ReviewBhagat DArticle S, et al: A Systematic Review of Antiviral Drugs for the Treatment of the COVID-19 Pandemic

A Systematic Review of Antiviral Drugs for the Treatment of the COVID-19 Pandemic D S Bhagat, Meghraj Suryawanshi*, Indranil Suryawanshi Email: [email protected] Abstract

The present outbreak of Corona Virus Disease-19 (COVID-19) is a challenge to human existence and act as a threat to humanity as a whole. It spread very fast from one country to another and has now affected almost the whole world. As of now, there is no definite curative medicine for this pandemic but there is a hope of discovery of an effective treatment for this viral infection. According to scientific literature and clinical researcher, there are many antiviral drugs namely Chloroquine, Hydroxychloroquine, , , Lopinavir, , , and Dexamethasone that are prominently used in the treatment of COVID-19. This review article gives a brief idea regarding these antiviral drugs and how they are effective in this pandemic and their role in future discovery.

Key Words: Antiviral, COVID-19, Infection, Pandemic, Self-isolation, Virus, WHO

Introduction WHO renamed it as COVID-19. COVID-19 was In December 2019, a group of peoples were identified declared as a pandemic on 11 March 2020 by the 1 as patients in Wuhan city, Hubei, . World Health Organization (WHO). Among them, some had health problems like fever, COVID-19 is a type of Severe Acute Respiratory cough, nausea, headache, and lung infiltration. The Syndrome. It belongs to a virus family named Chinese Centre for disease control (CCDC) found coronaviridae. In medical sciences, to prevent a out that these health issues are related to intake of viral infection, antiviral drugs are prescribed for bat, snake, and marmot. The CCDC concluded that treatment. Antiviral drugs are the medicines that this is because of a virus which is a powerful variant cure virus infection. The scientific survey states that of Severe Acute Respiratory Syndrome (SARS). The there are many antiviral medicines which are being newly found virus was named SARS-CoV-2, and used for the treatment of various viruses, and such medicines are also used as a preliminary treatment for this pandemic.2 D S Bhagat1, Meghraj Suryawanshi2, 3, Indranil 4 Suryawanshi Chloroquine, Hydroxychloroquine, Favipiravir, 1 Department of Forensic Chemistry and Toxicology, Government Institute of Forensic Science, Aurangabad, Maharashtra - Remdesivir, Umifenovir, Lopinavir/, 431004 Ribavirin, and dexamethasone are currently 2 Department of Pharmaceutics, Shree Dhanvantary Pharmacy undergoing phases of a to test if they College, Kim, Surat, Gujarat -394110 are effective and safe to be used against COVID-19.3 3 School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan - 302017 and their role in COVID-19 4 Department of Forensic Chemistry and Toxicology, Government Institute of Forensic Science, Aurangabad, Maharashtra - treatment 431004 Chloroquine phosphate and Hydroxychloroquine * Corresponding Author Since chloroquine is known to have antiviral and Date of Submission: 24 Jul 2020, Date of Revision: 25 Aug 2020, anti-inflammatory activity, it has led to urgent trials Date of Acceptance: 27 Aug 2020 in many government and private organization. It is

How to cite this article: Bhagat D S, Suryawanshi M, Suryawanshi I:A Systematic Review of Antiviral Drugs for the Treatment of the COVID-19 Pandemic. MJPS 2020; 6(2): 109-113.

Manipal Journal of Pharmaceutical Sciences | September 2020 | Volume 6 | Issue 2 109 Bhagat D S, et al: A Systematic Review of Antiviral Drugs for the Treatment of the COVID-19 Pandemic the first drug used in the treatment of COVID-19. well as . It is used together with other China has included chloroquine to prevent and medications such as , , and treat COVID-19 pneumonia, as many patients were peginterferon alfa-2b or peginterferon alfa-2a for recovered by the treatment of this drug, and hence hepatitis C treatment. Ribavirin has interfered with the WHO officially announced the prescription RNA and DNA replication. Its antiviral activity is of the same in the treatment of COVID-19. not just interference with polymerase, but also with Chloroquine shows a direct antiviral effect by RNA capping that blocks the replication process in inhibiting virus replication, including inhibition the virus. The antiviral properties of Ribavirin were of flavi-virus, coronavirus, and retrovirus such as first noted in the treatment of hepatitis C, resulting HIV. Furthermore, it is known to have an immune- in the blockage of replication within the cell and modulatory effect involving reduction in synthesis cure the disease. Due to such an effective mechanism and release of tumor necrosis factor-α (TNFα) and against viruses, many drug authorities give clinical interleukin (IL)-6. Chloroquine is responsible for the trials approval to treat COVID-19.6 prevention of deleterious mechanisms which cause Umifenovir acute respiratory syndrome, for example, alteration In 1993, Russian Drug authorities granted a of tight junctions, pro-inflammatory cytokines licensed to Umifenovir to treat A and B release, and increase in the permeability of micro virus infection. Umifenovir is rapidly absorbed vasculature. Chloroquine and Hydroxychloroquine and distributed in the internal organs and tissues. (which is an analogue of chloroquine) are clinically Umifenovir inhibits the fusion of the virus with the relevant inhibitors of autophagy.4 membrane of the host cell and its subsequent entry. Remdesivir It is a hydrophobic molecule and has the ability to Remdesivir, originally developed in 2009 by Gilead form aromatic stacking interaction with a certain Sciences, was part of a program for hepatitis C amino acid residue which directly acts against the research and development. But unfortunately, it was virus. This aromatic residue interaction within the not effective against hepatitis C. Additional studies viral glycoprotein is involved in fusion and cellular showed that it could be used against virus recognition, thus resulting in plasma membrane disease and virus infection. Remdesivir interfere with clathrin-mediated exocytosis and is a nucleotide analog and it has shown activity prevent .7 against Lassa fever virus, respiratory syncytial virus, Favipiravir Nipah virus, Hendra virus, Junín virus, and Middle Favipiravir is a licensed drug that has been developed East respiratory syndrome (MERS) and SARS against influenza in Japan. One of its exclusive coronavirus. Remdesivir inhibits RNA-dependent features is that it has broad-spectrum activity against RNA polymerase, resulting in termination of RNA RNA viruses, including respiratory syncytial virus, chain in the cell. Hence, it is one of the best compounds rhinovirus, and influenza virus. Previous studies against COVID-19. The drug is currently being confirmed that Favipiravir can be used for treatment tested as a specific treatment for COVID-19, and against Ebola virus, , and Lassa virus, and has been authorized for emergency use in countries severe fever with thrombocytopenia syndrome. such as India, Japan, Singapore, and US for patients Favipiravir blocks RNA synthesis of the virus by with severe symptoms. Recently, The Central Drug terminating the chain at the site where the RNA Standard Control Organization (CDSCO) of India is incorporated into the host cell. In comparison, granted emergency approval to Hetero Pharma and Tamiflu inhibits the sialic Cipla to manufacture and market generic product of acid cleavage and the subsequent entry of the Remdesivir to treat severe cases of COVID-19.5 virus into the cell. This property of Favipiravir Ribavirin implies a potential for treating critical infectious Ribavirin (or Tribavirin) is an antiviral drug used diseases like COVID-19.8 Strides Pharma Science against RSV infection, viral hemorrhagic fever as Ltd. Delhi has developed the generic product of

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Table 1: List of antiviral drugs for COVID-19 treatment2,3 Drug Name Type of drug Actual Role Role in COVID-19 Dosage Used to prevent and treat Prevent deleterious mechanisms 500mg Chloroquine Chloroquine Anti-malarial malaria which might cause an acute twice a day respiratory syndrome Used to treat malaria and Inhibit RNA replication by 400mg Hydroxychloroquine Anti-malarial may work in rheumatoid blocking the activity of RNA Hydroxychloroquine arthritis polymerase once a day Used against Ebola and Inhibits RNA-dependent RNA 200mg Remdesivir Remdesivir Antiviral infection polymerase, resulting in RNA once a day chain termination in cell Used to treat viral 500mg Ribavirin once Chemical structure of ribavirin hemorrhagic fever, a day interferes with RNA capping Ribavirin Antiviral hepatitis C and that results in blockage of Respiratory syncytial replication process in virus virus (RSV) infection Used to treat influenza A Inhibits the fusion of the virus 200mg Umifenovir and B virus infection with the cell membrane of the twice a day Umifenovir Antiviral host thus preventing entry into the host cell Used against respiratory Inhibit viral RNA synthesis by 600mg Favipiravir syncytial virus, rhinovirus chain termination mechanism at once a day Favipiravir Antiviral and influenza virus the site of RNA incorporation into the host cell This combination 200mg is used for the Lopinavir/50mg Act as a protease inhibitor and Lopinavir/Ritonavir Antiviral treatment of human Ritonavir two tablets cytochrome P 3A inhibitor immunodeficiency virus 450 twice daily (HIV) infection Used in various conditions 6mg Dexamethasone like arthritis, immune once a day Anti- Show anti-inflammatory action Dexamethasone system disorder and inflammatory in severe COVID-19 patients allergic reaction of skin and eyes

Favipiravir originally developed by Avigan of prescribed to patients with haemophilia, cardiac Toyama Chemical, Japan, and become the first conduction disorder, cardiovascular disease, and Indian company to have commenced the export of those with structural heart diseases. Many scientists Favipiravir . Favipiravir has demonstrated recommend the Lopinavir for the treatment of positive outcome in COVID-19 treatment globally. COVID-19 and clinical trials are under process.10 Recently, the Glenmark Pharmaceuticals Pvt. Ltd, Dexamethasone has been launched a generic Favipiravir tablet under Dexamethasone is a glucocorticoid drug and its the brand name Fabiflu.9 action is generic. It is used in various condition Lopinavir/Ritonavir like arthritis, immune system disorder, and allergic Lopinavir is a protease inhibitor, which is has been reaction of skin and eyes. Dexamethasone inhibits widely used against HIV and is now a promising the phospholipase A2 and blocks the inflammatory drug for the treatment of COVID-19. It is given activity of mediators. Researchers of Oxford in combination with another protease inhibitor, University claimed that dexamethasone was found Ritonavir. The latter inhibits the activity of as an effective medicine against severe COVID-19 cytochrome P450 3A, and therefore it increases patient. In severe COVID-19 patients, due to the half-life of Lopinavir. Lopinavir/ritonavir is prolonged virus infection, there is inflammation in

Manipal Journal of Pharmaceutical Sciences | September 2020 | Volume 6 | Issue 2 111 Bhagat D S, et al: A Systematic Review of Antiviral Drugs for the Treatment of the COVID-19 Pandemic the lung sac, and the anti-inflammatory mechanism Corona Virus: An Epidemic to Pandemic. of dexamethasone play an important role against International Journal of Research in the infection.11 Pharmaceutical Science, April, 2020. 2. Singh AK, Singh A, Shaikh A, Singh R, Misra Future aspect A. Chloroquine and hydroxychloroquine in As discussed, antiviral drugs are being used for the treatment of COVID-19 with or without the treatment of COVID-19. Many government diabetes: A systematic search and a narrative research organization, doctors, clinical researchers, review with a special reference to India and other and industry experts are engaged in the development developing countries. Diabetes & Metabolic of target-oriented medicine for COVID-19. In the Syndrome: Clinical Research & Review, March, current situation, some pharmaceutical companies have launched generic products to cure this 2020. pandemic. As academicians and researchers, we 3. Serap Simsek, Serhat Unal. Antiviral treatment suggest that nowadays it is better to follow the rules of COVID-19. Turkish Journal of Medical and guidelines given by WHO and respective state Sciences, April, 2020. governments to avoid infection and become a self- 4. Kerstin Frie and Kome Gbinigie. Chloroquine protector. and Hydroxychloroquine: Current evidence of their effectiveness for treating COVID-19. Conclusion Centre for Evidence Based Medicine, Nuffield From literature survey and other studies, Department of Primary Care Health Sciences, we concluded that antiviral drugs namely University of Oxford, March, 2020. Chloroquine, Hydroxychloroquine, Remdesivir, 5. Abinit Saha, Ashish Ranjan Sharma, Manojit Ribavirin, Lopinavir, Umifenovir, Favipiravir, and Bhattacharya, Garima Sharma, Sang-Soo Dexamethasone are being used as initial treatment Lee, and Chiranjib Chakrabortya. Probable for COVID-19, resulting in an increased percentage Molecular Mechanism of Remdesivir for the of the recovery. Among them, Remdesivir and Treatment of COVID-19: Need to Know More. Favipiravir have positive outcomes against the Archives of Medical Research, May 2020. infection. The pharmaceutical companies have 6. Khalili JS, Zhu H, Mak NS, Yan Y, Zhu Y. developed generic products of both drugs under Novel coronavirus treatment with ribavirin: the brand name Cipremi by Cipla and Fabiflu by Groundwork for an evaluation concerning Glenmark. These products are a milestone for the COVID‐19. Journal of Medical Virology, whole world to overcome on this pandemic. For the March, 2020. need of humanity and society, research communities 7. Naveen Vankadari. Arbidol: A potential antiviral and organizations are trying to find out a definite drug for the treatment of SARS-CoV-2 by and curative medicine for the disease and hope that blocking trimerization of the spike glycoprotein. within a short time, it will be available. International Journal of Antimicrobial Agent, Acknowledgement April, 2020. Authors would like to express their gratitude 8. Yousuke Furita, Takashi Komeno and Takaaki towards medical responders, doctors, researchers, Nakamura. Favipiravir (T-705), a broad and COVID-19 warriors, who are globally spectrum inhibitor of viral RNA polymerase”, supporting humanity in such a critical situation. In The Proceedings of Japan Academy, Series B, this sequence, we as academicians have taken steps Physical and Biological Sciences, August, 2017. to collect scientific information and have submitted 9. “Strides develop Favipiravir antiviral tablets; a manuscript for publication. drug shows positive outcome in Covid-19 treatment”, April 29, 2020. References 10. Matthieu Gregoire et.al. Lopinavir 1. Sarkar A, Kundu M, Venkataramana P, in COVID-19 Patients. Chakraborty P. SARS-CoV-2/2019-Novel

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Journal of Antimicrobial Chemotherapy, Oxford by up to one third in hospitalized patients Academy, May, 2020 with the severe respiratory complication of 11. “Recovery Randomised Evaluation of COVID-19 COVID-19”. Oxford University News Released, Therapy, Low-cost dexamethasone reduce death June 16, 2020.

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