IJHAS_89_20R3_LTE

 Letter to Editor AQ1

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COVID‑19 infection: The prospects of 4
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pharmacotherapy 6
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8 Shashank M Patil, V B Chandana Kumari, Prithvi S Shirahatti1, S Sujay, 8
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9 M Tejaswini, Lakshmi V Ranganath2, M K Jayanthi3, Ramith Ramu 9
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Website:
12 www.ijhas.in Abstract: 12
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DOI:
The disastrous outbreak of coronavirus disease 2019 (COVID‑19) has triggered the investigation of
14 several therapeutic options following the redundancy of specific drugs against it. The virus possesses 14
10.4103/ijhas.IJHAS_89_20
15 advanced molecular mechanisms to effectively invade the host cell compared to its counterparts. 15
16 It results in a seamless and coherent infection and transmission, attributing to its enhanced 16
17 pathogenicity. The drugs that are currently being employed against COVID‑19 inhibit the viral load 17
18 in different stages of infection, including host cell–virus interaction, viral entry into the host cell, and 18
19 viral replication inside the host including genome replication and polypeptide chain production. This 19
20 commentary emphasizes the pharmacotherapeutic options available from the perspective of viral 20
21 life cycle and pathogenicity. 21
22 Keywords: 22
23 Coronavirus disease 2019, diagnosis, SARS‑CoV‑2, therapeutics, transmission 23
24 24
25 25
26
27 T he ongoing detrimental effects of the
coronavirus disease 2019 (COVID‑19)
have stipulated the investigation of
virus have been discussed alongside with
original indication, possible COVID‑19
indication, dosage information, and side
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28 28
Department of
29 Biotechnology and
numerous therapeutics in the absence of effects. 29
30 Bioinformatics, School specific treatment.[1,2] Unlike MERS‑CoV 30
31 of Life Sciences, JSS and SARS‑CoV‑1, the other two viruses of Most of the drugs that are currently being 31
Academy of Higher the family, COVID‑19 or SARS‑CoV‑2 has used to treat COVID‑19 were once used
32 32
Education and Research, against both MERS‑CoV and SARS‑CoV‑1,
33 1
Department of
been a global pandemic and it is reported 33
34 Biotechnology, Teresian by the WHO as such. [3,4] The pandemic as the SARS‑CoV‑2 possesses >80% 34
35 College, 2Department has spread over 208 counties, with China similar genome to that of SARS‑CoV‑1.[6,7] 35
of Chemistry, The reporting more than 90% of the cases and Along with these, antiviral, antimalarial,
36 36
National Institute of antiparasitic, and anti‑protozoans are also
37 Engineering, 3Department
deaths, being the central hub.[5] Although 37
38 of Pharmacology, JSS the disease shows symptoms associated being used.[8] Although a majority of drugs 38
39 Medical College, JSS with pneumonia, its genetic constitution are designed to interfere with the viral 39
Academy of Higher and structural features have been attributed genome replication,[9] they also display an
40 40
Education and Research, array of mechanisms such as inhibiting
41 Mysuru, Karnataka, India
to its extensive pathogenicity and infection 41
42 across the globe.[5,6] Herein, we report the host cell–virus interaction. For example, 42
43 Address for various pharmacotherapeutics used against hemagglutinin, a viral glycoprotein that 43
44 correspondence: COVID‑19 in brief, so that it can facilitate mediates the adsorption of viral particles 44
Dr. Ramith Ramu, to host cell membrane, can be targeted by
45 health‑care providers with foundational 45
Department of
46 Biotechnology and knowledge on pharmacotherapeutics that nitazoxanide, an antiprotozoal drug which 46
47 Bioinformatics, School are both currently being used and under was used against diarrhea.[10] A metabolite 47
48 of Life Sciences, JSS clinical investigation at the molecular level. of the drug known as tizoxanide binds 48
Academy of Higher to hemagglutinin to deactivate it. Doses
49 The mechanisms of the drugs targeting the 49
Education and Research,
50 Mysuru ‑ 570 015,
recommended are based on age groups; 50
51 Karnataka, India. This is an open access journal, and articles are 1–3‑year‑olds were recommended with 51
52 E‑mail: ramithramu@ distributed under the terms of the Creative Commons 52
jssuni.edu.in Attribution‑NonCommercial‑ShareAlike 4.0 License, which How to cite this article: Patil SM, Kumari VB,
53 allows others to remix, tweak, and build upon the work S h i r a h a t t i P S , S u j a y S , Te j a s w i n i M , 53
54 Received: 05‑04‑2020 non‑commercially, as long as appropriate credit is given and Ranganath LV, et al. COVID‑19 infection: The 54
Revised: 05‑05‑2020 prospects of pharmacotherapy. Int J Health Allied Sci
55 Accepted: 13‑05‑2020
the new creations are licensed under the identical terms. 55
56 2020;9:XX-XX. 56
Published: *** For reprints contact: reprints@medknow.com

© 2020 International Journal of Health & Allied Sciences | Published by Wolters Kluwer ‑ Medknow S1

 Letter to Editor

1 100 mg, 4–11 years with 200 mg, and above 12 years 14 days, twice a day. Remdesivir has been associated 1
2 with 300 mg for 5 days, orally. Adverse effects of with adverse effects such as nausea, vomiting, and rectal 2
3 nitazoxanide include nausea, headache, and abdominal bleeding, whereas ribavirin results in hemolytic anemia, 3
4 cramps. Patients may also come across discoloration hypocalcemia, hypomagnesemia, and embryonic toxicity 4
5 of urine and eyes, dizziness, and skin rash.[10] Another in pregnant women.[10] The other two drugs, favipiravir 5
6 drug known as arbidol hydrochloride or umifenovir and sofosbuvir, with the same molecular mechanism are 6
7 also works in the same mechanism. It was originally under clinical investigation with their dosage and side 7
8 designed to treat influenza and arbovirus.[8,9] Since it is effects yet to be revealed.[8] 8
9 under clinical investigations, the doses and side effects 9
10 are yet to be revealed. In addition to the binding to RNA as a nucleoside analog, 10
11 few drugs act as inhibitors of aspartic acid protease 11
12 In case of successful adsorption, SARS‑CoV‑2 tends to inhibitors. These proteases are needed for the production 12
13 enter the host cell using ACE2 protein as a gateway.[10] In and maturation of viral genomes.[10] The combination 13
14 this stage, few drugs try to inhibit the virus from entering of lopinavir and ritonavir is one of the most practiced 14
15 the host cell. Chloroquine and hydroxychloroquine therapies against COVID‑19. Known for their antiviral 15
16 impair the glycosylation of ACE2, by disrupting viral effects against HIV‑1, they are used to treat SARS‑CoV‑2 16
17 S protein, thereby preventing the entry of SARS‑CoV‑2 by inhibiting the protease enzyme.[8,9] It is recommended 17
18 into the host cell. Both were used to treat malaria, HIV‑1, that 100–200 mg  of the drug should be given for 14 days 18
AQ4
19 and autoimmune diseases due to their anti‑inflammatory for patients with symptoms of COVID‑19. However, 19
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AQ2 and immunomodulatory effects. [8,11] Apart from these drugs can cause intolerable gastrointestinal toxic 20
21 impairing ACE2, they also increase intracellular pH in effects such as diarrhea, fatal pancreatitis, and hepatic 21
22 host cells, thus inhibiting RNA synthesis. Being weak maladies.[10] Alongside lopinavir/ritonavir, several other 22
23 bases, they impair acid vesicles and inhibit the activity drugs are present that are potent enzyme inhibitors. 23
24 of viral enzymes, ultimately inhibiting the viral entry For example, nelfinavir is another protease inhibitor, 24
25 to the cell in case of pH‑dependent endocytosis. [12] which is reported to have similar properties like that 25
26 Chloroquine is consumed as 500 mg twice for 5 days and of lopinavir/ritonavir. It prevents proteolytic cleavage 26
27 hydroxychloroquine as 400 mg on the 1st day, followed by of the viral polyprotein precursors into individual 27
28 200 mg twice a day for 4 days, orally.[10] Adverse effects functional proteins. Ivermectin is an antiviral drug once 28
29 of these drugs include nausea, vomiting, abdominal used to treat HIV‑1 and dengue, which is now employed 29
30 cramps, and a metallic taste, whereas acute toxicity may against SARS‑CoV‑2.[11] It can dissociate the preformed 30
31 pose in the development of neuropathy, retinopathy, IMPα/β1 heterodimer, which aids in the viral protein 31
32 and cardiopathy.[10] In addition to these drugs, two more displacement. As the protein displacement is essential 32
33 drugs known as emodin and promazine also inhibit for maintenance of viral replication, targeting this 33
34 ACE2 by the same mechanism. However, their dosage displacement across the host cell would be a feasible 34
35 and adverse effects are not reported because they are yet option to inhibit the viral life cycle.[11] Yet another 35
36 to clear the clinical trials.[8] serine protease inhibitor, nafamostat, is said to inhibit 36
37 transmembrane protease serine 2 associated with the 37
38 Owing to the modified genome structure and advanced fusion process that facilitates the entry of SARS‑CoV‑2. 38
39 structural features, SARS‑CoV‑2 is more lethal than In addition to this, two more antiviral drugs used to 39
40 its counterparts.[6] It can invade the host cell despite treat influenza known as oseltamivir and zanamivir 40
41 maximal efforts from the innate immune system. In are reported to inhibit neuraminidase enzyme that may 41
42 such cases, the impairment of its replication proves to prevent the entry of the virus into host cells.[8] These 42
43
AQ3 be an efficient objective. Drugs are designed to impair drugs also reported to aid in the reduction of viral load 43
44 this process exhibit a mechanism known as molecular by reducing the shedding. These drugs, i.e., nelfinavir, 44
45 mimicry, where a biomolecule is replaced by another ivermectin, nafamostat, oseltamivir, and zanamivir, have 45
46 nonfunctional, yet structurally similar molecule. For not cleared the clinical tests; hence, their dosage level for 46
47 example, an antiviral drug known as remdesivir, which treating COVID‑19 remains unknown.[8] 47
48 was used against Ebola and MERS‑CoV viruses, mimics 48
49 guanosine nucleoside, and its incorporation into the Among the different types of drugs used against 49
50 RNA replication impairs the process finally halting the SARS‑CoV‑2, we comment on only one drug with 50
51 viral replication and growth.[11,12] The same mechanism original antibacterial indication. Azithromycin possesses 51
52 is being used by ribavirin, which was formulated to treat the ability to prevent secondary bacterial infection.[14] 52
53 hepatitis viruses and SARS‑CoV‑1.[13] Both the drugs Originally designed for treating bacterial infections, it is 53
54 are now been used to treat COVID‑19.[9,13] Remdesivir is also reported to have antiviral activity. Although precise 54
55 taken as 200 mg on the 1st day, followed by 100 mg for mechanisms remain unknown, potential mechanisms 55
56 up to 10 days intravenously, and ribavirin as 400 mg for have been proposed for the putative antiviral properties. 56

S2 International Journal of Health & Allied Sciences - Volume 9, Supplement 1, 2020

 Letter to Editor

1 One of the first mechanisms is similar to chloroquine and understanding of clinical features, diagnosis, pathogenesis, and 1
2 hydroxychloroquine, by increasing the intracellular pH treatment options. Pathogens 2020;9:???. AQ5
2
2. Hamid S, Mir MY, Rohela GK. Noval coronavirus
3 level to dismantle the viral replication process, thereby disease (COVID‑19): A pandemic Epidemiology, Pathogenesis and
3
4 leading to inhibition of viral growth. [11] The second potential therapeutics. New MicrO New Infect 2020;???:100679. 4
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5 mechanism proposed is mediated by the amplification 3. World Health Organization. WHO Director‑General’s Opening 5
6 of interferon (IFN) pathway of the host cell. Clinical data Remarks at the Media Briefing on COVID‑19; 11  March, 2020. 6
7 Available from: https://www.who.int/dg/speeches/detail/ 7
suggest that the viral load reduction is attributed to the
who‑director‑general‑s‑opening‑remarks‑at‑the‑media-brie
8 ability of azithromycin to induce pattern recognition fing‑on‑covid‑19‑11‑march‑2020. [Last accessed on 2020 May 04]. 8
9 receptors (IFNs and IFN‑stimulated genes). In addition 4. World Health Organization. Novel Coronavirus Disease 2019 9
10 to this, it acts directly on bronchial epithelial cells to (COVID‑19) Situation Update Report. No. 101. Available from: 10
11 regulate their normal function by reducing mucus https://www.who.int/docs/default‑source/coronavi ruse/ 11
situation‑reports/20200504‑covid‑19‑sit rep‑105.pdf?sfvrsn=4cd
12 secretion.[11] The recommended dosage of azithromycin 12
da8af_2. [Last accessed on 2020 May 04].
13 is 500 mg on the 1st day, followed by 250 mg for 4 days.[8] 5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features
13
14 of patients infected with 2019 novel coronavirus in Wuhan, China. 14
15 In conclusion, owing to the pharmacotherapeutic Lancet 2020;395:497‑506. 15
16 options currently available, we highlight the fact that 6. Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID‑19 16
infection: Origin, transmission, and characteristics of human
17 the pandemic can be controlled with effective treatment, 17
coronaviruses. J Adv Res 2020;???:???. AQ7
18 along with the maintenance of social distancing and 7. Yi Y, Lagniton PN, Ye S, Li E, Xu RH. COVID‑19: What has been
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19 quarantine. This is supported by many studies that learned and to be learned about the novel coronavirus disease. 19
20 have been conducted and reported on the significance Inter J of Bio Sci 2020;16:1753. 20
21 of stringent lockdown regulations in reducing the 8. Shetty R, Ghosh A, Honavar SG, Khamar P, Sethu S. Therapeutic 21
22 opportunities to manage COVID‑19/SARS‑CoV‑2 infection: 22
viral escalation. Apart from this nonpharmacological Present and future. Indian J Ophthalmol 2020;68:693.
23 management, some of the drugs are now being used, 9. McCreary EK, Pogue JM. Coronavirus disease 2019 treatment:
23
24 which have already cleared the clinical trials. We also A review of early and emerging options. InOpen Forum Infect 24
25 emphasize that, with the absence of specifically designed Dis 2020;7:???. 25
AQ5
26 drug as well as a potential vaccine, a combination of 10. Barlow A, Landolf KM, Barlow B, Yeung SY, Heavner JJ, 26
27 Claassen CW, et al. Review of emerging pharmacotherapy for 27
drugs with different and effective doses is the only the treatment of coronavirus disease 2019. Pharmacotherapy
28 solution to bring out the optimal management of the 2020;???:???. 28
AQ7
29 disease. 11. Choudhary R, Sharma AK, Choudhary R. Potential use of 29
30 hydroxychloroquine, ivermectin and azithromycin drugs in 30
31 Financial support and sponsorship fighting COVID‑19: Trends, scope and relevance. New Microbes 31
32 New Infect 2020;???:100684. AQ6
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Nil. 12. Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, et al.
33 A Review of SARS‑CoV‑2 and the ongoing clinical trials. Inter J
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34 Conflicts of interest of MolSci 2020;21:2657. 34
35 There are no conflicts of interest. 13. Khalili JS, Zhu H, Mak A, Yan Y, Zhu Y. Novel coronavirus 35
36 treatment with ribavirin: Groundwork for evaluation concerning 36
37 COVID-19. J Med Virol 2020;???:???. AQ7
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International Journal of Health & Allied Sciences - Volume 9, Supplement 1, 2020 S3