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Journal of Drug Delivery and Therapeutics
Open Access to Pharmaceutical and Medical Research
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Open Access Full Text Article Review Article
Therapeutic measures for COVID-19 and their clinical relevance of hERG channel translocation: A Pharmacodynamic approach
Trilochan Satapathy1*, Kunal Chandrakar2, Abinash Satapathy3, Neha Yadav3, Shivangee Singh2, Dheeraj Kumar2
1 Columbia Institute of Pharmacy, Vill-Tekari, Near Vidhansabha, Raipur-493111, Chhattisgarh, India
2 University College of Pharmacy Raipur, Pt. Deendayal Upadhyay Memorial Health Sciences and Ayush University of Chhattisgarh, Raipur, 492001, India
3 College of Veterinary Science and Animal Husbandry, Anjora- 491001, Durg, Chhattisgarh, India
Article Info: _____________________________________________ Article History: Received 08 Aug 2023 Reviewed 26 Sep 2023 Accepted 29 Oct 2023 Published 15 Nov 2023 _____________________________________________ Cite this article as: Satapathy T, Chandrakar K, Satapathy A, Yadav N, Singh S, Kumar D, Therapeutic measures for COVID-19 and their clinical relevance of hERG channel translocation: A Pharmacodynamic approach, Journal of Drug Delivery and Therapeutics. 2023; 13(11):165-175 DOI: http://dx.doi.org/10.22270/jddt.v13i11.6007 _____________________________________________ *Address for Correspondence: Dr. Trilochan Satapathy, Columbia Institute of Pharmacy, Vill-Tekari, Near Vidhansabha, Raipur-493111, C.G., India |
Abstract _____________________________________________________________________________________________________________________ The COVID-19 caused by SARS-CoV-2 poses a massive challenge to the medical system, especially the safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials attracting significant attention. Clinically, however, many medications, including those currently shown to be effective against COVID-19, such as Chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir, may cause cardiotoxicity by acting on cardiac potassium channel, hERG channel due to their off-target effect. Blocking of hERG prolongs QT intervals on the electrocardiogram and thus might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG from causing arrhythmias cannot be ignored. To develop safe and effective drugs, it is necessary to understand the interactions between drugs and hERG channels and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of related drug blockade in the hERG, trying to provide insights into the QT interval prolongation caused by potential therapeutic drugs for COVID-19 and hope to weigh the risks and benefits when using related drugs. Keywords: COVID-19; Therapeutic measures; hERG channel; Pharmacodynamic; Vaccines
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Introduction
A novel coronavirus disease known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly known as 2019-nCoV) that causes illness 1 . The angiotensin-converting enzyme 2 (ACE2) receptor is the target of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an RNA virus genetically belonging to the genus Betacoronavirus 2 . The serine protease TGRBSS2 increases viral entrance into the cell after binding. Corona viruses (Omicron, Delta, Alpha, and Beta) are a varied group of viruses that can infect a wide range of animals and cause mild to severe respiratory illnesses in humans. Two highly pathogenic zoonotic coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), caused fatal respiratory illness in humans in 2002 and 2012, respectively, making emerging coronavirus a new public health concern in the twenty-first century. Confirm case of covid is 533,816,957, confirm death due to covid-19 are 6,309,633 and total vaccine administered are 11,854, 673,610 data given by WHO. The newly detected coronavirus, known as "COVID-19," can cause pneumonia and, like other respiratory viruses, has a 2 to 14-day incubation period 3 . Several health facilities in Wuhan, Hubei Province, China, reported clusters of patients with pneumonia of unknown origin in late December 2019. These patients, like those with SARS and MERS, had symptoms of viral pneumonia, such as fever, cough, and chest pain, as well as dyspnea and bilateral lung infiltration in severe instances. The complete size of the SARS-CoV-2 S protein is 1,273 amino acids, which is longer than SARS-CoV (1,255 amino acids) and known other SARSr-CoVs (1,245–1,269 amino acids). It differs from the S proteins of most members of the subgenus Sarbecovirus, with 76.7–77.0 percent amino acid sequence similarity to SARS-CoV from civets and humans, 75–97.7% amino acid sequence similarity to bat coronaviruses in the same subgenus, and 90.7–92.6 percent amino acid sequence similarity to pangolin coronaviruses 4 . The amino acid similarity between SARS-CoV-2 and SARS-CoV is only 73 percent in the S protein's receptor-binding domain (RBD). The insertion of four amino acid residues (PRRA) at the junction of S protein subunits S1 and S2 is another unique genomic trait of SARS-CoV-2 5 .
Figure 1: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
History and Discovery
On March 11th, 2020, the World Health Organization (WHO) proclaimed the "Coronavirus Disease 2019" (COVID-19) epidemic 6 which initially started in Asia, had become a pandemic. The first known infections from SARS-CoV-2 were discovered in Wuhan, China. The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic before or after the spillover event 7 . It's still unclear how this virus spread from animal to human populations. The outbreak obviously began epidemiologically at the Wuhan market, and a number of environmental samples from surrounding the live animal portion of the market were later discovered to be positive for SARS-CoV-2, but it may not have really arisen in the market, based on current findings. An elderly and infirm man who experienced symptoms on December 1, 2019, was the first known case of SARS-CoV-2 infection.
The Structure of SARS-CoV-2
Coronaviruses are members of the Coronavirinae subfamily in the Coronaviridae family, which includes four genera: Alpha coronavirus, Gamma coronavirus, and Delta coronavirus.CoVs have a single-stranded positive-sense RNA (+ssRNA) genome that is larger than any other RNA virus ,The capsid is generated outside the genome by the nucleocapsid protein (N), and the genome is further packed by an envelope made up of three structural proteins: membrane protein (M), spike protein (S), and envelope protein (E). The genome size of SARS-CoV-2, which was recently sequenced as a member of the coronavirus family, is around 29.9 kb. Spike(S) comprises sixteen non-structural proteins (nsp16) and four structural proteins (S, E, M, and N) in SARS-CoV-2. The combination of nsp12 and template-primer RNA was greatly boosted when nsp7 and nsp8 were present. Nsp9 is a protein that binds to ssRNA. Nsp10 is required for viral mRNA cap methylation. The RNA-dependent RNA polymerase (RdRp), which is a crucial component of coronavirus replication and transcription, is found in Nsp12. The zinc-binding domain in nsp13 participates in the ATP binding process 8 .
Coronavirus Structure
The COVID-19 was rapidly identified as being caused by a coronavirus that was eventually dubbed SARS coronavirus 2. (SARS-CoV-2) 9 the coronavirus is a virus that belongs to the coronavirus family. It is the sixth coronavirus to infect humans; four of the other coronaviruses (229E, NL63, OC43, and HKU1) only induce minor cold symptoms. The other three, SARS-CoV, MERS-CoV, and SARS-CoV-2, on the other hand, are capable of causing severe symptoms and even death, with fatality rates of 10%, 37%, and 5%, respectively. Despite the fact that COVID-19 is the subject of numerous investigations and clinical trials around the world 9 , 10 As the pandemic grows, finding a particular COVID-19 treatment is important, and vaccines targeting several SARS-CoV-2 proteins are now being developed. SARS-CoV-2 is an RNA-enveloped single-stranded virus 11 .
Figure 2: Structure of Coronavirus
Its whole genome, which is 29,881 bp long (GenBank no. MN908947) and encodes 9860 amino acids, was characterized using an RNA-based metagenomic next-generation sequencing technique 12 . One study looked at the genomes of SARS-CoV-2 and related isolates from the GISATD and NCBI, as well as the coding sequences of spike protein (S), nucleoprotein (N), and polyproteins (P) from additional SARS-CoV-2 isolates, finding 4, 2, and 22 amino acid residue changes in S, N, and P, respectively. At least two SARS-CoV-2 strains are implicated in the outbreak, according to the findings. SARS-CoV shares 79.5 percent sequence identity with the genome sequences. SARS-CoV-2 is not the same as SARS-CoV. Acute respiratory distress syndrome (SARDS) is a severe form of acute respiratory distress the ongoing coronavirus illness 2019 (COVID-19) pandemic is caused by Coronavirus 2 (SARS-CoV-2). Upstream ORFs that are anticipated to play a regulatory role, numerous in-frames internal ORFs within existing ORFs that result in N-terminally truncated products, and internal out-of-frame ORFs that generate unique polypeptides are all examples of these ORFs. We further show that viral mRNAs are not translated more efficiently than host mRNAs rather, due to the enormous amounts of viral transcripts, virus translation dominates host translation. SARS-CoV-2 and SARS-like coronavirus strain BatCov RaTG13 share 96 percent of their genomic nucleotides. There have been 13 mutations found in the spike protein thus far. Special attention should be paid to the mutation D614G. Spike D614G, a mutation, first appeared in Europe in early February. When it was introduced to new areas, it quickly displaced the original strain, eventually becoming the dominant strain 13 SARS-CoV-2 with the D614G mutation is eight times more effective at transducing cells than wild-type spike protein in numerous cell lines, indicating that the D614G mutation in SARS-CoV-2 spike protein could boost the transduction of multiple human cell types 14 .
Variants of COVID-19
Viruses, such as SARS-CoV-2, evolve throughout time and will continue to evolve as they spread. Virus variations can emerge from time to time. A variation is a virus that differs from the original virus in at least one way.
Table 1: Covid-19 variant
These are variants of covid 19Alpha (B.1.1.7 and Q lineages),Beta (B.1.351 and descendent lineages),Gamma (P.1 and descendent lineages),Delta (B.1.617.2 and AY lineages),Epsilon (B.1.427 and B.1.429),Eta (B.1.525),Iota (B.1.526),Kappa (B.1.617.1),Mu (B.1.621, B.1.621.1),Zeta (P.2) 15 .
Mode of Transmission
The most common way for humans to become infected with SARS-CoV-2 (the virus that causes COVID-19) is by contact with infectious respiratory fluids. There are three main methods to be exposed: (1) inhalation of extremely small respiratory droplets and aerosol particles, (2) Direct splashes and sprays depositing respiratory droplets and particles on exposed mucous membranes in the mouth, nose, or eye, (3) contacting mucous membranes with hands that have been soiled by virus-infected respiratory fluids or indirectly by touching virus-infected surfaces. Exhalation releases respiratory fluids in the form of droplets of various sizes (e.g., calm breathing, speaking, and singing, exercising, coughing, and sneezing).Viruses is carried by these droplets, which spread illness. Within seconds to minutes, the larger drops settle out of the air. The tiniest very thin droplets, as well as the aerosol particles created when these fine droplets quickly dry, are so minuscule that they can float in the air for minutes to hours. Infectious exposures to SARS-CoV-2-infected respiratory secretions can arise in three ways (not all of which are mutually exclusive: Inhalation of air containing infectious virus in the form of very small fine droplets and aerosol particles. Within three to six feet of an infectious source, where the concentration of these very small droplets and particles is highest, the risk of transmission is greatest.
Deposition:
Exhaled viral droplets and particles deposit virus on exposed mucous membranes (i.e., "splashes and sprays," such as being coughed on). Close to an infectious source, where the concentration of these inhaled droplets and particles is highest, the risk of transmission is also highest.
Touching:
Contacting mucous membranes with hands soiled by virus-infected exhaled respiratory secretions or from touching virus-infected inanimate surfaces 16 .
Drug Used During Covid-19
COVID-19 Treatment Guidelines are provided by the National Institutes of Health (NIH) to assist healthcare providers in working with their patients and determining the best treatment options for them. COVID-19 can be treated at home or in an outpatient environment in a variety of ways.
Antiviral agents:
Many protease inhibitors, such as darunavir and atazanavir, which are already used to treat HIV, might inhibit SARS-CoV-2 from replicating by inactivating the proteases, which are essential for replication. The Italian Medicines Agency (Agenzia Italiana del Farmaco - AIFA) has given the go-ahead for the ARCO-Home study, which aims to evaluate the effectiveness of home treatments such as hydroxychloroquine, lopinavir-ritonavir, favipiravir, and darunavir-cobicistat in treating early COVID-19 patients without the need for hospitalisation or invasive procedures like intubation 17 .
Table 2: Various drugs and their routes of administration for the treatment of covid-19
Treatment |
Who |
When |
How |
Nirmatrelvir with Ritonavi (Paxlovid) |
Adults; children 12 years and older
|
Start as soon as possible; must begin within 5 days of when symptoms start |
Taken at home by mouth (orally)
|
Remdesivir (Veklury) |
Adults and children |
Start as soon as possible; must begin within 7 days of when symptoms start |
Intravenous (IV) infusions at a healthcare facility for 3 consecutive days |
Bebtelovimab |
Adults, children 12 years and older |
Start as soon as possible; must begin within 7 days of when symptoms start |
Single IV injection |
Molnupiravir (Lagevrio) Antiviral |
Adults age 18 years and older |
Start as soon as possible; must begin within 5 days of when symptoms start |
Taken at home by mouth (orally) |
Invermectin |
Adult age |
Start as soon as possible; must begin within 5 days of when symptoms start |
Taken at home by mouth (orally) |
Vitamin-c (500mg) |
Adult age |
Start as soon as possible; must begin within 5 days of when symptoms start |
1 to 2 in a day( orally) for 5days |
Zink (220mg) |
Adult age |
Start as soon as possible; must begin within 5 days of when symptoms start |
Twice a day (orally)for 5days |
Pentop (20mg) |
Adult age |
Start as soon as possible; must begin within 5 days of when symptoms start |
Taken at home by mouth (orally) for 5 days |
Cetirizine |
Adult age |
Start as soon as possible; must begin within 5 days of when symptoms start |
Taken at home by mouth (orally) for 5 days |
PCM |
Adult age |
Start as soon as possible; must begin within 5 days of when symptoms start |
Take twice a day at home by mouth (orally) for 5days |
Chloroquine/hydrocholoroquine:
Both chloroquine and hydroxychloroquine (HCQ) are weak bases that are mostly found in a protonated state with a positive charge in the extracellular environment. They are unable to pass the plasma membrane due to their positive charge. In the acidic, low-pH organelles like endosomes, Golgi vesicles, and lysosomes, the non-protonated fraction that enters a cell is immediately protonated. Additionally, chloroquine phosphate showed promise in the control of the SARS-CoV and Zika virus outbreaks 18 . Through the action of acidic hydrolases in the lysosomes, macromolecule production in the endosomes, and post-translational protein modification in the Golgi apparatus, chloroquine alters the pathways by which proteins degrade. Chloroquine inhibits antigen processing in macrophages and other antigen-presenting cells, which leads in an antirheumatic response 19 .
Azithromycin:
The reason behind the use of AZM against inflammatory symptoms that cause interstitial lung disease is its immunomodulation capabilities. By preventing the production of many cytokines linked to COVID-19 severe respiratory syndrome, AZM has an intriguing immunomodulatory profile. It is true that AZM controls and/or lowers the levels of IL-1, IL-6, IL-8, IL-10, IL-12, and IFN-α 20 .
Remdesivir:
Remdesivir is a once-daily nucleoside ribonucleic acid polymerase inhibitor that prevents the reproduction of the coronavirus 2 that causes severe acute respiratory syndrome. Remdesivir has received permission for treatment in adults and children hospitalized with severe coronavirus illness in a number of nations in 2019. Remdesivir is subjected to metabolic activation inside the cell, resulting in the formation of the intracellular active triphosphate metabolite GS-443902 (detected in peripheral blood mononuclear cells), and finally the renally removed plasma metabolite GS-441524. The pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treating patients with COVID-19, and potential drug-drug interactions based on available in vitro and clinical data in healthy volunteers are all covered in this review. Following a 3-225 mg single-dose intravenous infusion of an RDV solution formulation over a two-hour period .The results supported this clinical dosage schedule for the treatment of COVID-19 because they revealed significant intracellular concentrations of GS-443902, which is suggestive of an effective conversion from the RDV into the triphosphate form. RDV has a limited potential for drug-drug interactions, according to mathematical projections based on in vitro and phase I data, as the effect of inducers or inhibitors on RDV distribution is reduced by the parenteral mode of administration and thorough extraction. RDV is not projected to be a clinically relevant inhibitor of drug-metabolizing enzymes or transporters in individuals infected with COVID-19 at therapeutic RDV levels, according to physiologically based pharmacokinetic modeling.
Nirmatrelvir/Ritonavir:
Nirmatrelvir/ritonavir received an EUA for the treatment of mild-to-moderate COVID-19 in adults and pediatric outpatients (aged 12 years and older and weighing at least 40 kg) who are at high risk of severe COVID-19, which could result in hospitalizations or death.
Molnupiravir:
Is the oral form of beta-D-N4-hydroxycytidine (NHC), an RNA virus-specific ribonucleoside with wide antiviral action. Viral mutations and fatal mutagenesis are caused by NHC absorption by viral RNA-dependent RNA-polymerases.
Tocilizumab:
A humanized monoclonal antibody called tocilizumab has been studied for its effectiveness in treating severe COVID-19 because it can target the IL-6 receptor in both its membrane-bound and soluble versions 21 , Use of tocilizumab resulted in a quick and lasting response as well as a considerable clinical improvement. Patients using tocilizumab had greater levels of two cytokine storm biomarkers, C-reactive protein (CRP) and IL-6 22 .
Baricitinib:
Another cytokine-release inhibitor, baricitinib, appears to be a promising anti-inflammatory medication. It is a Janus kinase inhibitor (anti-JAK) with a solid safety and effectiveness track record that is approved for the treatment of rheumatoid arthritis (RA). Additionally, it appears to have antiviral effects due to its affinity for the SARS-CoV-2 endocytosis-reducing AP2-associated protein AAK1 23 .
Mechanism of Action
Nirmatrelvir/ritonavir:
Nirmatrelvir is an orally accessible protease inhibitor that inhibits MPRO, a viral protease that cleaves the two viral polyproteins required for viral replication 24 .
Molnupiravir:
Molnupiravir inhibits the reproduction of a variety of viruses, including SARS-CoV, including SARS-CoV-2.SARS-CoV-2 replication is inhibited in human lung tissue, SARS-CoV-2 transmission is blocked in ferrets and SARS-CoV-2 RNA is reduced in patients 25 .
Remdesivir:
They discovered that remdesivir inhibits a specific enzyme necessary for viral replication. Coronaviruses replicate by employing an enzyme called RNA-dependent RNA polymerase to copy their genetic material 26 .
Tocilizumab:
Tocilizumab, a monoclonal antibody that can block the IL-6 receptor, has a bright future. Based on the results of various CRS studies 27 , 28 . Tocilizumab mechanism of action in the treatment of COVID-19 is unknown. IL-6 is secreted by almost all stromal cells and immune system cells, including B lymphocytes, T lymphocytes, macrophages, monocytes, dendritic cells, mast cells, and other non-lymphocytes like fibroblasts, endothelial cells, keratinocytes, glomerular meningeal cells, and tumor cells, according to previous studies 29 . The body's level of IL-6 is quite low under normal circumstances, but it can be swiftly produced to increase the body's defense function when an infection or injury occurs. CRS is caused by excessive IL-6 secretion, and the more severe the CRS, the greater the IL-6 serum peak concentration. To initiate signal transduction and stimulate downstream signal transduction and gene expression, IL-6 forms a complex with its receptor IL-6R and then attaches to the signal transducer glycoprotein 130 (gp-130). There are two types of IL-6R: membrane-bound (mIL-6R) and soluble (IL-6R) (sIL-6R). In the traditional signal transduction route, IL-6 forms a complex with mIL-6R and then binds to gp-130, resulting in downstream Reactions Anti-inflammatory actions, for example, are restricted to cells that express mIL-6R. IL-6 forms a complex with sIL-6R and gp-130 in the trans-signaling pathway, which activates intracellular signal transduction in the absence of mIL-6R and has inflammatory effects 30 . The next step was to stimulate the production of acute reactive protein via two distinct signaling mechanisms. The JAK/STAT tyrosine kinase system mediates one IL-6 signaling pathway, whereas the Ras/mitogen-activated protein kinase (MAPK)/NF-B-IL-6 pathway mediates the other. The former is a significant route 31 , 32 . Many cells cannot respond to IL-6 signal due to the lack of expression of IL-6R in the traditional signal pathway, but some of these cells can be stimulated by the sIL-6R-IL-6 complex to respond to IL-6 signal and cause cell signal transduction 33 . Extracellular gp-130 suppresses the trans-presentation signal, and extracellular gp-130 can form a complex with sIL-6R to prevent sIL-6R from interacting with membrane-bound gp-130. The classical signal is restricted to cells that express IL-6R (macrophages, neutrophils, T cells, etc.) and plays a key role in the low level of IL-6. However, because gp-130 is present everywhere, when the amount of IL-6 rises, the IL-6 signal is extensively expressed. IL-6 Trans signaling via the sIL-6R can then activate practically all cells in the body and regulate pro-inflammatory responses in this way. In a range of preclinical chronic and autoimmune illness models, blocking trans-signaling proved successful. Tocilizumab, a humanized anti-IL-6R monoclonal antibody, binds to both mIL-6R and sIL-6R, inhibiting both classical and trans-signals. This could be a possible strategy for treating cytokine storm in COVID-19 34 .
Vaccines
It is urgent to develop effective and safe vaccines to control the new occurrence of COVID-19 and to reduce SARS-CoV-2-infection-related morbidity and mortality 35 . Almost one billion people in low-income nations are still unvaccinated as of May 22, 2022.Only 57 countries practically all of them high-income countries have immunized 70% of their population (WHO).
Corbevax:
In phase 1 and 2 investigations, Biological E's CORBEVAXTM vaccine, which comprises the protein subunit of the receptor binding domain (RBD) from the spike protein of SARS-COV-2, was chosen and shown to be safe, well tolerated, and immunogenic in healthy adult populations.
Covaxin:
Bharat Biotech produced COVAXIN, India's indigenous COVID-19 vaccine, in conjunction with the Indian Council of Medical Research (ICMR) - National Institute of Virology (NIV).The vaccine is being developed using a platform derived from Whole-Virion Inactivated Vero Cells. Because inactivated vaccinations do not multiply, they are unlikely to revert and cause disease. They include dead viruses that are unable to infect humans but can nevertheless teach the immune system to mount a defensive response in the face of infection. It’s a two-dose immunization schedule that's spread out over 28 days. It’s a vaccination that doesn't require sub-zero storage, doesn't require reconstitution, and comes in ready-to-use liquid form in multi-dose vials that's stable at 2-8 degrees Celsius. In July 2020, the vaccine gained DCGI approval for Phase I and II Human Clinical Trials 36 .
Covishield:
It's a chimp adenovirus vector encoding the SARS-CoV-2 Spike (S) glycoprotein that's recombinant and replication-deficient. It is divided into two 0.5 ml doses. COVISHIELD TM must be taken in both doses for maximum protection. The following are contraindications to receiving a second dose of vaccine: After a previous injection of this vaccination, I had a severe adverse response. If your doctor diagnosed your reaction as a severe allergic reaction to the vaccine, you should not receive a second dose. You can take the second dose if you have any more side events (known or unknown) after the first dose. Following the first dose of vaccination, patients who had severe blood clotting (venous and/or arterial thrombosis) and a low platelet count (thrombocytopenia). In clinical trials, COVISHIELDTM was given to persons with and without comorbid illnesses, and the safety profile was similar in both groups (e.g.: Hypertension, Cardiovascular Disease, Asthma, Diabetes, etc.). The vaccine is only available to people who have clinically stable comorbid illnesses. Before receiving the vaccination, please see your treating physician for a risk-benefit analysis based on clinical judgment. The vaccine is not contraindicated if you have a history of G6PD deficiency. Before getting the vaccine, make sure to check with your doctor for a risk-benefit analysis based on clinical judgment 37 .
The Janssen COVID-19
Vaccine (Janssen Biotech, Inc., a Janssen Pharmaceutical company, Johnson & Johnson; New Brunswick, New Jersey) received an emergency use authorization (EUA) from the Food and Drug Administration (FDA) on February 27, 2021, and the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for its use in people over the age of 18 on February 28. Following reports of six occurrences in the United States of cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare thromboembolic condition, in people who had received the Janssen COVID-19 vaccination, the CDC and FDA advised against using the vaccine on April 13, 2021. Two urgent ACIP meetings were quickly called to assess instances of thrombosis with thrombocytopenia syndrome (TTS) that had been reported and to discuss revised guidelines for the use of the Janssen COVID-19 vaccination in the US. On April 23, 2021, ACIP reiterated its intermediate recommendation for the use of Janssen COVID-19 vaccine in all individuals aged 18 years under the FDA's EUA. This recommendation now includes a warning that uncommon clotting events may occur following immunization, mostly among women aged 18–49 years. The risk for TTS associated with the Janssen COVID-19 vaccine, particularly in women over 50, as well as the availability of alternative COVID-19 vaccines must be discussed with patients and healthcare providers in order to help them make informed vaccine decisions and ensure early diagnosis and clinical management of TTS 38 .
Moderna:
The severe acute respiratory syndrome coronavirus 2's perfusion stabilized full-length spike protein is encoded by the mRNA-based vaccination known as mRNA-1273 (Moderna) (SARS-CoV-2) 39 . By encapsulating the mRNA into lipid nanoparticles (LNPs), which shield the mRNA from RNases' destruction, the efficacy of these vaccines has been maximised 40 .
Primary Series:
In the primary series, 2 doses of Moderna are given 4–8 weeks apart. People who are immunocompromised (have a weakened immune system) should receive a third dose at least four weeks following the second dosage in the initial series.
Boosters: A booster should be given to everybody who obtained a Moderna primary series. A second booster dose is only available to a select few people. To find out if and when you can obtain boosters for your COVID-19 immunizations, use the CDC's COVID-19 booster tool.
Novavax:
According to preliminary results from clinical studies, the SARS-CoV-2 vaccine made by the US biotechnology company Novavax is 95,6% effective against the original strain of SARS-CoV-2 and also offers protection against the later variants B.1.1.7 (85.6%) and B.1.351 (60%) of the virus. According to preliminary results from clinical studies, the SARS-CoV-2 vaccine made by the US biotechnology company Novavax is 95,6% effective against the original strain of SARS-CoV-2 and also offers protection against the later variants B.1.1.7 (85.6%) and B.1.351 (60%) of the virus 41 . Nuvaxovid (NVX-CoV2373) and Covovax (NVX-CoV2373) vaccines against COVID-19 were listed for emergency use by the Technical Advisory Group for Emergency Use Listing on December 20, 2021 and December 17, 2021, respectively. The Novavax vaccine will be produced in two separate locations. The vaccine will be manufactured under the trade name Nuvaxovid in Europe and has been approved by the European Medicines Agency, while it will be manufactured under the trade name Covovax in India by Serum Institute of India and has been approved by the Drugs Controller General of India. The WHO's Strategic Advisory Group of Experts on Immunization (SAGE) has produced interim vaccine policy recommendations for the Novavax (NVX-CoV2373) vaccine. The interim recommendations are summarized in this article. There is currently no information on the safety and efficacy of the Novavax (NVX-CoV2373) vaccination in pregnant women. However, efficacy is likely to be equivalent to non-pregnant women of a similar age based on recent findings from other protein-based vaccines during pregnancy.
Sputnik Light:
Recent developments include the registration and approval for use in Russia of the single-component Sputnik Light vaccine, which is the first part of the Sputnik V vaccine (recombinant human adenovirus serotype 26 containing the gene of the SARS-CoV-2 spike (S) protein(ClinicalTrials.gov identifier NCT04741061) 42 . In an open, non-randomized, 1/2 Phase study, Sputnik Light was very well tolerated and elicited potent humoral and cellular immune responses in both seronegative and seropositive subjects 43 .
Sputnik-V:
The Russian Gamaleya National Center of Epidemiology and Microbiology created the Sputnik V COVID-19 vaccine, also known as Gam-COVID-Vac. It is a two-part vaccination using an adenovirus (Ad) viral vector to promote the development of antibodies against the spike protein (S) 44 Ads serve as the delivery vehicle for the DNA instructions to produce the S of the SARS-CoV-2 virus in the body. They have been designed to enter cells but not multiply. Sputnik V is composed of two distinct Ads, Ad26 and Ad5, both of which are administered independently, three weeks apart, and both of which are carriers of the SARS-CoV-2 glycoprotein S gene. To increase the effectiveness of the vaccination, Ad26 is used in the first dosage and Ad5 in the second. By using two separate vectors, the risk of the body producing Ad antibodies after the first dosage is reduced; this might render the second dose ineffective 45 . According to the manufacturer's statement, the Sputnik V vaccine is exclusively manufactured using non-replicating Ad vectors of type E1 and E3, which are created and grown on HEK293 cells 46 .
ZyCoV-D:
India's Ahmedabad-based Cadila Healthcare Limited produced the ZyCoV-D vaccine. The DNA vaccine candidate for SARS-CoV-2 is a DNA plasmid vector called pVAX1 that carries a gene that expresses the spike-S protein of the virus as well as an IgE signal peptide. The submitted Wuhan Hu-1 isolate's spike gene region was chosen (Gene bank Accession No. MN908947.3). The SARS-CoV-2 DNA vaccine construct was produced using the pVAX-1 plasmid vector. Spike regions and the signal peptide gene were chemically created and introduced into the pVAX-1 plasmid DNA vaccination vector. After receiving the plasmid DNA constructions, the construct was transformed in DH5-alphaTM chemically competent cells. The National Regulatory Authority-approved manufacturing facility used current Good Manufacturing Practices to replicate the DH5-alpha E coli containing the plasmid DNA for large-scale production. Five mg of DNA plasmid containing spike protein gene region insert from SARS-CoV-2 virus are suspended in phosphate buffer saline in each 0.5 mL of ZyCoV-D vaccine 47 .
Drug Act via hERG Channel:
The potassium channel Kv11.1 or the ERG1 are other names for the hERG channel. The three-phase repolarization of the ventricular action potential, or cardiac myocyte repolarization, is mediated by the pore-forming alpha subunit of a fast component of the delayed rectifier potassium channel (IKr), which is encoded by the hERG gene 48 hERG channel failure causes a partial or total reduction in the IKr current, resulting in a prolonged action potential duration (APD) on an ECG and if the extension exceeds the normal range (440 ms in men, 460 ms in women), LQTS occurs 49 LQTS caused by hERG deficiency is referred to as type 2 LQTS (LQT2) in clinical terms, and it is the second most frequent form of LQTS 50 . Increased inward current and weaker outward currents caused by medicines (A) and displayed on an electrocardiogram (ECG) result in a prolonged action potential duration (APD) (B). The hERG channel goes through a brief activation process that includes channel opening, fast inactivation, and recovery from inactivation. The channel reopens at this point, followed by a gradual deactivation process to seal it. The channel must be open for drug binding to occur, and when it is closed, the drug is trapped by the blocking action and released when the channel reopens (C). The electrical activity of the heart is mediated by the regulation of the channels in which ions flow into and out of cardiomyocytes. Theoretically, ion currents that constitute the ventricular action potential include inward and outward currents, and the balance of outward and inward currents is the key to the formation of normal APD. Na+ and L-type Ca2+ currents (INa and ICaL, respectively) are the most important inward currents in cardiomyocytes, and the K+ current (IK) is the major outward current. Increased inward current or a weakening of outward currents due to drug effects can result in a prolongation of APD, leading to a prolonged QT interval 51 . Excessive prolongation can facilitate the production of early after depolarization (EAD) in three-phase repolarization that will trigger TdP and even ventricular fibrillation if EAD reaches its threshold 52 .
Mechanism Linking Cardiac Arrest with Covid-19
cardiac causes of CA in covid-19 infection Figure depicts the conditions linked to Covid-19-related CA. Because the focus of this review is on the pathophysiology of Covid-19-related cardiac arrest, a detailed discussion of the cardiovascular consequences of Covid-19 infection in general is beyond the scope of this paper. Covid-19 has the potential to disrupt the cardiovascular system both directly and indirectly, resulting in problems such as acute myocardial infarction, acute cardiac injury, myocarditis, arrhythmias, and acute heart failure 53 . In agreement with prior evidence from different SARS viruses, the presence of Covid-19 viral components in endothelial cells with endotheliitis-like features has been reported 54 .
Drug cardiac toxicity related to cardiac arrest in Covid-19 infection:
Depicts the medications that are currently being used or studied to treat Covid-19 infection, which could lead to CA either directly or indirectly. Arrhythmias are the most common symptom in individuals with Covid-19 infection who are predisposed to CA and are the most common cardiac medication toxicity associated with Covid-19 treatment 55 . Arrhythmias are caused by cardiac injury, heart failure, metabolic derangements, and neurohormonal or inflammatory stress caused by the viral infection and hypoxemia, and is attributed to cardiac injury, heart failure, metabolic derangements, and neurohormonal or inflammatory stress caused by the viral infection and hypoxemia 54 Patients with elevated troponin T levels with Covid-19 infection were shown to have a higher rate of malignant arrhythmias (ventricular tachycardia or ventricular fibrillation). In terms of electrolytic imbalances, people with Covid-19 infection have been found to have hypokalemia, which is commonly accompanied by gastrointestinal complaints 56 QT prolongation is common in Covid-19 infection, regardless of electrolytes, and has been associated to systemic inflammation. Through cytokine-mediated cardiac electrical remodeling, regardless of concomitant antimicrobial therapy, the latter causes considerable QTc prolongation, which is quickly reversed after lowering C-reactive protein and cytokine levels). Furthermore, higher interleukin-6 (IL-6) levels contribute to the risk of QTc prolongation by suppressing IKr in heterologous cells and myocyte, which increases the risk of QTc prolongation. In response to myocardial ischemia, IL-6 levels rise. It is a symptom of the disease's severity and poor prognosis. In support, Patients with cardiovascular signs of Covid-19 infection, such as myocardial ischemia and myocarditis, have been found to have QT prolongation. Toxicity of drugs in Covid-19 patients linked to cardiac arrest.
Table 3: Mechanism of actions and risk factors of cardiac arrest drugs
Pharmaceutical agent |
Mechanism related to cardiac arrest |
Ongoing Clinical Trials |
Interactions with drugs enhancing risk of cardiac arrest* |
Chloroquine/ Hydroxychloroquine* |
Causes QT prolongation by blocking the hERG potassium channel (common mechanism) and TdP |
Phase 2/3/4 |
CYP3A4 substrate |
Associated with HF, conduction system abnormalities, cardiomyopathy, hypokalemia, diarrhea |
Severe with amiodarone, flecainide, mexiletine, sotalol, dofetilide |
||
Pharmaceutical agent |
Causes QT prolongation by blocking the hERG potassium channel and TdP |
Phase 2/3/4 |
Weak CYP3A4 inhibitor, Severe with amiodarone, flecainide, disopyramide, sotalol, dofetilide, propafenone |
Chloroquine/ Hydroxychloroquine* |
Causes cardiac conduction abnormalities |
Phase 2/3/4 |
CYP3A4 inhibitor and substrate |
May cause QT prolongation May cause electrolytic imbalances due to vomiting and diarrhea |
Severe with amiodarone, dronedarone, disopyramide, |
Conclusions:
COVID-19 is considered a potentially preventable disease. Many countries have implemented multiple infection control measures. Many governments face uncertainties about how to prioritize at this time when the pandemic appears to be in transition but when the risk of new variants and future surges remains real. So many drugs have been repurposed and already employed for effective COVID-19 treatment. Still, no specific and effective cure has been confirmed and approved by the regulatory authorities to treat this disease. Many monoclonal antibodies those act via various mechanisms on inflammatory cytokines. These include Tocilizumab, Sarilumab (IL-6 receptor antagonist) and α, and β- interferon therapy was proved successful, especially when combined with other anti-viral oral drugs. The current research revealed that “one hundred seventy-two” countries are doing their research for the development of an effective and safe vaccine against SARS-CoV-2. In the recent future, it is expected that the efforts of researchers and scientists will see the light of day.
Acknowledgements:
The authors are thankful to the Principal and Management of Columbia Institute of Pharmacy Raipur and Dean, College of Veterinary Science and animal Husbandry, Anjora, Durg for providing facilities to complete this manuscript.
Conflict of Interest: The authors declare no conflicts of interest.Bottom of Form
Funding source: The authors received no funding for preparation of this manuscript.
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