Pentoxifylline and Oxypurinol: Potential Drugs to Prevent the “Cytokine Release (Storm) Syndrome” Caused by SARS-CoV-2?

Author(s): Francisco J. López-Iranzo, Ana M. López-Rodas, Luis Franco, Gerardo López-Rodas*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 35 , 2020


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Abstract:

Background: COVID-19, caused by SARS-CoV-2, is a potentially lethal, rapidly-expanding pandemic and many efforts are being carried out worldwide to understand and control the disease. COVID-19 patients may display a cytokine release syndrome, which causes severe lung inflammation, leading, in many instances, to death.

Objective: This paper is intended to explore the possibilities of controlling the COVID-19-associated hyperinflammation by using licensed drugs with anti-inflammatory effects.

Hypothesis: We have previously described that pentoxifylline alone, or in combination with oxypurinol, reduces the systemic inflammation caused by experimentally-induced pancreatitis in rats. Pentoxifylline is an inhibitor of TNF-α production and oxypurinol inhibits xanthine oxidase. TNF-α, in turn, activates other inflammatory genes such as Nos2, Icam or IL-6, which regulate migration and infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the lung parenchyma. In acute pancreatitis, the anti-inflammatory action of pentoxifylline seems to be mediated by the prevention of the rapid and presumably transient loss of PP2A activity. This may also occur in the hyperinflammatory -cytokine releasing phase- of SARS-CoV-2 infection. Therefore, it may be hypothesized that early treatment of COVID-19 patients with pentoxifylline, alone or in combination with oxypurinol, would prevent the potentially lethal acute respiratory distress syndrome.

Conclusion: Pentoxifylline and oxypurinol are licensed drugs used for diseases other than COVID-19 and, therefore, phase I clinical trials would not be necessary for the administration to SARS-CoV-2- infected people. It would be worth investigating their potential effects against the hyperinflammatory response to SARS-CoV-2 infection.

Keywords: Pentoxifylline, oxypurinol, SARS-CoV-2, COVID-19, pro-inflammatory cytokines, systemic inflammatory response, serine/ threonine phosphatase PP2A, cytokine release syndrome.

[1]
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020; 181(2): 271-280. e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052 ] [PMID: 32142651]
[2]
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration. UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395(10229): 1033-4.
[http://dx.doi.org/10.1016/S0140-6736(20)30628-0] [PMID: 32192578]
[3]
Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368(6490): 473-4.
[http://dx.doi.org/10.1126/science.abb8925] [PMID: 32303591]
[4]
Zhang C, Wu Z, Li J-W, Zhao H, Wang G-Q. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents 2020; 55(5) 105954
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105954] [PMID: 32234467]
[5]
Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol 2020; 20(5): 271-2.
[http://dx.doi.org/10.1038/s41577-020-0312-7] [PMID: 32296135]
[6]
Wong CK, Lam CWK, Wu AKL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004; 136(1): 95-103.
[http://dx.doi.org/10.1111/j.1365-2249.2004.02415.x] [PMID: 15030519]
[7]
He L, Ding Y, Zhang Q, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol 2006; 210(3): 288-97.
[http://dx.doi.org/10.1002/path.2067] [PMID: 17031779]
[8]
Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013; 19(10): 1313-7.
[http://dx.doi.org/10.1038/nm.3362] [PMID: 24013700]
[9]
Faure E, Poissy J, Goffard A, et al. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PLoS One 2014; 9(2) e88716
[http://dx.doi.org/10.1371/journal.pone.0088716] [PMID: 24551142]
[10]
Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 2018; 104: 8-13.
[http://dx.doi.org/10.1016/j.cyto.2018.01.025] [PMID: 29414327]
[11]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[12]
Szatmary P, Arora A, Raraty MGT, Dunne DFJ, Baron RD, Halloran CM. Emerging phenotype of SARS-CoV2 associated pancreatitis. Gastroenterology 2020 In press
[13]
Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action. Br J Haematol 2020; 189(5): 846-7.
[http://dx.doi.org/10.1111/bjh.16727] [PMID: 32304577]
[14]
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunologic features in severe and moderate Coronavirus Disease 2019. J Clin Invest 2020; 130(5)
[http://dx.doi.org/10.1172/JCI137244]
[15]
Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest 2020; 130(5): 2202-5.
[http://dx.doi.org/10.1172/JCI137647] [PMID: 32217834]
[16]
Ruan Q, Yang K, Wang W, Jiang L, Song J. 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(5): 846-8.
[http://dx.doi.org/10.1007/s00134-020-05991-x]
[17]
Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front Immunol 2019; 11: 827.
[18]
Chiappelli F, Khakshooy A, Greenberg G. CoViD-19 Immunopathology and Immunotherapy. Bioinformation 2020; 16(3): 219-22.
[http://dx.doi.org/10.6026/97320630016219] [PMID: 32308263]
[19]
Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature 2020; 582(7813): 469.
[http://dx.doi.org/10.1038/d41586-020-01824-5] [PMID: 32546811]
[20]
Russell B, Moss C, George G, et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience 2020; 14: 1022.
[http://dx.doi.org/10.3332/ecancer.2020.1022] [PMID: 32256705]
[21]
Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol 2020. 214108393
[http://dx.doi.org/10.1016/j.clim.2020.108393] [PMID: 32222466]
[22]
Sarzi-Puttini P, Giorgi V, Sirotti S, Marotto D, Ardizzone S, Rizzardini G, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?Clinical and experimental rheumatology NLM (Medline). 2020; 38: pp. 337- 42.
[23]
Tufan A, Avanoğlu Güler A, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turk J Med Sci 2020; 50(SI-1): 620-32.
[http://dx.doi.org/10.3906/sag-2004-168] [PMID: 32299202]
[24]
Irrera N, Bitto A, Interdonato M, Squadrito F, Altavilla D. Evidence for a role of mitogen-activated protein kinases in the treatment of experimental acute pancreatitis. World J Gastroenterol 2014; 20(44): 16535-43.
[http://dx.doi.org/10.3748/wjg.v20.i44.16535] [PMID: 25469021]
[25]
Pereda J, Sabater L, Cassinello N, et al. Effect of simultaneous inhibition of TNF-α production and xanthine oxidase in experimental acute pancreatitis: the role of mitogen activated protein kinases. Ann Surg 2004; 240(1): 108-16.
[http://dx.doi.org/10.1097/01.sla.0000129343.47774.89] [PMID: 15213626]
[26]
Zhang D, Jiang H, Wang Y, Ma J. Pentoxifylline inhibits hepatic stellate cells proliferation via the Raf/ERK pathway. APMIS 2012; 120(7): 572-81.
[http://dx.doi.org/10.1111/j.1600-0463.2011.02868.x] [PMID: 22716212]
[27]
Escobar J, Pereda J, Arduini A, et al. Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases. Curr Pharm Des 2009; 15(26): 3027-42.
[http://dx.doi.org/10.2174/138161209789058075] [PMID: 19754377]
[28]
Escobar J, Pereda J, Arduini A, et al. Protein phosphatases and chromatin modifying complexes in the inflammatory cascade in acute pancreatitis. World J Gastrointest Pharmacol Ther 2010; 1(3): 75-80.
[http://dx.doi.org/10.4292/wjgpt.v1.i3.75] [PMID: 21577300]
[29]
Escobar J, Pereda J, Arduini A, et al. Role of redox signaling, protein phosphatases and histone acetylation in the inflammatory cascade in acute pancreatitis. Therapeutic implications. Inflamm Allergy Drug Targets 2010; 9(2): 97-108.
[http://dx.doi.org/10.2174/187152810791292773] [PMID: 20361855]
[30]
Escobar J, Pereda J, Arduini A, et al. Oxidative and nitrosative stress in acute pancreatitis. Modulation by pentoxifylline and oxypurinol. Biochem Pharmacol 2012; 83(1): 122-30.
[http://dx.doi.org/10.1016/j.bcp.2011.09.028] [PMID: 22000995]
[31]
Escobar J, Pereda J, López-Rodas G, Sastre J. Redox signaling and histone acetylation in acute pancreatitis. Free Radic Biol Med 2012; 52(5): 819-37.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.11.009] [PMID: 22178977]
[32]
Sandoval J, Escobar J, Pereda J, et al. Pentoxifylline prevents loss of PP2A phosphatase activity and recruitment of histone acetyltransferases to proinflammatory genes in acute pancreatitis. J Pharmacol Exp Ther 2009; 331(2): 609-17.
[http://dx.doi.org/10.1124/jpet.109.157537] [PMID: 19671881]
[33]
Sandoval J, Pereda J, Rodriguez JL, et al. Ordered transcriptional factor recruitment and epigenetic regulation of tnf-α in necrotizing acute pancreatitis. Cell Mol Life Sci 2010; 67(10): 1687-97.
[http://dx.doi.org/10.1007/s00018-010-0272-3] [PMID: 20130956]
[34]
Sandoval J, Pereda J, Pérez S, et al. Epigenetic regulation of early-and late-response genes in acute pancreatitis. J Immunol 2016; 197(10): 4137-50.
[http://dx.doi.org/10.4049/jimmunol.1502378] [PMID: 27798150]
[35]
Pereda J, Sabater L, Aparisi L, et al. Interaction between cytokines and oxidative stress in acute pancreatitis. Curr Med Chem 2006; 13(23): 2775-87.
[http://dx.doi.org/10.2174/092986706778522011] [PMID: 17073628]
[36]
Pérez S, Pereda J, Sabater L, Sastre J. Redox signaling in acute pancreatitis. Redox Biol 2015; 5: 1-14.
[http://dx.doi.org/10.1016/j.redox.2015.01.014] [PMID: 25778551]
[37]
Closa D, Sabater L, Fernández-Cruz L, Prats N, Gelpí E, Roselló-Catafau J. Activation of alveolar macrophages in lung injury associated with experimental acute pancreatitis is mediated by the liver. Ann Surg 1999; 229(2): 230-6.
[http://dx.doi.org/10.1097/00000658-199902000-00011] [PMID: 10024105]
[38]
Lentsch AB, Czermak BJ, Bless NM, Van Rooijen N, Ward PA. Essential role of alveolar macrophages in intrapulmonary activation of NF-kappaB. Am J Respir Cell Mol Biol 1999; 20(4): 692-8.
[http://dx.doi.org/10.1165/ajrcmb.20.4.3414] [PMID: 10101001]
[39]
Lentsch AB, Czermak BJ, Bless NM, Ward PA. NF-kappaB activation during IgG immune complex-induced lung injury: requirements for TNF-alpha and IL-1beta but not complement. Am J Pathol 1998; 152(5): 1327-36.
[PMID: 9588901]
[40]
Manohar M, Verma AK, Venkateshaiah SU, Sanders NL, Mishra A. Chronic Pancreatitis Associated Acute Respiratory Failure. MOJ Immunol 2017; 5(2): 00149.
[PMID: 29399623]
[41]
Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 1998; 175(1): 76-83.
[http://dx.doi.org/10.1016/S0002-9610(97)00240-7] [PMID: 9445247]
[42]
Bhatia M, Wong FL, Cao Y, et al. Pathophysiology of acute pancreatitis. Pancreatology 2005; 5(2-3): 132-44.
[http://dx.doi.org/10.1159/000085265] [PMID: 15849484]
[43]
Szatmary P, Gukovsky I, Angeles L. The Role of Cytokines and Inflammation in the Genesis of Experimental cell recruitment 2016.
[44]
Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58(1): 87-114.
[http://dx.doi.org/10.1124/pr.58.1.6] [PMID: 16507884]
[45]
Maiti R, Agrawal NK, Dash D, Pandey BL. Effect of Pentoxifylline on inflammatory burden, oxidative stress and platelet aggregability in hypertensive type 2 diabetes mellitus patients. Vascul Pharmacol 2007; 47(2-3): 118-24.
[http://dx.doi.org/10.1016/j.vph.2007.05.004] [PMID: 17613279]
[46]
Goicoechea M, García de Vinuesa S, Quiroga B, et al. Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol 2012; 25(6): 969-75.
[http://dx.doi.org/10.5301/jn.5000077] [PMID: 22241639]
[47]
Fernandes JL, de Oliveira RTD, Mamoni RL, et al. Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease-a randomized placebo-controlled study. Atherosclerosis 2008; 196(1): 434-42.
[http://dx.doi.org/10.1016/j.atherosclerosis.2006.11.032] [PMID: 17196208]
[48]
Eisendle K, Thuile T, Deluca J, Pichler M. Surgical Treatment of Pyoderma Gangrenosum with Negative Pressure Wound Therapy and Skin Grafting, Including Xenografts: Personal Experience and Comprehensive Review on 161 Cases. J Am Acad Dermatol 2016; 74(4): 760-5.
[http://dx.doi.org/10.1016/j.jaad.2015.09.009] [PMID: 26979359]
[49]
Sunil VR, Vayas KN, Cervelli JA, et al. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation. Exp Mol Pathol 2014; 97(1): 89-98.
[http://dx.doi.org/10.1016/j.yexmp.2014.05.009] [PMID: 24886962]
[50]
de Prost D. Pentoxifylline: a potential treatment for thrombosis associated with abnormal tissue factor expression by monocytes and endothelial cells. J Cardiovasc Pharmacol 1995; 25(Suppl. 2): S114-8.
[http://dx.doi.org/10.1097/00005344-199500252-00024] [PMID: 8699848]
[51]
Seirafianpour F, Mozafarpoor S, Fattahi N, Sadeghzadeh-Bazargan A, Hanifiha M, Goodarzi A. Treatment of COVID-19 with pentoxifylline: Could it be a potential adjuvant therapy? Dermatol Ther (Heidelb) 2020; 33(4) e13733
[http://dx.doi.org/10.1111/dth.13733] [PMID: 32473070]
[52]
Feily A, Daneshpay K, Alighadr A. COVID-19: Pentoxifylline as a potential adjuvant treatment. Int J Clin Pharmacol Ther 2020; 58(7): 406-7.
[http://dx.doi.org/10.5414/CP203782] [PMID: 32449676]
[53]
Maldonado V, Loza-Mejía MA, Chávez-Alderete J. Repositioning of pentoxifylline as an immunomodulator and regulator of the renin-angiotensin system in the treatment of COVID-19. Med Hypotheses 2020; 144 109988
[http://dx.doi.org/10.1016/j.mehy.2020.109988] [PMID: 32540603]


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Article Details

VOLUME: 26
ISSUE: 35
Year: 2020
Published on: 11 August, 2020
Page: [4515 - 4521]
Pages: 7
DOI: 10.2174/1381612826666200811180232
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