Therapeutic mechanisms and impact of traditional Chinese medicine on COVID-19 and other influenza diseases

Coronavirus disease 2019 (COVID-19), first reported in Wuhan, China, has rapidly spread worldwide. Traditional Chinese medicine (TCM) has been used to prevent and treat viral epidemics and plagues for over 2,500 years. In the guidelines on fighting against COVID-19, the National Health Commission of the People's Republic of China has recommended certain TCM formulas, namely Jinhua Qinggan granule (JHQGG), Lianhua Qingwen granule (LHQWG), Qingfei Paidu decoction (QFPDD), Xuanfei Baidu granule (XFBD), Xuebijing injection (XBJ), and Huashi Baidu granule (HSBD) for treating COVID-19 infected individuals. Among these six TCM formulas, JHQGG and LHQWG effectively treated mild/moderate and severe COVID-19 infections. XFBD therapy is recommended for mild COVID-19 infections, while XBJ and HSBD effectively treat severe COVID-19 infections. The internationalization of TCM faces many challenges due to the absence of a clinical efficacy evaluation system, insufficient research evidence, and a lack of customer trust across the globe. Therefore, evidence-based research is crucial in battling this infectious disease. This review summarizes SARS-CoV-2 pathogenesis and the history of TCM used to treat various viral epidemics, with a focus on six TCM formulas. Based on the evidence, we also discuss the composition of various TCM formulas, their underlying therapeutic mechanisms, and their role in curing COVID-19 infections. In addition, we evaluated the roles of six TCM formulas in the treatment and prevention of other influenza diseases, such as influenza A (H1N1), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Furthermore, we highlighted the efficacy and side effects of single prescriptions used in TCM formulas.Copyright © 2021

New insights for infection mechanism and potential targets of COVID-19: Three Chinese patent medicines and three Chinese medicine formulas as promising therapeutic approaches.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high pathogenicity and infectiousness has become a sudden and lethal pandemic worldwide. Currently, there is no accepted specific drug for COVID-19 treatment. Therefore, it is extremely urgent to clarify the pathogenic mechanism and develop effective therapies for patients with COVID-19. According to several reliable reports from China, traditional Chinese medicine (TCM), especially for three Chinese patent medicines and three Chinese medicine formulas, has been demonstrated to effectively alleviate the symptoms of COVID-19 either used alone or in combination with Western medicines. In this review, we systematically summarized and analyzed the pathogenesis of COVID-19, the detailed clinical practice, active ingredients investigation, network pharmacology prediction and underlying mechanism verification of three Chinese patent medicines and three Chinese medicine formulas in the COVID-19 combat. Additionally, we summarized some promising and high-frequency drugs of these prescriptions and discussed their regulatory mechanism, which provides guidance for the development of new drugs against COVID-19. Collectively, by addressing critical challenges, for example, unclear targets and complicated active ingredients of these medicines and formulas, we believe that TCM will represent promising and efficient strategies for curing COVID-19 and related pandemics.

Jinhua Qinggan granules for non-hospitalized COVID-19 patients: A double-blind, placebo-controlled, and randomized controlled trial.

Background: Key findings from the World Health Organization Expert Meeting on Evaluation of Traditional Chinese Medicine (TCM) in treating coronavirus disease 2019 (COVID-19) reported that TCMs are beneficial, particularly for mild-to-moderate cases. The efficacy of Jinhua Qinggan granules (JHQG) in COVID-19 patients with mild symptoms has yet to be clearly defined. Methods: We conducted a phase 2/3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with JHQG in mild, non-hospitalized, laboratory-confirmed COVID-19 patients. Participants were randomly assigned to receive 5 g/sacket of JHQG or placebo granules orally thrice daily for 10 days. The primary outcomes were the improvement in clinical symptoms and a proportion tested negative on viral polymerase chain reaction (PCR) after treatment. Secondary outcomes were the time to recover from clinical symptoms and changes in white blood cells (WBC) and acute phase reactants (C-reactive protein (CRP) and ferritin) on the 10th day after treatment initiation. Results: A total of 300 patients were randomly assigned to receive JHQG (150 patients) and placebo (150 patients). Baseline characteristics were similar in the two groups. In the modified intention-to-treat analysis, JHQG showed greater clinical efficacy (82.67%) on the 10th day of the trial compared with the placebo group (10.74%; rate difference: 71.93%; 95% CI 64.09-79.76). The proportion of patients with a negative PCR after treatment was comparable (rate difference: -4.67%; 95% CI -15.76 to 6.42). In contrast, all changes in WBC, ferritin, and CRP levels showed a statistically significant decline in JHQG (P ≤ 0.044) after treatment, but not the latter in placebo (P = 0.077). The median time to recovery of COVID-19-related symptoms including cough, sputum, sore throat, dyspnea, headache, nasal obstruction, fatigue, and myalgia was shorter in the JHQG group compared to the placebo group (P < 0.001 for all). Three patients experienced mild-to-moderate adverse events (AEs) duringthe treatment period in the JHQG group. Findings were similar between the modified intention-to-treat and the per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen. Conclusion: Based on the time to recover from the COVID-19-related symptoms and AEs, it is concluded that JHQG is a safe and effective TCM for symptomatic relief of patients with mild COVID-19. A symptomatic improvement in the JHQG group patients was observed and JHQG use would have important public health implications in such patients. Clinical Trial Registration: The Trial was prospectively registered on www.clinicaltrials.gov with registration number: NCT04723524.

Jinhua Qinggan granules attenuates acute lung injury by promotion of neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is one of the fatal complications of respiratory virus infections such as influenza virus and coronavirus, which has high clinical morbidity and mortality. Jinhua Qinggan granules (JHQG) has been approved by China Food and Drug Administration in the treatment of H1N1 influenza and mild or moderate novel coronavirus disease 2019 (COVID-19), which is an herbal formula developed based on Maxingshigan decoction and Yinqiao powder that have been used to respiratory diseases in China for thousands of years. However, the underlying mechanism of JHQG in treating infectious diseases remains unclear. AIM OF THE STUDY: This study investigated the effects of JHQG on neutrophil apoptosis and key signaling pathways in lipopolysaccharide (LPS) -induced ALI mice in order to explore its mechanism of anti-inflammation. MATERIALS AND METHODS: The effect of JHQG on survival rate was observed in septic mouse model by intraperitoneal injection of LPS (20 mg/kg). To better pharmacological evaluation, the mice received an intratracheal injection of 5 mg/kg LPS. Lung histopathological changes, wet-to-dry ratio of the lungs, and MPO activity in the lungs and total protein concentration, total cells number, TNF-α, IL-1ß, IL-6, and MIP-2 levels in BALF were assessed. Neutrophil apoptosis rate was detected by Ly6G-APC/Annexin V-FITC staining. Key proteins associated with apoptosis including caspase 3/7 activity, Bcl-xL and Mcl-1 were measured by flow cytometry and confocal microscope, respectively. TLR4 receptor and its downstream signaling were analyzed by Western blot assay and immunofluorescence, respectively. RESULTS: JHQG treatment at either 6 or 12 g/kg/day resulted in 20% increase of survival in 20 mg/kg LPS-induced mice. In the model of 5 mg/kg LPS-induced mice, JHQG obviously decreased the total protein concentration in BALF, wet-to-dry ratio of the lungs, and lung histological damage. It also attenuated the MPO activity and the proportion of Ly6G staining positive neutrophils in the lungs, as well as the MIP-2 levels in BALF were reduced. JHQG inhibited the expression of Mcl-1 and Bcl-xL and enhanced caspase-3/7 activity, indicating that JHQG partially acted in promoting neutrophil apoptosis via intrinsic mitochondrial apoptotic pathway. The levels of TNF-α, IL-1ß, and IL-6 were significantly declined in LPS-induced mice treated with JHQG. Furthermore, JHQG reduced the protein expression of TLR4, MyD88, p-p65 and the proportion of nuclei p65, suggesting that JHQG treatment inhibited TLR4/MyD88/NF-κB pathway. CONCLUSION: JHQG reduced pulmonary inflammation and protected mice from LPS-induced ALI by promoting neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway, suggesting that JHQG may be a promising drug for treatment of ALI.

The Possibility of Using Traditional Chinese Medicine for the Treatment of COVID-19: A Narrative Review

In the face of the COVID-19 pandemic, there is still a lack of miracle drugs for treatment. Repurposing drugs such as Remdesivir and corticosteroids to treat COVID-19 are being studied. Traditional Chinese medicine was widely used during the outbreak of Severe Acute Respiratory Syndrome (SARS) coronavirus infection in China in 2003. It was found that standard medical treatment combined with Chinese medicine treatment may improve the symptoms of SARS patients and speeding resolution of lung infiltration. The commonly used prescriptions for preventing the coronavirus infection are Sangjuyin plus Yupingfeng powder. Various Traditional Chinese medicines with potential to fight SARS-CoV-2 include Liquorice Root and Rhizome, Rhubarb, Heartleaf Houttuynia Herb, Indi-gowoad Root, Tangerine Peel, Scutellaria Root, and Red Sage Root and Rhizome etc. In addition, Chinese patent medicines including Shuanghuanglian Oral liquid, Lianhua Qingwen Capsule, Jinhua Qinggan Granule and Taiwan Chingguan Yihau are recognized as plausible agents for the treatment of novel coronavirus pneumonia. The antiviral, anti-inflammatory and immunomodulatory effects of selected Chinese herbal drugs may attribute to their inhibiting the binding of the coronavirus spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor, inhibiting key enzymes such as 3-chymotrypsin-like protease and ribonucleic acid (RNA)- dependent RNA polymerase during viral replication, and reducing pro-inflammatory cytokines. Since most of the relevant studies mentioned the potential anti-SARS-CoV-2 activity of these agents were only in vitro and animal experiments, more randomized double-blind controlled trials are needed to provide reliable evidence of clinical efficacy in future.

Identification of components in vitro and plasma of Jinhua Qinggan granules and preliminary pharmacokinetics analysis

As one of the "Three Drugs Three Prescriptions" anti-COVID-19 traditional Chinese medicine, Jinhua Qinggan granules (JHQG) has been proved to have clear clinical effects. With complex medicinal flavors and ingredients, there is no systematic research report on chemical composition in vivo or in vitro. An ultrahigh pressure liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) method was developed in this study to identify the components of the anti-COVID-19 traditional Chinese medicine JHQG granules. Analyze the collected rat plasma samples after administration and explore the exposed components in rats within 8 hours after intragastric administration. Preliminary pharmacokinetic analysis was then performed on this basis. Through UPLC-QTOF/MS analysis and verification by standard products, a total of 77 chemical components in JHQG formula have been identified, among which 22 compounds were highly exposed in vivo, mainly derived from three medicinal materials of honeysuckle, scutellaria and forsythia. Through the assessment of the blood drug concentration by the compartment model, 6 PK parameters of 4 high-exposure chemical components have been obtained, clarifying the metabolic characteristics of the main exposed components in JHQG briefly. The method is simple, efficient, sensitive and accurate and provides research basis to the clarification of the pharmacodynamics material basis and mechanism of JHQG, which has certain reference significance for the basics and applications research of the traditional Chinese medicine prescriptions in fighting the SARS-CoV-2.

Therapeutic effects and safety of oral Chinese patent medicine for COVID-19: A rapid systematic review and meta-analysis of randomized controlled trials

Introduction: Chinese patent medicine (CPM) is an indispensable part of traditional Chinese medicine. Coronavirus Disease 2019 (COVID-19) manifests is an acute respiratory infectious disease. This systematic review aimed to evaluate the therapeutic effects and safety of oral CPM for COVID-19. Methods: We included randomized controlled trials (RCTs) that tested oral CPM for the treatment of COVID-19 identified from publications in CNKI, Wanfang, VIP, Web of Science, SinoMed, PubMed, Embase, BioRxiv, MedRxiv and arXiv before November 2nd, 2020. The risk of bias for each trial was assessed using the Cochrane Risk of Bias Tool 2.0. RevMan 5.4 software was used for data analyses. The certainty of the evidence was assessed using the online GRADEpro tool. Results: Seven RCTs including 1079 participants were identified. The overall bias was assessed as “some concerns” for all included trials. Oral CPM investigated were: Lianhua Qingwen capsule/granules (连花清瘟胶囊/颗粒, LHQW), Jinhua Qinggan granules (金花清感颗粒, JHQG), Huoxiang Zhengqidripping pills (藿香正气滴丸, HXZQ), Toujie Quwen granules (透解祛瘟颗粒, TJQW) and Lianhua Qingke granules (连花清咳颗粒, LHQK). Compared with conventional western therapy alone for people with COVID-19: regarding the main outcomes, the results showed that oral CPM combined with conventional western therapy improved cure rate (RR = 1.20, 95% CI 1.04 to 1.38, involving LHQW and TJQW), reduced aggravation rate (RR = 0.50, 95% CI 0.29 to 0.85, involving LHQW, JHQG, LHQK and TJQW);with regard to additional outcomes, the results showed that add-on oral CPM shortened the duration of fever, cough and fatigue, improved the recovery rate of cough and fatigue, and increased the improvement and recovery rate of chest CT manifestations. There were some differences in therapeutic effects among various CPMs for the same COVID-19 outcome. The use of TJQW and LHQG appeared not to increase the risk of adverse events, but JHQG may cause mild diarrhea. Conclusions: Low-certainty or very low-certainty evidence demonstrated that oral CPM may have add-on potential therapeutic effects for patients with non-serious COVID-19. There are some differences in therapeutic effects between different oral CPMs for the same outcome of COVID-19. The use of TJQW and LHQG probably does not increase the risk of adverse events, but JHQG may cause mild diarrhea in patients. The conclusion of this review needs to be further confirmed by well-designed clinical trials with adequate sample sizes. Keywords: Coronavirus Disease 2019;COVID-19;Chinese patent medicine;Chinese herbal medicine;Systematic review;Meta-analysis

Jinhua Qinggan granule, a Chinese herbal medicine against COVID-19, induces rapid changes in the neutrophil/lymphocyte ratio and plasma levels of IL-6 and IFN-γ: An open-label, single-arm pilot study

Traditional Chinese herbal medicine has provided clinical benefits to patients infected with coronavirus 2019 (COVID-19) in China. Jinhua Qinggan granule (JHQGG) is a Chinese multi-herbal formula previously developed for the treatment of H1N1 influenza and has been encouraged for use in patients with clinically suspected COVID-19 infection. However, the immunopharmacological mechanism for the efficacy of JHQGG has not yet been confirmed. To obtain insight into this issue, the present study examined the acute effects of JHQGG ingestion on hematological and immunological parameters using uninfected individuals as subjects. For this purpose, 18 healthy volunteers were enrolled, all of whom tested negative for prior and current severe acute respiratory syndrome coronavirus 2 infection. Peripheral blood samples were collected 1 h after a single oral JHQGG administration and subjected to hematological, biochemical and cytokine tests. JHQGG rapidly induced a significant decrease in the plasma level of interleukin (IL)-6 (P=0.00309) and an increase in the plasma level of interferon (IFN)-γ (P=0.0268). A decrease in IL-6 and an increase in IFN-γ levels were observed in 14 (77.8%) and 13 (72.2%) subjects, respectively. Notably, JHQGG significantly decreased the proportion of neutrophils (P=0.00561) and increased that of lymphocytes (P=0.00485);accordingly, the neutrophil/lymphocyte ratio (NLR) was significantly reduced by JHQGG (P=0.00649). These findings suggest that the clinical benefits of the use of JHQGG against COVID-19 are, at least in part, associated with its rapid modulatory effects on IL-6, IFN-γ and NLR. Considering that IL-6 and NLR are critical biomarkers for severe COVID-19 infection, JHQGG may thus be suitable not only for suppressing disease onset in suspected and asymptomatic cases, but also for preventing disease progression in patients with mild to severe infection. The present open-label, single-arm study has been prospectively registered on the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under the trial no. UMIN000040407 on May 15, 2020. Copyright: © 2021 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.

Efficacy of Jinhua Qinggan Granules Combined With Western Medicine in the Treatment of Confirmed and Suspected COVID-19: A Randomized Controlled Trial.

Objective: To conduct a randomized controlled clinical trial to evaluate the clinical efficacy and prognostic value of Jinhua Qinggan granules in patients with confirmed and suspected coronavirus disease 2019 (COVID-19). Methods: A total of 123 suspected and confirmed COVID-19 patients participated in this clinical trial and were randomly divided into Jinhua and Western medicine groups. For 14 days, the Jinhua group was treated with Jinhua Qinggan granules and antiviral drugs, and the Western medicine group was treated with antiviral drugs alone. We collected information on clinical symptoms, disease aggravation rates, and negative conversion rates of nucleic acids in patients, and observed the effects of anti-infective drugs. Results: There was no significant difference in symptom improvement rates between the two groups, both confirmed and suspected patients (P > 0.05). Both treatments relieved symptoms such as fever, fatigue, and diarrhea. However, the Jinhua treatment was superior in relieving fever and poor appetite. Anti-infective drug use rates were significantly lower in the Jinhua group than in the control group. Conclusion: Jinhua Qinggan granules combined with Western medicine could relieve the clinical symptoms of fever and poor appetite in COVID-19 patients, reduce the use of antibiotics to a certain extent. Clinical Trial Registration: The registration number at China Clinical Trial Registry is ChiCTR2000029601.

Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms.

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.