Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial

Adel A Gomaa, Hamdy S Mohamed, Rasha B Abd-Ellatief, Mohamed A Gomaa, Doaa S Hammam, Adel A Gomaa, Hamdy S Mohamed, Rasha B Abd-Ellatief, Mohamed A Gomaa, Doaa S Hammam

Abstract

Recent evidence points to a potential therapeutic role for glycyrrhizin(GR) and boswellic acids (BA) in the treatment of COVID-19 but conclusive evidence is lacking. Our aim is to investigate the efficacy of GR + BA versus placebo for the treatment of hospitalized patients with moderate SARS-CoV-2 or COVID-19 variants infection. The current study is a randomized, double-blind, placebo-controlled, single-center trial. Patients with SARS-CoV-2 or COVID-19 variants diagnosed by PCR test who were admitted to Sohag University hospital were eligible if they were at least 18 years of age and had moderate symptoms. Patients were randomly assigned to receive oral GR capsule (60 mg) and BA (200 mg) twice daily for 14 days or a matching placebo. All patients also received treatment with the institutional protocol for COVID-19. The primary outcome was mortality and time to recovery. Secondary outcome was clinical status score, 14 days after receiving study drugs. Adverse events from use of study drugs have been evaluated for up to 14 days. The trial is registered at ClinicalTrials.gov (Identifier NCT04487964). During the 6-month enrollment period (June-November, 2021) only 50 patients (54% women; median age 60 years, IQR 54-65) met eligibility and were randomly assigned. Evaluation of the primary outcome at 14 days showed that there were five deaths in the placebo group and no deaths in the GR + BA group. With regard to recovery time, it was significantly shorter (p = 0.0001) in the group receiving GR + BA capsule compared to the placebo group (median 7.0; IQR 6.0-8.0 days vs. median 12.5; IQR 12-20 days). Clinical status on the ordinal score scale as a secondary outcome showed a significant difference between the GR + BA group (median (IQR) score, 2 [2-3]) and placebo groups (mean (IQR) score, 3 [3-5.5]). There was a significant decrease in CRB (p = 0.000041) in GR + BA compared with the placebo group. In conclusion, this safe, inexpensive, antiviral, immunomodulating and anti-inflammatory combination may be considered for use in mild to moderate infections of SARS-CoV-2 or COVID-19 variants. The study is limited by the small sample size; therefore, larger randomized trials are required.

Keywords: Boswellic aids; COVID-19; Clinical status score; Glycyrrhizin; Mortality rate; Time to recovery.

Conflict of interest statement

All authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study flow diagram

References

    1. Ahmad S, Waheed Y, Abro A, Abbasi SW, Ismail S. Molecular screening of glycyrrhizin-based inhibitors against ACE2 host receptor of SARS-CoV-2. J Mol Model. 2021;27(7):206. doi: 10.1007/s00894-021-04816-y.
    1. Alam S, Sarker MMR, Afrin S, Richi FT, Zhao C, et al. Traditional herbal medicines, bioactive metabolites, and plant products against covid-19: update on clinical trials and mechanism of actions. Front Pharmacol. 2021;12:671498. doi: 10.3389/fphar.2021.671498.
    1. Badria FA, Abu-Karam M, Mikhaeil BR, et al. Anti-herpes activity of isolated compounds from frankincense. Biosci Biotechnol Res Asia. 2003;1(1):1–10.
    1. Baram SM, Karima S, Shateri S, et al. Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double- blind, placebo-controlled, pilot trial. Inflammopharmacology. 2019;27:1101–1112. doi: 10.1007/s10787-019-00627-z.
    1. Beghelli D, Isani G, Roncada P, et al. Antioxidant and ex vivo immune system regulatory properties of Boswellia serrate extracts. Oxid Med Cell Longev. 2017 doi: 10.1155/2017/7468064.
    1. Bignardi PR, Vengrus CS, Aquino BM, Cerci NA. Use of hydroxychloroquine and chloroquine in patients with COVID-19: a meta-analysis of randomized clinical trials. Pathog Glob Health. 2021;115(3):139–150. doi: 10.1080/20477724.2021.1884807.
    1. Caliebe RH, Scior T, Ammon HP. T (2021) Binding of boswellic acids to functional proteins of the SARS-CoV-2 virus: Bioinformatic studies. Arch Pharm. 2021;354:2100160. doi: 10.1002/ardp.202100160.
    1. Cheng B, Hu J, Zuo X, et al. Predictors of progression from moderate to severe coronavirus disease 2019: a retrospective cohort. Clin Microbiol Infect. 2020;26(10):1400–1405. doi: 10.1016/j.cmi.2020.06.033.
    1. Choi HW, Tian M, Manohar M, Harraz MM, Park SW, et al. Human GAPDH is a target of aspirin's primary metabolite salicylic acid and its derivatives. PLoS ONE. 2015;10(11):e0143447. doi: 10.1371/journal.pone.0143447.
    1. Choi HW, Tian M, Song F, Venereau E, Preti A, Park SW, et al. Aspirin's active metabolite salicylic acid targets high mobility group box 1 to modulate inflammatory responses. Mol Med. 2015;21:526–535. doi: 10.2119/molmed.2015.00148.
    1. Ding N, Wei B, Fu X, Wang C, Wu Y. Natural products that target the NLRP3 inflammasome to treat fibrosis. Front Pharmacol. 2020;11:591393. doi: 10.3389/fphar.2020.591393.
    1. Diomede L, Beeg M, Gamba A, Fumagalli O, Gobbi M, Salmona M. Can antiviral activity of licorice help fight COVID-19 infection? Biomolecules. 2021;11(6):855. doi: 10.3390/biom11060855.
    1. Efferth T, Oesch F. Anti-inflammatory and anti-cancer activities of frankincense: targets, treatments and toxicities. Semin Cancer Biol. 2020 doi: 10.1016/j.semcancer.2020.01.015.
    1. Eltahir HM, Fawzy MA, Mohamed EM, et al. Antioxidant, anti-inflammatory and anti-fibrotic effects of Boswellia serrate gum resin in CCl4-induced hepatotoxicity. Exp Ther Med. 2020;19:1313–1321. doi: 10.3892/etm.2019.8353.
    1. Gomaa AA, Abdel-Wadood YA. The potential of glycyrrhizin and licorice extract in combating COVID-19 and associated conditions. Phytomedicine plus. 2021;1:100043. doi: 10.1016/j.phyplu.2021.100043.
    1. Gomaa AA, Mohamed HS, Abd-Ellatief RB, Gomaa MA. Boswellic acids/Boswellia serrata extract as a potential COVID-19 therapeutic agent in the elderly. Inflammopharmacology. 2021;29(4):1033–1048. doi: 10.1007/s10787-021-00841-8.
    1. Goswami D, Mahapatra AD, Banerjee S, Kar A, Ojha D, Mukherjee PK, Chattopadhyay D. Boswellia serrata oleo-gum-resin and β-boswellic acid inhibits HSV-1 infection in vitro through modulation of NF-кB and p38 MAP kinase signaling. Phytomedicine. 2018;51:94–103. doi: 10.1016/j.phymed.2018.10.016.
    1. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, et al. China Medical Treatment Expert Group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J 55:2000547. 2020 doi: 10.1183/13993003.00547-2020.
    1. Huan C, Xu Y, Zhang W, Guo T, Pan H, Gao S. Research progress on the antiviral activity of glycyrrhizin and its derivatives in liquorice. Front Pharmacol. 2021;12:680674. doi: 10.3389/fphar.2021.680674.
    1. Jin Y-H, Cai L, Cheng Z-S, et al. 2020) A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version. Mil Med Res. 2020;7:4.
    1. Kadhim MM, Washeel Salman A, Mrebee Zarzoor A, Kadhum WR. Inhibition of SARS-CoV-2 reproduction using Boswellia carterii: a theoretical study. J Mol Liq. 2021;337:116440. doi: 10.1016/j.molliq.2021.116440.
    1. Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee—a randomized double blind placebo controlled trial. Phytomedicine. 2003;10(1):3–7. doi: 10.1078/094471103321648593.
    1. Li J, Xu D, Wang L, Zhang M, Zhang G, Li E, He S. Glycyrrhizic acid inhibits SARS-CoV-2 infection by blocking spike protein-mediated cell attachment. Molecules. 2021;26(20):6090. doi: 10.3390/molecules26206090.
    1. Liu B, Yu J. Anti-NLRP3 inflammasome natural compounds: an update. Biomedicines. 2021;9:136. doi: 10.3390/biomedicines9020136.
    1. Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7:e001455. doi: 10.1136/rmdopen-2020-001455.
    1. Majeed M, Majeed S, Narayanan NK, Nagabhushanam K. A pilot, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of a novel Boswellia serrata extract in the management of osteoarthritis of the knee. Phytother Res. 2019;33(5):1457–1468. doi: 10.1002/ptr.6338.
    1. Majeed M, Nagabhushanam K, Lawrence L, Nallathambi R, Thiyagarajan V, Mundkur L. Boswellia serrata extract containing 30% 3-acetyl-11-keto-boswellic acid attenuates inflammatory mediators and preserves extracellular matrix in collagen-induced arthritis. Front Physiol. 2021;12:735247. doi: 10.3389/fphys.2021.735247.
    1. Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surg Neurol Int. 2010;1:80. doi: 10.4103/2152-7806.73804.
    1. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034. doi: 10.1016/S0140-6736(20)30628-0.
    1. Mollica L, De Marchis F, Spitaleri A, Dallacosta C, Pennacchini D, et al. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Biol. 2007;14:431–441. doi: 10.1016/j.chembiol.2007.03.007.
    1. Murck H. Symptomatic protective action of glycyrrhizin (Licorice) in COVID-19 infection? Front Immunol. 2020;11:1239. doi: 10.3389/fimmu.2020.01239.
    1. Ng SL, Khaw KY, Ong YS, Goh HP, Kifli N. Licorice: a potential herb in overcoming SARS-CoV-2 infections. J Evid Based Integr Med. 2021 doi: 10.1177/2515690X21996662.
    1. Rabaan AA, Al-Ahmed SH, Muhammad J, Khan A, Sule AA, et al. Role of inflammatory cytokines in COVID-19 patients: a review on molecular mechanisms, immune functions, immunopathology and immunomodulatory drugs to counter cytokine storm. Vaccines. 2021;9:436. doi: 10.3390/vaccines9050436.
    1. Rayner CR, Dron L, Park JJH, et al. Accelerating clinical evaluation of repurposed combination therapies for COVID-19. Am J Trop Med Hyg. 2020;103:1364–1366. doi: 10.4269/ajtmh.20-0995.
    1. Rejekia MS, Sarnadia N, Wihastutia R, Fazharyastia V, et al. Convalescent plasma therapy in patients with moderate-to-severe COVID-19: a study from Indonesia for clinical research in low- and middle-income countries. Eclinical Medicine. 2021;36:10093.
    1. Renda G, Gökkaya İ, Şöhretoğlu D. Immunomodulatory properties of triterpenes. Phytochem Rev. 2021;18:1–27. doi: 10.1007/s11101-021-09785-x.
    1. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2021;80:550–557. doi: 10.1136/annrheumdis-2020-219174.
    1. Rodrigues TS, de Sa KSG, Ishimoto AY, et al. Inflammasomes are activated in response to SARS-CoV- 2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2021;218:e20201707. doi: 10.1084/jem.20201707.
    1. Roy A, Menon T. Evaluation of bioactive compounds from Boswellia serrata against SARS-CoV-2. Vegetos. 2021;17:1–11. doi: 10.1007/s42535-021-00318-7.
    1. Roy NK, Parama D, Banik K, Bordoloi D, Devi AK, et al. An update on pharmacological potential of boswellic acids against chronic diseases. Int J Mol Sci. 2019;20(17):4101. doi: 10.3390/ijms20174101.
    1. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46:846–848. doi: 10.1007/s00134-020-05991-x.
    1. Si L, Meng K, Tian Z, et al. Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes. Sci Adv. 2018 doi: 10.1126/sciadv.aau8408.
    1. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–407. doi: 10.1016/j.healun.2020.03.012.
    1. Sun Z, He G, Huang N, Thilakavathy K, Lim JCW, Kumar SS, Xiong C. Glycyrrhizic acid: a natural plant ingredient as a drug candidate to treat COVID-19. Front Pharmacol. 2021;12:707205. doi: 10.3389/fphar.2021.707205.
    1. van de Sand L, Bormann M, Alt M, Schipper L, Heilingloh CS, et al. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses. 2021;13(4):609. doi: 10.3390/v13040609.
    1. Von Rhein C, Weidner T, Hens L, et al. Curcumin and Boswellia serrata gum resin extract inhibit chikungunya and vesicular stomatitis virus infections in vitro. Antiviral Res. 2016;125:51–57. doi: 10.1016/j.antiviral.2015.11.007.
    1. WHO (2020) Clinical management of COVID-19. . Accessed 18 Feb 2020
    1. WHO R&D (2020) Blueprintnovel Coronavirus COVID-19 Therapeutic Trial Synopsis. 2020 . Accessed 18 Feb 2020
    1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention. JAMA. 2020;323:1239–1242. doi: 10.1001/jama.2020.2648.
    1. Xiao S, Tian Z, Wang Y, et al. Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives. Med Res Rev. 2018;38(3):951–976. doi: 10.1002/med.21484.
    1. Xu W, Li Y, Ju M, Lai W, Lu X, et al. A multicenter, randomized, double-blind, placebo-controlled study of compound glycyrrhizin capsules combined with a topical corticosteroid in adults with chronic eczema. Evid Based Complement Alternat Med. 2020;2020:6127327. doi: 10.1155/2020/6127327.
    1. Yi Y, Li J, Lai X, Zhang M, Kuang Y, et al. Natural triterpenoids from licorice potently inhibit SARS-CoV-2 infection. J Adv Res. 2021;36:201–210. doi: 10.1016/j.jare.2021.11.012.
    1. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586–590. doi: 10.1007/s00134-020-05985-9.
    1. Zhang Q, Xiang R, Huo S, Zhou Y, Jiang S, Wang Q, Yu F. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Signal Transduct Target Ther. 2021;6(1):233. doi: 10.1038/s41392-021-00653-w.
    1. Zhang Q-h, Huang H-z, Qiu M, Wu Z-f, Xin Z-c, et al. Traditional uses, pharmacological effects, and molecular mechanisms of licorice in potential therapy of COVID-19. Front Pharmacol. 2021;12:719758. doi: 10.3389/fphar.2021.719758.
    1. Zhao C, Zhao W. NLRP3 inflammasome—a key player in antiviral responses. Front Immunol. 2020;11:211. doi: 10.3389/fimmu.2020.00211.
    1. Zheng W, Huang X, Lai Y, Liu X, Jiang Y, Zhan S. Glycyrrhizic acid for covid-19: findings of targeting pivotal inflammatory pathways triggered by SARS-CoV-2. Front Pharmacol. 2021;12:631206. doi: 10.3389/fphar.2021.631206.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever