COVID-19 Meds: Austrian Vitro Study Finds That Nasal Antihistamine Azelastine Could Be Repurposed To Reduce Viral Transmission Or As A Prophylaxis

COVID-19 Meds: A new vitro study led by Austrian researchers from the University of Vienna has demonstrated that the nasal antihistamine Azelastine was able to inhibit SARS-CoV-2 infections in assays using reconstituted human nasal tissue and Vero E6 monkey kidney epithelial cells. The study team says that Azalastine is a prospective drug candidate that could be used to reduce viral transmission in COVID-19 and also as a suitable prophylaxis but warrants more detailed research.

The study findings are published on a preprint server and have yet to have been peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.09.15.296228v1
 
The study was also supported by researchers from the University of Pécs and CEBINA GmbH, Vienna.
 
To date there are still no approved drugs to treat COVID-19 except two drugs that have been granted EUA (Emergency Use Authorization)  approvals by the U.S.FDA ie dexamethasone to help treat certain conditions in severe COVID-19 patients  and the questionable overpriced remdesivir that has only been shown to reduce hospitalization stays!(approved under pressure by the Trump administration).
 
Given the urgency, going through the traditional drug discovery and development pathway is not feasible. This is where approaches like drug repurposing or repositioning become attractive. Drug repurposing is nothing but identifying new indications and usages for existing, clinically approved drugs.  
 
Despite many such drugs passing silico computational molecular docking studies and vitro studies, many never made in animal vivo studies or in actual human clinical trials with the exception of drugs like famotidine, Inhaled Corticosteroids Formoterol/Budesonide, Tretracyclines, Heparin and a few others but all still needing more clinical trials. https://www.thailandmedical.news/news/breaking-covid-19-treatments-second-observational-study-shows-famotidine-associated-with-better-outcomes-for-hospitalized-covid-19-patients

https://www.thailandmedical.news/news/breaking-covid-19-drugs-study-trial-of-inhaled-corticosteroids-formoterol-budesonide-shows-potential-as-prophylactic-and-treatment-drugs
 
https://www.thailandmedical.news/news/covid-19-drugs-new-research-indicates-that-heparin-may-effectively-neutralize-sars-cov-2-coronavirus-that-causes-covid-19
 
The study team in this research applied a novel computational prediction approach that is based on biochemical pathways. Their strategy was based on the poly-pharmacological hypothesis that says drugs interact and interfere simultaneously with several different targets and thus rewire the biochemical pathway networks.
 
Thus in this approach, drug identification thus involves finding a drug that matches a pre-defined pathway modulation profile. The starting point of the team’s approach is a description of the inherent chemical properties of small drug molecules, with proven activity against the SARS-CoV-2 virus and implications for specificity to protein targets.
 
Utilizing this unique descriptor, the study team set off to identify unexpected or hidden drug similarities and identify new protein targets in the underlying biochemical pathways.
 
Corresponding author, Professor Dr Robert Konrat from the department of Structural and Computational Biology at Max F. Perutz Laboratories-University of Vienna told Thailand Medical News, “Key to our strategy is the poly-pharmacological hypothesis, that drugs simultaneously interact and interfere with numerous targets and thereby rewire the biochemical pathway networks.”
 
The study team tested the antiviral activity of the most predicted drug, azelastine in vitro in SARS-CoV-2 infection assays using reconstituted human nasal tissue and Vero E6 monkey kidney epithelial cells. The effect of this drug on viral replication was determined by viral genome quantification using digital droplet polymerase chain reaction (PCR).
 
In the study, the computational approach helped the team identify drugs and drug families, some with proven activity and clinical efficacy against SARS-CoV-2.  

Azelastine, an histamine 1 receptor-blocker, was predicted by the approach in multiple screens. Due to its attractive safety profile and easy availability in a nasal formulation, it was chosen for experimental testing.
 
The study results showed that azelastine significantly reduced cytopathic effect and inhibited SARS-CoV-2 infection of Vero E6 cells both in preventive and treatment settings. They also tested a 5-fold dilution of azelastine in a commercially available nasal spray. They found that it was very potent in inhibiting the propagation of the SARS-CoV-2 virus in infected human nasal tissue. The team concluded that the antihistamine azelastine might be considered for use in topical prevention or treatment of SARS-CoV-2 nasal colonization.
 
The study team proposes that azelastine could be helpful in reducing viral transmission and prophylaxis of COVID-19. However, the potential benefits of the drug need to be proven in further clinical studies.
 
On another area, the team also noticed a significant overlap among the three predicted and the experimental KEGG  pathways, the most prominent between the SSAA09E2 and hydroxychloroquine pathways. The most common disease areas associated with the predicted pathways were viral infections including hepatitis C, measles, and influenza; parasitic infections such as Leishmaniasis, Trypanosomiasis, malaria; and bacterial infections such as tuberculosis, Salmonella, Shigella, and Pertussis.
 
Dr Konrat added, “Interestingly, the study found some overlap with drugs predicted by a complex network approach reported by the Barabási Lab, (https://www.barabasilab.com/) which relies on information about human protein binding partners where potential drug candidates are likely to perturb the interactome network relevant for viral infection.”
 
Interestingly most of the drugs that this research predicted are currently being tested in various clinical studies. Of note, dexamethasone has been shown to reduce mortality by one third in COVID-19 patients on mechanical ventilation.
 
Two other drugs, famotidine, an H2-blocker antihistamine that decreases gastric acid production, and telmisartan, an anti-hypertensive drug, have been recently shown to improve morbidity in hospitalized SARS-CoV-2 infected patients.
 
Dr Konrat added, “ This to be a more promising approach compared to conventional single-target drug design strategies, particularly in view of the multi-factorial disease phenotype of COVID-19.”
 
The team concluded, “The major implication of our findings is that a widely available nasal spray formulation containing azelastine might be an immediate solution to prevent and treat nasal colonization with SARS-CoV-2 therefore may have a great impact on the viral spread within the affected person (nose to lung) as well as within the population. This potential needs to be confirmed in clinical studies.
 
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