Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing, 100193, PR China.
Increasepharm (Hengqin) Institute Coporation Limited, No. 2522 Huan Dao North Road, Hengqin New Area, Zhuhai, 519000, PR China.
J Ethnopharmacol. 2021 Jun 28;274:114082. doi: 10.1016/j.jep.2021.114082. Epub 2021 Apr 1.
The off-label nebulization of Shuang-Huang-Lian (SHL) injection is often utilized to treat respiratory tract infections in China. However, the pulmonary biopharmaceutics of SHL was generally unknown, limiting the rational selection of therapeutic dose and dose frequency.
To characterize the size distribution of nebulized aerosols and to compare the pharmacokinetics and the lung distribution of three chemical makers of SHL, chlorogenic acid (CHA), forsythiaside A (FTA) and baicalin (BC), after intratracheal and intravenous administration of SHL to rats.
The droplet size distribution profiles over nebulization process were dynamically monitored using a laser diffraction method whereas the levels of CHA, FTA and BC in plasma, lung tissues and bronchoalveolar lavage fluids (BALF) were determined by a validated LC-MS/MS assay. The pulmonary anti-inflammatory efficacy was evaluated using a lipopolysaccharide (LPS) induced lung inflammation model as indicated by the level of tumor necrosis factor-α (TNF-α) in BALF.
The nebulization of SHL showed good inhalability and allowed the aerosols to reach the upper or lower respiratory tract dependent on the performance of selected nebulizers. Following intratracheal administration of SHL at different doses, CHA, FTA and BC were absorbed into the bloodstream with the mean absorption time being 67.5, 63.5 and 114 min, respectively, rendering mean absolute bioavailabilities between 42.4% and 61.4% roughly independent of delivered dose. Relative to the intravenous injection, the intrapulmonary delivery increased the lung-to-plasma concentration ratios of CHA, FTA and BC by more than 100 folds and markedly improved the lung availability by 563-676 folds, leading to enhanced and prolonged lung retention. The production of TNF-α in BALF was decreased by ~50% at an intratracheal dose of 125 μL/kg SHL to LPS-treated mice.
The nebulization delivery of SHL is a promising alternative to the intravenous injection for the treatment of respiratory tract infections.
在中国，双黄莲（SHL）注射液的标签外雾化常被用于治疗呼吸道感染。然而，SHL 的肺部生物药剂学特性通常不为人知，限制了治疗剂量和剂量频率的合理选择。
通过气管内和静脉内给予 SHL 后，对三种 SHL 化学标志物，绿原酸（CHA）、连翘酯苷 A（FTA）和黄芩苷（BC）进行雾化，以描述雾化气溶胶的粒径分布，并比较其药代动力学和肺部分布。
使用激光衍射法动态监测雾化过程中的液滴粒径分布情况，采用经验证的 LC-MS/MS 测定法测定血浆、肺组织和支气管肺泡灌洗液（BALF）中 CHA、FTA 和 BC 的水平。通过测定 BALF 中肿瘤坏死因子-α（TNF-α）的水平，评估肺部抗炎效果。
SHL 的雾化具有良好的吸入性，并且能够根据所选雾化器的性能使气溶胶到达上呼吸道或下呼吸道。以不同剂量经气管内给予 SHL 后，CHA、FTA 和 BC 被吸收到血液中，平均吸收时间分别为 67.5、63.5 和 114 分钟，平均绝对生物利用度约为 42.4%至 61.4%，大致与给药剂量无关。与静脉注射相比，肺内给药使 CHA、FTA 和 BC 的肺/血浆浓度比值增加了 100 多倍，使肺利用率提高了 563-676 倍，从而增强并延长了肺部滞留。以 125 μL/kg SHL 的气管内剂量给予 LPS 处理的小鼠后，BALF 中 TNF-α的产生减少了约 50%。
SHL 的雾化给药是治疗呼吸道感染的一种有前途的静脉注射替代方案。
