POTENTIAL DRUGS FOR COVID -19 TREATMENT MANAGEMENT WITH THEIR CONTRAINDICATIONS AND DRUG- DRUG INTERACTION

Novel Coronavirus (2019-nCOV) causes inflammatory response with worsening symptoms. Classification of potential anti-viral and anti-inflammatory drugs in managing the symptoms of the COVID-19 and reducing morbidity is important. The objective of this study is to identify a group of drugs, best suited for COVID-19 treatment based on recent developments in clinical trials, FDA drug evaluation, directions and developments and from drug therapies globally. Online literature search was done on Medline, PubMed and google scholar databases for studies on various treatments and drug therapies for COVID-19 and relevant studies were identified and the identified drugs are described in detail as per their Pharmacological, pharmaceutical properties of the drugs, mechanism of action, current COVID-19 drug therapy, contraindications and drug-drug interactions Certain drugs can inhibit action against viral infection and protect lungs from severe inflammatory response. This article summarizes several drugs like Hydroxychloroquine, Chloroquine, Remdesivir, Favipiravir, Lopinavir, Ritonavir, Dexamethasone, Ivermectin, Baricitinib, Casirivimab / imdevimab, Bamlanivimab along with auxiliary treatment like convalescent plasma transfusion. Remdesivir is first drug approved by FDA. Hydroxychloroquine, dexamethasone and remdesivir are showing results against COVID-19 but it is important to test the efficacy and safety of such drugs though some drugs have shown remarkable results.


Drug-Drug Interactions, Side Effects & Risks
There are several drugs interact with chloroquine phosphate. People need to be concerned if they are concomitantly taking non-steroidal anti-inflammatory drugs (NSAID), antacids, azithromycin, insulin, amiodarone, moxifloxacin, drugs for epilepsy or seizure, vitamins, methotrexate, digoxin, tamoxifen, vitamins, or herbal products with chloroquine. [18]. The side effects of chloroquine phosphate are fainting due to low blood sugar, irregular heartbeats, blurred vision, difficulty hearing, muscle weakness, convulsions, yellowing of eyes, difficulty breathing, ringing in the ears etc.
Chloroquine phosphate can cause QT prolongation for patients with serious comorbidities. It can also cause arrhythmias and retinal damage [19][20].

Pharmaceutical Properties
Hydroxychloroquine Sulfate is also known as hydroxychloroquine. It is a white crystalline powder

Mechanism of Action
Hydroxychloroquine Sulfate can inhibit certain enzymes through its interaction with DNA. It can inhibit processes like virus release, virus particle transport, viral protein glycosylation and DNA & RNA polymerase. It can cause inhibition of the fusion of the virus through acidification of the surface of cell membranes. It also inhibits polymerization of heme [24][25][26].

Drug Therapy for COVID-19 and Contraindications
FDA issued EUA for Hydroxychloroquine Sulfate in 2020 for treating patients suffering from COVID-19 and weighing 50 kgs or more. Based on certain parameters, FDA states that there is an optimal dosage for patients who tested positive for COVID-19. But, it recommends 800 mg of hydroxychloroquine sulfate base on the first day for COVID-19 positive patients and then 400 mg base dosage for the next 4-7 days, respectively [27][28]. The suggested dose can vary as per the results of ongoing clinical trials. It is also recommended that patients should be observed and monitored for QT interval prolongation along with renal and hepatic functions. Hydroxychloroquine sulfate is contraindicated for cardiac disease patients, specifically with bradycardia, ventricular arrhythmias, potassium or magnesium imbalances, etc. As per studies, it can have activity against SARS-CoV-2 and is more potent than chloroquine phosphate [29].

Drug-Drug Interactions, Side Effects & Risks
QT interval prolongation remains as a viable risk factor for patients undertaking drugs like azithromycin and other antibacterial drugs. Electrocardiograms of such patients should be monitored.
Retinopathy or retinal damage due to abnormal blood flow is also noted among patients receiving long term hydroxychloroquine sulfate. Hydroxychloroquine can also increase the risk of arrhythmia and cause myocarditis, pericarditis and cardiomyopathy. It can also cause severe hypoglycemia with decreased insulin clearance. Loss of consciousness is also reported among patients taking antidiabetic medication [30]. Drugs like cimetidine which can inhibit the metabolism of hydroxychloroquine sulfate thereby it increase the level of hydroxychloroquine in the blood plasma.
Hence, both drugs should not be consumed together. Similarly, serum digoxin levels can increase with hydroxychloroquine and its level should be monitored closely during combined dose intake.
Antacids can also reduce the absorption of hydroxychloroquine. It is recommended by the FDA that a gap interval of at least 4 hours should be observed between both the drugs [31-32].

Pharmaceutical Properties
Remdesivir is approved by the FDA for emergency use, and clinical studies are yet to be conclusive.
It has demonstrated activity against viral pathogens in animal models in-vitro and in-vivo, which causes middle east respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS).

Mechanism of Action
Remdesivir is an inhibitor of RNA dependent RNA polymerase (RdRp). It competes with adenosine triphosphate and assimilates into viral RNA chains. Remdesivir triphosphate (RDV-TP) does not cause immediate chain termination. Remdesivir is a prodrug of remdesivir triphosphate (RDV-TP) [35].

Drug Therapy for COVID-19 and Contraindications
FDA has conducted a rapid review of Gilead's investigational new drug (IND) -Remdesivir. It has initiated phase 3 clinical trials to evaluate the safety and efficacy of the drug. This randomized, openlabel study conducted globally in multiple centers allowing patients from high-risk COVID-19 countries to participate [36]. The studies are evaluating Remdesivir's role in COVID-19 positive patients with severe manifestation like oxygen requirement and also in patients with with no severe manifestation. Remdesivir is also being used in an independent study by the United States National Institute of Allergy and Infectious Diseases (NIAID) for the potential treatment of COVID-19 positive patients. Some of the contraindications of Remdesivir could be renal or hepatic dysfunction [37].

Pharmaceutical Properties
Lopinavir and Ritonavir are antiretroviral drugs classified as HIV-1 Protease inhibitors for adults and pediatric patients older than 14 days. The combination of these two drugs -Lopinavir and Ritonavir is also known as Kaletra. The molecular formula of Lopinavir is C37H48N4O5, (Fig 4) and the molecular weight is 628.8 g/mol. The molecular formula for Ritonavir is C37H48N6O5S2 (Fig 5) and the molecular weight is 720.95 g/mol [40]. The tablet is recommended to be swallowed as a whole instead of chewing, breaking or crushing it. It can be taken with or without food. The recommended dose varies for adults 800/200mg once or twice daily, and children 100/25mg as recommended by physician. It contains 15.3% propylene glycol and 42.4% alcohol volume per volume, respectively [41].

Mechanism of Action
As per clinical studies shown, Kaletra -Lopinavir; Ritonavir may suppress coronavirus activity by binding to one of the critical enzymes M pro . The plasma level of lopinavir is increased through ritonavir induced inhibition of CYP3A mediated metabolism of lopinavir [42]. taking Kaletra along with patients who have diabetes, Torsades de pointes (TdP), cardiomyopathy and low oxygen content in blood [44].

Drug-Drug Interactions, Side Effects & Risks
The potential plasma concentration of Kaletra can be reduced due to certain drugs which are potential CYP3A inducers, specifically lopinavir and reduce virologic response. Moreover, drugs that are dependent on CYP3A clearance can lead to high levels of Kaletra in plasma concentration and lead to serious health consequences. Some of the drugs which are contraindicated are -alfuzosin (alpha1 -adrenoceptor antagonist), which can lead to hypotension with Kaletra due to increased concentration of alfuzosin [45]. Drugs like dronedarone, antiarrhythmic drugs can lead to cardiac arrhythmias.
Similarly, certain muscle relaxants like propofol, sevoflurane can cause QT prolongation and TdP.
The concentration of analgesics can increase with Kaletra. Serious life-threatening reactions can be caused due to antipsychotics like pimozide and lurasidone with life-threatening manifestations.

Pharmaceutical Properties
Favipiravir is an investigational drug against SARS CoV-2 viruses. It is known for its activity against RNA viruses. It is a derivative of pyrazine carboxamide, and it inhibits influenza viral RNAdependent-RNA-polymerase through conversion to ribofuranosyl triphosphate derivate through host enzyme. The molecular formula of Favipiravir is C5H4FN3O2 ( Fig 6) and molecular weight is 157.

Mechanism of Action
Favipiravir inhibits viral RNA synthesis through RNA dependent RNA polymerase inhibition. It targets influenza viral polymerase without affecting host cellular RNA or DNA synthesis as host cell enzymes convert Favipiravir into Favipiravir ribofuranosyl phosphate [51][52].

Drug Therapy for COVID-19 and Contraindications
The clinical efficacy of Favipiravir against COVID-19 is being investigated through numerous studies worldwide. It is a broad-spectrum antiviral drug with in-vitro activity against RNA viruses as per research studies conducted. It is contraindicated in pregnant and lactating women [53].

Drug-Drug Interactions, Side Effects & Risks
Favipiravir is an investigational drug with ongoing clinical studies. The analgesic activity of paracetamol will increase with Favipiravir. It can also increase the potential of anti-diabetic medications like pioglitazone, rosiglitazone and repaglinide [54]. It can increase the anti-hypertensive potential of Treprostinil for pulmonary hypertension. Also, it can increase the antiviral potential of oseltamivir, ombitasvir/paritaprevir + dasabuvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir. Favipiravir can also increase the concentration of certain bronchodilators like aminophylline, montelukast and theophylline [55][56]. It produces side effect like diarrhoea, increases AST, ALT, γ-GTP, blood uric acid and triglyceride levels. It can decreases neutrophil count, WBC count and blood potassium. Moreover, asthma, duodenal ulcer, rhinitis blurred vision, eye pain and vertigo are less frequent adverse events.

Pharmaceutical Properties
Dexamethasone is a synthetic adrenal corticosteroid with potent anti-inflammatory properties. In addition to binding to specific nuclear steroid receptors, dexamethasone also interferes with NF-kB activation and apoptotic pathways. This agent lacks the salt-retaining properties of other related adrenal hormones. It is a glucocorticoid agonist and also known as dexone or decadron, belongs to the class of organic compounds known as 21-hydroxysteroids (Fig 7). These are steroids carrying a hydroxyl group at the 21-position of the steroid backbone. [55,57]

Mechanism of action
The exact mechanism of action is still unknown, but scientist find various mechanism behind its broad-spectrum antiviral activity. The first one is, inhibition of importin α/β1-mediated nuclear import of viral proteins of RNA viruses [81]. As SARS-CoV-2 is an RNA virus, so possibility of similar action is also higher [82].
The second one is based on ionophore concept because these molecules are considered as potential antiviral drugs [83]. In case of Ivermectin, both compound present shown in figure 9 interact with each other either spontaneously or by binding some plasma transport proteins, such as albumin.
Further, the oxygen atoms (shown in green), work as Lewis bases and could therefore coordinate a series of cations (Lewis acids). In addition, -OH groups are highlighted in pink and they could have a decisive role in the stabilization of the new structure. By this way an internal cavity and stabilized structure of Ionophore is formed [84].

Drug-Drug Interactions, Side Effects & Risks
If alcohol is taken with Ivermectin, it increases the plasma concentrations of ivermectin. Orange juice decreases the AUC and Cmax of Ivermectin due to potent inhibitors property of certain drug transporters [88]. Some side effects of this drug are pruritus, giddiness, nausea, abdominal pain, constipation, lethargy, transient ECG changes, fever, urticaria, myalgia, edema of lymph nodes.
Safety of ivermectin in pregnant women is not established [87][88].

Pharmaceutical Properties
Baricitinib is a small molecule and selective and reversible Janus kinase 1 (JAK1) and 2 (JAK2) inhibitor. The chemical formula of Baricitinib is C16H17N7O2S and molecular weight is 371.42. The 3D structure of Baricitinib is shown in figure 10.
In 2017, the European Union approved Baricitinib as a second-line orally administered treatment for moderate to severe active rheumatoid arthritis in adults [89].  years, a history of chronic or recurrent infections, creatinine clearance (CrCl) between 30mL/min and 60 mL/min, and concomitant use of a strong organic anion transporter-3 (OAT3) inhibitor .

Pharmaceutical Properties
This combination of drugs is discovered by Regeneron Pharmaceuticals Inc, USA. These Casirivimab is a monoclonal antibody combined with Imdevimab, an artificial antibody cocktail known as REGN-COV2 for the treatment of COVID-19. Recently in 2020, US-FDA issued EUA for this combination [97][98]. However, no information is available on pharmaceutical properties like formula and molecular weight.

Mechanism of Action:
Spike protein of SARS-CoV-2 is playing a quite important role in virus attachment, fusion and entry into the host cell. Casirivimab and imdevimab both are recombinant human IgG1 monoclonal antibody which binds to nonoverlapping epitopes of the spike protein of SARS-CoV-2. Together with casirivimab and imdevimab, neutralizes the spike protein of SARS-CoV-2 [98][99].

Drug Therapy for COVID-19 and Contraindications
Casirivimab and Imdevimab can be utilized for the treatment of confirmed SARS-CoV-2 infection who are adults and children aged 12 years of age and older, weighing at least 40 kg with mild to moderate COVID-19 symptoms. Along with that the patients who are at high risk for progressing to require hospitalization or severe COVID-19, this combination is reserved for them. This combination is allowed in single intravenous infusion with authorized dosage of 1,200 mg each drug in healthcare settings with immediate access to treat any hypersensitive reactions. However, the combination has some limitation as Casirivimab and Imdevimab is not for use in covid-19 patients who currently hospitalized, patients requiring oxygen therapy, patients requiring increases in baseline oxygen flow rate, or patients on oxygen therapy for non-COVID-19 related morbidity [99]. Still no contraindication found with this combination [99]. However, all events resolved after discontinuation of the infusion [99]. On the other hand, scientist associated with this research are awaiting the clinical trial results to confirm the high risk category patient.

Pharmaceutical Properties
Bamlanivimab

Mechanism of Action
Bamlanivimab binds the receptor-binding domain (RBD) of the S protein at a position overlapping the ACE2 binding site and which is accessible in both the up and down conformations of the RBD [100]. This binding of Bamlanivimab to RBD is confirmed by X-ray crystallography and cryo-EM.
Specifically, bamlanivimab binds to the S protein with a KD of 0.071 nM and blocks S protein-ACE2 interactions with an IC50 value of 0.025 μg/m

Drug Therapy for COVID-19 and Contraindications
Bamlanivimab can be utilized for the treatment of confirmed SARS-CoV-2 infection who are adults and children aged 12 years of age and older, weighing at least 40 kg with mild to moderate COVID-  [59]. It can be a potential risk factor for those who suffer from adverse transfusion reactions etc.

Drug-Drug Interactions, Side Effects & Risks
Convalescent Plasma is generally considered safe in terms of transfusion and tolerated well among the patients. A licensed physician can request the use of Convalescent Plasma for a single patient through emergency investigational new drugs (eIND). It also denotes that the probable risk factor of Convalescent Plasma is not greater than the disease or condition [60][61][62]

DISCUSSION
Battling the COVID-19 virus is a humanitarian challenge as thousands of health professionals worldwide are engaged in addressing the crisis globally. This review shows the importance of drugs

CONCLUSION
It is important to establish potential drug therapies against SARS CoV-2 based upon ongoing clinical trials, emergency use authorization and compassionate use protocols. As per studies conducted globally, certain antimicrobials have shown potent activity against SARS CoV-2 such as Hydroxychloroquine, Chloroquine, Remdesivir, Favipiravir, Lopinavir, Ritonavir, Dexamethasone, Ivermectin, Baricitinib, Casirivimab / imdevimab, Bamlanivimab. Investigational use of convalescent plasma from COVID-19 recovered patients is also being studied and these drug therapies have shown remarkable progress among COVID-19 patients in alleviating their symptoms, reducing morbidity and underlying comorbid conditions.