Clinical Pharmacology Institute, Xiyuan Hospital, China Academy of Chinese Medicine Science, Beijing, 100091, China.
Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu, 610041, China.
Phytomedicine. 2019 Aug;61:152828. doi: 10.1016/j.phymed.2019.152828. Epub 2019 Jan 10.
Alstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in 'dai' ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA).
The aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses.
In this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects' plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr.org.cn/showproj.aspx?proj=11736), number ChiCTR-IPR-15006976.
40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation.
Pharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen.
垂珠树（夹竹桃科）被报道是吲哚生物碱的丰富来源，具有显著的生物活性。垂珠树的叶子在“傣”民族医学中被用于治疗呼吸系统疾病，并且从垂珠树叶子中分离得到的定义明确的吲哚生物碱已被注册为新的植物药研究性新药（No.2011L01436），并已获得中国食品药品监督管理局（CFDA）批准进行 I/II 期临床试验。
该试验旨在评估口服垂珠树叶生物碱胶囊（CALAS）不同剂量后的安全性，并探讨给药频率与药代动力学之间的关系。
在这项随机、开放标签、单中心临床试验中，对符合条件的健康中国志愿者口服不同剂量 CALAS 后的安全性和药代动力学进行了评估。每个志愿者（每组 10 人）分别单次口服 20mg、40mg、80mg 和 120mg 的 CALAS。通过完全验证的 LC-MS/MS 方法，在健康中国受试者的血浆中研究 CALAS 的药代动力学。整个研究过程中通过生化和临床评估安全性，并进行药物再激发研究以验证受试物与轻微不良事件之间的相关性。该试验于 2015 年 8 月 26 日（http://www.chictr.org.cn/showproj.aspx?proj=11736）在临床试验注册中心进行注册，注册号为 ChiCTR-IPR-15006976。
40 名受试者完成了研究，结果表明，缬沙明在健康志愿者的血浆中浓度最高，各化合物的 AUC 暴露水平依次为缬沙明>垂珠树碱>19-表垂珠树碱>胡椒堿。对于 CALAS 的安全性评价，试验过程中观察到两例轻微不良事件，但药物再激发研究表明这两例不良事件与个体的生理变化有关。
各成分的药代动力学特征表现出不同的模式。19-表垂珠树碱、缬沙明和胡椒堿符合线性药代动力学特征，而垂珠树碱符合非线性药代动力学特征。在当前剂量方案下，CALAS 在健康受试者中是安全的。
