A Birds-Eye (Re)View of Acid-Suppression Drugs, COVID-19, and the Highly Variable Literature

Abstract

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), “…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not.” Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)–based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.

Inhibitors of SARS-CoV-2 PLpro

“…Famotidine, marketed as Pepcid ® , is an FDA approved histamine H2 receptor antagonist prescribed to treat heartburn. Two retrospective studies later conducted in the US also confirmed similar findings ( Freedberg et al, 2020 ; Mather et al, 2020 ), however, like most reports for repurposed drugs, the mechanism of action underlying the observed beneficial effects remain ill-defined ( Mura et al, 2021 ). One computational study suggested Mpro ( Wu C. et al, 2020 ) as the target, while another suggested PLpro ( Kandeel et al, 2020 ).…”

Experimental Search for New Means of Pathogenetic Therapy COVID-19: Inhibitor of H2-Receptors Famotidine Increases the Effect of Oseltamivir on Survival and Immune Status of Mice Infected by A/PR/8/34 (H1N1)

“…According to other researchers, this mechanism of action of famotidine as a component of etiotropic therapy is not proven, and the search for real mechanisms of its positive effect should be carried out from the standpoint of pathogenetic therapy, taking into account, first of all, the interaction of famotidine with H2-receptors [ 78 ]. At the same time, discussion of the efficacy of famotidine as an antagonist of H2-receptors often boils down to a discussion of its antacid properties associated with inhibition of the proton pump [ 79 – 81 ].…”

Identification of Novel Allosteric Sites of SARS-CoV-2 Papain-Like Protease (PLpro) for the Development of COVID-19 Antivirals

“…Many putative candidates against SARS-CoV-2 PLpro identified by in silico studies have yet to be biochemically confirmed 13,[28][29][30][31] . Several repurposed protease inhibitors with promising effects on PLpro in vivo or in vitro, such as simeprevir, tanshinones, famotidine, and ebselen, are either clinically ineffective or still in clinical trials [32][33][34][35][36] . Another class of inhibitors of interest against PLpro is FDA-approved zinc-ejecting drugs 15,17,37,38 .…”

“…Numerous in-silico attempts have been made in repurposing drugs to target SARS-CoV-2 PLpro, but putative drug candidates still remain to be biochemically confirmed (Klemm, Ebert et al 2020, Smith, Davis-Gardner et al 2020, Redhead, Owen et al 2021, Xu, Chen et al 2021, Zhao, Du et al 2021. Meanwhile, several repurposed drug candidates against PLpro have gained traction when tested in-vivo or in-vitro -Simeprivir, Tanshinone, Famotidine and Ebselen, to name a few (Jin, Du et al 2020, Gammeltoft, Zhou et al 2021, Lim, Tan et al 2021, Mura, Preissner et al 2021, https://doi.org/10.21203/rs.3.rs-26344/v1. However, these drug candidates are either found clinically ineffective, are still under clinical trials, or still require thorough biochemical assessment (Calleja, Lessene et al 2022).…”