Ibuprofen, Flurbiprofen, Etoricoxib or Paracetamol Do Not Influence ACE2 Expression and Activity In Vitro or in Mice and Do Not Exacerbate In-Vitro SARS-CoV-2 Infection

Abstract

SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications—including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)—have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.

Home as the new frontier for the treatment of COVID-19: the case for anti-inflammatory agents

“…46 Moreover, high concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro. 47 Data based on small population cohorts and observational and retrospective studies have consistently shown no association between ongoing NSAID therapy and increased mortality [48][49][50][51] or worsening of clinical outcomes 48,49,[51][52][53] in people with COVID-19 in the general population (ie, inpatient and outpatient population; appendix p 1). Similarly, in people with pre-existing rheumatic disease who were chronically exposed to NSAIDs, the ongoing use of these medicines did not increase the risk of hospitalisation for COVID-19 or COVID-19-related death compared with non-users.…”

Short-term celecoxib (celebrex) adjuvant therapy: a clinical trial study on COVID-19 patients

“…However, this speculation about celecoxib was later contradicted by Terrier et al They reported that only naproxen, among NSAIDS, could inhibit the replication of SARS-CoV-2 by binding to its nucleoprotein and that celecoxib did not possess such properties (Terrier et al 2021 ). Another study by de Burin et al concluded that etoricoxib, a selective COX-2 inhibitor, was capable of reducing the viral load in cells infected with SARS-CoV-2, possibly through downregulation of angiotensin-converting enzyme 2 (ACE2), which is a pivotal receptor for SARS-CoV-2 (de Bruin et al 2022 ), further indicating the effectiveness of COX-2 inhibitors as an adjuvant treatment for COVID-19. Speculation by Khupse et al argues that celecoxib competes with SARS-CoV-2 at binding the host cell's bromodomain proteins (BRD)-2/4 and, thus, abrogates SARS-CoV-2 infection (Khupse and Dixit 2020 ).…”

Analgesia and COVID‐19

“…In their comprehensive review of immunomodulatory effects of opioids and analgesics, Abdel Shaheed et al report research indicating that some NSAIDs demonstrate in vitro and in vivo anti‐viral activity against SARS‐CoV‐2, focussing particularly on indomethacin. 1 They point out that ibuprofen has not shown such activity, citing the work of Chen et al 2 However, more recent in vitro research in Caco‐2 cells indicates that ibuprofen does indeed suppress SARS‐CoV‐2 viral load, 3 albeit only at higher concentrations than those tested by Chen at al. 2 Flurbiprofen has similar anti‐viral activity at higher concentrations.…”

“… 2 Flurbiprofen has similar anti‐viral activity at higher concentrations. 3 The emerging evidence base for NSAIDs demonstrating in vitro anti‐SARS‐CoV‐2 activity now includes indomethacin, 1 naproxen, 4 flurbiprofen, 3 and ibuprofen. 3 …”

“…3 The emerging evidence base for NSAIDs demonstrating in vitro anti-SARS-CoV-2 activity now includes indomethacin, 1 naproxen, 4 flurbiprofen, 3 and ibuprofen. 3 The review also considers controversies surrounding immunization and whether the use of analgesics to treat post-vaccination symptoms adversely affects immunogenicity. This is particularly relevant in the present context of COVID-19 and concerns over vaccine hesitancy.…”