Clinical and pharmacological research progress of "three medicines and three formulae" for COVID-19 treatment

The COVID-19 outbreak has resulted in extensive human casualties and serious economic losses worldwide. The main pathogenesis of COVID-19 is viral lung infection, which causes excessive immune response and cytokine storm, leading to acute respiratory distress syndrome and multiple organ dysfunction syndrome. Due to China's long history of battling plagues, traditional Chinese medicine (TCM) has formulated herbal recipes and developed theories on infectious diseases. During the fight against COVID-19, "three medicines and three formulae", including Jinhua Qinggan granules, Lianhua Qingwen capsules, Xuebijing injection, Qingfei Paidu decoction, Huashi Baidu decoction, and Xuanfei Baidu decoction, were recommended by leading TCM experts and academicians. These remedies were adopted in the national guidelines for the prevention and treatment of COVID-19. Guided by the TCM theory of heat removal, humidity reduction and detoxification, the scope of the "three medicines and three formulae" approach covers the entire course of a COVID-19 infection, including the phase of pre-symptomatic medical observation and the different diagnostic stages (mild, moderate, severe, and critical) of the disease. This study reviewed progress in clinical research as well as the mechanisms of action, concerning "three medicines and three formulae" for COVID-19. Clinical evidence suggests that the "three medicines and three formulae" are effective in preventing and treating COVID-19 by alleviating typical symptoms such as fever, coughing, fatigue, phlegm and diarrhea, shortening nucleic acid-negative conversion time, improving computed tomography images feature, inhibiting lung inflammation, normalizing clinical biomarkers, and reducing COVID-19-related complications. The pharmacological mechanisms of the "three medicines and three formulae" mainly include: binding with ACE2, 3CLpro, PLpro, and TMPRSS2 to inhibit virus invasion and replication; reducing the production and secretion of pro-inflammatory factors (such as IL-6, TNF-alpha, IL-1, IL-10, CXCL8, CXCL10, and CCL2) to regulate immune function; and decreasing clinical indicators (such as IL-6, CRP, and D-dimer) associated with the crosstalk of viral toxicity, endothelial damage, cytokine storm, excessive immune response, and microthrombosis to protect multiple organs against damage. In the future, it is necessary to collect further clinical evidence of the "three medicines and three formulae" for COVID-19 by conducting high-quality, large-scale randomized controlled trials. Trials targeting different Chinese medicine syndromes in specific patient populations are particularly desirable. Big data collection and analysis of the efficacy and safety of the "three medicines and three formulae" for COVID-19 can be facilitated by artificial intelligence and deep learning. In addition, the active components of these treatments, in various combinations with one another, should be identified, and their respective underlying mechanisms of action should be assessed using advanced technologies, such as multi-omics integration and human induced pluripotent stem cell-derived disease models. Moreover, more attention should be paid to the COVID-19 patients of post-infection, with common syndromes such as fatigue or muscle weakness, sleep deprivation, and anxiety or depression especially for low-immunity children and elderly with chronic diseases. TCM has many advantages and should be actively explored for patients with unmet medical needs.