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Review
. 2020 Oct;28(5):1141-1152.
doi: 10.1007/s10787-020-00745-z. Epub 2020 Aug 14.

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality

Lucinda Smart  1 , Neil Fawkes  2 , Paul Goggin  3 , Graham Pennick  1 , K D Rainsford  4 , Bruce Charlesworth  1 , Neil Shah  3
Affiliations
Review

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality

Lucinda Smart et al. Inflammopharmacology. 2020 Oct.

Abstract

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19.

Keywords: ACE2; COVID-19; Ibuprofen; Immune system; SARS-CoV-2; Safety.

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Conflict of interest statement

KR has no conflict of interest to declare. All other authors are employees of Reckitt Benckiser Health Ltd.

Figures

Fig. 1
Fig. 1
The balancing role of angiotensin-converting enzyme 2 (ACE2) in the renin–angiotensin–aldosterone system (RAAS). In a situation where ACE2 is downregulated, AngII levels rise and its concomitant binding on AT1R increases systemic inflammation via production of inflammatory mediators. Ang angiotensin, NEP neprilysin, ACE angiotensin-converting enzyme, AT1R angiotensin type 1 receptor, AT2R angiotensin type 2 receptor, MasR Mas receptor
Fig. 2
Fig. 2
a The entry of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into cells is mediated by the binding of the viral spike (S) glycoprotein to membrane-bound angiotensin-converting enzyme 2 (ACE2). ACE2 levels on the plasma membrane are regulated by the metalloproteinase ADAM-17, which promotes shedding of ACE2 with its active N domain into the circulation. The cleaved portion of ACE2, which does not contain the membrane-bound domain necessary for viral entry into the cell, may act as a decoy for the viral spike proteins. It is hypothesised that ibuprofen may be able to activate ADAM-17 and thus prevent membrane-bound ACE2-dependent infection of the cell. b The enzyme transmembrane protein, serine 2 (encoded for by the TMPRSS2 gene) is necessary for the proteolytic cut at the S1/S2 site on the viral S glycoprotein for uptake into the cell and viral replication. It is hypothesised that ibuprofen may be able to downregulate expression of the enzyme, and thus prevent TMPRSS2-dependent viral entry into the cell
Fig. 3
Fig. 3
Balance in favour of the ACE–Ang II–AT1R axis over the ACE2–Ang(1–7)–Mas axis in the development of or injury in certain disease states. Infection with severe acute respiratory coronavirus 2 (SARS-CoV-2) only serves to further reduce levels of angiotensin-converting enzyme 2 (ACE2), pushing the balance further in the direction of injury for those with certain comorbidities. CV indicates cardiovascular disease
Fig. 4
Fig. 4
Interaction of severe acute respiratory coronavirus 2 (SARS-CoV-2) with the inflammatory system via downregulation of ACE2 and potential therapeutic effects of ibuprofen in reducing inflammation. In the presence of the virus, ACE2 is downregulated, thus preventing enzymatic hydrolysis of AngII into Ang(1–7). The resulting effect is there is increased production of the transcription factor NF-kB, which activates production of further inflammatory mediators. Ibuprofen has demonstrated ability to inhibit NF-kB, as well as other downstream inflammatory mediators such as interleukin-6, that seem to be upregulated upon viral infection. Furthermore, ibuprofen is hypothesised to activate ADAM-17 cleavage of ACE2 from the cell membrane, preventing viral entry into the cell. ACE = angiotensin-converting enzyme. Ang angiotensin, ATR1 type 1 angiotensin II receptor, AT2R type 2 angiotensin II receptor, COX2 cyclooxygenase 2, ICAM intercellular adhesion molecule, IL interleukin, IFN interferon, JAK Janus kinase, MasR Mas receptor, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, STAT3 signal transducer and activator of transcription 3, TGF transforming growth factor, TLR toll-like receptor, TNF tumour necrosis factor, TXA thromboxane, TYK tyrosine kinase, VEGF vascular endothelial growth factor
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