Analysis of mechanisms of Shenhuang Granule in treating severe COVID-19 based on network pharmacology and molecular docking.

OBJECTIVE: Severe cases of coronavirus disease 2019 (COVID-19) are expected to have a worse prognosis than mild cases. Shenhuang Granule (SHG) has been shown to be a safe and effective treatment for severe COVID-19 in a previous randomized clinical trial, but the active chemical constituents and underlying mechanisms of action remain unknown. The goal of this study is to explore the chemical basis and mechanisms of SHG in the treatment of severe COVID-19, using network pharmacology. METHODS: Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was employed to screen chemical constituents of SHG. Putative therapeutic targets were predicted by searching traditional Chinese medicine system pharmacology database and analysis platform, SwissTargetPrediction, and Gene Expression Omnibus (GEO) databases. The target protein-protein interaction network and enrichment analysis were performed to investigate the hub genes and presumptive mechanisms. Molecular docking and molecular dynamics simulations were used to verify the stability and interaction between the key chemical constituents of SHG and COVID-19 protein targets. RESULTS: Forty-five chemical constituents of SHG were identified along with 131 corresponding therapeutic targets, including hub genes such as HSP90AA1, MMP9, CXCL8, PTGS2, IFNG, DNMT1, TYMS, MDM2, HDAC3 and ABCB1. Functional enrichment analysis indicated that SHG mainly acted on the neuroactive ligand-receptor interaction, calcium signaling pathway and cAMP signaling pathway. Molecular docking showed that the key constituents had a good affinity with the severe acute respiratory syndrome coronavirus 2 protein targets. Molecular dynamics simulations indicated that ginsenoside Rg4 formed a stable protein-ligand complex with helicase. CONCLUSION: Multiple components of SHG regulated multiple targets to inhibit virus invasion and cytokine storm through several signaling pathways; this provides a scientific basis for clinical applications and further experiments.

Traditional Chinese medicine shenhuang granule in patients with severe/critical COVID-19: A randomized controlled multicenter trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is still a pandemic, with a high mortality rate in severe/critical cases. Therapies based on the Shenghuang Granule have proved helpful in viral infection and septic shock. HYPOTHESIS/PURPOSE: The objective of the current study was to compare the efficacy and safety of the traditional Chinese medicine, Shenhuang Granule, with standard care in hospitalized patients with severe/critical COVID-19. STUDY DESIGN AND METHODS: This was an open-label, multicenter, randomized, controlled clinical trial. At 4 medical centers, a total of 111 severe/critical patients were randomly assigned to receive Shenhuang Granule (SHG group) twice a day for 14 days, in addition to standard care, or to receive standard care alone (Control group). The maximal follow up time was 75 days. The clinical endpoint was clinical improvement and mortality. RESULTS: 54 patients were assigned to the control group and 57 to the SHG group. The overall mortality was 75.9% (41/54) in the control group, and 38.6% (22/57) in the SHG group (p < 0.01 vs. control). The post hoc analysis showed that in the severe category, the mortality of the control group vs. the SHG group was 58.8% (10/17) vs. 5.3% (1/19) (p < 0.01); while in the critical category, it was 83.8% (31/37) vs. 55.3% (21/38) (p < 0.05). In the severe category, the mortality of patients who eventually received an invasive ventilator in the control vs. the SHG group was 58.8% (10/17) vs. 0 (0/19) (p < 0.01). Administration of SHG was associated with increased lymphocytes and decreased adverse events. CONCLUSION: Shenhuang Granule is a promising integrative therapy for severe and critical COVID-19.

Clinical Effect of Traditional Chinese Medicine Shenhuang Granule in Critically Ill Patients with COVID-19: A Single-Centered, Retrospective, Observational Study.

The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency of global concern. In China, traditional Chinese medicine has been widely administered to COVID-19 patients without sufficient evidence. To evaluate the efficacy of Shenhuang Granule (SHG) for treating critically ill patients with COVID-19, we included in this study 118 patients who were admitted to the ICU of Tongji Hospital between January 28, 2020 and March 28, 2020. Among these patients, 33 (27.9%) received standard care plus SHG (treatment group) and 85 (72.1%) received standard care alone (control group). Enrolled patients had a median (IQR) age of 68 (57-75) years, and most (79 [67.1%]) were men. At end point of this study, 83 (70.3%) had died in ICU, 29 (24.5%) had been discharged from ICU, and 6 patients (5.2%) were still in ICU. Compared with control group, mortality was significantly lower in treatment group (45.4% vs. 80%, p < .001). Patients in treatment group were less likely to develop acute respiratory distress syndrome (ARDS) (12 [36.3%] vs. 54 [63.5%], p = 0.012) and cardiac injury (5 [15.1%] vs. 32 [37.6%], p = 0.026), and less likely to receive mechanical ventilation (22 [66.7%] vs. 72 [84.7%], p = 0.028) than those in control group. The median time from ICU admission to discharge was shorter in treatment group (32 [20-73] days vs. 76 [63-79] days, p = 0.0074). These findings suggest that SHG treatment as a complementary therapy might be effective for critically ill adults with COVID-19 and warrant further clinical trials.

Shenhuang granule in the treatment of severe coronavirus disease 2019 (COVID-19): study protocol for an open-label randomized controlled clinical trial.

BACKGROUND: Currently, coronavirus disease 2019 (COVID-19) is continuously and rapidly circulating, causing heavy damage on public health. No effective antiviral treatment has been proved thus far. Traditional Chinese medicine (TCM) has been widely applied in the treatment of a variety of infection diseases in China, hoping to produce clinical effects and reduce the use of antibiotics and glucocorticoid. The aim of this study is to evaluate the efficacy and safety of Shenhuang granule in treatment of severe COVID-19. METHODS/DESIGN: This multicenter, open-label randomized controlled trial is conducted in 160 participants with severe COVID-19. The participants will be randomly (1:1) divided into treatment group or control group. All participants are given standard therapy at the same time. The experiment will receive Shenhuang granule treatment twice a day for 14 days. The clinical indicators of patients will be assessed at baseline and at 3, 5, 7, and 14 days after treatment initiation. The primary outcome is 14-day clinical outcome. Adverse events will be monitored throughout the trial. DISCUSSION: This will be the first randomized controlled trial, which evaluate the effect of Shenhuang granule in patients with severe COVID-19 in China. The results of this trial may not only provide evidence-based recommendations to clinicians to treat severe COVID-19, but also enrich the theory and practice of TCM in treating infectious diseases. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000029777. Registered on 13 February 2020.