Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial

Abstract

We conducted a randomized, open-label, parallel-controlled, multicenter trial on the use of Shuanghuanglian (SHL), a traditional Chinese patent medicine, in treating cases of COVID-19. A total of 176 patients received SHL by three doses (56 in low dose, 61 in middle dose, and 59 in high dose) in addition to standard care. The control group was composed of 59 patients who received standard therapy alone. Treatment with SHL was not associated with a difference from standard care in the time to disease recovery. Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group (93.4% vs. 73.9%, P=0.006). Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia, which was evaluated by density reduction of inflammatory focus from baseline, at day 7 (mean difference (95% CI), −46.39 (−86.83 to −5.94) HU; P=0.025) and day 14 (mean difference (95% CI), −74.21 (−133.35 to −15.08) HU; P=0.014). No serious adverse events occurred in the SHL groups. This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.

Keywords

COVID-19 / SARS-CoV-2 / Shuanghuanglian oral liquid / clinical trial

References

[1] Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5(4): 536–544

[2] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506

[3] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513

[4] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061–1069

[5] Yu B, Li C, Chen P, Zhou N, Wang L, Li J, Jiang H, Wang DW. Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19. Sci China Life Sci 2020; 63(10): 1515–1521

[6] Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; the Northwell COVID-19 Research Consortium, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA 2020; 323(20): 2052–2059

[7] Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H, Wang H, Wang T, Guo W, Chen J, Ding C, Zhang X, Huang J, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020; 368: m1091

[8] Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382(19): 1787–1799

[9] Cyranoski D. China is promoting coronavirus treatments based on unproven traditional medicines. Nature 2020; [Epub ahead of print]

[10] Hu K, Guan WJ, Bi Y, Zhang W, Li L, Zhang B, Liu Q, Song Y, Li X, Duan Z, Zheng Q, Yang Z, Liang J, Han M, Ruan L, Wu C, Zhang Y, Jia ZH, Zhong NS. Efficacy and safety of Lianhuaqingwen capsules, a repurposed Chinese herb, in patients with coronavirus disease 2019: a multicenter, prospective, randomized controlled trial. Phytomedicine 2020; [Epub ahead of print]

[11] Chinese Pharmacopoeia Commission.Chinese Pharmacopoeia. 2015 ed. Beijing: China Medical Science and Technology Press, 2015 (in Chinese)

[12] Chinese Medical Association, China Association of Chinese Medicine.Notice on recommending the newly revised diagnosis and treatment program for SARS. Nalt Med J China (Zhonghua Yi Xue Za Zhi) 2003; 83: 1731–1752 (in Chinese)

[13] Mo H, Lai K, Jiang Y, Xie J,Zhong N. Anti-RSV effects of Shuanghuanglian and its disassembled prescription. China J Bas Med Trad Chin Med (Zhongguo Zhong Yi Ji Chu Yi Xue Za Zhi) 2005; 11: 194–196 (in Chinese)

[14] Ma Q, Liang D, Song S, Yu Q, Shi C, Xing X, Luo JB. Comparative study on the antivirus activity of Shuang-Huang-Lian injectable powder and its bioactive compound mixture against human adenovirus III in vitro. Viruses 2017; 9(4): E79

[15] Guo J,Song D. Research progress in pharmacological action, clinical application and adverse reactions of Shuanghuanglian. Chin J Clin Rationl Drug Use (Lin Chuang He Li Yong Yao Za Zhi) 2017; 21: 161–163 (in Chinese)

[16] Ministry of Health, the People’s Republic of China.Diagnosis and Treatment Program for Human Avian Influenza. 2005 ed. Ministry of Health, the People’s Republic of China, 2005 (in Chinese)

[17] Ministry of Health, the People’s Republic of China. Diagnosis and Treatment Program for Influenza A. H1N1. Trial Version 1. Ministry of Health, the People’s Republic of China, 2009 (in Chinese)

[18] National Administration of Traditional Medicine. Expert Guidance on the Treatment of Ebola Haemorrhagic Fever with Traditional Chinese Medicine. Version 1. National Administration of Traditional Medicine, the People’s Republic of China, 2014 (in Chinese)

[19] Su HX, Yao S, Zhao WF, Li MJ, Liu J, Shang WJ, Xie H, Ke CQ, Hu HC, Gao MN, Yu KQ, Liu H, Shen JS, Tang W, Zhang LK, Xiao GF, Ni L, Wang DW, Zuo JP, Jiang HL, Bai F, Wu Y, Ye Y, Xu YC. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Acta Pharmacol Sin 2020; 41(9): 1167–1177

[20] Ni L, Zhou L, Zhou M, Zhao J, Wang DW. Combination of western medicine and Chinese traditional patent medicine in treating a family case of COVID-19. Front Med 2020; 14(2): 210–214

[21] Gan W. The influence of small dose of glucocorticoid on immune function of children with Mycoplasma pneumoniae pneumonia. Chin Mod Med (Zhongguo Dang Dai Yi Yao) 2013; 20: 40–41 (in Chinese)

[22] Carazo MR, Kolodziej MS, DeWitt ES, Kasparian NA, Newburger JW, Duarte VE, Singh MN, Opotowsky AR. Prevalence and prognostic association of a clinical diagnosis of depression in adult congenital heart disease: results of the Boston Adult Congenital Heart Disease Biobank. J Am Heart Assoc 2020; 9(9): e014820

[23] Pang H, Xue W, Shi A, Li M, Li Y, Cao G, Yan B, Dong F, Xiao W, He G, Du G, Hu X, Cheng G. Multiple-ascending-dose pharmacokinetics and safety evaluation of baicalein chewable tablets in healthy Chinese volunteers. Clin Drug Investig 2016; 36(9): 713–724

[24] Li M, Shi A, Pang H, Xue W, Li Y, Cao G, Yan B, Dong F, Li K, Xiao W, He G, Du G, Hu X. Safety, tolerability, and pharmacokinetics of a single ascending dose of baicalein chewable tablets in healthy subjects. J Ethnopharmacol 2014; 156: 210–215

[25] Abe K, Inoue O, Yumioka E. Biliary excretion of metabolites of baicalin and baicalein in rats. Chem Pharm Bull (Tokyo) 1990; 38(1): 209–211

[26] Tian L. A preliminary study on the integrated pharmacokinetics of anti-virus components from Shuang-Huang-Lian oral liquid. Master Thesis. Nanjing University of Chinese Medicine, 2016(in Chinese)

[27] Konig MF, Powell M, Staedtke V, Bai RY, Thomas DL, Fischer N, Huq S, Khalafallah AM, Koenecke A, Xiong R, Mensh B, Papadopoulos N, Kinzler KW, Vogelstein B, Vogelstein JT, Athey S, Zhou S, Bettegowda C. Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. J Clin Invest 2020; 130(7): 3345–3347

[28] Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8(6): e46–e47

[29] Gao Y, Fang L, Cai R, Zong C, Chen X, Lu J, Qi Y. Shuang-Huang-Lian exerts anti-inflammatory and anti-oxidative activities in lipopolysaccharide-stimulated murine alveolar macrophages. Phytomedicine 2014; 21(4): 461–469

[30] Shi H, Ren K, Lv B, Zhang W, Zhao Y, Tan RX, Li E. Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice. Sci Rep 2016; 6(1): 35851

[31] Emilien G, van Meurs W, Maloteaux JM. The dose-response relationship in phase I clinical trials and beyond: use, meaning, and assessment. Pharmacol Ther 2000; 88(1): 33–58

Acknowledgements

This work was supported by the National Key R&D Program of China (No. 2020YFC0841400), Tongji Hospital Clinical Research Project (Nos. XXGZBDYJ009 and 2019YBKY019). We thank the patients who participated in this trial. We thank the participants for their involvement in the study, in particular, we want to thank Drs. Liming Xia and Chong Chen of Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Yan Ma of the First Affiliated Hospital of University of Science and Technology of China, for their contributions in this trial. We would like to thank Prof. Jingxin Li of Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China, for her constructive comments and great help in the statistical analysis. We thank Profs. Yechun Xu and Xiaoyan Chen at Shanghai Institute of Materia Medica, Chinese Academy of Sciences for their help in providing information of pharmacokinetic data of Shuanghuanlian and its active components. We thank Sanchine Pharmaceutical Co., Ltd., HPGC, for providing the medicine of Shuanghuanglian oral liquid for this trial. We also thank iFLYTEK for providing AI software to analyze the chest CT imaging data. We thank Prof. H. Eric Xu at Shanghai Institute of Materia Medica, Chinese Academy of Sciences, for his help in writing this paper and his constructive comments. Finally, we want to thank GX Pharma Technology (Beijing) Co. Ltd. for providing the CRO service in the trial for other hospitals except Tongji Hospital.

Compliance with ethics guidelines

Li Ni, Zheng Wen, Xiaowen Hu, Wei Tang, Haisheng Wang, Ling Zhou, Lujin Wu, Hong Wang, Chang Xu, Xizhen Xu, Zhichao Xiao, Zongzhe Li, Chenze Li, Yujian Liu, Jialin Duan, Chen Chen, Dan Li, Runhua Zhang, Jinliang Li, Yongxiang Yi, Wei Huang, Yanyan Chen, Jianping Zhao, Jianping Zuo, Jianping Weng, Hualiang Jiang, and Dao Wen Wang declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Informed consent was obtained from all the patients, in which their identifying information is included in this article. Other ethical board approval is not applicable in this manuscript.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0853-6 and is accessible for authorized users.

RIGHTS & PERMISSIONS

2021 Higher Education Press