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Covid-19: European drugs agency to review safety of ibuprofen

BMJ 2020; 368 doi: (Published 23 March 2020) Cite this as: BMJ 2020;368:m1168

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Re: Covid-19: European drugs agency to review safety of ibuprofen

Dear Editor,

Currently there are some concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin at conventional doses in the management of COVID-19 (coronavirus disease-19) in adult infected patients (1). We wish to briefly discuss the potential role of high doses of aspirin as a host direct strategy.

The main predictors of critical outcome in COVID-19 infections encompass age, the presence of underlying diseases, the presence of secondary infection and elevated inflammatory indicators in the blood (2). In fact, following COVID-19 infection a highly acute respiratory syndrome may be observed with release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6, and a strategy based on their signaling is currently under evaluation (3). In parallel, the recent awareness that COVID 2019 uses ACE2 (receptor Angiotensin converting enzyme 2) as its receptor (4) has led to a focus of attention in the use of angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) as a strategy to counteract COVID infection. Considering the crosstalk between ACE2 signaling and inflammation, Kickbusch and Leung G hypothesized that ACE2 dysregulation of the renin angiotensin system (RAS) may have a central role in the pathophysiology of COVID-19 associated acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). They additionally speculated that the virus binding to ACE2 may attenuate residual ACE2 activity, further skewing the ACE/ACE2 balance to a state of predominant ACE/AngII/AT1 axis signaling (5).

On the other hand, several seminal studies have previously investigated in renal and cardiovascular apparatus the link between Ang II and nuclear factor κB (NF-κB) (6-7) showing that Angiotensin II activates NF-kB through AT1 and AT2 receptors (8). NF-kB is a ubiquitous master regulator of immunology/inflammatory response (9-10). Consequently, the inhibition of its activity could be a successfully strategy in controlling also AT2 signaling.

Aspirin and salicylates at higher doses with respect to those used to inhibit cycloxygenase (COX) activity have been shown to inhibit NF-kb activity also in lung cells (11-12). Interestingly, in a model of rats harboring human renin and angiotensinogen genes high doses of aspirin were able to inhibit NF-κB and to protect from angiotensin II induced renal and cardiovascular damage (13). It is worth noting that 5 to 8 g aspirin, in multiple daily doses of 1 g, were traditionally administered in the management of rheumatoid arthritis (14). That a substantial inhibition of NF-κB activity “in vivo” by high doses of aspirin and salicylate could be achievable in clinical practice has been previously recognized and discussed as a potential anticancer strategy (15).

In conclusion, in COVID-19 infection, targeting NF-kb with high doses of aspirin or salicylate could be part of a host directed therapeutic strategy to treat or prevent fatal “cytokine storms” in which the immune system is at the basis of organ failure.

1. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020 Mar 17;368:m1086. doi: 10.1136/bmj.m1086.

2. 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 Mar 3. doi: 10.1007/s00134-020-05991-x. [Epub ahead of print]

3. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 16. pii: S0140-6736(20)30628-0.

4. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. Wan Y, Shang J, Graham R, Baric RS, Li F. J Virol. 2020 Mar 17;94(7).

5. Kickbusch I, Leung G. Response to the emerging novel coronavirus outbreak BMJ 2020; 368 MJ 2020;368:m406

6. Ruiz-Ortega, M., Lorenzo, O., Ruperez, M., Konig, S., Wittig, B., and Egido, J. Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms. Circ. Res. 2000; 86, 1266–1272

7. Klahr, S., and Morrissey, J. J. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int. 2000; 57 Suppl 75, S7–14

8. Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RA, Thaiss F. Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int. 2002 Jun;61(6):1986-95.

9. Barnes, P. J., and Karin, M. Nuclear factor-kappaB: a pivotal transcription factor in
chronic inflammatory diseases. N. Engl. J. Med. 1997; 336, 1066–1071

10. Karin, M., and Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu. Rev. Immunol. 2000;18, 621–663

11. Kopp, E., and Ghosh, S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994;265, 956–959

12. Yoo CG, Lee S, Lee CT, Kim YW, Han SK, Shim YS.Effect of acetylsalicylic acid on endogenous I kappa B kinase activity in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2001 Jan;280(1):L3-9.

13. Muller DN1, Heissmeyer V, Dechend R, Hampich F, Park JK, Fiebeler A, Shagdarsuren E, Theuer J, Elger M, Pilz B, Breu V, Schroer K, Ganten D, Dietz R, Haller H, Scheidereit C, Luft FC. Aspirin inhibits NF-kappaB and protects from angiotensin II-induced organ damage. FASEB J. 2001 Aug;15(10):1822-4.

14. Gilman AG, Rall TW, Nies AS, Taylor P. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York, NY: McGraw-Hill; 1993.

15. McCarty MF1, Block KI. Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integr Cancer Ther. 2006 Sep;5(3):252-68.

Competing interests: No competing interests

26 March 2020
Paolo Ricchi
Silvia Sale, Tiziana di Matola
AORN Cardarelli, Oncohematologic Department, Naples, Italy