Efficacy and safety of Chinese herbal medicine children's Zibei Xuanfei syrup in treating acute trachea-bronchitis with wind-heat invading lung syndrome: A randomized, double-blind, multicentre, controlled trial

Acute trachea-bronchitis (ATB) is an acute inflammation of the trachea bronchial mucosa caused by infection, physical or chemical irritation, or allergic factors, often occurring in the cold season or when the temperature suddenly becomes cold. The clinical presentation is dominated by cough, which may be accompanied by upper respiratory tracts infection symptoms such as nasal congestion, runny nose, sore throat, hoarseness, and/or systemic symptoms such as fever, chills, headache, and generalized aches and pains, and usually lasts no more than 3 weeks (Li et al., 2021). Clinically, this disease is very common. It is the most common non-inpatient disease and one of the top ten medical diseases (Ren et al., 2002).

Children have weak immunity compared with adults, and the lumens of children's nose, throat, trachea, and bronchus are relatively narrow, lack elastic tissue, mucus gland secretion is insufficient, children are more susceptible to ATB because of poor cilia movement and a poor ability to remove microorganisms. As the main cause of ATB in children is a viral infection, western medicine has many limitations in the selection of antiviral drugs. Antiviral drugs used in western medicine for children's respiratory diseases mainly include ribavirin, M2 membrane protein channel blockers amantadine, rimantadine, neuraminidase inhibitor oseltamivir, etc. However, there are many side effects of the use of these antiviral drugs, such as nausea and vomiting of gastrointestinal reactions, decreased white blood cell count, anemia, immunosuppression, abnormal liver function, and so on. In addition, M2 membrane protein ion channel blocker is prone to drug resistance, and the cases of drug resistance during treatment account for 25%–35% of patients (Jing and Yu, 2014). Another pathogenic factor contributing to acute bronchitis is a bacterial infection. Antibiotic abuse is very common in clinical settings, and it can increase bacteria that are resistant to antibiotics. The drug-resistant bacteria monitoring network of three children's hospitals in Beijing, Guangzhou, and Shanghai (Zhu et al., 2009) showed that Streptococcus pneumoniae was 39.8% resistant to penicillin, 19%–25% resistant to second-generation cephalosporins, and 84.2% resistant to erythromycin. This indicates that the rational use of antibiotics to suppress the increasing resistance of bacteria is becoming more and more serious.

Compared with western antiviral drug side effects and drug resistance and antibiotic resistance, Traditional Chinese medicine (TCM) has its advantages. Hospital is the cradle of the development of TCM preparations, with the added benefit of observing clinical efficacy and conducting clinical validation trials. It is also a significant source of new drug research(Chen et al., 2022).

At present, there is no specific Chinese herbal medicine on the market to treat the acute trachea-bronchitis with wind-heat invading lung syndrome in children under 14 years old. Hence, it is necessary to explore new treatment for symptomatic relief of this condition. Children's Zibei Xuanfei syrup is a prescription for treating children's cough due to exogenous factors created by lifetime professor Zhenyu Zhang, a famous old Chinese doctor and postgraduate supervisor of medical doctor at the Shandong University of TCM, according to his more than 50 years of clinical practice, based on treating children's cough due to exogenous factors caused by ATB with ancient prescription Sangju drink.

The efficacy and safety of children's Zibei Xuanfei syrup had been studied twice for clinical use before the start of this phase III clinical trial. A previous multi-center, randomized, double-blind, three-arm parallel-controlled, phase II clinical trial had enrolled 342 subjects. The two controls were a very low dose group (similar to placebo) and a positive control Jizhi syrup group. The phase II trial results showed significantly better efficacy in the children's Zibei Xuanfei syrup group and the positive drug control group than the very low dose children's Zibei Xuanfei syrup group (each P < 0.05). Based on the previous phase II clinical trial, this study obtained the Phase III clinical trial registration number CTR20170873 from the China Food and Drug Administration (CFDA). Another clinical study on children's Zibei Xuanfei syrup was published in 2017 (Chen, 2017), in which 100 pediatric patients were divided into the children's Zibei Xuanfei syrup group and the Jizhi syrup control group, with a stratified randomization method 1:1 ratio. The results indicated that after 7 days of medication, the total effective rate of cough was 93.33% in the children's Zibei Xuanfei syrup group vs. 86.96% in the Jizhi syrup group, with statistically significant difference (P < 0.05).

In the prescription, Arctiumlappa L.(hereinafter “A.lappa”) and Morus alba L.(hereinafter “M.alba”)is Jun (sovereign) medicine. Mentha haplocalyx Briq.(hereinafter “M.haplocalyx”) and Schizonepeta tenuifolia (Benth.) Briq. (hereinafter “S.tenuifolia”) help A. lappa and M. alba to promote lung and pharynx; Fritillaria unibracteata P.K.Hsiao & K.C.Hsia (hereinafter “F.unibracteata”), Peucedanum praeruptorum Dunn(hereinafter “P.praeruptorum”) and Aster tataricus L. f.(hereinafter “A.tataricus”)three herbs help A. lappa and M. alba to reduce sputum and relieve cough, the five are Chen (minister)medicine. Citrus. x aurantium L. (hereinafter “C.x aurantium”) and Isatis indigoticaFortuneex Lindl (hereinafter “I.indigotica”) are Zuo (assistant) medicine. Glycyrrhizauralensis Fisch.(hereinafter “G.uralensis”) is used as a Shi (messenger) medicine to blend various herbs.

The result of high performance liquid chromatography (HPLC) analysis method for the simultaneous determination of active constituents of children's Zibei Xuanfei syrup showed that The linear range of glycyrrhizin, naringin, neohesperidin and arctiin was 0.98–9.77 μg ml−1 (r = 0.9997),12.96–129.64 μg ml−1(r = 0.9998),10.16–101.59 μg ml−1(r = 0.9998) and 30.91–309.09 μg ml−1 (r = 0.9998),respectively. The average recoveries of the four index components were 99.1% (RSD = 1.1%), 101.3% (RSD = 0.8%), 98.7% (RSD = 1.0%) and 99.7% (RSD = 0.8%), respectively (Zhang et al., 2021). The established fingerprint of children's Zibei Xuanfei syrup was precise and stable, and 7 of the 17 common peaks in the fingerprints were identified, with fingerprint similarity values greater than 0.90 for the 10 batches of children's Zibei Xuanfei syrup (Xiong, 2020).

The plants studied complied with the relevant laws and regulations of the local governments and the state to protect biodiversity. A clinical trial on children's Zibei Xuanfei syrup was conducted under the presumption of CFDA clinical trial approval to obtain the marketing approval of innovative TCM. The low-dose children's Zibei Xuanfei syrup (10% content) was used as a control in this study, to explore the efficacy and safety of the children's Zibei Xuanfei syrup in treating ATB with wind-heat invading lung syndrome.

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