Comparison of pulmonary availability and anti-inflammatory effect of dehydroandrographolide succinate via intratracheal and intravenous administration
Graphical abstract
Introduction
Andrographolides represent the major active components in the famous Chinese herb, Andrographis paniculata (Burm.f) Nees (Chuan-Xin-Lian), which belongs to the Acanthaceae family. The herb has been widely used for the treatment of common cold, fever and detoxification in Chinese medicine whereas purified andrographolides and their analogs have been prepared as injectables, such as Xi-Yan-Ping (sulfonated derivatives of total andrographolides), Chuan-Hu-Ning (dehydroandrographolide disuccinate monopotassium salt), and Yan-Hu-Ning (dehydroandrographolide disuccinate potassium-soldium salt), etc., for the treatment of respiratory diseases (Zhao et al., 2016). Extensive reports have revealed that andrographolides have a broad range of pharmacological effects such as antibacterial, antiviral, anti-inflammatory and immune-stimulatory activities (Jarukamjorn and Nemoto, 2008; Shao et al., 2012; Jayakumar et al., 2013; Zhu et al., 2013; Peng et al., 2016).
In clinical, andrographolide injections have been the best-selling traditional Chinese medicine formulas for respiratory diseases, mainly viral pneumonia and upper respiratory infections, in the recent decade (Zhao et al., 2016a; Peng, 2020). A great number of clinical studies have demonstrated that these injections appeared to be an effective treatment against upper respiratory tract infections, bronchitis/bronchiolitis and pneumonia (e.g. Xu and Xu, 2005; Liu et al., 2013; Sun et al., 2015; Zhang et al., 2015; Sun and Yuan, 2020). However, the wide use of andrographolide injections has brought about high incidence of adverse drug reactions (ADRs). For example, NMPA (China National Medical Products Administration) previously issued ADRs warning on Yan-Hu-Ning and Chuan-Hu-Ning in 2009 (NMPA, 2009) and on Xi-Yan-Ping in 2012 (NMPA, 2012) in the 23rd and 48th issues of Adverse Drug Reaction Information Bulletin, respectively. In addition, a systematic review suggested that the characteristics of ADRs induced by andrographolide injections reported during 2000–2015 was broadly similar to those associated with other injections of traditional Chinese medicine. The ADRs could be mainly attributable to systemic allergic reactions, leading to diverse clinical manifestations, including skin disorders (e.g. itching, redness, rash, etc.) and whole-body complaints (e.g. fever, chills, and even anaphylactic shock, etc.) (Xiang et al., 2016).
In order to maintain the advantages of rapid onset and favorable efficacy and yet to minimize ADRs associated with injections, alternative delivering means to the injections have been investigated. For the treatment of respiratory diseases, pulmonary route of drug delivery has gained particular attention since it enables to deliver the drug directly to lung for local treatment. Indeed, over 100 clinical trials have been performed to evaluate the efficacy and safety of nebulized andrographolides (Zhao et al., 2016b). Many of these studies had reported better efficacy for the treatment of bronchitis or bronchiolitis, pneumonia and upper respiratory tract infections with nebulized therapy than with the control groups in terms of effective rates and improved symptoms and function. For example, in a comparative efficacy study between nebulized and intravenously infused dehydroandrographolide succinate (DAS) involving 500 children aged 1–4 years with upper respiratory infections. The result demonstrated that the nebulization therapy was associated with superior treatment successes where a total clinical effective rate of 95.2% was achieved, significantly higher than 84.0% of the intravenous administration (P < 0.05). In addition, nebulized DAS showed significantly better responses in terms of time to relieve clinical symptoms, e.g. decreases in resolution time of fever (1.4 ± 0.9 versus 2.4 ± 1.0 days), cough (2.5 ± 1.2 versus 3.7 ± 1.1 days) and sore throat (2.3 ± 0.9 versus 3.4 ± 1.2 days) compared to the intravenous counterpart (Yang, 2014). Nonetheless, it should be noted that the nebulization therapy of andrographolides was off-label clinical practice and many clinical studies were generally poorly performed as the nebulization parameters were lacking of adequate quality control. For example, the droplet/particle size distribution of nebulizer generated aerosols, one of the most important quality characteristics, was not tested in these earlier studies. In addition, since the approval of andrographolide injections was not intended for inhalation delivery, pulmonary fate of inhaled andrographolides was largely unknown. Therefore, in the present study, DAS was utilized as a model andrographolide drug to evaluate the aerodynamic performances of the nebulizer generated aerosols and also to comparatively investigate the local drug availability and anti-inflammatory efficacy between intratracheal and intravenous dosing.
Section snippets
Reagents and chemicals
Potassium dehydroandrographolide succinate (DAS, HPLC ≥ 98%) was purchased from Nanjing Chunqiu Biological Engineering Co., Ltd. (Nanjing, China). Chuan-Hu-Ning (Potassium dehydroandrographolide succinate) injection (freeze-dried powders) was sourced from Chengdu Tiantaishan Pharmaceutical Co., Ltd. (Chengdu, China). Lipopolysaccharide (Escherichia coli O55:B5, LPS) was bought from Beijing Solarbio Science & Technology Co., Ltd. (Beijing, China). Mouse TNF-α ELISA kits were obtained from Wuhan
Characterization of nebulizer generated aerosols
DAS injections are often off-label used for nebulization therapy in clinical application. Nonetheless, the nebulizing performances such as particle size distribution were not documented in the earlier clinical studies. Aerodynamic properties and droplet size distribution are compendial requirements for the quality characterization of nebulizer-generated aerosols (Berg et al., 2007; Song et al., 2016).
Dynamic changes in droplet size and concentration over time of nebulizer generated aerosols
Conclusions
The present study demonstrated that nebulized DAS conferred excellent aerodynamic properties, facilitating a favorable lung deposition. In addition, the intratracheal administration increased the drug availability in the lung tissue by more than 80-fold compared to the intravenous delivery, leading to an improved and prolonged local anti-inflammatory efficacy. Therefore, the nebulization therapy of DAS could represent an intriguing alternative to the intravenous injections.
CRediT authorship contribution statement
Chen Wei-Ya: Writing - original draft, Formal analysis. Wang Yuan-Song: Investigation. Liu Chun-Yu: Methodology. Ji Yu-Bin: Software. Yang Fei-Fei: Supervision, Validation, Funding acquisition. Liao Yong-Hong: Conceptualization, Writing - review & editing, Funding acquisition.
Acknowledgments
This work was supported by National Natural Science Foundation of China (Grant No. 81603052) and CAMS Initiative for Innovative Medicine (CAMS-I2M, Grant No. 2017-I2M-1-013).
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