Re: Covid-19: what treatments are being investigated? ; Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. Cromolyn Sodium May Attenuate Covid-19 SARS and Systemic Complications and May Be Useful ...
Re: : 1) Mahase Elisabeth. Covid-19: what treatments are being investigated? BMJ 2020; 368 :m1252, 2) Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
Cromolyn Sodium May Attenuate Covid-19 SARS and Systemic Complications and May Be Useful Prophylactically.
Fatalities due to SARS-COV2 (COVID 19) infection continue rising worldwide. The need exists for additional treatment options addressing antiviral replication, Severe acute respiratory syndrome (SARS) and the cytokine storm (1-4).
In the most recent article by Tao Chen et al (2), it is noted that interferon treatment has more recovered patients than deceased. Modulation of the host immune response may be an important strategy to improve patient survival. Interferon b 1a trial is underway in the U.K. (1).
Severe acute respiratory syndrome (SARS) and the cytokine storm account for a large part of the high mortality in intensive care units (2).
The NF-κB pathway is often targeted by viral pathogens to enhance viral replication, host cell survival and host immune evasion. Viruses may activate or suppress NF-kB. (5). There have many studies on SARS-COV since 2002-2003 SARS epidemic. SARS-COV2 (COVID-19) belongs to the same family of corona viruses and shares many similarities (3)
COVID 19 activates NF-kB pathway, like MERS and SARS-COV (3). SARS-COV virus has been studied in vitro and in mice and was shown to promote inflammatory mediators in vitro and in vivo through actions on NF-kB. Levels of NF-kB were higher in lungs of (recombinant SARS (rSARS)-infected mice. Inhibitors of NF-kB improved survival of BALB/c mice and reduced rSARS-COV-induced inflammation, without influencing viral titers (6) . NF-kB is specifically induced by SARS-COV S protein to produce inflammatory mediators that are associated with ARDS in SARS in vitro (7).
NF-kB pathway has complex interactions with interferons. Suppression of NF-kB may enhance IFN-mediated antiviral activity (8). Suppression of NF-kB needs to be carried out cautiously due to the central role this pathway plays in maintaining normal cellular functions (9).
In addition to many substances that have been described to inhibit NF-kB and hence may be candidates for attentuating inflammation responses in SARS-COV2 infection (10,11), Cromolyn may be proposed as an adjunct treatment. Cromolyn has been found to have broader anti-inflammatory and anti-tumor mechanisms than what has been described historically as an antiallergy and mast cell stabilizer (12). Cromolyn has been identified to inhibit of S100P activation of RAGE and inhibited elevated basal activity of NF-kB pathway in pancreatic cancer cells in vitro and in vivo in (13). S100P proteins as therapeutic targets has been reviewed elswhere (14). Cromolyn binds S100P in a stable complex (15 ). Cromolyn has been found to be effective in reducing inflammation pathways in several other diseases (16 - 22).
Another reported mechanism of Cromolyn sodium is that it acts as a chloride channel inhibitor (Reviewed in reference 12, 28). Viral infections and replication depend on host cell membrane chloride channels (29, 30, 31, 32, 33, 34), . Viruses posses ion channels called viroporins (30, 31). Cromolyn may also directly affect these channels. Furthermore, Cromolyn may attenuate innate immune responses that are influenced by chloride ion channels (35).
Some of deaths due to COVID 19 are due to cardiac involvement (2). Cromolyn may also act on NF-kB mediated remodeling in the inflamed heart in acute viral myocarditis (36).
Inhaled Cromolyn has a favorable safety profile and having been used for asthma treament for several decades since the sixties, including children and pregnant women, and with renewed interest in for repurposing in other diseases, has well-studied pharmacokinetics (37).
In summary, Cromolyn may be effective in decreasing inflammation, ARDS, and cytokine storm in COVID 19 patients. It may also reduce viral replication and systemic inflammation, in particular cardiac inflammation. It may be administerd in a variety of ways. It may be administered as a nebulized therapy, oral, nasal and IV. Nebulized therapy may achieve better penetration of the inflammed tissues of the lung of progressively worsening patients. Cromolyn sodium may be included as part of the treatment of COVID 19 patient at different stages in their infection, mild, moderate or severe. Cromolyn may work synergistically with interferon therapy. Exploration of using Cromolyn prophylactically intranasal, inhaled or oral cromolyn sodium may also be feasible.
1. Mahase Elisabeth. Covid-19: what treatments are being investigated? BMJ 2020; 368 :m1252
2. Chen Tao, Wu Di, Chen Huilong, Yan Weiming, Yang Danlei, Chen Guang et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study BMJ 2020; 368 :m1091
3. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11. Published 2020 Mar 13. doi:10.1186/s40779-020-00240-0
4. Adhikari SP, Meng S, Wu YJ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020;9(1):29. Published 2020 Mar 17. doi:10.1186/s40249-020-00646-x
5. Human Coronaviruses: A Review of Virus–Host Interactions. Yvonne Xinyi Lim, Yan Ling Ng, James P. Tam and Ding Xiang Liu *
6. DeDiego ML, Nieto-Torres JL, Regla-Nava JA, et al. Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. J Virol. 2014;88(2):913–924. doi:10.1128/JVI.02576-13
7. Dosch SF, Mahajan SD, Collins AR. SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Res. 2009;142(1-2):19–27. doi:10.1016/j.virusres.2009.01.005
8. Pfeffer LM. The role of nuclear factor κB in the interferon response. J Interferon Cytokine Res. 2011;31(7):553–559. doi:10.1089/jir.2011.0028
9. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023–. doi:10.1038/sigtrans.2017.23
10. Epinat JC, Gilmore TD. Diverse agents act at multiple levels to inhibit the Rel/NF-kappaB signal transduction pathway. Oncogene. 1999;18(49):6896–6909. doi:10.1038/sj.onc.1203218
11. Gilmore TD, Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene. 2006;25(51):6887–6899. doi:10.1038/sj.onc.1209982
12. Sinniah A, Yazid S, Flower RJ. The Anti-allergic Cromones: Past, Present, and Future. Front Pharmacol. 2017 Nov 14;8:827. doi: 10.3389/fphar.2017.00827. PMID: 29184504; PMCID: PMC5694476.
13. Arumugam T, Ramachandran V, Logsdon CD. Effect of cromolyn on S100P interactions with RAGE and pancreatic cancer growth and invasion in mouse models. J Natl Cancer Inst. 2006 Dec 20;98(24):1806-18. doi: 10.1093/jnci/djj498. PMID: 17179482; PMCID: PMC4461034.
14. Bresnick AR. S100 proteins as therapeutic targets. Biophys Rev. 2018;10(6):1617–1629. doi:10.1007/s12551-018-0471-y
15. Penumutchu SR, Chou RH, Yu C. Interaction between S100P and the anti-allergy drug cromolyn. Biochem Biophys Res Commun. 2014;454(3):404–409. doi:10.1016/j.bbrc.2014.10.048
16. Yazid S, Leoni G, Getting SJ, Cooper D, Solito E, Perretti M, Flower RJ. Antiallergic cromones inhibit neutrophil recruitment onto vascular endothelium via annexin-A1 mobilization. Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1718-24. doi: 10.1161/ATVBAHA.110.209536. Epub 2010 Jun 17. PMID: 20558817; PMCID: PMC4365443.
17. Granucci EJ, Griciuc A, Mueller KA, Mills AN, Le H, Dios AM, McGinty D, Pereira J, Elmaleh D, Berry JD, Paganoni S, Cudkowicz ME, Tanzi RE, Sadri-Vakili G. Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis. Sci Rep. 2019 Nov 27;9(1):17728. doi: 10.1038/s41598-019-53982-w. PMID: 31776380; PMCID: PMC6881366.
18. Elmaleh DR, Farlow MR, Conti PS, Tompkins RG, Kundakovic L, Tanzi RE. Developing Effective Alzheimer's Disease Therapies: Clinical Experience and Future Directions. J Alzheimers Dis. 2019;71(3):715-732. doi: 10.3233/JAD-190507. PMID: 31476157; PMCID: PMC6839593.
19. Nizamutdinova IT, Dusio GF, Gasheva OY, Skoog H, Tobin R, Peddaboina C, Meininger CJ, Zawieja DC, Newell-Rogers MK, Gashev AA. Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation. Aging (Albany NY). 2016 Nov 21;8(11):3065-3090. doi: 10.18632/aging.101113. PMID: 27875806; PMCID: PMC5191886.
20. Weng Z, Zhang B, Asadi S, Sismanopoulos N, Butcher A, Fu X, Katsarou-Katsari A, Antoniou C, Theoharides TC. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One. 2012;7(3):e33805. doi: 10.1371/journal.pone.0033805. Epub 2012 Mar 28. PMID: 22470478; PMCID: PMC3314669.
21. Cimpean AM, Raica M. The Hidden Side of Disodium Cromolyn: from Mast Cell Stabilizer to an Angiogenic Factor and Antitumor Agent. Arch Immunol Ther Exp (Warsz). 2016;64(6):515–522. doi:10.1007/s00005-016-0408-8
22. Sivandzade F, Prasad S, Bhalerao A, Cucullo L. NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biol. 2019;21:101059. doi:10.1016/j.redox.2018.11.017
23. Choi JS, Kim JK, Yang YJ, et al. Identification of cromolyn sodium as an anti-fibrotic agent targeting both hepatocytes and hepatic stellate cells. Pharmacol Res. 2015;102:176–183. doi:10.1016/j.phrs.2015.10.002
24. Cimpean AM, Raica M. The Hidden Side of Disodium Cromolyn: from Mast Cell Stabilizer to an Angiogenic Factor and Antitumor Agent. Arch Immunol Ther Exp (Warsz). 2016;64(6):515–522. doi:10.1007/s00005-016-0408-8
25. Raithel M, Winterkamp S, Weidenhiller M, Müller S, Hahn EG. Combination therapy using fexofenadine, disodium cromoglycate, and a hypoallergenic amino acid-based formula induced remission in a patient with steroid-dependent, chronically active ulcerative colitis. Int J Colorectal Dis. 2007;22(7):833–839. doi:10.1007/s00384-006-0120-y
26. Shishibori T, Oyama Y, Matsushita O, et al. Three distinct anti-allergic drugs, amlexanox, cromolyn and tranilast, bind to S100A12 and S100A13 of the S100 protein family. Biochem J. 1999;338 ( Pt 3)(Pt 3):583–589.
27. Jha NK, Jha SK, Kar R, Nand P, Swati K, Goswami VK. Nuclear factor-kappa β as a therapeutic target for Alzheimer's disease. J Neurochem. 2019;150(2):113–137. doi:10.1111/jnc.14687
28. Heinke S, Szücs G, Norris A, Droogmans G, Nilius B. Inhibition of volume-activated chloride currents in endothelial cells by chromones. Br J Pharmacol. 1995;115(8):1393–1398. doi:10.1111/j.1476-5381.1995.tb16629.x
29. Hover S, Foster B, Barr JN, Mankouri J. Viral dependence on cellular ion channels - an emerging anti-viral target?. J Gen Virol. 2017;98(3):345–351. doi:10.1099/jgv.0.000712
30. Wang K, Xie S, Sun B. Viral proteins function as ion channels. Biochim Biophys Acta. 2011;1808(2):510–515. doi:10.1016/j.bbamem.2010.05.006
31. Müller M, Slivinski N, Todd EJAA, et al. Chikungunya virus requires cellular chloride channels for efficient genome replication. PLoS Negl Trop Dis. 2019;13(9):e0007703. Published 2019 Sep 4. doi:10.1371/journal.pntd.0007703
32. Igloi Z, Mohl BP, Lippiat JD, Harris M, Mankouri J. Requirement for chloride channel function during the hepatitis C virus life cycle. J Virol. 2015;89(7):4023–4029. doi:10.1128/JVI.02946-14
33. To J, Surya W, Torres J. Targeting the Channel Activity of Viroporins. Adv Protein Chem Struct Biol. 2016;104:307–355. doi:10.1016/bs.apcsb.2015.12.003
34. Castaño-Rodriguez C, Honrubia JM, Gutiérrez-Álvarez J, et al. Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. mBio. 2018;9(3):e02325-17. Published 2018 May 22. doi:10.1128/mBio.02325-17
35. Ramalingam S, Cai B, Wong J, et al. Antiviral innate immune response in non-myeloid cells is augmented by chloride ions via an increase in intracellula35. r hypochlorous acid levels. Sci Rep. 2018;8(1):13630. Published 2018 Sep 11. doi:10.1038/s41598-018-31936-y
36. Remels AHV, Derks WJA, Cillero-Pastor B, et al. NF-κB-mediated metabolic remodelling in the inflamed heart in acute viral myocarditis. Biochim Biophys Acta Mol Basis Dis. 2018;1864(8):2579–2589. doi:10.1016/j.bbadis.2018.04.022
37. Brazier D, Perry R, Keane J, Barrett K, Elmaleh DR. Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Elderly Volunteers. Clin Drug Investig. 2017 Nov;37(11):1025-1034. doi: 10.1007/s40261-017-0549-5. PMID: 28856569; PMCID: PMC5643367.
Competing interests: No competing interests