NSAIDs and Kelleni's protocol as potential early COVID-19 treatment game changer: could it be the final countdown?

We have previously published several papers illustrating numerous immunomodulatory and anti-inflammatory potential benefits when we repurposed safe, generic non-steroidal anti-inflammatory drugs (NSAIDs)/nitazoxanide/azithromycin (Kelleni's protocol), to early manage our COVID-19 pediatric, adult, and pregnant patients. In this manuscript, we discuss some recently published meta-analysis and clinical studies supporting our practice and discuss a molecular study that might be interpreted as an academic proof that our protocol might also prevent SARS-CoV-2 replication. Moreover, after aspirin has been suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19, we claim that the molecular interpretation of the results that led to this suggestion was not scientifically accurate, and we provide our academic interpretation confirming that low-dose aspirin is least likely to improve COVID-19 mortality through anticoagulation as was suggested. Furthermore, we describe other potential benefits related to aspirin-triggered lipoxins and resolvins while illustrating how NSAIDs interfere with COX-1, COX-2, SARS-CoV-2/SARS-CoV-2 ORF protein-dependent activation of caspases and their subsequent mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis and necroptosis which were associated with COVID-19 complications. Similarly, NSAIDs are known caspase inhibitors and thus they might independently inhibit other caspase-related COVID-19-associated downstream pathological signaling mechanisms. Finally, we postulated that CARD-14, a caspase recruitment domain-containing protein, polymorphisms might play a role in the development of severe and critical COVID-19 and confirmed our old call to early adopt NSAIDs, as an integral part of Kelleni's protocol, as of choice in its management aiming to end this pandemic.

Automated summary

The manuscript discusses the immunomodulatory and anti-inflammatory benefits of repurposing generic non-steroidal anti-inflammatory drugs in managing COVID-19 patients. It also highlights the potential role of aspirin and other NSAIDs in preventing SARS-CoV-2 replication and reducing COVID-19-associated complications. Additionally, the paper explores the molecular mechanisms by which NSAIDs may interfere with certain pathological signaling pathways in COVID-19.