The mechanism of action of Pudilan Xiaoyan oral liquid against LPS-induced acute respiratory infection in mice based on biological network analysis and metabolomics / 药学学报

This study integrates metabolomics and network pharmacology techniques to systematically analyze the possible mechanism of Pudilan Xiaoyan oral liquid (PDL) in the treatment of acute respiratory infections. GC-MS metabolomics analysis found 8 endogenous metabolites, 3-phosphoglycerate, α-aminoadipate, D-ribulose-5-phosphate, β-mannosylglyceric acid, D-fructose, urea, D-maltose and ornithine in the serum of mice with acute respiratory infection induced by LPS; these substances can be used as biomarkers for PDL use in the treatment of acute respiratory infections. Biological network studies revealed 10 potential targets for intervention by PDL in the glycolysis and pentose phosphate pathways, including GPI, G6PD, H6PD, PFKM, TALDO1, TKT, GAPDH, HK1, PKLR and TPI1. All animal experiments were carried out with approval of the Animal Ethics Committee of Nanjing University of Chinese Medicine. Our findings indicate that the strategy of combining metabolomics and network analysis can provide information on the possible mechanism of PDL in acute respiratory infections, and reveal that PDL may ameliorate the pathological process of acute respiratory infections by regulating disordered metabolic pathways.

Meta-analysis on effectiveness and safety of Pudilan Xiaoyan Oral Liquid on child upper respiratory infection / 中国中药杂志

To systematically review the effectiveness and safety of Pudilan Xiaoyan Oral Liquid on child upper respiratory infection and conduct Meta-analysis. We electronically retrieved databases, including PubMed, Web of Science, VIP, WanFang and CNKI, for published articles of randomized controlled trials(RCTs) of Pudilan Xiaoyan Oral Liquid on child upper respiratory infection from inception to April 2019. According to the inclusion and exclusion criteria, two reviewers independently screened out literatures, extracted data and assessed the risk of bias in included studies. Then, Meta-analysis were conducted by Stata 15.0 software. A total of 16 RCTs involving 1 924 patients with upper respiratory infection were included. The results of Meta-analysis showed that the improvement of clinical symptoms, such as fever subsided time(WMD=-3.66, 95%CI[-4.61,-2.72], P<0.001), cough time(WMD=-1.89, 95%CI[-2.51,-1.27], P<0.001), time of runny noses(WMD=-4.60, 95%CI[-5.85,-3.34], P<0.001) and time of sore throat(WMD=-2.62, 95%CI[-3.54,-1.70], P<0.001). Meanwhile, the results of Meta-analysis showed the improvement of laboratory indications, including TNF-α(WMD=-2.68, 95%CI[-2.98,-1.58], P<0.001) and IL-6(WMD=-2.26, 95%CI[-3.36,-2.36], P<0.01). The current evidence shows that Pudilan Xiaoyan Oral Liquid may significantly improve the effectiveness and safety. According to the limited quality of included studies, the above conclusion needs be to verified with more high-quality studies.

Simultaneous Determination of 12 Components in Pudilan Xiaoyan Oral Liquid by Ultra-high Performance Liquid Chromatography Coupled with Triple Quadrupole Mass Spectrometry / 中国实验方剂学杂志

Objective: To establish an ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ MS) method for the simultaneous determination of twelve components (wogonoside,baicalin,wogonin,chrysin,uteolin,caffeic acid,acetylcorynoline,corynoline,protopine,salicylic acid,uracil and adenosine) in Pudilan Xiaoyan oral liquid. Method: The analysis was performed on an Agilent Extend C18 column(3.0 mm×150 mm,3.5 μm),with a gradient elution by using the mobile phase of methanol-water(0.1%formic acid). The flow rate was 0.3 mL·min-1. Triple quadrupole mass spectrometry, electrospray ionization source (ESI),DMRM mode, and positive and negative ions alternate mode were adopted. Result: The 12 reference substances had a good specificity. Wogonoside,baicalin,wogonin,chrysin,uteolin,caffeic acid,acetylcorynoline,corynoline,protopine,salicylic acid,uracil and adenosine showed good linear relationships within the range of 0.062 24-16.24,33.95-530.4,0.013 64-3.558,0.001 157-0.302 4,0.001 199-0.313 0,0.014 64-3.821,0.000 739 5-0.038 59,0.060 83-3.174,0.002 443-0.637 4,0.021 80-1.138,0.022 99-6.000,0.006 046-1.578 μg·L-1,with a good precision,stability and repeatability. And the average recoveries were 98.9%,100.2%,106.9%,100.8%,101.7%,99.3%,94.6%,100.0%,100.5%,103.4%,96.8%,98.1%. Conclusion: This method was simple,sensitive and reliable. It laid a foundation to promote the quality control standard of Pudilan Xiaoyan oral liquid.

Effect of Pudilan Xiaoyan Oral Liquid on Acute Lung Injury Rat Induced by Lipopolysaccharide / 中国实验方剂学杂志

Objective:To explore the effect and mechanism of Pudilan Xiaoyan oral liquid(PDL) on the acute lung injury rat induced by lipopolysaccharide (LPS). Method:The 72 Wistar rats were randomly divided into control group, model group, dexamethasone group, PDL 7, 3.5, 1.75 g·kg-1·d-1 group according to body weight.The acute lung injury model was made through inhalation with lipopolysaccharide in the model group, hexadecadrol group, PDL 7, 3.5, 1.75 g·kg-1·d-1 group.To examining each rat alveolar lavage fluid (BALF) of the total number of white blood cells, enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of nuclear transcription factors-kappa B (NF-κB) and interleukin-10 (IL-10).Hematoxylin-eosin(HE) staining was used to observe morphological changes of lung tissue and explore different doses of PDL effect on acute lung injury in rats. Result:Compared with model group, the account of leukocyte in BALF decreased significantly in PDL 7 g·kg-1·d-1 group and PDL 3.5 g·kg-1·d-1 group (PκB significantly decreased in PDL 7, 3.5, 1.75 g·kg-1·d-1 group (P-1·d-1 group (P-1·d-1 group, the inflammation, edema and congestion in lung tissue reduced (PConclusion:PDL has a significant protective effect on the inflammation of acute lung injury model, and its mechanism is related to the expressions of NF-κB and IL-10. PDL could also repair the injury of lung in acute lung injury model.

Pharmacokinetics of active ingredients of Pudilan Xiaoyan Oral Liquid in rats and effect on liver drug-metabolizing enzymes / 中国中药杂志

This study is aimed to establish a method for the determination of baicalin,baicalin and purpurin in the plasma of rats after oral administration of Pudilan Xiaoyan Oral Liquid( PDL) by using liquid chromatography-mass spectrometry( LC-MS),analyze the pharmacokinetics of three components in rats,and investigate the effects of PDL on drug-metabolizing enzymes in rat liver. C18 column was used for liquid chromatography separation,with acetonitrile-water( containing 0. 2% formic acid) as the mobile phase for gradient elution. The mass spectrometry was detected by electrospray ion source( ESI) under multi-reaction monitoring mode( MRM),as well as positive and negative ion alternating mode. Plasma sample collection was performed by using an automatic blood collection meter for small animals. The pharmacokinetic parameters were calculated by Win Nonlin software. The total protein concentration of rat liver microsomes and the total enzyme content of CYP450 were determined by BCA method and spectrophotometry respectively. The methodological study in terms of linear range,recovery rate,precision and sample stability,was used to confirm that the LC-MS analysis method established in this experiment was simple,exclusive,accurate and reliable,and can meet the requirement of determining the content of baicalin,oroxindin and corynoline in plasma after PDL administration in rats. The drug-time curve showed that baicalin and oroxindin had a bimodal phenomenon,and the pharmacokinetic parameters indicated that baicalin,oroxindin and corynoline in PDL had certain drug-like properties. After 7 consecutive days of PDL administration,the rat liver coefficient,total liver microparticle protein and CYP450 enzyme content were increased,but there was no significant difference,indicating that PDL was less likely to develop drug-drug interaction based on CYP enzyme. The results of this experiment can provide reference for the research on in vivo efficacy and drug interaction of PDL as well as on its clinical application.

Expert consensus statement on Pudilan Xiaoyan Oral Liquid in clinical practice / 中国中药杂志

Pudilan Xiaoyan Oral Liquid has effects in clearing away heat and detoxifying,and is used to treat pharynx and throat swelling caused by the syndrome of excessive heat and toxin accumulation. Its efficacy is to relieve swelling and pain( redness,swelling and hot pain). It is included in the Chinese Pharmacopoeia of 2015 Edition,and has been listed in provincial health insurance directories of Shaanxi,Jiangsu,Liaoning,Hunan,Tianjin,Xinjiang and Hebei. It has been recommended by health departments of Beijing,Chongqing and other provinces as a preferred drug for the prevention and treatment of H1 N1 and HFMD,and listed in the diagnosis and Treatment Guide of HFMD by the Ministry of Health,the Clinical Application Guide of Chinese Patent Medicine edited by the Lung Department Disease Branch of China Association of Chinese Medicine,and the Clinical Practice Guide of Single Administration/Combined Administration of Antibiotics in Treatment of Common Infectious Diseases by China Association of Chinese Medicine. To further improve the clinician's understanding of drugs and better guide the rational clinical application,we invited front-line clinical experts from respiratory department,infectious department and dermatology of traditional Chinese and Western medicine to develop and compile the expert consensus. The consensus fully considered the clinical evidence and the expert clinical experience to give recommendations for clinical problems with evidence support and consensus suggestions for clinical problems without evidence support by the nominal group method.This consensus is based on clinical research evidence and expert experience in a simple and clear format,which provides a preliminary reference for the clinical use of the drug.

Metabolomics on Pudilan Xiaoyan Oral Liquid in treatment of Influenza A/H1N1-induced pneumonia based on GC-MS / 中草药

Objective To screen the pneumonia-related abnormal metabolites in lung tissue of mice infected by Influenza A/H1N1, and to monitor the regulation effect of Pudilan Xiaoyan Oral Liquid and to explore potential anti-pneumonia mechanism. Methods ICR mice were randomly divided into four groups with ten mice in each group: normal group, model group, Pudilan group, and Ribavirin group. The mice were infected with H1N1 virus intranasally and gavage once every-day for six consecutive days. 2 h after the last dose, the mice were sacrificed and lungs were collected. Metabolomics based on GC-MS was applied to analyze the changes of metabolites in the lung tissue of each group. The potential biomarkers of H1N1-induced pneumonia were screened by three conditions: P 1.0, and Fold Change > 1.5. Metabolic pathways related to the treatment mechanism of Pudilan Xiaoyan Oral Liquid were analyzed. Results The infection of H1N1 virus leads to infiltration of inflammatory cells in the lungs of mice and various degrees of pneumonitis and metabolic disorders. Pudilan Xiaoyan Oral Liquid and ribavirin can both ameliorate the symptoms of pneumonia and play role in callback of various metabolites. Conclusion The treatment effect of Pudilan Xiaoyan Oral Liquid on H1N1-induced pneumonia is related to the regulation effects on 14 potential biomarkers and 12 associated metabolic pathways.

Clinical Observation of Pudilan Xiaoyan Oral Liquid in the Treatment of Children Acute Upper Respiratory Tract Infection / 中国药房

OBJECTIVE: To investigate the time of clinical symptom disappearance, therapeutic efficacy and safety of Pudilan xiaoyan oral liquid and its effects on immune factors in the treatment of pediatric acute upper respiratory tract infection. METHODS: A total of 142 children aged 3-17 with acute upper respiratory tract infection selected from Chongqing Jiulongpo District Second People's Hospital during May 2015-May 2016 were divided into observation group (72 cases) and control group (70 cases) according to random number tablet. Both groups received symptomatic treatment as antivirus, antipyretic. Observation group was additionally given Pudilan xiaoyan oral liquid 10 mL each time, 3 times a day, treated for consecutive 7 d. The defervescence time, the disappearance time of rhinobyon, coughing, diarrhea and pharynx swelling were compared between 2 groups. The levels of TNF-α, IL-6 and immune factors (CD3+, CD4+ and CD4+/CD8+) were determined in 2 groups before and after treatment. Clinical efficacies and the occurrences of ADR were observed in 2 groups. RESULTS: Compared to control group, the defervescence time, the disappearance time of rhinobyon, coughing, diarrhea, pharynx red and swelling were significantly shortened in observation group (P<0. 05). Before treatment, there was no statistical significance in the serum levels of TNF-α, IL-6 or immune factors between 2 groups (P>0. 05). After treatment, the serum levels of TNF-α and IL-6 in 2 groups were significantly lower than before treatment (P<0. 05). The serum levels of CD3+, CD4+ and CD4+/CD8+ were significantly higher than before treatment of each group (P<0. 05), while the improvement of observation group was significantly better than that of control group (P<0. 05). Total response rate of observation group was significantly higher than that of control group (P<0. 05), but there was no statistical significance in the incidence of ADR between 2 groups (P>0. 05). CONCLUSIONS: Pudilan xiaoyan oral liquid can shorten the time of acute upper respiratory tract infection disapperance as defervescence, nasal congestion and cough. It combined with antiviral drug is better than antiviral drug alone, but antiviral drug combined with it or alone have same safety.

A multi-center clinical trial: Evaluation on effectiveness and safety of different dosages of Pudilan Xiaoyan Oral Liquid in treatment of infantile acute pharyngitis-tonsillitis with lung-stomach excess-heat syndrome / 中草药

Objective: To evaluate the efficacy and safety of different dosages of Pudilan Xiaoyan Oral Liquid (PXOL) in treatment of infantile acute pharyngitis-tonsillitis with lung-stomach excess-heat syndrome. Methods: A randomized controlled, double-blind, positive drug parallel controlled, and multi-center clinical trial was conducted. Totally 324 children from seven research centers were included, 108 cases in experimental high dose group (A Group), 108 cases in experimental low dose group (B Group), 54 cases in positive medicine group (Xiaoer yanbian Granula, C Group), and 54 cases in placebo group (D Group), with the ratios of 2:2:1:1.5 in a course. Results: (1) Totally 317 cases were in full analysis set (FAS), 284 cases in per-protocol set (PPS) and 324 cases in Safety Set (SS). (2) Evaluation on effectiveness: There was significant difference (P<0.001) between each two groups in the total effective rate of pharyngalgia and pharyngeal swelling. A Group and B Group were both superior to D Group, and were non-inferior to C Group. B Group was non-inferior to A Group. There was significant difference (P<0.001) between each two groups in total effective rate of syndrome of traditional Chinese medicine. There was significant difference (P<0.05) between each two groups in the median time of improving pharyngalgia syndrome. There was significant difference (P<0.001) between each two groups in the median time of pharyngalgia syndrome disappearing. There were significant differences (P<0.05) between each two groups in total effective rate of halitosis, cough, thirst, deep-colored urine, and dry stool. The analysis on PPS agrees with that of FAS. (3) Evaluation on safety: No adverse reactions in clinical significant laboratory examination were found during the trial. Conclusion: High and low dosages of PXOL show advantages over placebo and are non-inferior to the positive medicine Xiaoer Yanbian Granula. High dose group does not show advantage comparing with low dose group. No adverse reactions are found during the trial. Low dose therapy is recommended.

Antiviral effects of pudilan xiaoyan oral liquid on respiratory syncytial virus and adenovirus in vitro / 实用医学杂志

Objective To study the antiviral effects of Pudilan xiaoyan oral liquid on Hep-2 cell models infected with respiratory syncytial virus (RSV), adenoviruses serotype 3 strains (ADV3) in vitro. Methods The cell cytotoxic and inhibition effect of Pudilan xiaoyan oral liquid on RSV or ADV3 were investigated by MTT assay and the inhibitory assay for cytopathic effect (CPE) in Hep-2 cell cultures to detect its antiviral effects. Results The median toxic concentration (TC50) of Pudilan xiaoyan oral liquid on Hep-2 cells was 776.97 mg/L. The median effective concentration (EC50) of inhibiting RSV and ADV3 were 28.08, 28.10 mg/L,whose therapeutic index (TI) were 27.67 and 27.65 respectively. The safety coefficient of Pudilan xiaoyan oral liquid is higher than that of control, ribavirin. Compared with the virus control group, Pudilan xiaoyan oral liquid can obviously produce actions of a dose-dependent relationship to inhibit CPE in Hep-2 cells infected with RSV or ADV3 virus. Conclusions Pudilan xiaoyan oral liquid significantly improves the protection against RSV and ADV3 virus infection in Hep-2 cells. And the inhibition of CPE induced by viruses infection increased with the elevation of higher drug concentration for its antiviral effect augmented in vitro.

Clinical Observation of Pudilan Xiaoyan Oral Liquid Combined with Bronchial Dilatation Drugs in the Treat-ment of Moderate and Severe Stable Chronic Obstructive Pulmonary Disease / 中国药房

OBJECTIVE:To observe the clinical efficacy and safety of Pudilan xiaoyan oral liquid combined with bronchial dil-atation drugs in the treatment of moderate to severe stable chronic obstructive pulmonary disease(COPD). METHODS:According to admission time,102 patients with stable moderate to severe COPD were randomly divided into treatment group(n=53)and con-trol group(n=49). Control group received Budesonide and formoterol fumarate powder for inhalation and Tiotropium bromide pow-der for inhalation;based on control group,treatment group was additionally treated with Pudilan xiaoyan oral liquid,10 ml/time, 3 times a day, for 12 weeks. The lung function index, number of acute COPD attack, modified medical research council (mMRC),CAT and CCQ were performed and comparison in the two groups. RESULTS:After 12 weeks of treatment,the IC of treatment group was improved significantly,compared to before treatment and control group;there was statistical significance(P0.05);there was no statistical significance in the number of acute COPD attack between 2 groups(P>0.05). mMRC,CAT score and CCQ total score of treatment group were improved significantly,compared to before treatment and control group;there was statistical significance (P<0.05). No obvious ADR was found in 2 groups. CONCLUSIONS:Pudilan xiaoyan oral liquid combined with bronchial dilatation drugs for inhalation is better than powder for inhalation in the treatment of moderate to serve stable COPD,can improve pulmonary function significantly,exercise tolerance and quality of life.