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 Table of Contents  
EDITORIAL
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 1-3

Newer medications in coronavirus disease-2019 (COVID-19) infection


Department of Medicine, Assam Medical College and Hospital, Dibrugarh, Assam, India

Date of Submission24-Jul-2021
Date of Acceptance28-Jul-2021
Date of Web Publication05-Oct-2021

Correspondence Address:
Dr. S M Baruah
Department of Medicine, Assam Medical College and Hospital, Dibrugarh 786002, Assam.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-8239.327551

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How to cite this article:
Baruah S M. Newer medications in coronavirus disease-2019 (COVID-19) infection. Assam J Intern Med 2021;11:1-3

How to cite this URL:
Baruah S M. Newer medications in coronavirus disease-2019 (COVID-19) infection. Assam J Intern Med [serial online] 2021 [cited 2021 Dec 3];11:1-3. Available from: http://www.ajimedicine.com/text.asp?2021/11/2/1/327551

Over 3 crore cases in India and 18.3 crore cases worldwide have been reported to be infected with coronavirus disease-2019 (COVID-19) virus. There have been 4.2 lakh deaths in India and 40 lakh worldwide. Many believe that these numbers could be significantly underreported. These numbers have overwhelmed the health sector, with repurcations in all the fields, most importantly economic and mental health. Assam has reported more than 5 lakh cases and nearly 5000 deaths. The health sector has been specially put to the test with an ultimate result of tremendous development in the medical research, starting from vaccine, ventilators, oxygen delivery system to newer medications antivirals to immunomodulators.

Out of the various antiviral medications, remdesivir has been extensively used and studied. Many studies have claimed the benefit to shortened hospital stay and to improve viral clearance), whereas some studies have failed to show a clear mortality benefit. Oseltamivir, lopinavir, ritonavir, darunavir/ritonavir, and ribavirin were studied in various trials but none of them were able to show any benefit.

Favipiravir, a nucleoside analog that inhibits RNA-dependent RNA polymerase, taken in a dose of 1800mg per orally for 2 doses on day 1 and 800mg twice daily orally till 14 days may be of doubtful benefit only in moderate cases.[1] Molnupiravir, an oral antiviral prodrug of N-4-hydroxycytidine, which blocks replications of some RNA virus by introducing copying errors during replication (RDRP), is under clinical trial and has been showing the promising result.[2]

Tocilizumab, an anti-interleukin 6 (anti-IL-6) receptor inhibitor, may have benefits in patients with cytokine storm, especially in those with elevated IL-6 levels, high CRP, and other acute-phase reactants, mainly in critically ill patients, within 48h. It is given at a dose of 400mg intravenously for 2 days (12h apart) or 6mg per kg body weight intravenously for 2 dose––12h apart.[3]

Baricitinib, a JAK (Janus Kinase) inhibitor, has shown benefit when used in hospitalized patients requiring oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygen (ECMO). It is given at the dose of 4mg per day in combination with remdesivir.[4] Casirivimab/imdevimab is a monoclonal antibody combination that specially binds to spike protein receptor-binding domain (RBD) of SARS-COV-2 and thereby blocks the human angiotensin-converting enzyme 2 (ACE-2) receptor. It is said to reduce disease progression in high-risk outpatients with mild disease. The combination therapy of this drug has been recommended to prevent development of escape mutants and resistance. It is given as a single intravenous infusion of 1200mg + 1200mg.[5] Bamlanivimab and etesevimab are monoclonal antibody against S protein and prevent its engagement with ACE-2 receptor. They have been also recommended in mild cases and are said to prevent mutant and resistance.[6]

Bevacizumab, which is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor-A (VEGF-A), has shown beneficial effects especially if given at the beginning of clinical decompensation and early ARDS. It has been shown to prevent endothelial proliferation and alveolar hemorrhage or exudates or ARDS and fibrosis. It is given as a single intravenous (IV) dose of 400mg.[7]

Nitazoxanide, which is a broad-spectrum anti-parasitic and antiviral drug, is researched in clinical trials at a dose of 500mg thrice daily for 5 days in mild cases of COVID-19. It was shown that nitazoxanide therapy was safe and reduced viral load significantly compared to placebo. It acts by interfering with host-regulated pathways involved in viral replication amplifying cytoplasmic RNA sensing and type-1 IFN pathway. Nitazoxanide is often used with ivermectin in trails.[8]

Camostat mesilate originally developed for chronic pancreatitis in Japan is in clinical trials for use in COVID-19. It is a potent serine protease inhibitor. It inhibits TMPRSS2-13 and 11D/E/F. TMPRSS2 is a type 2 transmembrane serine protease that is widely expressed in epithelial cells that have been shown to facilitate cell entry of numerous viruses such as influenza, severe acute respiratory syndrome (SARS), and middle east respiratory syndrome (MERS). Dose used in trials is 200mg orally thrice daily for 5 days.[9]

Umifenovir, a fusion inhibitor, can prevent contact and penetration of virus to host cells via avoiding the fusion of the virus lipid shell to the cell membrane. It has been shown that ARB could inhibit COVID-19 infection by interfering the release of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from intracellular vesicles. Dose used in a study in Iran was 200mg thrice daily for 7 to 14 days. It has shown promising results.[10]

Itolizumab, anti-CD6 monoclonal antibody, selectively targets CD6, a pan T-cell marker involved in co-stimulation, adhesion, and maturation of T-cells. Itolizumab binding to domain 1 of CD6 blocks the co-stimulation pathway and leads to inhibition of proliferation of native T cells. This leads to a marked reduction in pro-inflammatory cytokines involving the Th-1 and Th-17 pathways namely IL-17A, TNF-ALFA, IL-6, IFN-Y, and IL-2. Marked elevation of cytokines/chemokines leads to hyper-inflammation and organ dysfunction. The first dose of itolizumab is administered at 1.6mg/kg. In some patients, an additional dose of 0.8mg/kg is administered after 1 week, if required.[11]

Ibrutinib and acalabrutinib are both bruton tyrosine kinase (BTK) inhibitors. Ibrutinib is used to treat indolent B-cell malignancies and chronic graft-versus-host disease (cGVHD). The potential for ibrutinib to abrogate pulmonary inflammatory cytokines, lung injury, and death was shown in a highly relevant lethal flu animal model. A study conducted in Boston at a dosage of 420mg/day has shown promising results in preventing severe disease in COVID-19 patients who were on treatment for Waldenstrom macroglobulinemia.[12]

Leflunomide is an immune-modulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Teriflunomide also has antiviral effects against numerous viruses which it achieves by inhibiting viral replication by interfering with nucleocapsid tegumentation and hence virion assembly. However, there are limited data from clinical studies to prove the application of DHODH inhibitors in COVID-19 patients. In a clinical trial done in Wuhan, China, it has shown promising results with decreased viral shedding time, reduction of inflammatory markers, and reduced hospital stay of patients.[13]

Baloxavir marboxil and favipiravir are novel inhibitors of the influenza RNA replication process by targeting different protein subunits of the influenza polymerase complex. Briefly, Baloxavirmarboxil is pro-drug and baloxavir acid is its active metabolite. Baloxavir acid inhibits cap-dependent endonuclease and favipiravir inhibits polymerase basic protein 1. As the SARS-CoV-2 and the influenza virus are both RNA viruses, baloxavir acid, and favipiravir are considered to be potentially effective against SARS-CoV-2 by blocking its RNA synthesis.[14]

Most of the drugs currently available for COVID-19 are not specifically designed against SARS-Cov-2. The researches for specific drugs are still going on. In the early stage of the disease inhibition of viral replication can prevent subsequent severity; whereas in severe cases antiviral in conjugation with anti-inflammatory molecules may be beneficial as the cytokines are the cause of multi-organ failure and death. Out of all antivirals, remdesivir is extensively studied and recommended in most of the protocols worldwide. The clinical efficacy and safety profile of anti-inflammatory agents like IL-6 inhibitors are controversial owing to the limited experiences; of course, it is still too early to draw a conclusion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis 2021;102:501-8.  Back to cited text no. 1
    
2.
Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, et al. Human safety, tolerability, and pharmacokinetics of molnupiravir: A novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chemother2021;65:e02428-20.  Back to cited text no. 2
    
3.
Klopfenstein T, Zayet S, Lohse A, Balblanc JC, Badie J, Royer PY, et al; HNF Hospital Tocilizumab Multidisciplinary Team. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect 2020;50:397-400.  Back to cited text no. 3
    
4.
Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al; ACTT-2 Study Group Members. Baricitinib plus remdesivir for hospitalized adults with covid-19. N Engl J Med 2021;384:795-807.  Back to cited text no. 4
    
5.
An EUA for casirivimab and imdevimab for COVID-19. Med Lett Drugs Ther2020;62:201-2.  Back to cited text no. 5
    
6.
Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: A randomized clinical trial. JAMA 2021;325:632-44.  Back to cited text no. 6
    
7.
Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M, et al. Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun 2021;12:814.  Back to cited text no. 7
    
8.
Rocco PRM, Silva PL, Cruz FF, Junior MACM, Tierno PFGMM, Moura MA, et al. Early use of nitazoxanide in mild Covid-19 disease: Randomised, placebo-controlled trial. Eur Respir J2021;58:2003725.  Back to cited text no. 8
    
9.
Breining P, Frølund AL, Højen JF, Gunst JD, Staerke NB, Saedder E, et al. Camostatmesylate against SARS-CoV-2 and COVID-19-rationale, dosing and safety. Basic Clin Pharmacol Toxicol 2021;128:204-12.  Back to cited text no. 9
    
10.
Nojomi M, Yassin Z, Keyvani H, Makiani MJ, Roham M, Laali A, et al. Effect of arbidol (umifenovir) on COVID-19: A randomized controlled trial. BMC Infect Dis 2020;20:954.  Back to cited text no. 10
    
11.
Loganathan S, Athalye SN, Joshi SR. Itolizumab: An anti-CD6 monoclonal antibody, as a potential treatment for COVID-19 complications. Expert Opin Biol Ther 2020;20:1025-31.  Back to cited text no. 11
    
12.
Treon SP, Castillo JJ, Skarbnik AP, Soumerai JD, Ghobrial IM, Guerrera ML, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients. Blood 2020;135:1912-5.  Back to cited text no. 12
    
13.
Hu K, Wang M, Zhao Y, Zhang Y, Wang T, Zheng Z, et al. A small-scale medication of leflunomide as a treatment of COVID-19 in an open-label blank-controlled clinical trial. Virol Sin 2020;35:725-33.  Back to cited text no. 13
    
14.
Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, et al. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: An exploratory randomized, controlled trial. Eur J Pharm Sci 2021;157: 105631.  Back to cited text no. 14
    




 

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