Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19)

Marvin R McCreary, Patrick M Schnell, Dale A Rhoda, Marvin R McCreary, Patrick M Schnell, Dale A Rhoda

Abstract

Resveratrol is a polyphenol that has been well studied and has demonstrated anti-viral and anti-inflammatory properties that might mitigate the effects of COVID-19. Outpatients (N = 105) were recruited from central Ohio in late 2020. Participants were randomly assigned to receive placebo or resveratrol. Both groups received a single dose of Vitamin D3 which was used as an adjunct. The primary outcome measure was hospitalization within 21 days of symptom onset; secondary measures were ER visits, incidence of pneumonia, and incidence of pulmonary embolism. Five patients chose not to participate after randomization. Twenty-one-day outcome was determined of all one hundred participants (mean [SD] age 55.6 [8.8] years; 61% female). There were no clinically significant adverse events attributed to resveratrol. Outpatients in this phase 2 study treated with resveratrol had a lower incidence compared to placebo of: hospitalization (2% vs. 6%, RR 0.33, 95% CI 0.04-3.10), COVID-19 related ER visits (8% vs. 14%, RR 0.57, 95% CI 0.18-1.83), and pneumonia (8% vs. 16%, RR 0.5, 95% CI 0.16-1.55). One patient (2%) in each group developed pulmonary embolism (RR 1.00, 95% CI: 0.06-15.55). This underpowered study was limited by small sample size and low incidence of primary adverse events consequently the results are statistically similar between treatment arms. A larger trial could determine efficacy.Trial Registrations: ClinicalTrials.gov NCT04400890 26/05/2020; FDA IND #150033 05/05/2020.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Summary of potential resveratrol effects on virus and host. 1. Inhibits Spike protein to ACE2 binding,. 2. Inhibits transcription of viral proteases (Mpro and PLpro)–. 3. Inhibits RNA-dependent RNA polymerase. 4. Inhibits proinflammatory cytokines–. 5. Inhibits platelet aggregation,. 6. Activates endothelial Nitric Oxide (antiviral and vasoprotective)–. 7. Inhibits proinflammatory NF-kB. 8. Inhibits proinflammatory Th-17 T-cells. 9. Stimulates the production of glutathione in lung epithelium cells–.
Figure 2
Figure 2
CONSORT Diagram.

References

    1. Tomé-Carneiro J, et al. Resveratrol and clinical trials: The crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 2013;19:6064–6093. doi: 10.2174/13816128113199990407.
    1. Abba Y, Hassim H, Hamzah H, Noordin MM. Antiviral activity of resveratrol against human and animal viruses. Adv. Virol. 2015;2015:1. doi: 10.1155/2015/184241.
    1. Li M, et al. De novo production of resveratrol from glucose or ethanol by engineered Saccharomyces cerevisiae. Metab. Eng. 2015;32:1–11. doi: 10.1016/j.ymben.2015.08.007.
    1. Wahedi HM, Ahmad S, Abbasi SW. Stilbene-based natural compounds as promising drug candidates against COVID-19. J. Biomol. Struct. Dyn. 2020;39:1–10. doi: 10.1080/07391102.2020.1762743.
    1. Pandey P, et al. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. Null. 2020;39:1–11. doi: 10.1080/07391102.2020.1796811.
    1. Ranjbar, A., Jamshidi, M. & Torabi, S. Molecular modelling of the antiviral action of Resveratrol derivatives against the activity of two novel SARS CoV-2 and 2019-nCoV receptors. Eur. Rev. Med. Pharmacol. Sci. 7834–7844 (2020).
    1. Mishra, A., Pathak, Y. & Tripathi, V. Natural compounds as potential inhibitors of novel coronavirus (COVID-19) main protease: An in silico study. Res. Square. Preprint (2020) 10.21203/-22839/v2.
    1. Shin D, Mukherjee R, Grewe D, et al. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature. 2020;587:657–622. doi: 10.1038/s41586-020-2601-5.
    1. Rathnayake, A., Zheng, J., Kim, Y., & et al. 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice. Sci. Transl. Med.12, (2020).
    1. El-Aziz, N. M. A., Shehata, M. G., Awad, O. M. E. & El-Sohaimy, S. A. Inhibition of COVID-19 RNA-dependent RNA polymerase by natural bioactive compounds: Molecular docking analysis. Res. Square. Preprint (2020). 10.21203/-25850/v1.
    1. Maity B, Bora M, Sur D. An effect of combination of resveratrol with vitamin D3 on modulation of proinflammatory cytokines in diabetic nephropathy induces rat. Orient. Pharm. Exp. Med. 2018;18:127–138. doi: 10.1007/s13596-018-0311-4.
    1. Estrov Z, Shishodia S, Faderl S, et al. Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood. 2003;102:987–995. doi: 10.1182/blood-2002-11-3550.
    1. Zhu J, Yong W, Wu X. Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes. Biochem. Biophys. Res. Commun. 2008;369:471–477. doi: 10.1016/j.bbrc.2008.02.034.
    1. Sun J, et al. Suppression of TLR4 activation by resveratrol is associated with STAT3 and Akt inhibition in oxidized low-density lipoprotein-activated platelets. Eur. J. Pharmacol. 2018;836:1–10. doi: 10.1016/j.ejphar.2018.08.014.
    1. Shigematsu S, et al. Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radical Biol. Med. 2003;34:810–817. doi: 10.1016/S0891-5849(02)01430-2.
    1. Xia N, Förstermann U, Li H. Resveratrol and endothelial nitric oxide. Molecules. 2014;19:16102–16121. doi: 10.3390/molecules191016102.
    1. Åkerström S, et al. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J. Virol. 2005;79:1966–1969. doi: 10.1128/JVI.79.3.1966-1969.2005.
    1. Åkerström S, Gunalan V, Keng CT, Tan Y-J, Mirazimi A. Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected. Virology. 2009;395:1–9. doi: 10.1016/j.virol.2009.09.007.
    1. Ren X, et al. Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities. Pharmazie. 2013;68:689.
    1. Xuzhu G, Komai-Koma M, Leung B, et al. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann. Rheum. Dis. 2021;71:129–135. doi: 10.1136/ard.2011.149831.
    1. Polonikov A. Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in COVID-19 patients. ACS Infectious Diseases. 2020;6:1558–1562. doi: 10.1021/acsinfecdis.0c00288.
    1. Kode A, et al. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2008;294:L478–L488. doi: 10.1152/ajplung.00361.2007.
    1. Horowitz RI, Freeman PR, Bruzzese J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir. Med. Case. Rep. 2020;30:101063.
    1. Kuba K, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 2005;11:875–879. doi: 10.1038/nm1267.
    1. Mehta P, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034. doi: 10.1016/S0140-6736(20)30628-0.
    1. Nicholls J, Peiris M. Good ACE, bad ACE do battle in lung injury, SARS. Nat. Med. 2005;11:821–822. doi: 10.1038/nm0805-821.
    1. Gu H, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci. Rep. 2016;6:19840–19840. doi: 10.1038/srep19840.
    1. Yan T, Xiao R, Lin G. Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A double-edged sword? FASEB J. 2020;34:6017–6026. doi: 10.1096/fj.202000782.
    1. Moran CS, et al. Resveratrol inhibits growth of experimental abdominal aortic aneurysm associated with upregulation of angiotensin-converting enzyme 2. Arterioscler. Thromb. Vasc. Biol. 2017;37:2195–2203. doi: 10.1161/ATVBAHA.117.310129.
    1. Imai Y, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116. doi: 10.1038/nature03712.
    1. Horne JR, Vohl M-C. Biological plausibility for interactions between dietary fat, resveratrol, ACE2, and SARS-CoV illness severity. Am. J. Physiol. Endocrinol. Metab. 2020;318:E830–E833. doi: 10.1152/ajpendo.00150.2020.
    1. Magrone T, Magrone M, Jirillo E. Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target - a perspective. Endocr. Metab. Immune Disord. Drug Targets. 2020;20:1–11. doi: 10.2174/187153032001191213111933.
    1. Lin S-C, et al. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect. Dis. 2017;17:144. doi: 10.1186/s12879-017-2253-8.
    1. Olejnik J, Hume AJ, Mühlberger E. Toll-like receptor 4 in acute viral infection: Too much of a good thing. PLoS Pathog. 2018;14:e1007390. doi: 10.1371/journal.ppat.1007390.
    1. Conti, P. et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies. J. Biol. Regulat. Homeostatic Agents34, (2020).
    1. Patterson, B. K. et al. Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. 10.1101/2020.05.02.20084673 (2020).
    1. Wang W, et al. Up-regulation of IL-6 and TNF-α induced by SARS-coronavirus spike protein in murine macrophages via NF-κB pathway. Virus Res. 2007;128:1–8. doi: 10.1016/j.virusres.2007.02.007.
    1. Zhu X, Lei X, Dong W. Resveratrol as a potential therapeutic drug for respiratory system diseases. Drug Des. Dev. Ther. 2017;11:3591–3598. doi: 10.2147/DDDT.S148868.
    1. Culpitt SV, et al. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax. 2003;58:942–946. doi: 10.1136/thorax.58.11.942.
    1. DeDiego ML, et al. Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. J. Virol. 2014;88:913–924. doi: 10.1128/JVI.02576-13.
    1. Alghetaa H, et al. Resveratrol protects mice against SEB-induced acute lung injury and mortality by miR-193a modulation that targets TGF-β signalling. J. Cell Mol. Med. 2018;22:2644–2655. doi: 10.1111/jcmm.13542.
    1. Jiang L, et al. Resveratrol ameliorates LPS-induced acute lung injury via NLRP3 inflammasome modulation. Biomed. Pharmacother. 2016;84:130–138. doi: 10.1016/j.biopha.2016.09.020.
    1. Chen H, Bai C, Wang X. The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine. Expert Rev. Respir. Med. 2010;4:773–783. doi: 10.1586/ers.10.71.
    1. Shah, A. Novel coronavirus-induced NLRP3 inflammasome activation: A potential drug target in the treatment of COVID-19. Front. Immunol.11, (2020).
    1. Wang J-Z, Zhang R-Y, Bai J. An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients. Int. J. Cardiol. 2020;312:137–138. doi: 10.1016/j.ijcard.2020.04.009.
    1. Zhao X, et al. Antiviral effect of resveratrol in piglets infected with virulent pseudorabies virus. Viruses. 2018;10:457. doi: 10.3390/v10090457.
    1. Fagone P, et al. Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies. Autoimmun. Rev. 2020;19:102571–102571. doi: 10.1016/j.autrev.2020.102571.
    1. Palamara AT, et al. Inhibition of influenza a virus replication by resveratrol. J. Infect. Dis. 2005;191:1719–1729. doi: 10.1086/429694.
    1. Zang N, et al. Resveratrol-mediated gamma interferon reduction prevents airway inflammation and airway hyperresponsiveness in respiratory syncytial virus-infected immunocompromised mice. J. Virol. 2011;85:13061–13068. doi: 10.1128/JVI.05869-11.
    1. Grant W, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12:988. doi: 10.3390/nu12040988.
    1. Aslan MT, Aslan İÖ, Özdemir Ö. Is vitamin D one of the key elements in COVID-19 days? J Nutr Health Aging. 2020;24:1038–1039. doi: 10.1007/s12603-020-1517-y.
    1. Ilahi M, Armas LAG, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. Am. J. Clin. Nutr. 2008;87:688–691. doi: 10.1093/ajcn/87.3.688.
    1. Harris PA, et al. Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 2009;42:377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Obeid JS, et al. Procurement of shared data instruments for research electronic data capture (REDCap) J. Biomed. Inform. 2013;46:259–265. doi: 10.1016/j.jbi.2012.10.006.
    1. National Cancer Institute Division of Cancer Control & Population Services. Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). .
    1. CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020. Morbidity Mortality Week. Rep.69, 343 (2020).
    1. Saldanha J, et al. Effects of resveratrol supplementation in nrf2 and NF-κB expressions in nondialyzed chronic kidney disease patients: A randomized, double-blind, placebo-controlled, crossover clinical trial. J. Ren. Nutr. 2016;26:401–406. doi: 10.1053/j.jrn.2016.06.005.
    1. R Core Team. R: A language and environment for statistical computing. (R Foundation for Statistical Computing, 2020).
    1. StataCorp. Stata Statistical Software: Release 17. (2021).
    1. White I, Joseph R, Best N. A causal modelling framework for reference-based imputation and tipping point analysis in clinical trials with quantitative outcome. J. Biopharm. Stat. 2020;30:334–350. doi: 10.1080/10543406.2019.1684308.
    1. Walle T. Bioavailability of resveratrol. Ann. N. Y. Acad. Sci. 2011;1215:9–15. doi: 10.1111/j.1749-6632.2010.05842.x.
    1. Sergides C, Chirilă M, Silvestro L, Pitta D, Pittas A. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers. Exp. Ther. Med. 2016;11:164–170. doi: 10.3892/etm.2015.2895.
    1. Christrup L. Morphine metabolites. Acta Anaesthesiol Scand. 1997;41:116–122. doi: 10.1111/j.1399-6576.1997.tb04625.x.
    1. Lauer, M. Continued Impact of COVID-19 on Biomedical Research. (2020).
    1. The Economist. Pandemic mortality - See how age and illnesses change the risk of dying from covid-19. (2021).
    1. Ohio Department of Health. COVID-19 Dashboard. (2021).
    1. Merzon E, et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study. FEBS J. 2020;287:3693–3702. doi: 10.1111/febs.15495.
    1. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Clinician Summary. (2021).
    1. Bertelli A, et al. Analgesic resveratrol? Antioxid. Redox Signal. 2008;10:403–404. doi: 10.1089/ars.2007.1926.
    1. Rossi GA, Sacco O, Capizzi A, Mastromarino P. Can resveratrol-inhaled formulations be considered potential adjunct treatments for COVID-19? Front. Immunol. 2021;12:1591.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren