ABSTRACT
Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).
ABSTRACT
Background: Although vaccines have been launched, COVID-19 has not been effectively curbed, and the number of infections is increasing. Compared with western medicine, Traditional Chinese Medicine has made some achievements in the treatment of COVID-19, which should be paid attention to and play a greater role. As a classical Chinese medicine prescription for treating pestilence, Lianhuaqingwen (LHQW) has gone to many countries with the Chinese medical team to participate in the local fight against the epidemic, which has been widely recognized. Method(s): We searched MEDLINE, EMBASE, AMED, Chchrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), VIP Information Database (VIP), Chinese Biomedical Literature Database (CBM), and Wanfang Database from inception up to November 24, 2021, which formed the basis for evidence used to formulate recommendations. Sixteen randomized controlled trials (RCTs) involving 1896 patients were enrolled. LHQW is a traditional Chinese medicine compound preparation, which contains 13 traditional Chinese medicine (TCM) components. Two dosage formulations of LHQW were included: granule and capsule. The most commonly used dosage formulation was granule (15/17, 88.24%), followed by capsule (2/17, 11.76%). Conclusion(s): This systematic review and Meta analysis suggested that, in the treatment of COVID-19, LHQW Capsule (Granule) could not only significantly improve the fever symptoms, shorten the fever time, but also reduce the cough and fatigue symptoms, improve the clinical efficiency, improve the lung CT, significantly reduce the number of patients with mild to severe diseases, and have certain anti-inflammatory effect. And there is no server adverse events which support the safety of LHQW Capsule (Granule) for the treatment of COVID-19. As a classic formula of TCM, LHQW Capsule (Granule) could be used as potential candidates for COVID-19 in this battle.Copyright © 2022
ABSTRACT
Purpose: 2019 Coronavirus disease (COVID-19) is endangering health of populations worldwide. Latest research has proved that Lianhua Qingwen granules (LHQW) can reduce tissue damage caused by inflammatory reactions and relieve patients' clinical symptoms. However, the mechanism of LHQW treats COVID-19 is currently lacking. Therefore, we employed computer simulations to investigate the mechanism of LHQW treats COVID-19 by modulating inflammatory response. Methods: We employed bioinformatics to screen active ingredients in LHQW and intersection gene targets. PPI, GO and KEGG was used to analyze relationship of intersection gene targets. Molecular dynamics simulations validated the binding stability of active ingredients and target proteins. Binding free energy, radius of gyration and the solvent accessible surface area were analyzed by supercomputer platform. Results: COVID-19 had 4628 gene targets, LHQW had 1409 gene targets, intersection gene targets were 415. Bioinformatics analysis showed that intersection targets were closely related to inflammation and immunomodulatory. Molecular docking suggested that active ingredients (including: licopyranocoumarin, Glycyrol and 3-3-Oxopropanoic acid) in LHQW played a role in treating COVID-19 by acting on CSF2, CXCL8, CCR5, NLRP3, IFNG and TNF. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets. Conclusion: The mechanism of active ingredients in LHQW treats COVID-19 was investigated by computer simulations. We found that active ingredients in LHQW not only reduce cell damage and tissue destruction by inhibiting the inflammatory response through CSF2, CXCL8, CCR5 and IFNG, but also regulate cell survival and growth through NLRP3 and TNF thereby reducing apoptosis.
Subject(s)
COVID-19 , Molecular Dynamics Simulation , Humans , Molecular Docking Simulation , Cell Survival , Computational BiologyABSTRACT
Traditional Chinese medicine (TCM) has been employed as complementary medication against COVID-19 in China since 2020. Two years since then, TCM, with Lianhua Qingwen (LHQW) as an example, has been included in every version of official clinical protocol guidelines. Recently, LHQW is even distributed to general public at risk but not yet infected. Such common application and widely claimed positive outcome among mild to moderate patients were accompanied by a number of published studies on antiviral, antiinflammatory, and immune modulatory potential using either in vitro or animal models. However, aside from retrospective understanding and open-labeled clinical trials with relatively small subject size, major gap in conclusive proof for efficacy and safety remains due to the lack of double-blind placebo-controlled studies and comprehensive pharmacodynamic and kinetic investigations. This is also supported by a recent WHO expert meeting on this subject, which acknowledged the potential benefits of TCM in mild-moderate cases, while recommended more rigorous studies to further understand effect size, application implications, and outcome determinants. Therefore, there is an urgent need to address the exact role TCM like LHQW could play in COVID-19 management from translational evidence-based perspective. High-quality clinical trials, pharmacological studies, and real-world data from recent outbreak are recommended.
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BACKGROUND: Lianhua Qingwen Capsules (LHQW) is a traditional Chinese medicine prescription commonly used to treat viral influenza in China. There has been sufficient evidence that LHQW could effectively treat COVID-19. Nevertheless, the potential anti-(mutant) SARS-CoV-2 and anti-inflammation compounds in LHQW are still vague. METHODS: The compounds of LHQW and targets were collected from TCMSP, TCMID, Shanghai Institute of Organic Chemistry of CAS database, and relevant literature. Autodock Vina was used to carry out molecular docking. The pkCSM platform to predict the relevant parameters of compound absorption in vivo. The protein-protein interaction (PPI) network was constructed by the STRING database. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was carried out by Database for Annotation, Visualization, and Integrated Discovery (DAVID). The anti-(mutant) SARS-CoV-2 and anti-inflammation networks were constructed on the Cytoscape platform. RESULTS: 280 compounds, 16 targets related to SARS-CoV-2, and 54 targets related to cytokine storm were obtained by screening. The key pathways Toll-like receptor signaling, NOD-like receptor signal pathway, and Jak-STAT signaling pathway, and the core targets IL6 were obtained by PPI network and KEGG pathway enrichment analysis. The network analysis predicted and discussed the 16 main anti-SARS-CoV-2 active compounds and 12 main anti-inflammation active compounds. Ochnaflavone and Hypericin are potential anti-mutant virus compounds in LHQW. CONCLUSIONS: In summary, this study explored the potential anti-(mutant) SARS-CoV-2 and anti-inflammation compounds of LHQW against COVID-19, which can provide new ideas and valuable references for discovering active compounds in the treatment of COVID-19.
ABSTRACT
Background : Although vaccines have been launched, COVID-19 has not been effectively curbed, and the number of infections is increasing. Compared with western medicine, Traditional Chinese Medicine has made some achievements in the treatment of COVID-19, which should be paid attention to and play a greater role. As a classical Chinese medicine prescription for treating pestilence, Lianhuaqingwen (LHQW) has gone to many countries with the Chinese medical team to participate in the local fight against the epidemic, which has been widely recognized. Methods : We searched MEDLINE, EMBASE, AMED, Chchrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), VIP Information Database (VIP), Chinese Biomedical Literature Database (CBM), and Wanfang Database from inception up to November 24, 2021, which formed the basis for evidence used to formulate recommendations. Sixteen randomized controlled trials (RCTs) involving 1896 patients were enrolled. LHQW is a traditional Chinese medicine compound preparation, which contains 13 traditional Chinese medicine (TCM) components. Two dosage formulations of LHQW were included: granule and capsule. The most commonly used dosage formulation was granule (15/17, 88.24 %), followed by capsule (2/17, 11.76 %). Conclusion : This systematic review and Meta analysis suggested that, in the treatment of COVID-19, LHQW Capsule (Granule) could not only significantly improve the fever symptoms, shorten the fever time, but also reduce the cough and fatigue symptoms, improve the clinical efficiency, improve the lung CT, significantly reduce the number of patients with mild to severe diseases, and have certain anti-inflammatory effect. And there is no server adverse events which support the safety of LHQW Capsule (Granule) for the treatment of COVID-19. As a classic formula of TCM, LHQW Capsule (Granule) could be used as potential candidates for COVID-19 in this battle.
ABSTRACT
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.
Subject(s)
COVID-19 Drug Treatment , COVID-19 , Drugs, Chinese Herbal/pharmacology , Glycation End Products, Advanced/metabolism , Interleukin-6/metabolism , Receptor for Advanced Glycation End Products/metabolism , SARS-CoV-2 , Antiviral Agents/pharmacology , COVID-19/immunology , Cytokine Receptor gp130/metabolism , Flavanones/pharmacology , Humans , Luteolin/pharmacology , Molecular Docking Simulation , Quercetin/pharmacology , Receptors, Interleukin-6/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction/drug effects , Signal Transduction/immunology , Spike Glycoprotein, Coronavirus/metabolismABSTRACT
COVID-19 has remained an uncontained, worldwide pandemic. While battling for the disease in China, six Traditional Chinese Medicine (TCM) recipes have been shown to be remarkably effective for treating patients with COVID-19. The present review discusses principles of TCM in curing infectious disease, and clinical evidence and mechanisms of the 6 most effective TCM recipes used in treating COVID-19 in 92% of all of the confirmed cases in China. Applications of TCM and specific recipes in the treatment of other viral infections, such as those caused by SARS-CoV, MERS-CoV, hepatitis B virus, hepatitis C virus, influenza A virus (including H1N1 and H7N9), influenza B, dengue virus as well as Ebola virus, are also discussed. Among the 6 TCM recipes, Jinhua Qinggan (JHQG) granules and Lianhua Qingwen (LHQW) capsules are recommended during medical observation; Lung Cleansing and Detoxifying Decoction (LCDD) is recommended for the treatment of both severe and non-severe patients; Xuanfeibaidu (XFBD) granules are recommended for treating moderate cases; while Huashibaidu (HSBD) and Xuebijing (XBJ) have been used in managing severe cases effectively. The common components and the active ingredients of the six TCM recipes have been summarized to reveal most promising drug candidates. The potential molecular mechanisms of the active ingredients in the six TCM recipes that target ACE2, 3CLpro and IL-6, revealed by molecular biological studies and/or network pharmacology prediction/molecular docking analysis/visualization analysis, are fully discussed. Therefore, further investigation of these TCM recipes may be of high translational value in enabling novel targeted therapies for COVID-19, potentially via purification and characterization of the active ingredients in the effective TCM recipes.
Subject(s)
COVID-19 Drug Treatment , Medicine, Chinese Traditional/methods , Humans , Medicine, Chinese Traditional/adverse effects , SARS-CoV-2 , Virus Diseases/drug therapyABSTRACT
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.
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BACKGROUND: The traditional Chinese Medicine (TCM) herbal formula Lian Hua Qing Wen (LHQW) improves the results of COVID-19 treatment. Three very recent studies analyzed with network pharmacology some working mechanisms of LHQW. However, we used more techniques and also included Angiotensin converting enzyme 2 (ACE2) (a SARS-CoV receptor, possibly the viral entry point in alveolar lung cells) and the immune system, as cytokine storm is essential in the late phase. PURPOSE: Extensive detailed Network Pharmacology analysis of the LHQW- treatment mechanism in COVID-19. METHODS: TCM-herb-meridian and protein interaction network (PIN) of LHQW, based on LHQW herbs meridian information and the protein-protein interaction (PPI) information of the LHQW-component targets. Hub and topological property analyses to obtain crucial targets and construct the crucial LHQW-PIN. Functional modules determination using MCODE, GO and KEGG pathway analysis of biological processes and pathway enrichment. Intersection calculations between the LHQW-proteins and ACE2 co-expression-proteins. RESULTS: LHQW herbs have relationships to Stomach-, Heart-, Liver- and Spleen-systems, but most (10 of the 13 herbs) to the Lung system, indicating specific effects in lung diseases. The crucial LHQW PIN has the scale-free property, contains 2,480 targets, 160,266 PPIs and thirty functional modules. Six modules are enriched in leukocyte-mediated immunity, the interferon-gamma-mediated signaling pathway, immune response regulating signaling pathway, interleukin 23 mediated signaling pathway and Fc gamma receptor-mediated phagocytosis (GO analysis). These 6 are also enriched in cancer, immune system-, and viral infection diseases (KEGG). LHQW shared 189 proteins with ACE2 co-expression proteins. CONCLUSIONS: Detailed network analysis shows, that LHQW herbal TCM treatment modulates the inflammatory process, exerts antiviral effects and repairs lung injury. Moreover, it also relieves the "cytokine storm" and improves ACE2-expression-disorder-caused symptoms. These innovative findings give a rational pharmacological basis and support for treating COVID-19 and possibly other diseases with LHQW.