COVID19-Drugs: Indomethacin In The Treatment Of SARS-CoV-2 Infections: A Promising Option

COVID-19 Drugs: Since the beginning of the COVID-19 pandemic, researchers have been exploring various treatment options to combat the virus. One such option is the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin. While the use of NSAIDs in COVID-19 treatment remains a topic of debate, several studies have suggested that indomethacin, in particular, could be an effective treatment option.

 
Indomethacin is a nonsteroidal anti-inflammatory drug that is commonly used to reduce inflammation, fever, stiffness, swellings and pain. It works by inhibiting the production of prostaglandins, which are responsible for pain and inflammation.
 
In addition to its anti-inflammatory properties, indomethacin has also been shown to have antiviral effects. For example, in the case of cytomegalovirus, prostaglandin E2 (PGE2) stimulates the activity of the main immediate-early promoter, which controls the synthesis of viral regulatory proteins that are essential for its replication. Therefore, indomethacin's ability to inhibit prostaglandin production may indirectly have antiviral effects.
https://pubmed.ncbi.nlm.nih.gov/17006962/
 
A group of researchers from India performed in silico screening of existing drugs against the crucial proteins of SARS-CoV-2, and a few existing drugs, among which was indomethacin, were shortlisted. In addition, they analyzed the gene expression data of SARS-CoV-2 in human lung epithelial cells and investigated which molecules can reverse the cellular mRNA expression profiles in the diseased state. Indomethacin was found effective to treat SARS-CoV-2 infection. The in-silico findings on indomethacin were also successfully validated by in vitro testing in Vero CCL-81 cells with ah IC₅₀ of 12 µM.
https://www.sciencedirect.com/science/article/pii/S0010482522005558
 
Various other computational, in vitro and vivo studies have shown that indomethacin is a potent inhibitor of coronavirus replication in vitro against human SARS-CoV-1 and 2, and in vivo against canine coronavirus, without cytotoxic effects, and that, having both anti-inflammatory and antiviral activity, it could be repurposed as a treatment in COVID-19 therapy.
https://link.springer.com/article/10.1186/s40360-021-00519-5
 
https://www.sciencedirect.com/science/article/pii/S0223523421006632
 
https://pubmed.ncbi.nlm.nih.gov/32435882/
 
A retrospective study reported a beneficial effect of indomethacin in refractory headaches in COVID-19 and post-COVID-19 patients.
https://pubmed.ncbi.nlm.nih.gov/34546559/
 
 Another recent clinical trial reported the results of a randomized controlled study of indomethacin versus paracetamol, added to standard background therapy, in patients with mild-to-moderate COVID-19. The study’s main objective was the prevention of desaturation at a value <93% of O2. Importantly, the results showed that no patients in the indomethacin group desaturated, while as many as 20 patients desaturated in the paracetamol group.
https://pubmed.ncbi.nlm.nih.gov/33496060/
 
In one study involving a model of vesicular stomatitis infection, indomethacin-activated PKR (double-stranded RNA-dependent protein kinase), resulting in the phosphorylation of elF2α and, in turn, disrupting translation of the viral protein and inhibiting viral replication.
https://journals.sagepub.com/doi/pdf/10.1177/135965350601100803
 
Direct evidence of the antiviral efficacy of indomethacin against SARS-CoV-2 has been provided in cellular models and in vivo in another canine model of infection.
https://www.mdpi.com/1999-4915/13/4/558
 
When compared with a control anti-inflammatory drug (aspirin), indomethacin significantly reduced mortality in experimentally infected dogs, suggesting that the effect is independent of anti-inflammatory action.
 
Molecular docking studies have suggested that indomethacin is able to down-regulate genes involved in virus entry (ACE2 and TMPRSS2), as well as other genes involved in the same pathways, and is a potential antagonist of the main SARS-CoV-2 protease and of non-structural protein 10.
https://www.biorxiv.org/content/10.1101/2020.04.01.017624v1.abstract
 
https://www.biorxiv.org/content/10.1101/2020.04.01.017624v1.abstract
 
https://www.mdpi.com/1420-3049/26/12/3772
 
Models based on systems biology suggest that the action of indomethacin against SARS-CoV-2 depends on its preferred interaction with viral proteins .
https://pubmed.ncbi.nlm.nih.gov/35847618/
 
Furthermore, it was found that indomethacin inhibits the function of membrane-associated prostaglandin E synthase (PTGES2), which catalyzes the conversion of prostaglandin H2 to prostaglandin E2 .
https://pubmed.ncbi.nlm.nih.gov/32654489/
 
As PTGES2 interacts with the viral protein NSP7, the complex function of NSP7/NSP8 is slowed down or blocked, and this could constitute a mechanism of inhibition of viral growth.
 
Several other COVID-19 Drugs studies have reported the positive effects of indomethacin in the treatment of COVID-19.
 
One observational study reported that indomethacin, when combined with two flavonoids (hesperidin and quercetin), an anti-platelet dose of aspirin, vitamin C, and omeprazole, showed relevant positive effects when started within 72 hours of symptom onset. The combination of these substances, which have synergistic mechanisms, led to a significant reduction in the duration of symptoms, practically eliminating hospitalizations, and nullifying the onset of side effects.
https://medscimonit.com/abstract/full/idArt/935379
 
The two flavonoids were chosen for their potent antioxidant action, but also for their anti-inflammatory and antiviral actions, which were strongly synergic with those of indomethacin. An anti-platelet dose of aspirin was associated in order to boost the effects already present in indomethacin, aiming to completely block the platelet hyper-aggregation that the virus can cause once it has entered the bloodstream.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917781/
 
Other studies reported that indomethacin was associated with reduced mortality and fewer hospitalizations in COVID-19 patients. The study included 398 COVID-19 patients who were treated with indomethacin along with other standard therapies. The authors reported that the use of indomethacin was associated with a significantly lower risk of mortality and hospitalization, suggesting that it could be a useful treatment option for COVID-19 patients.
https://www.tandfonline.com/doi/full/10.1080/14787210.2022.1990756
 
https://www.nature.com/articles/s41598-022-10370-1
 
https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1366118
 
However, despite the positive results reported in these studies, the use of NSAIDs in COVID-19 treatment remains a topic of debate. Some experts have expressed concern that NSAIDs could exacerbate COVID-19 symptoms, particularly in patients with pre-existing cardiovascular or renal conditions.
 
Other experts at the same time have argued that the benefits of NSAIDs in COVID-19 treatment outweigh the risks, particularly when used in combination with other substances that can mitigate side effects and increase efficacy.
 
In conclusion, the use of indomethacin in the treatment of COVID-19 holds promise. While more research is needed to fully understand its potential benefits and risks, the positive results reported in several studies suggest that it could be a useful treatment option, particularly when used in combination with other substances that have synergistic mechanisms. As the pandemic continues to evolve, it is important for researchers and healthcare professionals to explore all possible treatment options in order to better combat the virus and reduce its impact on public health.
 
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