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Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation

Chen Cheng1, Chao Ren2,3, Mu-zi Li4, Yi-hui Liu4, Ren-qi Yao2, Yang Yu5, Xuan Yu1,6, Jian-li Wang5, Li-xue Wang2, Yu-chun Leng1,6, Hui Zhang2, Fei-fei Du1, Ning Dong2, Feng-qing Wang1, Yao Wu2, Fang Xu1, Xiao-mei Zhu2, Gui-ping Zhang5, Kai Dong5, Si Liu5, Xiao-qing Yao5, Chuan Li1,4,6,7,8, Yong-ming Yao2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
3 Department of Pulmonary and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
5 Tianjin Chasesun Pharmaceutical Co., Ltd, Tianjin 301700, China
6 School of Pharmacy, University of Chinese Academy of Sciences, Shanghai 201203, China
7 Zhongshan Institute for Drug Discovery, Zhongshan 528400, China
8 Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
Correspondence to: Chuan Li: chli@simm.ac.cn, Yong-ming Yao: c_ff@sina.com,
DOI: 10.1038/s41401-023-01224-1
Received: 16 November 2023
Accepted: 26 December 2023
Advance online: 24 January 2024

Abstract

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.
Keywords: Traditional Chinese medicine; XueBiJing; sepsis; mortality; pharmacokinetic compatibility; polypharmacology

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