Zhao Yun-Li, Cao Jing, Shang Jian-Hua, Liu Ya-Ping, Khan Afsar, Wang Heng-Shan, Qian Yi, Liu Lu, Ye Min, Luo Xiao-Dong
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
Phytomedicine. 2017 Apr 15;27:63-72. doi: 10.1016/j.phymed.2017.02.002. Epub 2017 Feb 17.
Alstonia scholaris (L.) R. Br. (Apocynaceae), an important herbal medicine, has been widely used to treat respiratory tract diseases, such as cough, asthma, phlegm, and chronic obstructive pulmonary disease.
To evaluate pharmacological effect of alkaloids from A. scholaris on ovalbumin induced airways allergic inflammatory model, and explore whether the dosing frequency is related to pharmacokinetics.
After oral administration of total alkaloids, the pharmacokinetic study of it was investigated. In addition, anti-allergic studies were carried out on ovalbumin-sensitized airways allergic inflammatory model of mice.
The pharmacokinetics of total alkaloids (TA) was investigated in SD rat plasma by a fully-validated LC-MS/MS method. Then, an ovalbumin (OVA)-sensitized airways allergic inflammatory model was established, in which mice were intra-gastrically administrated by 3 times a day (8.3 and 16.7mg/kg) based on the pharmacokinetic behavior of TA) and single (25, 50mg/kg) treatment regimen. Dexamethasone was used as a positive control for corticosteroid drugs. Cellular infiltration was assessed in the broncho-alveolar lavage fluid (BALF). Expressions of interleukin-4 (IL-4) and interleukin-10 (IL-10) in the BALF were determined, levels of immunoglobulin E (IgE) and eotaxin in serum were measured, and superoxide dismutase (SOD) activities as well as malondialdehyde (MDA) content in the serum and BALF were examined. Finally, histopathological examination in the lung was assessed by H. E. staining.
The time course of plasma concentration of 4 bioactive indole alkaloids fitted an open two-compartment model after oral administration of total alkaloids at doses of 10, 25, and 50mg/kg. The area under the curve and the maximum concentration values of four major alkaloids increased dose-dependently, and half-life suggested a short-lasting pharmacological effect. Then, an ovalbumin-provoked airways allergic inflammatory model indicated that the pharmacological effect of administration of total alkaloids 3 times a day was a little better than that of single dose daily. The percentage of eosinophils in BALF was reduced obviously and the pathological damage of lung was also attenuated. There was also a significant reduction in IL-4 and promotion in IL-10 in the BALF. Serum IgE and eotaxin expression also significantly decreased in treated animals. Furthermore, the activity of SOD elevated remarkably and lipid peroxidation product (MDA) decreased in the administrated mice.
The pharmacological effects administrated for 3 times a day had precedence over single dose daily, which was related to the prolonged retention time and the maintained plasma concentration. Moreover, scholaricine and vallesamine might be responsible for the treatment of allergic asthma, mainly in total alkaloids.
印度萝芙木（夹竹桃科）是一种重要的草药，已被广泛用于治疗呼吸道疾病，如咳嗽、哮喘、痰和慢性阻塞性肺疾病。
评价印度萝芙木生物碱对卵清蛋白诱导的气道过敏性炎症模型的药理作用，并探讨给药频率是否与药代动力学相关。
口服总生物碱后，对其进行药代动力学研究。此外，对卵清蛋白致敏的小鼠气道过敏性炎症模型进行抗过敏研究。
采用经过充分验证的液相色谱-串联质谱法（LC-MS/MS）研究SD大鼠血浆中总生物碱（TA）的药代动力学。然后，建立卵清蛋白（OVA）致敏的气道过敏性炎症模型，根据TA的药代动力学行为，小鼠每天灌胃3次（8.3和16.7mg/kg）以及单次（25、50mg/kg）给药方案。地塞米松用作皮质类固醇药物的阳性对照。评估支气管肺泡灌洗液（BALF）中的细胞浸润情况。测定BALF中白细胞介素-4（IL-4）和白细胞介素-10（IL-10）的表达，测量血清中免疫球蛋白E（IgE）和嗜酸性粒细胞趋化因子的水平，并检测血清和BALF中超氧化物歧化酶（SOD）活性以及丙二醛（MDA）含量。最后，通过苏木精-伊红（H.E.）染色评估肺组织的组织病理学检查。
口服10、25和50mg/kg剂量的总生物碱后，4种生物活性吲哚生物碱的血浆浓度-时间过程符合开放二室模型。四种主要生物碱的曲线下面积和最大浓度值呈剂量依赖性增加，半衰期表明药理作用持续时间较短。然后，卵清蛋白诱发的气道过敏性炎症模型表明，每天给药3次的总生物碱的药理作用略优于每日单次给药。BALF中嗜酸性粒细胞百分比明显降低，肺组织的病理损伤也有所减轻。BALF中IL-4也显著降低，IL-10有所升高。治疗动物血清中IgE和嗜酸性粒细胞趋化因子表达也显著降低。此外，给药小鼠的SOD活性显著升高，脂质过氧化产物（MDA）降低。
每天给药3次的药理作用优于每日单次给药，这与延长的保留时间和维持的血浆浓度有关。此外，scholaricine和vallesamine可能是治疗过敏性哮喘的主要成分，主要存在于总生物碱中。
