DRUG Vs COVID-19

 CORONA VIRUS:

- Corona virus was discovered in 1960s. The thought at that time, they are responsible for mild disease of respiratory and intestinal infections in animals and humans with strain HCoV 229E and HCoV OC43. That change in 2003 as SARS ( Pandemic) and in 2012 as MERS {Ref ncbi.nlm.nih.gov}

- Seven of this viruses can infect the people: (1) 229E (2) NL63 (3) OC43 (4) HKU1 (5) MERS-CoV (6) SARS-CoV (7) SARS-CoV-2, COVID-19.   {Ref webmd.com}

VIRUS LIFECYCLE and Drug Target :

As shows in above figure virus enter into the cells and goes to different stages of life cycle and come outs by exocytosis.

DRUGS:

Direct Acting:

1) Hydroxychlorouine (HCQ):

In 1956 USFDA approved HCQ for symptoms lupus and rheumatoid arthritis. (Ref Lupus.org)

During first wave of SARS-CoV-2, HCQ got the emergency use authorization for this disease but after solidarity trial (international clinical trials) it found ineffective. (Ref  WHO)

HCQ acts by suppressing Toll-like receptors to trigger important immunomodulatory effects. (Ref ccjm.org)  

HCQ used for malaria and in autoimmune condition such as chronic discoid erythematosus and systemic lupus erythematosus in adults and in rheumatoid arthritis.

HCQ act by increasing lysosomal pH in antigen presenting cells. Its accumulation in lysozymes raises the intralysosomal pH, and in parasite it interfere with endocytosis and proteolysis of hemoglobin and inhibits the activity of lysosomal enzyme and raising the lysosomal pH. (Ref. wikipedia)

Common side effect of HCQ are vomiting, headache, allergic reaction, vision problem and heart problem.

2) Remdesivir : (Brand name : Veklury)

Innovator : Gilead Science

Manufacturer in India : Dr. Reddy's, Zydus Cadila, Cipla, Hetero labs.

Remdesivir initially developed for treatment of Hepatitis C and investigated for Ebola virus and Marburg virus infection also. (Ref wikipedia). Recently many country gives emergency use authorization of Remdesivir to treat COVID-19 patient.

As an adenosine nucleoside triphosphate analogue, Active metabolite of remdesivir interferes with the action of viral RNA dependent RNA polymerase, it divert it and avoid proofreading by viral exoribonuclease thus decrease viral RNA production.  

3) Favipiravir : ( Brand name : Avigan) (Fabiflu)

Innovator : Toyama Chemical (Fujifilm)

Manufacture in India : Glenmark Pharmaceuticals, Brand : Fabiflu

Favipiravir is broad spectrum antiviral drug developed and manufactured by Toyama chemical and got approval to treat novel or emerging influenza viral infection in Japan in 2014. In 2019 it became generic medicine. Recently many country gives emergency use authorization of Favipiravir to treat COVID-19 mild to moderate patient.

It is prodrug which metabolite to active form Favipiravir ribofuranosyl-5'-triphophate. It is nucleoside analogue and mimics the guanosine and adenosine for viral RNA dependent RNA polymerase. Thus by incorporating it inhibits RNA polymerase and slow down the viral load from the body. 

Major side effects of this drug are increase uric acid level in blood, diarrhoea, decrease WBC, increase liver enzyme.

4) 2-Deoxy-D-Glucose (2DG) : 

The institute of nuclear medicine and allied science (INMAS) a lab of DRDO in collaboration with Dr. Reddy's Laboratories has been studying this drug.

2DG has been extensively tested for cancer but is so far unapproved. Recently it got emergency use authorization to treat COVID-19 patient. 

It is glucose analogue which looks like glucose but is not. In 2DG the 2 hydroxy group replaced with two hydrogen so  The basic mechanism is inhibiting glycolysis as virus cells are dependent on glycolysis for replication.

Indirect Acting Drugs

1) Tocilizumab : ( Brand name : ACTEMRA)

Manufacture : Roche and Marketed by Cipla in india

Tocilizumab was first approved for the treatment of castleman's disease (Lymphoproliferative disease) in 2005. Latter on its used in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arthritis, large cell vasculitis. (Ref ncbi.nlm.nih.gov, Tocilizumab Martin sheppard ). Tocilizumab got emergency use approval for addressing the COVID-19 related cytokine storm and its complications.  

Tocilizumab is recombinant humanized anti interleukin-6 receptor (IL-6R) monoclonal antibody. It inhibits binding of IL-6 to both soluble and membrane bound IL6 receptor. (Ref medscape .com).IL6 proinflammatory cytokines produced by various cell types including lymphocytes, monocytes and fibroblasts. 

 IL6 also control the activation, differentiation and survival of T cells. It also play a role in antiody secretion from B cell, autoimmunity, chronic inflammation.

SARS CoV-2 infection induces a dose dependent production of IL6 from bronchial epithelial cells. Acute increase in the level of circulating cytokines including IL6, IL1, TNF-α, IFN is the reason for the cytokine storm. As cytokine storm studied in COVID-19 patient which causing pulmonary inflamation and extensive lung disease thus Tocilizumab acts on cytokine storm and treat the patient.   (Ref Futuremedicine.com)

2) Itolizumab : (Brand name: ALZUMAB)

Manufacturer : Biocon

Itolizumab approved for use of severe chronic plaque psoriasis in 2013  and currently got emergency use approval for addressing the COVID-19 related cytokine storm and its complications. (Ref pumed.nci.nlm.nih.gov)

Itolizumab is humanized IgG1 monoclonal antibody, it binds to domain  of CD 6 so called anti CD6 antibody. CD 6 play a role in immune system, activation and differentiation of T cells. Thus Itolizumab reduces T cells proliferation and reduces the production of cytokines. As cytokine storm studied in COVID-19 patient which causing pulmonary edema and lung infection thus Itolizumab acts on cytokine storm and treat the patient.   (Ref pumed.nci.nlm.nih.gov) 

3) Bevacizumab : (Brand name: AVASTIN)

Manufacturer : Innovator - Genetech (Roche), in India Intas Pharmaceutical Ltd. 

Bevacizumab was approved in 2004 in US for use in metastatic colorectal cancer. Latter on it uses for  colon cancer, lung cancer, Breast cancer, Ovarian cancer, glioblastoma and renal cell carcinoma, diabetic retinopathy. Currently got emergency use approval to treat the COVID-19.

Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor (VEGF). 

Autopsy of patients died from COVID-19, reported that pulmonary mucus exudation is severe and more obvious than SARS infection. Pulmonary CT scanning and pathological also suggest that pulmonary edema caused by inflammatory exudation is a distinguished features of COVID-19. VEGF is known as the most potent inducing factor to increase vascular permeability, and high levels of VEGF in COVID 19 patients compared with healthy controls. (Ref Clinical Trials.gov) 

4) Pegylated IFN α-2B : (Brand name: VIRAFIN)

Manufacture : Zydus Cadila

IFN was approved to use for hepatitis B & C, currently it got the emergency use approval to treat the COVID-19.

Interferon are classified in two class, class 1 having Interferon α and Interferon β, Class 2 having Interferon γ. 

Class 1 interferon have broad spectrum antiviral activities against RNA viruses. They are produces by almost any cells in body upon viral infection and induce viral resistance in cells. They are approved to use for Hepatitis B and C and it is also reported it able to inhibits SARS CoV reproduction in vitro.

Class 2 mainly secreted by natural killer cells and T cells, and main purpose to signal the immune system to respond to infection agents or cancerous cells. (Ref  Britannica) 

Every cells in body make the interferon. When cell infected by viruses or germs give off the interferon α and interferon β as a warning signal to your immune system. IFN is cytokines that are released by one cell to regulate the function of other cells and serves as intercellular chemical messengers. IFN stimulate the infected cells to produces proteins that prevent the virus from replicating within them.

5) Steroids :

As first week of covid illness is mainly about the virus causing havoc, while in second week the body mounts an immune response so steroids mainly prescribed in second stage of infection.

Steroids i.e. dexamethasone, hydrocortison, prednisone mainly prescribed for severe and critical covid cases while corticosteroids is prescried for non sever 

VACCINES

Vaccines are designed in different way for active immuniation,

1) Live Attenuated Vaccine

2) Inactivated or Killed Vaccine

3) Subunit Vaccine like inactivated exotoxin or toxoids, capsular polysaccharides and recombinant protein

4) DNA Vaccine

5) Recombinant Vector Vaccine

(Ref.  Kuby immunology textbook by Thomas kindt, Richard Goldsby, Barbara Osborne)

 Many companies are developed the vaccine and got the emergency use authorization in number of countries. Some listed vaccines are,

Type of Vaccine	Company	Dose	Storage
RNA	Pfizer (BioNTech)	2	2 to 8 °C for 5 days and -80 to -60 °C for 6 months
	Moderna	2	2 to 8 °C for 30 days and -25 to -15 °C for 6 months
Viral Vector	Oxford-Astrazeneca (Serum Institute)	2	2 to 8 °C for 6 months
	Sputnik V (Gamaleya)	2	2 to 8 °C dry form,      -18.5 °C liquid form
	Johnson & Johnson (Janssen	1	2 to 8 °C for 3 months
Inactivated virus	Coronavac (Sinovac)	2	2 to 8 °C
	Sinopharm	2	2 to 8 °C
	Covaxin (Bharat Biotech)	2	2 to 8 °C
Protein based	Novavax	2	2 to 8 °C
Source: Wellcome Trust, BBC research