Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing’s anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing’s pharmacologically significant constituents supports the medicine’s anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

XueBiJing is an intravenous five-herb injection used to treat sepsis in China. The study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS)- or liquid chromatography-ultraviolet (LC-UV)-based assay for quality evaluation of XueBiJing. Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel. Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition, pharmacokinetics, and pharmacodynamics. A selectivity test (for "similarity of response") was developed to identify and minimize interference by non-target constituents. Then, an intercept test was developed to fulfill "linearity through zero" for each analyte (absolute ratio of intercept to C response, <2%). Using the newly developed assays, we analyzed samples from 33 batches of XueBiJing, manufactured over three years, and found small batch-to-batch variability in contents of the marker constituents (4.1%-14.8%), except for senkyunolide I (26.5%).

目的:探讨血必净注射液(XBJJ)不良反应是否以类过敏反应为主,并挖掘其可能引起类过敏反应的影响因素.方法:借助小鼠类过敏反应模型,分别选取XBJJ临床最高浓度的0.5,1,2倍进行类过敏反应研究,以判断不同浓度XBJJ是否诱发小鼠类过敏反应;比较配制后存放不同时间的XBJJ诱发小鼠类过敏反应是否存在差异,具体为配制XBJJ到不同浓度后,分别存放10 min,2.5 h,6 h,24 h后再给小鼠尾静脉注射;最后取选3 s,45 s,90 s3个推注时间进行XBJJ注射,再对不同注射速度的XBJJ诱发小鼠类过敏反应差异进行比较.结果:XBJJ在药物浓度高于临床推荐浓度时会诱发小鼠类过敏反应;与配制后存放10 min比较,随着存放时间的延长,相同浓度XBJJ诱发小鼠类过敏反应的程度加重;另外,当XBJJ以3s注射完时(注射速度达0.083 mL·s-1),其产生的类过敏反应最强.结论:XBJJ诱发的不良反应以类过敏反应为主.XBJJ配制后存放时间过长和注射速度过快,都会导致其诱发小鼠类过敏反应加重.XBJJ临床使用时,应严格按照药品使用说明书推荐的用法、用量、配制浓度、滴注速度,并现用现配,合理用药,对于提高XBJJ的用药安全性具有积极意义.

Mas‐related G protein‐coupled receptor‐X2 (MRGPRX2) expressed on mast cells (MCs) has been shown to be a pivotal target for pseudo‐allergic diseases. Therefore, MRGPRX2 might be a therapeutic target for allergic contact dermatitis, atopic dermatitis, and red man syndrome. Paeoniflorin (PF) was reported to have an antiinflammatory effect in neuroinflammation, enteritis, and so forth. In this study, we investigated the anti‐pseudo‐allergic effect of PF and the underlying molecular mechanisms. Our results showed that PF can suppress compound 48/80 (C48/80)‐induced PCA and MCs degranulation in vivo, in a dose‐dependent manner. Moreover, PF can reduce C48/80‐induced calcium influx and suppress MC degranulation and chemokines release in vitro. PF can downregulate the phosphorylation levels of key kinases in PLCγ‐regulated calcium influx and subsequent cytokine synthesis pathways. Our study revealed that PF could inhibit C48/80‐induced allergic responses both in vivo and in vitro. As such, it may be regarded as a novel inhibitor for preventing MRGPRX2‐mediated allergic diseases.

目的 建立血必净注射液中总糖的含量测定方法.方法 通过HPGPC、GC-MS法对血必净注射液中糖类成分进行了定性分析,确定以葡萄糖比果糖为19:1的混标为对照品,苯酚-硫酸为显色剂,利用酶标仪在490 nm波长处测定样品溶液吸光度,计算总糖含量.结果 对照品溶液在19.3～96.5μg线性关系良好,回归方程为:Y=0.0081X+0.0131(R2=0.9995);三个比例的加样回收率为99.0％,98.2％,97.7％,RSD分别为2.1％,0.7％,1.3％;6份样品的重复性RSD为1.1％.结论 该方法准确可靠,可操作性强,可用于血必净注射液中总糖含量的检测.

药物分析在药物研究、药物生产以及临床应用中具有非常重要的作用.而色谱联用技术的发展在很大程度上促进了药物分析领域的进步.目前色谱联用技术主要包括气相色谱联用技术、液相色谱联用技术、色谱与核磁共振联用技术以及毛细管电泳与质谱联用技术.本文重点对这几类色谱联用技术的应用特点进行分析,以期能够为药物分析工作的开展提供借鉴.

Sepsis has been defined as life-threatening organ dysfunction caused by dysregulated host response to infection, associated with an in-hospital mortality in excess of 10% and leading to high treatment cost and medical resources consumption, has become a huge threat to human health. Antibiotics, antiviral drugs, vasoactive agents, etc. have been used in the traditional therapy of sepsis, but there are also not enough specific therapeutic drugs for clinical practice. How to rectify systemic inflammatory response, coagulation disorders, and immune dysfunction, contributing to return to pro- and anti-inflammatory homeostasis, and improve patient outcomes, is the key problem in anti-sepsis drug development. According to the differences of disease stage and treatment purposes, specific therapeutic drugs for the treatment of sepsis are divided into drugs aiming at uncontrolled inflammatory response, coagulation disorders, immune function inhibition, and modern Chinese medicine. Research progress on those specific therapeutic drugs for the treatment of sepsis are reviewed in this paper.

目的:考查血必净注射液分别与注射用七叶皂苷钠和注射用血塞通的配伍稳定性.方法:观测血必净注射液分别与注射用七叶皂苷钠和注射用血塞通(以10％葡萄糖溶液为溶媒)配伍后,室温放置8h内的可见异物、pH值、不溶性微粒、渗透压及羟基红花黄色素A、芍药苷含量(采用高效液相色谱法测定)的变化.结果:血必净注射液分别与注射用七叶皂苷钠和注射用血塞通配伍后8h内可见异物、pH值、不溶性微粒、渗透压及羟基红花黄色素A和芍药苷含量均无明显变化.结论:血必净注射液与注射用七叶皂苷钠或注射用血塞通配伍8h内稳定.

Sepsis,a life-threatening syndrome with a complex pathogenesis,is one of the leading causes of death among severe cases. Since sepsis defined in 1990s,the evolution of sepsis definition has experienced from sepsis-1 to sepsis-3,but there was no change in basic cores of sepsis-1 and sepsis-2. In 45th Critical Care Congress of the Society of Critical Care Medicine′s(SCCM)in 2016,sepsis-3 was defined as life-threatening organ dysfunction caused by a dysregulated host responseto infection. Sepsis-3 not only reflected the deeper understanding of the pathogenesis of sepsis,but also met needs of rationalized diagnostic criteria,accurate and convenient clinical diagnosis.

Aim: Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides.Methods: Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro.Results: A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability.Conclusion: Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

脓毒症引起的器官功能障碍或组织灌注不足，是重症医学面临的主要临床问题。近年来，经大数据回顾性分析，结合微阵列技术和白细胞基因表达分析，人们逐渐认识到脓毒症不仅是一个全身炎症反应或免疫失调的过程，而且是一个持续炎症、免疫抑制、分解代谢3者相结合的复杂慢性危重病。血必净注射液属于化瘀解毒类中药，该药通过抑制早晚期炎性因子的表达保护血管内皮细胞，减弱炎症和凝血两大系统的交互影响，保护主要器官生理功能，降低多器官功能障碍综合征（MODS）发生率，改善脓毒症早期天然免疫系统亢奋状态，缓解潜在的、逐渐加重的免疫抑制状态，综合调理脓毒症发生发展过程中的全身性炎症、凝血功能障碍和免疫功能紊乱，更有利于机体促炎-抗炎动态平衡的及早恢复，改善患者预后，充分体现了中药多成分、多环节、多渠道、多靶点的整合调节作用，同时也是对中医学整体观念、辨证论治思想的集中诠释。