Li Rui, Zhao Yun-Li, Qin Feng, Zhao Yang, Xiao Xue-Rong, Cao Wei-Yi, Fan Mao-Rong, Wang Shu-Ge, Wu Yi, Wang Bing, Fan Chang-Zheng, Guo Zhong-Ning, Yang Qiao-Ning, Zhang Wan-Tong, Li Xin-Gang, Li Fei, Luo Xiao-Dong, Gao Rui
Institute of Clinical Pharmacology of Xiyuan Hospital, National Clinical Research Center for Chinese Medicine Cardiology, China Academy of Chinese Medical Sciences, No. 1, R. Xiyuangcaochang, Haidian District, Beijing 100091, China; NMPA Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China.
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, PR China.
Phytomedicine. 2022 Apr;98:153979. doi: 10.1016/j.phymed.2022.153979. Epub 2022 Feb 5.
Capsule of alkaloids from leaf of Alstonia scholaris (CALAS) is a new investigational botanical drug (No. 2011L01436) for respiratory disease. Clinical population pharmacokinetics (PK), metabolomics and therapeutic data are essential to guide dosing in patients. Previous research has demonstrated the potential therapeutic effect of CALAS on acute bronchitis. Further clinical trial data are needed to verify its clinical efficacy, pharmacokinetics behavior, and influence of dosage and other factors.
To verify the clinical efficacy and explore the potential biomarkers related to CALAS treatment for acute bronchitis.
Oral CALAS was assessed in a randomized, double-blind, placebo-controlled trial. Fifty-five eligible patients were randomly assigned to four cohorts to receive 20, 40 or 80 mg, of CALAS three times daily for seven days, or placebo. Each CALAS cohort included 15 subjects, and the placebo group included 10 subjects. A population PK model of CALAS was developed using plasma with four major alkaloid components. Metabolomics analysis was performed to identify biomarkers correlated with the therapeutic effect of CALAS, and efficacy and safety were assessed based on clinical symptoms and adverse events.
The symptoms of acute bronchitis were alleviated by CALAS treatment without serious adverse events or clinically significant changes in vital signs, electrocardiography or upper abdominal Doppler ultrasonography. Moreover, one compartment model with first-order absorption showed that an increase in aspartate transaminase will reduce the clearance (CL) of scholaricine, and picrinine CL was inversely proportional to body mass index, while 19-epischolaricine and vallesamine CL increased with aging. The serum samples from acute bronchitis patients at different time points were analyzed using UPLC-QTOF in combination with the orthogonal projection to latent structures-discriminant analysis, which indicated higher levels of lysophosphatidylcholines, lysophosphatidylethanolamines and amino acids with CALAS treatment than with placebo.
This is the first study to evaluate the clinical efficacy and explored the potential biomarkers related to CALAS therapeutic mechanism of acute bronchitis by means of clinical trial combined the metabolomics study. This exploratory study provides a basis for further research on clinical efficacy and optimal dosing regimens based on pharmacokinetics behavior. Additional acute bronchitis patients and CALAS PK samples collected in future studies may be used to improve model performance and maximize its clinical value.
鸡骨常山叶生物碱胶囊（CALAS）是一种用于治疗呼吸系统疾病的新型植物药（编号2011L01436）。临床群体药代动力学（PK）、代谢组学和治疗数据对于指导患者用药至关重要。先前的研究已证明CALAS对急性支气管炎具有潜在治疗作用。需要更多临床试验数据来验证其临床疗效、药代动力学行为以及剂量和其他因素的影响。
验证CALAS治疗急性支气管炎的临床疗效，并探索与之相关的潜在生物标志物。
在一项随机、双盲、安慰剂对照试验中评估口服CALAS的效果。55名符合条件的患者被随机分为四组，分别每日三次接受20、40或80mg的CALAS治疗，持续7天，或接受安慰剂治疗。每个CALAS组包括15名受试者，安慰剂组包括10名受试者。利用含有四种主要生物碱成分的血浆建立CALAS的群体PK模型。进行代谢组学分析以鉴定与CALAS治疗效果相关的生物标志物，并根据临床症状和不良事件评估疗效和安全性。
CALAS治疗可缓解急性支气管炎症状，且无严重不良事件发生，生命体征、心电图或上腹部多普勒超声检查也无临床显著变化。此外，具有一级吸收的单室模型显示，天冬氨酸转氨酶升高会降低鸡骨常山碱的清除率（CL），苦味质碱CL与体重指数成反比，而19-表鸡骨常山碱和瓦氏胺CL随年龄增长而增加。采用超高效液相色谱-四极杆飞行时间质谱联用结合正交投影到潜在结构判别分析对急性支气管炎患者不同时间点的血清样本进行分析，结果表明CALAS治疗组的溶血磷脂酰胆碱、溶血磷脂酰乙醇胺和氨基酸水平高于安慰剂组。
本研究首次通过临床试验结合代谢组学研究评估了CALAS治疗急性支气管炎的临床疗效，并探索了与之治疗机制相关的潜在生物标志物。这项探索性研究为基于药代动力学行为进一步研究临床疗效和优化给药方案提供了依据。未来研究中收集的更多急性支气管炎患者和CALAS PK样本可用于改善模型性能并最大化其临床价值。
