INTRODUCTION:

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a class of the Nidovirus family; the external surface of the virus has a circlet shape and is thus called coronavirus. This virus is microscopic, i.e., about 66-124nm in diameter, and has a single strand of RNA, approximately 26-32 Kb in length. There are four corona subgroups, such as alpha, beta, gamma, and delta. The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), H5N1 Influenza A, and H1N1-2009 infected the lungs and causes Acute Lung Injury (ALI). The Acute Respiratory Distress Syndrome (ARDS) was caused by respiratory failure and, thus, by the death of the patient.¹ Previously it was assumed that the SARS virus only infects the animals, but after that, it was observed first time in humans in Guangdong, China, in 2002. Earlier, this virus was dubbed the MERS-CoV attack in the Middle East.² At the end of 2019, the famous butcher market in Wuhan (China) caused massive damage to human life due to the viral infection that infected about 18,000 people and killed over 17,000 people within 50 days of the outbreak. Which was further recognized as a beta group of coronaviruses. The Chinese research centres name this virus on behalf of the city of Wuhan as Wuhan coronavirus or 2019 as a novel coronavirus (2019–nCoV).³ ICTV (International Committee on Virus Taxonomy) referred to this virus as SARS-COV-2 and its disease name is COVID 19. During the year 2003 SARS-CoV affected about 8098 people from different 26 countries with a mortality rate of 9% and to date in the year 2020 more than 2 lakh people were killed all over the world. It appears that SARS-CoV-2 is more active than SARS-CoV-1 because the genetic difference that occurred in viruses mainly affects the recombination of the SARS-CoV-2 S-phase protein receptor-binding domain (RBD) area.⁴

History:

In the year 1960, coronavirus was first reported with common cold symptoms. In 2001 more than 500 patients in Canada were reported with flu-like symptoms, while in 2002, the virus had been treated as a typical virus. Between 2002 and 2003, this virus was detected in many countries such as Taiwan, Singapore, Vietnam, Hong Kong, Thailand, and the United States of America. It triggered SARS and more than 1,000 patients died. As a result of the microbiologist and infectious disease, experts analyze 8096 samples of infected people leads to 774 deaths in 2004 forced the Central for Disease Control (CDC) and World Health Organization (WHO) to declare an emergency in the states.^5-6 In the same year in Hong Kong, about 50 patients were reported to be positive for SARS and approximately 60% of patients were found to be infected with this virus. However, an analysis of the growth of this virus reveals that this virus is not stable and can develop further and become more durable as well as resistant to other antiviral drugs and become more familiar to humans. As studies have advanced with the use of serological techniques that provide information on the human respiratory epidemiology of COVID-19, it has also been found that coronavirus infection has increased more in the temperate climate compared to winter and spring.⁷ All this information shows that this virus also affects 35% of the respiratory tract, including the lungs, during infection. Recently, human strains OC43 and 229E have been identified where OC43 is similar to the mouse hepatitis virus, while 229E virus having 9 strains cause infection.^8-9

Property of coronavirus:

Coronavirus is a single-strand virus whose size ranges found between 26,000 and 37,000 bases in a non-segmented positive-strand; which was considered as the largest genome in the ribonucleic acid (RNA) family. The coronavirus genomic structure was found to be 5'-leader-UTR-replicas, the virus has four proteins namely S (Spike), E (Envelop), M (Membrane), and N (Nucleocapsid)-3' UTRpoly (A) tail. The S (spike) protein is used by the virus for binding to the host cell, the protein M and E play role in RNA synthesis and the N protein has an essential and significant role in the viral assembly.¹⁰

Evolution of virus:

The evolution of viruses is very rapid because they contain RNA in the genome, which is very unstable, expedite changes in its existence, and become a more prominent virus. Because of this, the virus is more potent and resistant to anti-viral medications. The research was conducted to see that the basic phenomena of the evolution of the virus, which can clarify the relationship between evolutionary and phylogenetic relations, are the main objective of testing the hypotheses such that the phylogenetic distances between the pairs of sequences are functions of the evolutionary path lengths between them.^10-11

Modes of Transmission of the Virus:

To develop good strategies to combat the virus, it is mandatory to determine the origin and transmission of the virus. SARS-CoV virus career may be a raccoon, dog, and civet palm. However, the positive test result from the Wuhan food market revealed that it’s an RNA virus, and civet palm could be a secondary disease of the virus. In 2001, a sample was taken from a healthy person in Hong Kong, and the result showed that a 2.5 percent antibody was formed against SARS coronavirus, which shows that the virus was transmitted between humans before the pandemic outbreak¹. Rhinolophus bat (a species of bats) was identified with anti-SARS-CoV antibodies. In the year 2012, MERS coronavirus beta CoV was spotted in camels in Saudi Arabia that indicate camels may be the primary host of this virus. Following the positive tests of the last few days of a bat species, called Pipistrellus and Perimyotis, which have MERS-CoV, shows that bat is the virus's career, research shows that the virus has come from snakes.¹¹

Animal to human transmission:

SARS and MERS, detected in humans only when the human comes into close contact with infected animals, directly consumes them or their products, such as milk, urine, and uncooked meat. The Pangolin may be the coronavirus career that was sold in the Wuhan seafood market.¹²

Human to human transmission:

The mode of transmission of the virus is of two types i.e., direct or indirect. In direct transmission, the healthy person comes in direct contact with the patient having coughing, sneezing, and handshaking, whereas in an indirect mode of transmission the healthy person touches the infected surface and materials used by the patients. The most popular way of spreading the virus is the hospitals, where the virus may spread from the patient to their family member and others. The transmission spreads rapidly when a healthy person comes into the contact with an infected person within a range of 2-5 m.¹³ The virus may also be transmitted through the droplets when an infected person coughs or sneezes, and a healthy person comes in contact with these droplets. The infection transmitted by bat and pangolin is more prominent than the droplet process and also people get infected compared to another human who is at a safe distance from the infected person.¹⁴ In the indirect types of transmission, the contamination can be transmitted through the contaminated surfaces by touching them by hands this contamination can go to the face mouth eyes and cause COVID 19. As it was seen that the virus is alive in the air for around 1 hour and on the surface, it can live for a longer duration of time.^13-14

Transmission through the environment:

It was observed that the low sunlight, less humidity, low temperature, and less amount of vitamin D are responsible for the faster growth of the virus as per a recent report. Similarly, these climatic conditions are also responsible for the cause of immunodeficiency in humans. Further, the linkage between the outdoor and indoor climate which affects the growth of the respiratory virus was correlated with that variation in temperature and environmental conditions could affect the transmission rate and stability rate of coronavirus. However, still proper evidence that SARS-CoV 2 cannot survive in high temperate countries such as Africa is lacking.¹⁵

Transmission from humans to the animals:

On 6^th April 2020, a human to animal transmission case was reported at Bronx Zoo in New York, USA, where a corona positive tiger was reported via the infection through a zookeeper. It showed that human transmission to the animal could be very disturbing, as transmission can be transmitted to domestic animals such as cats, dogs, and even to wild gorillas, chimps, and orang-utans.

Symptoms of COVID-19:

Symptoms of human and animal infection include sepsis and septic shock, multi-organ failure, including acute kidney damage and cardiac damage. In children and babies, the case was identified less, and the symptoms of infection were the same during pregnancy and non-pregnancy. But recent studies have shown that the virus is not spread from mother to fetus¹⁵. The virus creates a major problem in the patient’s lungs through the angiotensin-converting (ACE-2) enzyme, found in type 2 alveolar cells of the lungs.¹⁶

Effect of COVID-19 on Patients:

It was indicated that the COVID 19 can affect the pathophysiology of various organs. As evidence obtained from the mortality data collected all over the world revealed that mortality rate was higher to people infected with coronavirus are already suffering from various diseases e.g., cardiovascular, diabetes, asthma, and lung disease, etc.

Effect of COVID-19 on cardiovascular patients:

SARS-CoV 2 viral infection may cause damage to cardiomyocytes, may cause severe hypoxia, leads to acute respiratory damage and myocardial injury. Further, ACE-2 has also been seen in the heart and this virus uses the enzyme as a receptor that helps the virus to enter the host cell.¹⁷

Effect of COVID-19 on the paediatrics:

The impact of coronavirus was studied by the Chinese Centre for Disease Control and Prevention and suggested that only 1% of cases of virus infection were seen in children less than 10 years of age out of 72,314. Similarly, another study on 1,391 children, under 16 years of age suggested only 171 children were found to be positive. Further, only 6% of children have developed lymphopenia and most of the children were found to be uninfected without pneumonia-like symptoms.¹⁷

Effect of COVID-19 on Central Nervous System Patient:

The COVID-19 has an RNA-negative strand that causes respiratory infection and is capable of multiplication in the Central Nerves System which is seen in patients with multiple sclerosis. This virus is implicated in neuropsychiatric diseases that involve the past onset of psychosis. Further, COVID-19 can be associated with mood swings and may lead to cause suicidal tendencies in the patient.¹⁸Moreover, a study carried out on approximately 257 samples including 95 males and 162 females resulted in only 39 patients being stable with mild symptoms, whereas other patients were found affected by mood swing disorder and suicidal behaviour.¹⁹

Proposed Synthetic Drug Therapy for the Management of COVID-19:

Multiple medicines in clinical trials are being used all over the world to treat and prevent the current pandemic situation. Several drug groups have been shown to have a positive impact on the virus that can minimize the viral load and relieve symptoms of COVID-19 are discussed herewith.

Antimalarial Drugs:

Hydroxychloroquine (HCQ)/Chloroquine (CQ):

Hydroxychloroquine (HCQ)/Chloroquine (CQ) are used to treat and prevent malaria caused by Plasmodium falciparum. Hydroxychloroquine is a chloroquine derivative, which is an N-ethyl beta hydroxyl substitute.¹⁹ In the host cell, HCQ accumulates in lysosomes, Golgi complexes, and endoplasm. Further, it was transformed into a protonic form, and then gets accumulated in the liver, which causes an increase in the pH of surroundings. The level of ACE-2 enzyme, a key target of SARS-CoV-1 and 2, is increased in the cell that prevents viral infection. Whereas CQ does not show any effect on the ACE-2 level, but it slows down the ACE-2, due to which the binding of the virus to the host cell is impaired. Moreover, CQ suppresses the expression of clathrin assemblage protein that binds to phosphatidylinositol and regulates the clathrin-assisted endocytosis.²⁰ Simultaneously, concurrent use of some drugs with a combination including Remdesivir and other anti-viral drugs may suppress the effects of COVID 19 on the lungs and other organs of the patient.²¹Both HCQ and CQ are metabolized in the liver and converted into desethylhydroxychloroquine (DHCQ), bisdesethylchloroquine (DCQ), and desethylchloroquine (BDCQ). DHCQ is the major metabolite among all the three metabolites with a half-life of approximately 3-4 hours, whereas terminal half-life is approximately between 40-50 days.²² Some clinical trials reports in China have shown that this drug has a positive effect on the treatment of COVID-19.²³ethylation and production of desethylchloroquine are the primary routes of metabolism for CQ. HCQ has been subjected to Tertiary Amin N-dealkylation and primary amine oxidation resulting in carboxylic acid derivatives, desethyl hydroxychloroquine, and desethyl chloroquine.²² Further, FDA approved the emergency use of hydroxychloroquine and chloroquine under the Emergency Use Authorization (EUA) on 28 March 2020. Experimental therapy was only approved for alternative use in patients who were hospitalized but were not able to seek therapy in a clinical trial. Additionally, FDA has announced product-specific guidelines for chloroquine phosphate and hydroxychloroquine sulphate for generic drug producers.²⁴ On 24 April 2020, severe heart rhythm issues were reported leads FDA to revoke an emergency usage authorization for chloroquine and hydroxychloroquine on 15 June 2020. Henceforth, FDA issued a precautionary note against the use of these medications for COVID-19 outside the hospital or in a clinical trial.

Anti-viral drug:

Favipiravir:

Favipiravir is also known by T-705, Avigan, Abigan, FabiFlu, and Favilavir. Favipiravir was developed by Toyama Chemical Company (Fujifilm Group), Japan, and approved for medicinal use in Japan in 2014 against several RNA viruses. Favipiravir shows antiviral effects against influenza viruses, western Nile, yellow fever, foot, and mouth, as biennia, arenaviruses, bunia viruses, and alphaviruses.²⁵ In 2016, Fujifilm licensed it to Zhejiang Hisun Pharmaceutical Company of China and became a generic drug in 2019. Favipiravir was evaluated on emerging COVID 19 (novel coronavirus) for experimental use in China in February 2020 and subsequently approved for use in the 2019 Coronaviruses Clinical Trials.²⁶ In March 2020, Italy licensed the drug against COVID-19 and started to carry out trials in three regions, most affected by the disease. Nevertheless, the Italian Pharmaceutical Agency has reminded the public of the current data in favour of drugs.²⁷This drug inhibits RNA-dependent RNA virus, mainly effective against influenza species and synthesized by pyrazine-modifying analogues. Further, also effective against all viruses by its phosphoribosylated cell enzyme and ribofuranosyl-5-triphosphate. When used in combinations with others, the combinations of Favipiravir with Azithromycin and Hydroxychloroquine is found to be more effective in overcoming the sign and symptoms of COVID-19.²⁸

Oseltamivir:

Oseltamivir is a drug of choice for the prevention and treatment of influenza A and B (flu) virus, marketed under the brand name ‘Tamiflu’. In 1999, the Food and Drug Administration (FDA) approved influenza treatment for adults with oseltamivir phosphate²⁹. Oseltamivir phosphate was approved for prophylaxis and influenza diagnosis by the European Medicines Agency (EMA) in June 2002.²⁹ In 2003, a group of 10 clinical trials randomized on oseltamivir showed that lower respiratory risk was decreased.³⁰ Mechanistically, oseltamivir is from the neuraminidase inhibitors family that helps to prevent influenza virus infections in the respiratory tract through competitive inhibition. Basically. Neuraminidase is an essential part of glycoprotein that is found on the surface of human cells mainly responsible for silica acid cleavage. Oseltamivir continues to determine its therapeutic ability for SARS-CoV-2 infections. Recently, a few combination medicines, including ASC09F and Ritonavir, are being researched and are currently in clinical studies, along with Oseltamivir.

Lopinavir and Ritonavir:

In continuation with value addition in earlier protease inhibitors i.e., ritonavir, Abbott further developed Lopinavir with additional serum protein binding properties and human immunodeficiency virus (HIV) tolerance profile.³¹ Lopinavir/ritonavir was approved by the FDA of the United States on 15 September 2000 and in Europe on 19 March 2001.³² Recently, anti-HIV medications and protease inhibitors such as Lopinavir and Ritonavir were found to be effective against SARS-CoV infections and are currently being tested for effectiveness and protection against SARS-CoV-2 through clinical trials.³³ Initial trial for the treatment of adult SARS-CoV-2 Patients with oral Lopinavir and Ritonavir, twice daily for 14 days suggesting promising results. It was concluded that there is a need to perform more studies to draw any decision for the use of Lopinavir and Ritonavir in SARS-CoV-2 infection.³⁴ The drug, sold by AbbVie under the brand name Kaletra, is a combination of both Lopinavir and Ritonavir protease inhibitors. It was approved in the US in September 2000 and the EU in March 2001.³⁵ Generic versions of the Lopinavir/Ritonavir combination has also been approved by the FDA.³²

Remdesivir:

Remdesivir is a broad spectrum anti-viral medicine, marketed under the brand name of Veklury. It has been validated as a potential therapy for COVID-19 and approved for use with extreme symptoms in the US, India, Singapore, and Japan.³⁶ Remdesivir targets both virus protein and the replication process. Remdesivir was initially developed for hepatitis C and not shown any effect against Ebola and Marburg was tested earlier. In April 2020, the most effective therapy for COVID-19 was found to be Remdesivir. In January 2020, Remdesivir against SARS-CoV-2 was released in Gilead Sciences and tested in animal models for severe ARS and Middle East Respiratory Syndrome (MERS) treatments. On 21 January 2020 Wuhan Institute of Virology filed a patent in China for use of Remdesivir against COVID-19.^37-39

EIDD-1931:

EIDD-1931 or N-4-hydroxycytidine is a cytidine analogue was shown a positive effect on the SARS-CoV-1-2 and MERS-CoV virus and the zoonotic group of 2b and 2c through experimental study.⁴⁰ Earlier in the 1980s, EIDD-1931 was reported as a potent mutagen of bacteria. It has also shown anti-viral activity against the Venezuelan equine encephalitis virus and the human coronavirus HCoV-NL63 through in-vitro study. N-4-hydroxycytodine has been shown to inhibit SARS-CoV-2 as well as other human and bat coronaviruses in mice and human airway epithelial cells.⁴⁰ Additionally, EIDD-2801 has wide-spectrum anti-viral action against influenza viruses, several coronaviruses, including SARS-CoV-2, MERS-CoV, and SARS-CoV.⁴¹

Angiotensin-Converting Enzyme Antagonists/ Angiotensin-Receptors:

SARS CoV-1 and 2 viruses are attached to the ACE-2 receptor in the host cell, which has a special impact on the oral mucosa.⁴² ACE inhibitors generally inhibit ACE-2; however, ACE-2 acts as a non-clinically inhibited carboxypeptidase (an enzyme responsible for the rise of hypertension and diabetes). Some drugs such as captopril and losartan act as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).²¹

Immunosuppressant/Arthritic Drugs:

Actemra (Tocilizumab):

Actemra was recently approved in China, Japan, and the United States in its Phase III clinical trial as a drug of choice for COVID-19. Earlier, this drug was developed and approved by the FDA in European countries for the treatment of arthritis via IL-6 inhibition.²¹

Kevzara (Sarilumab):

Kevzara acts as an antagonist to the IL-6 receptor and functions as a monoclonal antibody for humans. The FDA approved this drug for the treatment of Rheumatoid arthritis and recently tested it against coronavirus for faster recovery from fever and manage oxygen deficiency.²¹

Ruxolitinib:

Ruxolitinib was a JAK1/2 antagonist and also act through multiple cell signals including IL-6. Recently, the use of Ruxolitinib has been successfully performed in coronavirus patients through clinical studies for phases 1 and 2. Additionally, it acts as an immunomodulatory and supports in reducing the effects of pneumonia and other respiratory symptoms via suppressing the immune response.²¹

Baricitinib:

Baricitinib was JAK 1/2 agonist and commonly used in the treatment of Rheumatoid arthritis. Recently, this drug is considered for the treatment of coronavirus as evidenced by clinical trials. Additionally, no potential drug interaction in combination with the other anti-viral drugs has been recorded.²¹

Proposed Natural Drug Therapy for the Management of COVID-19:

The anti-viral herbal drugs have been used since ancient times and from various past studies, these were found to be effective against several viral infections including SARS virus.^43-45 Some of the recently investigated medicine are mentioned below:

Quercetin:

Quercetin is a flavonoid compound found mostly in fruit and vegetables responsible majorly for anti-inflammatory and vasoprotective action. Additionally, it has been found role against multiple viruses such as influenza A, Hepatitis C, and Enterovirus. A recent, study reported that Quercetin can fight against COVID-19 infection via action on 3CLpro.^46-47

Andrographolide:

Andrographolide is an important compound isolated from Andrographis paniculata herb and found to improve immunity against multiple conditions such as antivirus, anti-bacterial, anti-parasite, anti-tumour, and anti-hyperglycaemic action.⁴⁸

Liquorice:

Liquorice contains various bioactive ingredients such as glycyrrhizic acid, thymol, and carvacrol, which exhibit potent antiviral and antibacterial activity.⁴⁹ Recent research findings indicated that glycyrrhizic acid has a more significant SARS CoV2 and SARS CoV1 viral inhibitory effect than ribavirin, 6-azouridine, pyrazofurin, and mycophenolic acid.^50-51

Baicalin:

Baicalin was mainly isolated from Scutellaria baicalensis has an extensive range of sensitization and anti-apoptosis effects. Further, it has been found to inhibit ACE as evidence from an in vitro study suggested its use against SARS CoV as CoV 1 and 2.⁵²

Patchouli Alcohol (PA):

Patchouli alcohol is a tricyclic sesquiterpene found to exhibit a wide range of biological activity such as anti-viral, immunomodulatory, anti-inflammatory, anti-oxidative, and anti-tumour activity. It was found to be effective against H1N1 through intracellular 13K and mitogen-activated protein kinase (MAPK) pathways. Further, Patchouli alcohol (PA) acts in the early stages of the virus by inhibiting virus growth to stop the spreading of infection. Recently, a molecular docking study with SARS-CoV2 has shown promising results to develop future drug.⁵³

Vitamin C and zinc:

Vitamin C and zinc are used to promote innate immunity and act on cellular components to form lymphocytes in the bone marrow. Zinc is mainly used for subsequent differentiation into B and T lymphocytes, essential for the T lymphocytes production and effective for interaction between T lymphocytes and B lymphocytes. These micronutrients provide anti-oxidant protection and improve overall immune functions.⁵⁴ Vitamin C is a source of oxidants and is thought to be particularly useful in strengthening the upper respiratory tract.⁵⁵Vitamin C is mainly essential for the biosynthesis of collagen, L-carnitine, and other neurotransmitters involved in protein metabolism.⁵⁶

Role of Ayurveda During the COVID-19 Crisis:

Ayurveda plays an important role in the prevention of COVID-19 through various designed regimen and multiple research projects. Several remedies have been trialled and many of them found to be effective including Yogasana, Pranayama, and Meditation for a minimum of 30 minutes. Further, the use of spices in food such as Jeera (Cumin), Haldi (Turmeric), Dhaniya (Coriander), and Lahsun (Garlic) is also recommended. Additionally, some immunity boosters include the use of Chyavanprash and herbal tea/decoction containing Tulsi (basil), kalimirch (black pepper), dalchini (cinnamon), shunthi (dry ginger), and mahaka (raisin) is also recommended.

Current Strategies:

The coronavirus transition is highly contagious for humans, mainly transmitted through the air by droplet, and require serious attention of prevention only through social distancing and isolation methods.⁵⁷ Considering this a triage station has been built just outside the hospitals, having adequate ventilation and enough space for social distancing. By adopting sub-sequential measures of treatment including specifications provided by WHO are recommended including proper sanitization and documentation.^58-59

Vaccine:

Scientists from all over the world succeed to develop several vaccines including Covishield and Covaxine. Covishield was developed by Oxford/AstraZeneca and marketed by Serum India. Covishield is a recombinant vaccine prepared from replication-deficient chimpanzee adenovirus. Covaxin was developed by Bharat Biotech and the vaccine is composed of attenuated virus extracted from a COVID-19 patient. Russia has launched the Sputnik V vaccine. Janssen (Johnson and Johnson) also developed the vaccine Ad26.COV2. S. Vaccines are developed from the inactivated virus, a protein fragment, genetically modified RNA or DNA vector, and viral vector that mimics the virus activity.⁵⁹

CONCLUSION:

For the last two SARS CoV-2 virus has affected the lives of many people very badly all over the World. The first case of SARS-CoV-2 infection in a human was reported in Wuhan city of China, in December 2019. The virus reaches pulmonary cells via endocytosis through the ACE-2 receptor and causes mild to extreme symptoms similar to other viruses. As the virus is new and treatment choices are limited the complete management is still lacking. The ongoing trials were undertaken for the proposed drugs such as Remdesivir, Chloroquine (CQ), Hydroxychloroquine (HCQ), and Tocilizumab for treating COVID-19 disease as discussed. Further, Lopinavir and ritonavir do not seem to be active on their own, but in combination with other drugs have a much better effect. From the above discussion, it was concluded that still, no proper medication is available. However, treatment through antiviral drugs, ACE inhibitors, immunosuppressant drugs, natural products, and traditional medicine has been shown promising results in the management of COVID-19. Vaccines are also available which can generate antibodies against COVID 19. Further, due to ongoing viral mutation and chances of more infectious mutants such as Omicron may be of future challenges for treatment and require serious attention towards therapeutic management.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors are thankful to the Department of Pharmaceutical Sciences, Sir J. C. Bose Technical Campus Bhimtal, Kumaun University, Nainital-263136, Uttarakhand, India, and Faculty of Pharmacy, DIT University for consistent support and encouragement.

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Received on 03.01.2022 Modified on 12.03.2022

Research J. Pharm. and Tech 2023; 16(2):908-916.

DOI: 10.52711/0974-360X.2023.00153