The dawn of the year 2020 witnessed the surge of one of the biggest pandemics known to mankind. COVID-19 spread through continents affecting millions of humans and causing great damage to life and property.
Histamine is a potent inflammatory mediator, commonly associated with allergic reactions, promoting vascular and tissue changes and possessing high chemoattractant activity. The use of antihistamine medications can cause significant immune-modulation which may help in the treatment of cytokine storm of COVID-19.(6)
Research suggests that histamine is a potential therapeutic target to prevent COVID-19 from progressing to acute respiratory distress syndrome (ARDS).(7) Fexofenadine belonging to the first generation class of antihistaminics can be postulated to be beneficial in this respect.
Montelukast and the impact on COVID-19's cytokine storm:
The "cytokine storm" due to angiotensin-converting enzyme-2 (ACE2) downregulation by SARS-CoV-2 (8), triggers a pro-inflammatory environment which is strongly associated with severe tissue damages and contributes to ARDS and fatal outcomes in COVID-19 patients. (9)
In this regard, leukotriene receptor antagonist
Montelukast exerts various beneficial effects like- direct antiviral actions, reduction of endothelial inflammation, protection of blood-brain barrier, limitation of ischemia/reperfusion phenomenon, decrease in tumour necrosis factor (TNF) induced endothelial lesions along with various antioxidant and anti-fibrosis properties.(3)
Montelukast is associated with a marked decrease in frequency and intensity of cytokine reactions and this action seems to be strengthened by the addition of an anti-H1 drug. (10) Khan et al have shown that COVID-19 infected patients receiving montelukast experience significantly fewer events of clinical deterioration compared with patients not receiving it. (11)
Late COVID, a special consideration: Initial resolution of the acute COVID-19 illness may be followed by a combination of clinical sequelae, including but not limited to pulmonary, neurologic, dermatologic, cardiac, renal, endocrine and autoinflammatory phenomena, collectively described as long-COVID. (12) Glynne et al have shown that histamine receptor antagonist reduce long-COVID symptoms when given in the acute phase of infection. This effect is mediated by blocking histamine dependent paracrine regulation of T-cell function. (13)
Which antihistamine drug is the best? The answer lies in Mpro substrate binding.
With the above data indicating a protective role of antihistaminics, the question arises- which antihistaminic to choose from the wide choices available? Virulence of this novel coronavirus is due to the presence of the main protease (Mpro) responsible for virus replication along with many major functions.(14)
High throughput virtual screening is the fastest approach in finding the probable drug against a target microbial protein.(15)
Through this molecular docking technique, Singh et al have found fexofenadine acetate as one of the best therapeutic drugs with an inhibitory effect on COVID-19 by its binding to Mpro.(15)
Further, Farag et al while screening around 2000 FDA approved drugs against COVID-19 virus Mpro terminal site found montelukast and fexofenadine to be the top hits among antihistaminics and antiasthma drugs.(1)
A recent in silico exploration identified montelukast, among the top-scoring clinically-oriented drugs likely to inhibit SARS-CoV-2 main protease.(16)
Thus with the evidence available at hand, it can be hypothesized that this drug combination can prove to be highly effective against COVID-19.
Other COVID-19 protein targets:
ARS-CoV-2 gains entry into cells by intermolecular interactions between the virus spike glycoprotein and Angiotensin-converting enzyme 2 (ACE2).(17) The sigma receptor-1 protein binds the SARS-CoV-2 protein nonstructural protein 6 (NSP6) which prevents viral degradation.(18)
Efforts to identify approved drugs with in vitro activity against SARS-CoV-2 resulted in the identification of antiviral ACE-2 and sigma-1 receptor ligands, including antihistamines in the histamine-1 receptor binding class.(2) Fexofenadine binds to these H1 receptors and ongoing research may further strengthen its role in COVID-19 management.
Take away message for clinicians:
Besides very effective symptomatic control of respiratory complaints in acute COVID infections, the recent data now suggest that the pleiotropic benefits of fexofenadine-montelukast combination may have remarkable effects on cytokine storm and further clinical course of infected patients.
Following are the key takeaways from this review:
1. Early COVID-19 symptoms show overlap with SAR. Proper treatment of rhinitis, sneezing and cough with a fexofenadine-montelukast combination at this stage will prevent viral dissemination and spread to others.(5)
2. Besides controlling early symptoms, this drug combination can prevent progression to severe infection and ARDS by blocking histamine release and subsequent cytokine storm.(6,9)
3. Use of this combination in the acute phase has been shown to reduce the chances of developing "late-COVID". (13)
4. Fexofenadine and montelukast have been found to be one of the best anti-COVID molecules by structure-based drug repositioning studies. Hence their use can potentially promote rapid recovery besides effective symptom control. (1,15)
REFERENCES
1. Farag A, Wang P, Ahmed M, Sadek H. Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning. ChemRxiv. Cambridge: Cambridge Open Engage; 2020
2. Reznikov, L, Michael H., Vashisht R. et al. Identification of antiviral antihistamines for COVID-19 repurposing. Biochemical and Biophysical Research Communications. 538. 10.1016/j.bbrc.2020.11.095.
3. Barré J, Sabatier JM, Annweiler C. Montelukast Drug May Improve COVID-19 Prognosis: A Review of Evidence. Front Pharmacol. 2020 Sep 4;11:1344. doi: 10.3389/fphar.2020.01344. PMID: 33013375; PMCID: PMC7500361.
4. CDC COVID-19 Response Team Coronavirus disease 2019 in children - United States, february 12-april 2, 2020. MMWR Morb Mortal Wkly Rep. 2020 Apr 10;69(14):422–426.
5. Scadding G.,Hellings P., Bachert C., et al. Allergic respiratory disease care in the COVID-19 era: A EUFOREA statement World Allergy Organ J. 2020 May; 13(5): 100124
6. Eldanasory, Omar Abdelhay et al. "Histamine release theory and roles of antihistamine in the treatment of cytokines storm of COVID-19." Travel medicine and infectious disease vol. 37 (2020): 101874.
7. Johnson M. Histamine as a potential therapeutic target for preventing COVID-19 progression to ARDS.
https://www.researchgate.net/publication/340575298 Histamine as a Potential Therapeutic Target for Preventing COVID-19 Progression to ARDS.
8. Bourgonje A. R., Abdulle A. E., Timens W., Hillebrands J. L., Navis G. J., Gordijn S. J., et al. (2020). Angiotensin-converting enzyme-2 (ACE2), SARS-CoV-2 and Pathophysiology of Coronavirus Disease 2019 (COVID-19). J. Pathol. 251, 228–248. 10.1002/path.5471
9. Kimura H., Yoshizumi M., Ishii H., Oishi K., Ryo A. (2013). Cytokine production and signaling pathways in respiratory virus infection. Front. Microbiol. 4, 276. 10.3389/fmicb.2013.00276
10. Kotchetkov R., McLean J., Nay D., et al (2020). Premedication with montelukast and rupatadine decreased rituximab infusion time, rate, severity of reactions and use of rescue medications. Int. J. Cancer 147, 1979–1986. 10.1002/ijc.32985
11. Khan AR, Misdary C, Yegya-Raman N, et al. Montelukast in hospitalized patients diagnosed with COVID-19. J Asthma. 2021 Mar 4:1-7.
12. Nalbandian A, Sehgal K, Gupta A, Madhavan M v, McGroder C, Stevens JS, et al. Postacute COVID-19 syndrome. Nature Medicine. Nature Research; 2021
13. Paul Glynne, Natasha Tahmasebi, Vanya Gant, et al.Long-COVID following mild SARS CoV-2 infection: characteristic T cell alterations and response to antihistamines medRxiv 2021.06.06.21258272.
14. Hall DC, Jr, Ji HF: A search for medications to treat covid-19 via in silico molecular docking models of the sars-cov-2 spike glycoprotein and 3cl protease. Travel Med Infect Dis. 2020;101646.
15. Singh, Sweta, and Hector Florez. "Coronavirus disease 2019 drug discovery through molecular docking." F1000Research vol. 9 502. 3 Jun. 2020, doi:10.12688/f1000research.24218.1
16. Huynh T., Wang H., Luan B. (2020). In Silico Exploration of the Molecular Mechanism of Clinically Oriented Drugs for Possibly Inhibiting SARS-CoV-2's Main Protease. J. Phys. Chem. Lett. 11, 4413–4420. 10.1021/acs.jpclett.0c00994
17. R. Yan, Y. Zhang, Y. Li, et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Science, 367 (6485) (2020), pp. 1444-1448
18. Close E.M. Cottam, M.C. Whelband, T. Wileman Coronavirus NSP6 restricts autophagosome expansion Autophagy, 10 (8) (2014), pp. 1426-1441
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