Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2021 | Month : August | Volume : 15 | Issue : 8 | Page : LE01 - LE08 Full Version

Hype and Hope of Emerging Therapies to Safeguard against COVID-19 Pandemic


Published: August 1, 2021 | DOI: https://doi.org/10.7860/JCDR/2021/49181.15257
Sunil Shewale, Vaishali Undale, Sameer Parekh, Pramod Pujari, Maruti Shelar, Sohan Chitlange

1. Research Student, Department of Pharmacology, Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune, Maharashtra, India. 2. Head, Department of Pharmacology, Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune, Maharashtra, India. 3. Assistant General Manager, Department of Clinical Research and Pharmacovigilance, Serum Institute of India Pvt. Ltd., Pune, Maharashtra, India. 4. Senior Manager, Department of Clinical Research and Pharmacovigilance, Serum Institute of India Pvt. Ltd., Pune, Maharashtra, India. 5. Assistant Professor, Department of Pharmacognosy Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune, Maharashtra, India. 6. Principal, Department of Pharmaceutical Chemistry, Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune, Maharashtra, India.

Correspondence Address :
Sunil Shewale,
Research Student, Department of Pharmacology, Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune-411018, Maharashtra, India.
E-mail: ms.shewale85@gmail.com

Abstract

The Coronavirus Disease-2019 (COVID-19) is a highly contagious disease presenting with multiple non specific symptoms and caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Despite its dissemination and worsening trends researchers are still searching for the best treatment option. Timely diagnosis is the key to get more appropriate treatment regimen. Several clinical trials are ongoing to determine the efficacy and safety of existing and new therapies against Coronavirus Disease -2019 (COVID-19). These include corticosteroids, antivirals, monoclonal antibodies, interferon Alpha 2b and other immune modulators. In addition to treatment, efficacious and safe vaccines are required to slow viral transmission and to prevent further morbidity and mortality. The vaccination is useful tool to get control over the virus. Although, mass immunisation campaigns are ongoing in many countries, global coverage is crucial for getting the pandemic under control. This descriptive review collated the information on current diagnostics tools for determination of COVID-19 infection and available preventive and therapeutic strategies based on the ongoing clinical trials data and published literature.

Keywords

Coronavirus disease-2019, Diagnostic tools, Treatment, Vaccines

The Coronavirus Disease -2019 (COVID-19) is an infectious disease which has spread to almost every part of the world. This disease is caused by SARS-CoV-2, belonging to Coronaviridae family (1). The clinical manifestation of disease ranges from asymptomatic case to severely ill patients and deaths. Those who get infected experience mild to moderate symptoms such as cough, dyspnea, fever, bodyache and viral pneumonia and recover without any special cure (2). Elders and those with underlying medical problems such as cardiovascular disease, chronic respiratory disease, diabetes, and cancer are more in danger to develop serious illnesses (2). With the increasing number of cases daily, globally multiple drugs are being tested as possible candidates. Researchers are also testing the use of drugs which were found to be effective against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV disease (3). However, there are currently no specific antivirals or drug combinations introduced for SARS-CoV.

The COVID-19 vaccination is an important tool with multiple possible benefits. An effective vaccine could prevent the infection, reduce progression to severe disease, or block the transmission within a population. However, the vaccine effectiveness depends on multiple factors including the host factors, virus factors (e.g., viral mutations), programmatic factors (e.g., storage and handling of vaccine). The need of the hour is wearing masks, social distancing, getting vaccinated and an early diagnosis of the infection which enables initiating the standard of care at earliest. All the necessary steps taken can reduce the chance of being exposed to the virus and also the chance of infecting the community.

DIAGNOSTIC TOOLS

1. Screening Test

The amplification of the viral genetic material extracted from the saliva or mucus sample is done using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and is a widely-used method. Isothermal nucleic acid amplification test is another rapid and robust diagnostic method conducted in the field and at the local Point-of-Care (POC) centres without the usage of specialised equipment and trained professionals to interpret the results (4). Rapid antigen test is carried out to determine the proteins that are present on the virus surface. Since this process is quick, it is more useful to accelerate the testing at all government hospitals, private health facilities, community settings and remote regions (5). Recently, Indian Council of Medical Research (ICMR) has approved CoviselfTM home based self-test kit manufactured by Mylab discovery solutions ltd., Pune (6). On the other hand, rapid antibodies test is a quantitative test for the detection of SARS-CoV-2 IgG antibodies. Positive test result indicates past exposure. Neutralising antibodies are also measured by Plaque Reduction Neutralisation Test (PRNT), but it is not practical for large scale serodiagnosis (7). Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) is an FDA-approved diagnostic tool for detection of SARS-CoV-2 E gene and N2 region of the N gene (8). This test is conducted using nasal or oral swabs like RT-PCR. However, the testing machine is costlier it can run only few samples at a time and requires to run under Biosafety 2 Level (BSL-2) conditions with appropriate biosafety precautions (9).

Artificial Intelligence and voice forensic technologies can search specific patterns in voice, tone and other sounds post COVID-19 infection. The analysis of speech, cough and respiratory segment using smartphones or other machine learning classifiers have shown up to 80% accuracy while distinguishing between healthy and COVID-19 sounds (10),(11).

2. Biomarkers Test

Several laboratory parameters are indicative of the SARS-CoV-2 infection in early stage. For example, increased values of liver enzymes, Lactate Dehydrogenase (LDH), muscle enzymes, and C-reactive protein can be detected (12). The elevated Neutrophil to Lymphocyte Ratio (NLR) and Platelet to Lymphocyte Ratio (PLR) could be the expression of the inflammatory storm. D-dimer value is also increased in COVID-19 cases (13). Blood lymphocytes are decreased and laboratory alterations of multi-organ imbalance (high amylase, coagulation disorders, etc.,) are also found to be raised (14).

3. Radio-imaging

In view of increasing number of confirmed cases and suspects of COVID-19 Indian Radiological and Imaging Association (IRIA) recommends that chest radiograph can be performed in suspect case if any ‘two’ of the following are present (15):

• Fever (without any apparent non respiratory cause)
• Shortness of breath
• Immunocompromised host
• Hypoxia (room air SpO2 < or equal to 94%)
• Respiratory rate > or equal to 20/min

It shows patchy or diffuse reticular-nodular opacities and consolidation, with basal, peripheral and bilateral predominance in advance stage of the disease. Finally, to quantify the extent of COVID-19 lung involvement, a severity score (Radiographic Assessment of Lung Oedema-RALE) between 0 and 48, ranging from the absence of any pathological sign (score 0) to the complete pathological involvement of lung parenchyma (score 48) will be given (16). Standard radiographic examination (X-ray) of the chest has a low sensitivity in identifying early lung changes (17).

In chest High Resolution Computed Tomography (HRCT), Ground Glass (GGO) pattern is the most common finding in COVID-19 infections. The severity of the lung involvement on the CT correlates with the severity of the disease. It is performed by scoring the percentages of each of the five lobes that is involved as <5% involvement, 5-25% involvement, 26-49% involvement, 50-75% involvement and >75% involvement. The total Cycle Threshold (CT) score is the sum of the individual lobar scores and can range from 0 (no involvement) to 25 (maximum involvement), when all the five lobes show more than 75% involvement (18). Ultrasonography (USG) a low cost, radiation free method has potential for rapid assessment of the severe pneumonia/Acute Respiratory Distress Syndrome (ARDS) and to track disease evolution (19).

PHARMACEUTICAL TREATMENT OPTIONS

The mass vaccination program is ongoing in many countries but it is a time-consuming process. Current, SARS-CoV-2 treatment protocol is based on development of signs and symptoms, to the COVID-19 infected individual. However, the oxygen therapy is the first option that addresses the respiratory difficulties developed. In cases of respiratory failure which could be refractory to Oxygen therapy, Non Invasive (NIV) and Invasive Mechanical Ventilation (IMV) might be essential. Apart from this, the intensive care unit is necessary to deal with the complicated forms of the disease. (Table/Fig 1) indicates the general COVID-19 management strategies which are followed in the hospital premises (20),(21).

1. Antiviral Drugs

Remdesivir is the most promising antiviral drug in the treatment of SARS-CoV-2 infection. It works by targeting viral Ribonucleic Acid (RNA)-dependent RNA polymerase (RdRp) while evading proofreading by viral exo-ribonuclease 17 that result in premature termination of viral RNA transcription (22). Remdesivir has initially shown its superiority against placebo in recovering the hospitalised patients suffering from the mild to severe COVID-19 disease (23),(24). However, World Health Organization (WHO) solidarity study conducted across 40 countries and prospective trial performed in India found that remdesivir therapy is not useful in improving clinical outcome and length of hospital stay of patients (25),(26). Nausea, vomiting, rectal haemorrhage, and hepatic toxicity are some of the uncertain adverse effects of this drug (27).

Same as remdesivir, another drug favipiravir act as an inhibitor of the RNA-dependent RNA polymerase and reduce the efficacy of viral replication (28). This drug has received approval for emergency use in mild to moderate COVID-19 infections in Italy, Japan, Russia, Ukraine, Uzbekistan, Moldova, Kazakhstan, Turkey, Bangladesh, UAE and India last year during the pandemic (29). In the clinical studies conducted in China, favipiravir has shown superior recovery rate compared to umifenovir and shorter viral clearance time than lopinavir/ritonavir, respectively (30),(31). Recent prospective, randomised phase-3 clinical trial of oral favipiravir plus supportive care versus supportive care alone in 18-75 years adults with mild to moderate coronavirus disease in India also suggest significant improvement in time to clinical cure (32). As of 21st of May, 2021; there are 23 studies registered on website clinical trials.gov; which are in active recruiting phase for assessment of this drug in COVID-19 management.

Ribavirin, a guanine analogue has its activity against other nCoVs and makes it a candidate for COVID-19 treatment. The drug had been earlier tested against MERS-CoV infection. There it has been reported to increase survival of patients compared to other treatments (33),(34). The combination of ribavirin and lopinavir-ritonavir with interferon-β-1b led to a significant shortening in the duration of viral shedding (35). Other studies reported that, ribavirin has failed to improve the clinical outcome or viral clearance in the treatment of MERS (36),(37). A systemic analysis, of more than 25 ribavirin studies for the treatment of SARS disease, revealed no conclusive results for efficacy (38). Similarly, a retrospective cohort study was conducted to study the effect of ribavirin therapy against severe COVID-19. In this study, 44 patients receiving intravenous ribavirin were analysed against 71 patients in control group. Patients in treatment group did not show improvement in mortality rate and time to recovery compared to control arm (39). At the same time, it also demonstrates the possibility of severe dose dependent haematologic disorders and liver toxicity (38).

The HIV protease inhibitors such as lopinavir and ritonavir are being used as a combination of HIV remedial drugs (40). The evidence also suggests that, these drugs also have inhibitory effects against 3-chymotrypsin-like protease of MERS and SARS disease (41),(42),(43). Whereas, a randomised control clinical trial of these drugs versus standard of care in 199 patients hospitalised with severe COVID-19 reported no benefits beyond standard of care and fails to decrease mortality rate (44). Moreover, A systematic review of randomised clinical trials of lopinavir-ritonavir for assessment of its efficacy and safety does not observed improvement in virological cure, radiological findings, mortality in COVID-19 patients (45).

Oseltamivir, a neuraminidase inhibitor approved for the treatment of influenza was included as a regimen for the treatment of COVID-19 in early stage of pandemic (46). A survival analysis of 1190 adults in retrospective cohort study indicated that, administration of oseltamivir reduces the risk of severe disease and is associated with slowing down the disease progression (47). However, in a retrospective case series of 79 adults with COVID-19 infection, early use of oseltamivir had no effect on COVID-19 and did not effectively slow the progression of the disease (48). Umifenovir (also known as Arbidol) is promising repurposed antiviral agent with a unique mechanism of action targeting the S protein or Angiotensin-Converting Enzyme 2 (ACE2) interaction and inhibiting membrane fusion of the viral envelope (49). In randomised, controlled study, Hydroxychloroquine (HCQ) followed by Arbidol compared to HCQ followed by Lopinavir/ritonavir, significantly contributes to clinical and laboratory improvements, including oxygen saturation, Intensive Care Unit (ICU) admissions, duration of hospitalisation, chest CT involvements, WBC, and ESR but study warranted more research (50). A systematic review and metal analysis of 12 studies conducted in 1052 COVID-19 patients found that, umifenovir was safe for administration but does not significantly reduces the hospital length of stay, symptoms or disease progression (51).

2. Anthelmintic

Ivermectin an anti-parasitic agent has also shown antiviral activities against SARS-CoV-2 (52). A single dose is found to effect ~5000-fold reduction in Corona virus at 48 hours in in-vitro study (53). A double blind, randomised, placebo contorolled clinical study of Ivermectin conducted in Cali, Coombia, in mild COVID-19 476 adult patients, did not observed improvement in illness (54). Similarly, other placebo controlled clinical study was conducted in Bihar, India. In this study, 55 patients administered with the ivermectin 12 mg on day 1 and day 2 of admission, does not show difference in primary outcome compared to 57 patients those who have received the placebo (55). Conversely, the case control study conducted in All India Institute of Medical Sciences, Bhubaneswar, India whereas two-dose ivermectin prophylaxis at a dose of 300 mcg/kg in a gap of 72 hours among healthcare workers indicated 73% reduction in SARS-CoV-2 infection for the following month (56).

3. Antimalarials

Chloroquine and hydroxychloroquine are well known drugs for the prevention and treatment of malaria as well as the treatment of chronic inflammatory diseases including Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) (57). Small, randomised study conducted in hospitalised adults in China, compared chloroquine with Lopinavir/Ritonavir (LPV/RTV) wherein 10 moderate to severe COVID-19 patients received 500 mg chloroquine and 12 patients received lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days. Chloroquine was associated with shorter time to RT-PCR conversion and quicker recovery of patients than LPV/RTV. However, total number of patients were limited in this study. Also, the median time of treatment initiation post onset of any symptom was shorter in patients treated with chloroquine compared to LPV/RTV (58). Many clinical trials are registered and active on clinicaltrials.gov but no high-quality evidence exists for the efficacy of chloroquine for treatment of SARS-CoV-2. Hydroxychloroquine is proposed to control the cytokine storm that occurs in critically ill late phase SARS-CoV-2 infected patients (59). In the systematic review, of 24 clinical studies for assessment of efficacy and safety of Chloroquine and hydroxychloroquine amongst the COVID-19 patients, 100% clinical trial data showed no significant difference in virus clearance or reduction in viral transmission compared to control group. Similarly, nearly 58% patients observed no benefit against achieving primary outcome of efficacy among the observational studies. Moreover, many clinical and observational studies had also reported high incidence of cardiac adverse events of QTc prolongation and/or arrhythmias in treated patients (60). The patients suffering from retinopathy, deficiency of glucose-6-phosphatase, QTc prolongation in electrocardiograms, history of allergy to hydroxychloroquine, pregnant women or the breastfeeding mothers are contraindicated for receiving hydroxychloroquine therapy too (61).

4. Antibiotics

Azithromycin is known to have good potential in preventing severe respiratory tract infections among pre-school children when it is administrated to patients suffering from viral infection (62). An open label, randomised, multicenter clinical trial was conducted in Brazil in which patients were randomised in 1:1 ratio to receive oral azithromycin (500 mg once daily for 10 days) plus standard of care (n=214) or standard of care alone. Addition of azithromycin to standard of care does not show any superiority in primary outcomes based on a 6-level ordinal scale that ranged from not hospitalised (1) to death (6) (63). Azithromycin has been studied in randomised, controlled clinical trial, conducted in hospitalised COVID-19 patients. One group of 2582 patients received 500 mg of azithromycin once daily for 10 day plus standard of care where as other group of 5181 patients were administered with standard of care alone. The mortality rate, time to hospital discharge, risk of disease progression rate was similar in both groups and thus the study found no benefit of azithromycin in hospitalised COVID-19 patients (64). Another study in UK observed that, the administration of azithromycin in outpatients with ≥65 years of age or ≥50 years with at least one co-morbidity was ineffective in terms of reducing the risk of hospitalisation or recovery time. While 80% and 77% patients were found recovered in azithromycin and standard of care group after 28 days respectively (65). The use of azithromycin in conjunction with the regimen of hydroxychloroquine might be a promising alternative but the documented evidence is limited. Whereas, the available data for this combination is based on observational, non randomised or other retrospective studies for evaluation of its possible benefit in patients with SARS-CoV-2 infection (66),(67),(68),(69).

5. Immunomodulators

Mesenchymal Stem Cells (MSCs) are proven to have an anti-inflammatory action by decreasing pro-inflammatory cytokines and producing paracrine factors to repair tissues. MSCs cannot only restore endothelial permeability but also reduce inflammatory infiltrate (70) and can thus alter the innate and adoptive immune responses in COVID-19 (71). Different sources of stem cells could be used for different groups of patients. The isolation and availability of clinical grade MSCs under GMP compliant cell processing facilities is a major challenge for a number of countries especially the developing and underdeveloped countries.

Tocilizumab, used in the treatment of RA exacerbation, is a monoclonal antibody developed and customised to inhibit the binding of interleukin-6 to its receptors alleviating cytokine release syndrome which is used in severe COVID-19 infection (72),(73). Two randomised, placebo controlled clinical trials of tocilizumab reported that use of tocilizumab is not associated with prevention of intubation, clinical outcome or mortality rate in hospitalised severe COVID-19 patients (74),(75). Another, COVINTOC trial conducted in India was open label phase 3 study wherein moderate to severe COVID-19 adult patients were randomised to receive tocilizumab 6 mg/kg plus standard care or standard care alone to assess the progression of COVID-19 disease from moderate to severe or sever to death during 28 days follow-up period. This study does not support the routine use of tocilizumab in hospitalised moderate to severe COVID-19 patients (76). There are few other immunomodulators like sarilumab, canakinumab, ravulizumab, gemtuzumab ozogamycin, namilumab, adalimumab, otilimab etc., which are being studied in various clinical trials for treatment against COVID-19 (77).

6. Steroids

Corticosteroids have anti-inflammatory, antifibrotic effects and research is ongoing for its use in patients with Acute Respiratory Distress Syndrome (ARDS) and septic shock (78). Use of corticosteroid has been evaluated in randomised, controlled, open label clinical trial conducted in SARS-CoV-2 patients. A 2104 patients received single daily dose of 6 mg dexamethasone plus standard of care by oral or intravenous route for 10 days, whereas 4321 patients received only standard of care. The result of this study indicated, lowering of 28 days mortality rate with IMV or oxygen support in patients receiving dexamethoasone compared to other group (79). Systemic review of 60 registered clinical studies also show promising results and recommend the use of methylpredinisolone and dexamethasone in severe COVID-19 patients (80).

7. Convalescent Plasma

Convalescent plasma has also been used as the last resort to improve the survival rate of critically ill patients. The immunoglobulin antibodies in the plasma of patients recovering from viral infection might suppress viremia (81). The Convalescent Plasma Therapy (CPT) was evaluated in past during H1N1, Ebola2 and SARS-CoV-1 pandemics, however controlled clinical trial data was limited to support its efficacy (82),(83),(84). Government of India, FDA approved off label use of CPT with dose of 4 to 13 mL/kg under emergency use during last year for patients with severe life threatening COVID-19 (85),(86). Even though it looks promising, data from multiple studies including India reported, no significant benefits of CPT in improving clinical outcome, hospital stay or overall mortality in COVID-19 patients treated with convalescent plasma versus standard therapy (87),(88),(89). Conversely, CPT might carry risk of transfusion-associated infections, allergic reactions, Transfusion-Related Acute Lung Injury (TRALI), Transfusion-Associated Circulatory Overload (TACO) and antibody-mediated enhancement and before its use various CPT parameters are required to be taken into consideration like donor selection, antibody quantification, timing of use, and dosing etc., (90). As such, people are not getting the benefit from CPT, Ministry of Health & family Welfare, Government of India released a revised treatment algorithm on 17-May-2021 in which plasma therapy is dropped (20).

8. Monoclonal Antibodies

The REGN-COV2 is the cocktail of two neutralising IgG1 monoclonal antibodies (mAbs) namely, casirivimab and imdevimab that inhibits the binding of virus to the human ACE2 receptor by attaching and blocking epitopes of S protein of SARS-CoV-2 virus indicating high neutralisation ability in non human primates (91). Interim analysis of an ongoing phase1/2/3 trial conducted by Regeneron evaluated the safety, tolerability, and efficacy of a single IV infusion of casirivimab and imdevimab against placebo in COVID-19 non-hospitalised patients. The analysis showed that, mAbs reduce the higher viral load in patients who were seronegative at baseline and the primary end point of time-weighted average change from baseline was achieved wherein 2.8% patients treated with casirivimab and imdevimab had COVID-19-related medically attended visits compared to 6.5% in placebo (92). Also, the preliminary result of a Phase 3 trial of REGN-COV (casirivimab/imdevimab) revealed that a single dose of 1.2 g of casirivimab and imdevimab administered subcutaneously to uninfected house-hold contacts reduced the risk of symptomatic SARS-CoV-2 infection by 72% during the first week and by 81% through day 29 compared with placebo (93).

Bamlanivimab and etesevimab are neutralising monoclonal IgG1 antibodies like REGN-COV2 which binds to S protein of coronavirus (94). COVID-19 related hospitalisation was 0.9% for bamlanivimab together with etesevimab compared to 5.8% in placebo with significant decrease in viral load from day 3 to day 11 (95). Initial data from randomised, placebo-controlled phase-III trial conducted by Eli Lilly in 12-17 years old adolescents and 18 years and above adults in 1035 patients randomised 1:1 to receive bamlanivimab together with etesevimab versus placebo demonstrated 70% reduction in COVID-19-related hospitalisations and deaths relative to placebo treatment (96).

9. Janus Kinase (JAK) Inhibitors

Baricitinib is a selective and reversible Janus Kinase 1 (JAK1) and 2 (JAK2) inhibitor (97). Its in vitro assessment was found to have an effect on cytokines signaling pathway which resulted in hyperinflammation and severe COVID-19 disease (98). A baricitinib plus remdesivir versus remdesivir alone in randomised, double blind clinical trial was found to be effective in reducing the recovery period and improving the clinical outcome of hospitalised COVID-19 patients indicating superiority of the combination (99). However, data is not available on effect of these drugs on different SARS-CoV-2 variants.

Another selective inhibitor of JAK 1 and 2 ruxolitinib did not show significant improvement compared to standard of care treatment in prospective, randomised, comparator phase 2 clinical study, but chest CT was found significantly improved in many patients (100).

AYURVEDIC, SIDDHA, UNANI AND HOMEOPATHY FORMULATIONS

Alternative medicine system includes Ayurveda, Siddha, Unanis and Homeopathy medicines are used as complimentary therapy for treatment of any disease. The Government of India has proposed various measures which could help to boost the immunity level against COVID-19 such as practicing yoga daily; drinking warm water throughout the day; judicious use of turmeric, coriander, and garlic (avoid excessive use); nasal application of sesame oil or ghee; oil pulling (oral rinse with oil); steam inhalation; and the use of clove powder for relief from sore throat (101). A prospective, randomised, control clinical trial of ayurvedic regimen; Dasamoolkaduthrayam Kashaya and Guluchyadi Kwatham in tablet form with standard of care versus standard of care alone showed improvement in breathlessness and reduces hospital stay in mild to moderate COVID-19 patients (102). More than 67 trials including Ayurveda, naturopathy, unani, siddha and homeopathy have been registered on clinical trials registry of India (103). Ayurveda and integrative medicines have potential for prophylactic, preventive and symptomatic management of COVID-19 disease. However, it is requiring to be explored more in clinical studies.

VITAMINS AND SUPPLEMENTS

In addition to the vitamin supplements (especially Vitamin C and D in recommended dosage); minerals; trace elements such as iron, selenium, and zinc; and flavonoids has been recommended for the clinical management of COVID-19 (104). A randomised, open label, pilot clinical trial conducted in COVID-19 hospitalised patients reported positive result. Only 1 out of 50 patients (2%) receiving oral calciferol and standard of care got admitted to ICU unit compared to 13 out of 26 (50%) who received standard of care alone (105). In contrast, clinical trial of single oral 2,00,000-unit dose of cholecalciferol in comparison with placebo observed, no significant difference in hospital stay, mortality rate and ICU admission in hospitalised adults with moderate to severe COVID-19 disease (106). Zinc was also evaluated in randomised clinical trial conducted at three major university hospitals in Egypt. In this study, 191 COVID-19 patients either received dose of 220 mg zinc sulfate and HCQ or HCQ alone, along with standard of care twice daily. A 79.2% patients in zinc group and 77.9% patients in HCQ group recovered after 28 days with no significant difference in both treatment arms (107).

BIOLOGICALS (VACCINES)

Regulatory authorities across the globe are moving fast to deliver the biggest ever vaccination programme to battle COVID-19. Currently, more than a dozen vaccines are being approved globally to fight the disease (108). More than 1.15 billion doses are distributed worldwide out of which 273 million people are fully vaccinated, covering 3.5% of the global population (109). Many COVID-19 vaccines have been approved in last six months (Table/Fig 2) (108),(110),(111),(112),(113),(114),(115),(116),(117),(118),(119),(120),(121),(122),(123). The data on duration of protection and long-term side effects is limited. Hence, the research is going on to confirm that COVID-19 vaccines are remains safe for all who receive them. The new virus variants are spreading fast resulting in successive deadly waves of infection. The Immunological Correlates of Protection (IPC) are not established in humans. It is important to established IPC and knows the effect of current licensed vaccines or other developing vaccines on new variants. Most of the current vaccines approved globally are useful in adults. Although, fewer children are infected because of COVID-19 compared to adults, risk of getting the infection and spreading it to others is high. Hence, CDC recommends two doses of Pfizer-BioNTech given 21 days apart in 12 years and older children (124). In view of, risk of infection at any age, the evaluation of vaccines in adolescent and children is going on (125),(126).

Conclusion

In the current scenario, patients admitted to hospital with COVID-19 infection might present with multiple symptoms. Development of new potent anti-COVID-19 agent could take 5-10 years which is not a feasible option in this pandemic situation. Hence, repurposing of widely acting antivirals and other drugs seems a relevant option. These drugs are easily available with known pharmacokinetics and pharmacodynamics properties. It is for sure that, overcoming COVID-19 will include a combination of measures including the medicinal therapies currently under investigation. Additionally, the worldwide endeavor to create a safe and effective COVID-19 vaccine is bearing fruit. A handful of vaccines now have been authorised around the globe. The race for safe and effective vaccine to combat the multiple variants is still on. Nevertheless, the main treatments like mechanical ventilation, ICU admission, symptomatic and supportive care are still recommended for severe cases.

Acknowledgement

The authors thankfully acknowledge Ms. Vrushali Bhalchim, Research student at Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pune, India, Dr. Rahul Nerlekar, Assistant General Manager and Dr. Ashwin Jadhav, Assistant Manager both from Department of Clinical Research and Pharmacovigilance working in Serum Institute of India Pvt. Ltd. for their support during the collation of data for manuscript preparation.

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DOI and Others

10.7860/JCDR/2021/49181.15257

Date of Submission: Feb 27, 2021
Date of Peer Review: Apr 20, 2021
Date of Acceptance: Jul 18, 2021
Date of Publishing: Aug 01, 2021

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? NA
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Mar 08, 2021
• Manual Googling: May 12, 2021
• iThenticate Software: Jul 31, 2021 (29%)

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