BREAKING! Stanford Study Shows That Aldactone, A Potassium Sparing Diuretic Drug Improves COVID-19 Clinical Outcomes.

COVID-19 Drugs: A new study by medical researchers from Stanford University-California has found that the commonly available and cheap generic drug, Spironolactone (Aldactone) improves clinical outcomes especially in severe COVID-19 infections.

Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. Spironolactone is a potassium-sparing diuretic (water pill). It prevents your body from absorbing too much salt and keeps your potassium levels from getting too low. This medicine is also used to treat or prevent hypokalemia (low potassium levels in the blood).  It is basically an aldosterone receptor antagonist. It blocks the action of aldosterone inhibiting the reuptake of sodium and water.
 
It is also interesting to note that as early as March 2020, Thailand Medical News covered research findings by doctors in China that showed that most SARS-CoV-2 infected patients exhibited hypokalemia. https://www.thailandmedical.news/news/covid-19-research-updates-chinese-study-reveals-that-hypokalemia-present-in-almost-all-covid-19-patients
 
To date, treatment strategies that target host entry factors have proven an effective means of impeding viral entry in HIV and may be more robust to viral evolution than drugs targeting viral proteins directly. High-throughput functional screens provide an unbiased means of identifying genes that influence the infection of host cells, while retrospective cohort analysis can measure the real-world, clinical potential of repurposing existing therapeutics as antiviral treatments.
 
The COVID-19 Drugs study team combined these two powerful methods to identify drugs that alter the clinical course of COVID-19 by targeting host entry factors.
 
The study team demonstrated that integrative analysis of genome-wide CRISPR screening datasets enables network-based prioritization of drugs modulating viral entry, and they identified three common medications (spironolactone, quetiapine, and carvedilol) based on their network proximity to putative host factors.
 
In order to understand the drugs’ real-world impact, the study team performed a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients and found that spironolactone use is associated with improved clinical prognosis, measured by both ICU admission and mechanical ventilation rates.
 
Most importantly, the study findings showed that spironolactone exerts a dose-dependent inhibitory effect on viral entry in a human lung epithelial cell line. Our results suggest that spironolactone may improve clinical outcomes in COVID-19 through tissue-dependent inhibition of viral entry.
 
The study further provides a potential approach to integrate functional genomics with real-world evidence for drug repurposing.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.07.02.22277181v1
 
The study basically involved an integrative analysis of clinical outcomes and viral entry networks in severe coronavirus disease 2019 (COVID-19) infection.
 
It has already been known that viral entry into the host cell is a critical step in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication cycle responsible for the virulence and tropism of the viral variants. SARS-CoV-2 entry into the host depends primarily on binding interactions between host angiotensin-converting enzyme-2 (ACE-2) and SARS-CoV-2 spike protein. However, research is needed to understand the entire process of host cell entry and the involvement of the network of several host genes. 
 
The study team used high-throughput functional screens and retrospective cohort analysis to recognize drugs that can alter the COVID-19 disease course by targeting factors influencing host entry.
 
The study team recognized host subnetworks that allow SARS-CoV-2 entry by collecting all genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens. These screens estimated the effect of individual genetic expression on SARS-CoV-2 infection.
 
Importantly, these screens provided data related to various cellular contexts such as lung and non-lung cell types as well as functional perturbations like loss-of-function or CRISPR-KO and gain-of-function or CRISPRa. The final dataset comprised three CRISPRa and five CRISPR-KO screens that allowed the resolution of viral entry mechanisms.
 
The research team also quantified the enrichment of functional pathways among each CRISPR screen. Furthermore, unweighted networks represented known interactions between drugs approved by the Food and Drug Administration (FDA) and entry genes detected in the individual screens.
 
The study team next performed downstream analysis on drugs according to the centrality of each hit network.
 
The researchers also further conducted a retrospective clinical analysis with the propensity scores matched to estimate whether the usage of the candidate drugs was related to COVID-19 disease severity.
 
The study team collected electronic medical records, including a total of 64,349 patient cases having a positive SARS-CoV-2 diagnosis.
 
The researchers also evaluated if the inhibition of SARS-CoV-2 entry could intervene in the mechanism of spironolactone. This was achieved by performing a SARS-CoV-2 pseudoviral entry assay at different spironolactone doses in a cell line derived from human lung epithelium.
    
Interestingly, the research findings showed that the three CRISPRa and five CRISPR-KO screens displayed different levels of correlation at single-gene levels consistent with the corresponding heterogeneous cellular contexts.
 
Almost 88% of the screens were substantially correlated to a minimum of one other CRISPR screen, and 26% of the pairwise comparisons showed a remarkable positive correlation after adjusting for multiple testing.
 
The study team also noted that the gene-level similarities were higher among each type of CRISPR screen. A positive correlation was found among 60% and 33% of CRISPR-KO and CRISPRa screen pairs, respectively.
 
The study findings also showed that a total of 20 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were substantially enriched in a minimum of two screens, among which were several pathways that were directly involved in the entry of SARS-CoV-2.
 
Importantly, pathways related to phosphoglycerides and glycosaminoglycans were the most enriched, consistent with their important function in viral attachment.
 
It is important to note that significant de-enrichment was also observed in pathways related to neurodegenerative diseases like Huntington’s, Parkinson’s, and Alzheimer’s.
 
The study team also found that the correlations among enrichment scores of normalized pathways for every screen were higher than those for individual genes.
 
The research findings showed that each unweighted network comprised an average number of 116 genes, 605 drugs, and 758 edges each which corresponded to a mean density of almost 1.06%. For each graph, the mean degree was estimated to be 6.50 for the gene nodes, 1.23 for the drug nodes, and 2.03 overall, with approximately 3.81% of genes detected per screen having unknown drug interactions.
 
Detailed analysis of spironolactone revealed a substantial negative correlation between the use of spironolactone and COVID-19 disease progression to admission to the intensive care unit (ICU). Moreover, the association between spironolactone usage and the need for a mechanical ventilator was significantly negative.
 
Another drug, Metformin, the positive control, also displayed a remarkable negative correlation with ICU admission and a nominally substantial correlation with intervention with a mechanical ventilator.
 
The study team noted a dose- and time-dependent effect of spironolactone on SARS-CoV-2 entry.
 
Significantly, there was an initial peak of SARS-CoV-2 entry at four to eight hours after infection when there was a slight but substantial increase in viral infection at the administration of the highest dose. After the initial peak, the team observed a larger and more robust reduction in viral infection at higher doses of spironolactone, which agreed with an overall inhibition of SARS-CoV-2 entry. 
On the whole, the study findings showed that spironolactone which is already an FDA approved drug with an established safety profile could serve as a potential candidate as a SARS-CoV-2 infection modulator.
 
Thailand Medical News however warns that readers should not attempt to self-prescribe and use Aldactone to treat COVID-19 without consulting a licensed doctor who knows anything. (These might be hard to come by these days!)
 
Spironolactone is typically also used to treat high blood pressure and heart failure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. It is also used to treat swelling (edema) caused by certain conditions (such as heart failure, liver disease) by removing excess fluid and improving symptoms such as breathing problems. This medication is also used to treat conditions in which the body is making too much of a natural substance (aldosterone).
 
It is also used to reduce hair growth in certain females and transgenders and tend to have a ‘feminizing’ effect.
 
Typical side effects of using the drug included drowsiness, dizziness, lightheadedness, stomach upset, diarrhea, nausea, vomiting, or headache may occur.
 
It can cause mental/mood changes, unusual fatigue/weakness, muscle spasms, menstrual period changes, breast pain, breast enlargement (gynecomastia) in men, sexual function problems, signs of infection (such as sore throat that doesn't go away, fever), severe stomach/abdominal pain, vomit that looks like coffee grounds, dark urine, yellowing of the eyes/skin, easy bruising/bleeding.
 
For the latest on COVID-19 Drugs, keep on logging to Thailand Medical News.
 
Read Also: https://www.thailandmedical.news/news/epstein-barr-virus-ebv-researchers-discover-mechanism-as-to-how-spironolactone-exhibits-antiviral-properties-on-the-virus
 
https://www.thailandmedical.news/pages/drugs/aldactone