The clinical population pharmacokinetics, metabolomics and therapeutic analysis of alkaloids from Alstonia scholaris leaves in acute bronchitis patients.

Autor: Li R; 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., Zhao YL; 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., Qin F; Department of Analytical Chemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China., Zhao Y; 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., Xiao XR; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China., Cao WY; 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., Fan MR; 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., Wang SG; 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., Wu Y; 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., Wang B; 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., Fan CZ; 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., Guo ZN; 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., Yang QN; 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., Zhang WT; 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., Li XG; Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 100050, PR China. Electronic address: lxg198320022003@163.com., Li F; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China; Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: lifeib@mail.kib.ac.cn., Luo XD; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR 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. Electronic address: xdluo@mail.kib.ac.cn., Gao R; 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. Electronic address: xyyygr@126.com.
Jazyk: angličtina
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2022 Apr; Vol. 98, pp. 153979. Date of Electronic Publication: 2022 Feb 05.
DOI: 10.1016/j.phymed.2022.153979
Abstrakt: Background: 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.
Purpose: To verify the clinical efficacy and explore the potential biomarkers related to CALAS treatment for acute bronchitis.
Materials and Methods: 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.
Results: 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.
Conclusion: 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.
(Copyright © 2022. Published by Elsevier GmbH.)
Databáze: MEDLINE
Externí odkaz: