A retrospective study of Pupingqinghua prescription versus Lianhuaqingwen in Chinese participants infected with SARS-CoV-2 Omicron variants.

Background: Coronavirus disease (COVID-19) seriously endangers global public health. Pupingqinghua prescription (PPQH) is an herbal formula from traditional Chinese medicine used for treatment of SARS-CoV-2 infection. This study aims to evaluate the clinical efficacy and safety of PPQH in Chinese participants infected with the SARS-CoV-2 Omicron variant. Methods: A total of 873 SARS-CoV-2 (Omicron)-infected patients were included. Among them, the patients were divided into the PPQH group (653 cases) and LHQW group (220 cases) according to different medications. The effectiveness indicators (hematological indicators, Ct values of novel Coronavirus nucleic acid tests, and viral load-shedding time) and safety indicators (liver and kidney function and adverse events) were analyzed. Results: There was no significant difference in baseline characteristics between the PPQH group and the LHQW group, except the gender; After the treatment, the levels of IL-5, IL-6, IL-10, NK cells, and INF-α of the patients in the PPQH group showed a downward trend (p < 0.05); The viral load shedding time was 5.0 (5.0, 7.0) in the PPQH group and 5.0 (4.0, 7.0) in the LHQW group; both PPQH and LHQW can shorten the duration of symptoms of fever, cough, and sore throat. The re-positive rate of COVID-19 test was 1.5 % in the PPQH group and 2.3 % in the LHQW group. In terms of safety, the levels of γ-GTT decreased significantly (p < 0.01); gastrointestinal reaction was the primary adverse reaction, and the reaction rate was 4.7 % in the PPQH group and 9.5 % in the LHQW group. Conclusion: PPQH can shorten the length of hospital stay and improve clinical symptoms of patients with SARS-COV-2 (Omicron), and it also has a good safety profile.

A new perspective to improve the treatment of Lianhuaqingwen on COVID-19 and prevent the environmental health risk of medication.

Lianhuaqingwen (LH), one traditional Chinese medicine (TCM), has been used to treat the coronavirus disease 2019 (COVID-19), but its ecotoxicity with potential human health security has not been well investigated. To overcome such adverse effects and improve its medication efficacy, an intelligent multi-method integrated dietary scheme, screening, and performance evaluation approach was developed. Thirteen LH compounds were selected, and the main protease (Mpro) was used as the potential drug target. Resulted information showed that the more compounds of LH added, the higher medication efficacy obtained using multi-method integrated screening system, expert consultation method, and molecular dynamics simulation. Pharmacodynamic mechanism analysis showed that low total energy and polar surface area of LH active compound (i.e., ß-sitosterol) will contribute to the best therapeutic effect on COVID-19 using quantitative structure-activity relationships (QSAR) and sensitivity models. Additionally, when mild COVID-19 patients take LH with the optimum dietary scheme (i.e., ß-lactoglobulin, α-lactalbumin, vitamin A, vitamin B, vitamin C, carotene, and vitamin E), the medication efficacy were significantly improved (23.58%). Pharmacokinetics and toxicokinetics results showed that LH had certain human health risks and ecotoxicity. This study revealed the multi-compound interaction mechanism of LH treatment on COVID-19, and provided theoretical guidance for improving therapeutic effect, evaluating TCM safety, and preventing human health risk.

New tale on LianHuaQingWen: IL6R/IL6/IL6ST complex is a potential target for COVID-19 treatment.

LianHuaQingWen (LHQW) improves clinical symptoms and alleviates the severity of COVID-19, but the mechanism is unclear. This study aimed to investigate the potential molecular targets and mechanisms of LHQW in treating COVID-19 using a network pharmacology-based approach and molecular docking analysis. The main active ingredients, therapeutic targets of LHQW, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, STRING, and GeneCards databases. According to the "Drug-Ingredients-Targets-Disease" network, Interleukin 6 (IL6) was identified as the core target, and quercetin, luteolin, and wogonin as the active ingredients of LHQW associated with IL6. The response to lipopolysaccharide was the most significant biological process identified by gene ontology enrichment analysis, and AGE-RAGE signaling pathway activation was prominent based on the interaction between LHQW and COVID-19. Protein-protein docking analysis showed that IL6 receptor (IL6R)/IL6/IL6 receptor subunit beta (IL6ST) and Spike protein were mainly bound via conventional hydrogen bonds. Furthermore, protein-small molecule docking showed that all three active ingredients could bind stably in the binding model of IL6R/IL6 and IL6ST. Our findings suggest that LHQW may inhibit the lipopolysaccharide-mediated inflammatory response and regulate the AGE-RAGE signaling pathway through IL6. In addition, the N-terminal domain of the S protein of COVID-19 has a good binding activity to IL6ST, and quercetin and wogonin in LHQW may affect IL6ST-mediated IL6 signal transduction and a large number of signaling pathways downstream to other cytokines by directly affecting protein-protein interaction. These findings suggest the potential molecular mechanism by which LHQW inhibits COVID-19 through the regulation of IL6R/IL6/IL6ST.

The mechanisms and clinical application of Traditional Chinese Medicine Lianhua-Qingwen capsule.

Lianhua-Qingwen capsule (LQC) is a commonly used Traditional Chinese Medicine (TCM) in China and has 11 herb components. The main active ingredient can target specific molecules and perform many clinic treatment roles. LQC has been authorized by National Medical Products Administration (NMPA) of China to treat severe acute respiratory syndrome (SARS) in 2002-2003, type A influenza virus HIN1 pandemic in 2009, H7N9, H3N2 and coronavirus disease-19 (COVID19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in 2020. It is also widely used to treat common cold with wind-heat syndrome, chronic rhinosinusitis (CRS), amygdalitis and chronic obstructive pulmonary disease. This article summarizes the advanced research progress of LQC in clinical application, mechanisms and provides new clues in the clinical application of LQC.

Broad Anti-Viral Capacities of Lian-Hua-Qing-Wen Capsule and Jin-Hua-Qing-Gan Granule and Rational use Against COVID-19 Based on Literature Mining.

The novel coronavirus disease 2019 (COVID-19) has become a matter of international concern as the disease is spreading exponentially. Statistics showed that infected patients in China who received combined treatment of Traditional Chinese Medicine and modern medicine exhibited lower fatality rate and relatively better clinical outcomes. Both Lian-Hua-Qing-Wen Capsule (LHQWC) and Jin-Hua-Qing-Gan Granule (JHQGG) have been recommended by China Food and Drug Administration for the treatment of COVID-19 and have played a vital role in the prevention of a variety of viral infections. Here, we desired to analyze the broad-spectrum anti-viral capacities of LHQWC and JHQGG, and to compare their pharmacological functions for rational clinical applications. Based on literature mining, we found that both LHQWC and JHQGG were endowed with multiple antiviral activities by both targeting viral life cycle and regulating host immune responses and inflammation. In addition, from literature analyzed, JHQGG is more potent in modulating viral life cycle, whereas LHQWC exhibits better efficacies in regulating host anti-viral responses. When translating into clinical applications, oral administration of LHQWC could be more beneficial for patients with insufficient immune functions or for patients with alleviated symptoms after treatment with JHQGG.

Positive effects of Lianhuaqingwen granules in COVID-19 patients: A retrospective study of 248 cases.

ETHNOPHARMACOLOGICAL RELEVANCE: Lianhuaqingwen (LHQW) is a Chinese medicine, developed from appropriate addition and reduction of combined traditional Chinese medicine (TCM) Yinqiao San and Maxing Shigan decoction. LHQW has been used in routine influenza treatment for decades and plays a role in a broad-spectrum therapy on various influenza viruses. AIMS OF THE STUDY: The therapeutic effects of LHQW in coronavirus disease 2019 (COVID-19) have not been fully elucidated. A retrospective study was conducted in patients with COVID-19 to evaluate the influence of LHQW on laboratory results related to the disease, and to provide evidence for the clinical practice of TCM. MATERIALS AND METHODS: We retrospectively collected 248 patients who met the moderate type COVID-19 diagnostic criteria, and received treatment in Tongji Hospital. Patients were divided into control (158 cases, standard treatment) and LHQW treatment (90 cases, standard treatment combined with LHQW) groups according to the different treatments administered. All laboratory data were obtained after 5-7 days' treatment. RESULTS: In this study, the average patient age was 58.95 years and 131 patients were male. The two groups were comparable in demographic characteristics, symptoms, and treatment. Compared with in the control group, D-dimer and erythrocyte sedimentation rate were significantly lower in the LHQW treatment group (2.47 ± 4.67 vs. 1.68 ± 3.61; 44.47 ± 30.24 vs. 35.39 ± 27.43; both P < 0.05). Lymphocyte counts, albumin and hemoglobin levels were higher in the LHQW treatment group than those in the control group (1.00 ± 0.46 vs. 1.13 ± 0.5; 34.39 ± 5.2 vs. 35.71 ± 4.76; 127.03 ± 16.58 vs. 131.11 ± 14.66; both P < 0.05). CONCLUSION: The study showed that LHQW significantly improved laboratory results of patients with COVID-19 and could be effectively applied alongside standard treatment of patients with moderate type COVID-19, providing preliminary clinical research evidence for the use of TCM in treatment of this disease.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

A network pharmacology based approach for predicting active ingredients and potential mechanism of Lianhuaqingwen capsule in treating COVID-19.

The outbreak of severe respiratory disease caused by SARS-CoV-2 has led to millions of infections and raised global health concerns. Lianhuaqingwen capsule (LHQW-C), a traditional Chinese medicine (TCM) formula widely used for respiratory diseases, shows therapeutic efficacy in the application of coronavirus disease 2019 (COVID-19). However, the active ingredients, drug targets, and the therapeutic mechanisms of LHQW-C in treating COVID-19 are poorly understood. In this study, an integrating network pharmacology approach including pharmacokinetic screening, target prediction (targets of the host and targets from the SARS-CoV-2), network analysis, GO enrichment analysis, KEGG pathway enrichment analysis, and virtual docking were conducted. Finally, 158 active ingredients in LHQW-C were screen out, and 49 targets were predicted. GO function analysis revealed that these targets were associated with inflammatory response, oxidative stress reaction, and other biological processes. KEGG enrichment analysis indicated that the targets of LHQW-C were highly enriched to several immune response-related and inflammation-related pathways, including the IL-17 signaling pathway, TNF signaling pathway, NF-kappa B signaling pathway, and Th17 cell differentiation. Moreover, four key components (quercetin, luteolin, wogonin, and kaempferol) showed a high binding affinity with SARS-CoV-2 3-chymotrypsin-like protease (3CL pro). The study indicates that some anti-inflammatory ingredients in LHQW-C probably modulate the inflammatory response in severely ill patients with COVID-19.

Insights into forsythia honeysuckle (Lianhuaqingwen) capsules: A Chinese herbal medicine repurposed for COVID-19 pandemic.

Background: In December 2019, a novel coronavirus, SARS-CoV-2 caused a series of acute atypical respiratory diseases worldwide. However, there is still a lack of drugs with clear curative effects, and the clinical trial research of vaccines has not been completely finished. Purpose: LH capsules are approved TCM patent medicine that are widely used for the treatment of respiratory tract infectious diseases caused by colds and flu. On April 12, 2020, LH capsules and granules were officially repurposed by the China Food and Drug Administration (CFDA) for patients with mild COVID-19 based on their safety and efficacy demonstrated through multicentre, randomized, controlled clinical trials. We hope to conduct a comprehensive review of it through modern pharmacy methods, and try to explain its possible mechanism. Methods: Using the full names of LH capsules Lianhuaqingwen, Lianhua Qingwen andSARS-COV-2, COVID-19 as the keywords of the search terms, systemically search for existing related papers in various databases such as Web of Science and PubMed. And completed the collection of clinical data in ClinicalTrials.gov and Chinese Clinical Trial Registry. Last but not least, we have sorted out the anti-inflammatory and antiviral mechanisms of LH capsules through literature and Selleck. Results: This review systematically sorted out the active ingredients in LH capsules. Furthermore, the related pharmacological and clinical trials of LH capsule on SARS-CoV-2, IAV and IBV were discussed in detail. Moreover, the present review provides the first summary of the potential molecular mechanism of specific substances in LH capsules involved in resistance to SARS-COV-2 infection and the inhibition of cytokine storm syndrome (CSS) caused by IL-6. Conclusion: This review summarizes the available reports and evidence that support the use of LH capsules as potential drug candidates for the prevention and treatment of COVID-19. However, TCM exerts its effects through multiple targets and multiple pathways, and LH capsules are not an exception. Therefore, the relevant mechanisms need to be further improved and experimentally verified.

Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening.

Lianhuaqingwen (LHQW) capsule, a herb medicine product, has been clinically proved to be effective in coronavirus disease 2019 (COVID-19) pneumonia treatment. However, human exposure to LHQW components and their pharmacological effects remain largely unknown. Hence, this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities. Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach, leading to detection of 132 LHQW prototype and metabolite components, which were absorbed via the gastrointestinal tract and formed via biotransformation in human, respectively. Together with data from screening by comprehensive 2D angiotensin-converting enzyme 2 (ACE2) biochromatography, 8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation. Results show that rhein, forsythoside A, forsythoside I, neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2. For the first time, this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human. It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.

Efficacy of Early Combination Therapy With Lianhuaqingwen and Arbidol in Moderate and Severe COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVE: Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan City, China, coronavirus disease 2019 (COVID-19) has become a global pandemic. However, no special therapeutic drugs have been identified for COVID-19. The aim of this study was to search for drugs to effectively treat COVID-19. MATERIALS AND METHODS: We conducted a retrospective cohort study with a total of 162 adult inpatients (≥18 years old) from Ruijin Hospital (Shanghai, China) and Tongji Hospital (Wuhan, China) between January 27, 2020, and March 10, 2020. The enrolled COVID-19 patients were first divided into the Lianhuaqingwen (LHQW) monotherapy group and the LHQW + Arbidol combination therapy group. Then, these two groups were further classified into moderate and severe groups according to the clinical classification of COVID-19. RESULTS: The early combined usage of LHQW and Arbidol can significantly accelerate the recovery of patients with moderate COVID-19 by reducing the time to conversion to nucleic acid negativity, the time to chest CT improvement, and the length of hospital stay. However, no benefit was observed in severe COVID-19 patients treated with the combination of LHQW + Arbidol. In this study, both Arbidol and LHQW were well tolerated without serious drug-associated adverse events. CONCLUSION: The early combined usage of LHQW and Arbidol may accelerate recovery and improve the prognosis of patients with moderate COVID-19.

Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2).

PURPOSE: Lianhuaqingwen (LH) as traditional Chinese medicine (TCM) formula has been used to treat influenza and exerted broad-spectrum antiviral effects on a series of influenza viruses and immune regulatory effects Ding et al. (2017). The goal of this study is to demonstrate the antiviral activity of LH against the novel SARS-CoV-2 virus and its potential effect in regulating host immune response. METHODS: The antiviral activity of LH against SARS-CoV-2 was assessed in Vero E6 cells using CPE and plaque reduction assay. The effect of LH on virion morphology was visualized under transmission electron microscope. Pro-inflammatory cytokine expression levels upon SARS-CoV-2 infection in Huh-7 cells were measured by real-time quantitative PCR assays. RESULTS: LH significantly inhibited SARS-CoV-2 replication in Vero E6 cells and markedly reduced pro-inflammatory cytokines (TNF-α, IL-6, CCL-2/MCP-1 and CXCL-10/IP-10) production at the mRNA levels. Furthermore, LH treatment resulted in abnormal particle morphology of virion in cells. CONCLUSIONS: LH significantly inhibits the SARS-COV-2 replication, affects virus morphology and exerts anti-inflammatory activity in vitro. These findings indicate that LH protects against the virus attack, making its use a novel strategy for controlling the COVID-19 disease.

Efficacy and safety of herbal medicine (Lianhuaqingwen) for treating COVID-19: A systematic review and meta-analysis.

BACKGROUND: Lianhuaqingwen (LH) has been proven effective for influenza. However, the promotion of LH for the treatment of patients with COVID-19 remains controversial. Therefore, our study aimed to assess the efficacy and safety of Lianhuaqingwen (LH) in treating patients with COVID-19 by a systematic review and meta-analysis. METHODS: We conducted the literature search using six electronic databases from December 1, 2019, to June 2, 2020. Cochrane Risk of Bias tool was used to assess the quality of randomized controlled trials. Newcastle-Ottawa Scale was used to assess the quality of case control studies. Agency for Healthcare Research and Quality checklist was used to assess the quality of case series. All analyses were conducted by RevMan 5.3. For outcomes that could not be meta-analyzed were performed a descriptive analysis. RESULTS: Eight studies with 924 patients were included. Three studies were RCTs, three were case control studies, and two were case series. The quality of the included studies was poor. Compared with patients treated by conventional treatment, patients treated by LH combined with conventional treatment have a higher overall effective rate (RR = 1.16, 95%CIs: 1.04∼1.30, P = 0.01) and CT recovery rate (RR=1.21, 95%CIs: 1.02∼1.43, P = 0.03). Patients of LH groups have a lower incidence of diarrhea (5.6% vs.13.4%), and have statistically significant (P = 0.026). But the rate of abnormal liver function in the combined medication group is higher than that in the single LH group. CONCLUSION: LH combined with conventional treatment seems to be more effective for patients with mild or ordinary COVID-19.

Bioactive natural compounds against human coronaviruses: a review and perspective.

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19.

Efficacy and safety of Lianhuaqingwen capsules, a repurposed Chinese herb, in patients with coronavirus disease 2019: A multicenter, prospective, randomized controlled trial.

BACKGROUND: Coronavirus disease 2019 (Covid-19) has resulted in a global outbreak. Few existing targeted medications are available. Lianhuaqingwen (LH) capsule, a repurposed marketed Chinese herb product, has been proven effective for influenza. PURPOSE: To determine the safety and efficacy of LH capsule in patients with Covid-19. METHODS: We did a prospective multicenter open-label randomized controlled trial on LH capsule in confirmed cases with Covid-19. Patients were randomized to receive usual treatment alone or in combination with LH capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the rate of symptom (fever, fatigue, coughing) recovery. RESULTS: We included 284 patients (142 each in treatment and control group) in the full-analysis set. The recovery rate was significantly higher in treatment group as compared with control group (91.5% vs. 82.4%, p = 0.022). The median time to symptom recovery was markedly shorter in treatment group (median: 7 vs. 10 days, p < 0.001). Time to recovery of fever (2 vs. 3 days), fatigue (3 vs. 6 days) and coughing (7 vs. 10 days) was also significantly shorter in treatment group (all p < 0.001). The rate of improvement in chest computed tomographic manifestations (83.8% vs. 64.1%, p < 0.001) and clinical cure (78.9% vs. 66.2%, p = 0.017) was also higher in treatment group. However, both groups did not differ in the rate of conversion to severe cases or viral assay findings (both p > 0.05). No serious adverse events were reported. CONCLUSION: In light of the safety and effectiveness profiles, LH capsules could be considered to ameliorate clinical symptoms of Covid-19.