). Two concentrations of HLE (500 and 1,000 µg/mL) for the in vitro study and one concentration (500 µg/mL) for the ex vivo study were compared using two gram‐positive bacterial strains (Micrococcus luteus and Staphylococcus epidermidis), and one gram‐negative bacterial strain (Moraxella sp.). The ex vivo antibacterial activity was evaluated on S. epidermidis CIP 55109 (SE) using an artificial contamination method. SE was inoculated for 12 h onto human skin fragment surfaces treated for 5 min either with HLE loaded, unloaded PLG‐NP, or HLE solution. In vitro, the two preparations inhibited completely the growth of all bacterial strains at 1,000 µg/mL. However, the HLE‐PLG‐NP had a significant antibacterial activity against SE (18.4±1.8–0.4±0.2 CFU/mL, P<0.05), and a marked antibacterial effect against M. luteus (ML) and Moraxella sp. (Msp) compared to HLE solution at 500 µg/mL. Ex vivo, HLE‐PLG‐NP at 500 µg/mL reduced viable bacteria (6.3–4.8 log₁₀), compared to the HLE solution (6.3–5.5 log₁₀) after 4 h artificial contamination (P<0.05). A thin layer chromatography study of both HLE solution and HLE‐PLG‐NP showed that among the seven components found on the chromatogram of the HLE solution, only two were present on the nanoparticles, one including a flavonoid heteroside fraction responsible for the antibacterial properties. The incorporation of the HLE into a colloidal carrier improved antibacterial performance. Drug Dev. Res. 65:26–33, 2005. © 2005 Wiley‐Liss, Inc.     

Vascular endothelial growth factor (VEGF) antibody significantly increases the risk of hand–foot skin reaction to multikinase inhibitors (MKIs): A systematic literature review and meta‐analysis

With the use of multikinase inhibitors (MKIs) having emerged in recent years, skin toxicities such as hand–foot skin reaction (HFSR) are primary side effects, and they lack effective prediction methods. Here, we updated a previous systematic review by establishing a meta‐analysis of the risk of developing HFSR among patients receiving MKIs and antivascular endothelial growth factor antibody. Publications from PubMed and abstracts presented at the American Society of Clinical Oncology Annual Meeting up to February 5, 2015, were searched to identify relevant studies, and a total of 236 patients with metastatic tumours in nine trials were included for analysis. In the meta‐analysis, the pooled incidence rates of all‐grade and high‐grade HFSR among patients who received the combination therapy were 56.9% [95% confidence interval (CI), 45%‐71.1%] and 14.3% (95% CI, 9%‐24.2%), respectively, with significant differences observed with MKI monotherapy (P < .05). Further subgroup analysis demonstrated that increasing the dosages of bevacizumab (77.8% vs 51.1%, P = .04) and MKIs (64.3% vs 52.6%, P = .02) significantly increased HFSR incidence. Moreover, combination with chemotherapy exerted a minimal effect on HFSR risk (61% vs 55.3%, P = .5). This updated review and meta‐analysis confirm the increased risk of HFSR incidence due to the use of MKIs and antivascular endothelial growth factor antibody. Thus, using these therapies requires safety standards.