Role of Drug Repurposing in Current Treatment Strategies Against Covid-19; Systemic Review

Pharmaceutical Resonance COVID - 19 Special Issue 2020

REVIEW ARTICLE

ROLE OF DRUG REPURPOSING IN CURRENT TREATMENT STRATEGIES AGAINST COVID-19; SYSTEMIC REVIEW

Eknath D. Ahire1, Vijayraj N. Sonawane2, Khemchand R. Surana2* 1Department of Pharmaceutics, SSS’s, Divine College of Pharmacy, Nampur Road, Satana, 423301. 2*Department of Phamaceutical Chemistry, SSS’s, Divine College of Pharmacy, Nampur Road, Satana, 423301

Abstract : COVID-19 has now been affirmedpandemic and novel therapies are immediatelydesirable as we arrive astageoutside containment. Because COVID-19 is now becoming pandemic and in the nonappearance of known authenticated efficient therapy, efforts of laboratories and medical teams have focused on repurposing FDA sanctioned drugs to treat the most severe cases of infection. Developing novel drugs from is a long-lasting process, consequentlyunfeasible to face the instantaneousworldwide challenge.Drug repurposing (also termed drug profiling re‑tasking) is an approach for recognizing new usages for official or new drugs that are separate the opportunity of the unique medical indication. Drug repurposing is a developing approach where prevailing medicines, having previously been tested safe in humans, are reorganized to combat difficult-to-treat diseases. Although using like repurposed drugs separately may eventually not yield an important clinical benefit, carefully combined combinations could be very operative, the current question now being which combination. In this present review we are trying to shedding light on the numerous previously well reported and recognized drug which can be mostly used as repurposed medicament in the management of COVID-19 pandemic. Keyworkd : Drug Repurposing,Pandemic, Novel Drug, COVID-19.

1. Introduction : the supreme severe cases of infection[1, 2].The recent A novel corona virus has come out which causes explores of new corona virus disease-19 (COVID-19) pneumonia explores first in the Wuhan region of initiates and explores different possible treatment China and now days with high transmission strategies by using drugs which are already available efficiency spreading worldwide. This novel corona in the market. Drug repurposing is a constructive way to rapidly identify curative drug with a known safety virus, named SARS-CoV-2 (COVID-19), which leads [3, 4] to respiratory infections including pneumonia and profile to treat a come out disease . having a death rate approximate about 2% to 2.5%, COVID-19 indicates a global health warning and it is increasing with age and the exciting with underlying a significant operator of possible economic crisis, so diseases. According to WHO, till date near about suppressing the current taking place matter of first 4006257 estimated cases (a number of cases priority for most pharma industries and biotech underestimated because of asymptomatic carriers) industries. Drug repurposing (also termed drug and the epidemic has already left 278892 dead from repositioning, re-profiling or re‑tasking) is a strategy COVID-19 disease, and the worldwide spread in near for recognizing new usages for official or new drugs about 215 countries. Since COVID-19 is nowadays that are separates the opportunity of the unique becoming pandemic and in the nonexistence of medical indication. This strategy proposals numerous recognized authenticated well-organized therapy, benefits over emerging an exclusively new drug for a efforts of laboratories and medical teams have given suggestion[1,5]. First, and maybe most attentive on repurposing FDA permitted drugs to treat prominently, the threat of failure is less; because the repurposed drug has previously been originate to be sufficiently safe in preclinical models and humans if early stage trials have been completed, it is less likely Mr. Khemchand R. Surana to fail at least from a safety point of view in Department of Phamaceutical Chemistry, SSS’s,Divine college of Pharmacy, Nampur road, subsequent efficacy trials. Second, the time frame for Satana, 423301, drug development can be reduced, because maximum eMail: [email protected] of the preclinical testing, safety assessment and, in Contact No. +91 95524 30729 some cases, formulation development will already have been completed. Third, less investment is

© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 24 Pharmaceutical Resonance COVID - 19 Special Issue 2020 needed, although this will fluctuate expressively dependent on the stage and process of development of the repurposing candidate [6-8]. The regulatory and phase III costs may persist more or less the same for a repurposed drug as for a novel drug in the same sign, but there could still be considerable investments in preclinical and phase I and II budgets. Together, these advantages have the potential to result in a less risky and more rapidreturn on investment in the Figure 1: Drug Repurposing from existing drugs development of repurposed drugs, with lower average associated costs once failures have been accounted for (indeed, the budgets of carrying a repurposed drug to market have been projected to be US$300 million on aver‑ age, compared with an estimated ~$2 –3 billion for a new chemical entity7). Finally, repurposed drugs may reveal new targets and [9, 10] Figure 2: Difference between conventional drug pathways that can be further exploited . discovery & drug repurposing The most of the drug molecules till date utilized for treatment of COVID-19 represents drug repurposing, when a drug molecule has previous known activity against some other target. Drug repurposing is the most promising alternative to originate with a lot of safety data and results of other studies which is previously at hand for the drug molecule which permits to substantially to run the drug development process[11, 12] Majority of the promising treatments against the corona virus (COVID-19) comes under two categories : 1. Treatments for the respiratory symptoms 2. Inhibitors of the viral growth Figure 3: Schematic representation of drug repur- 2. Potential repurposing drugs molecules for posing strategies COVID-19 Remdesivir is a phosphoramidate analogue, which 2. 1. Virtually targeted agent is prodrug of an adenine derivative through similar 2.1.1 Approved Nucleoside Analogues: structure to that of tenofovir, alafenamide which is accepted human immunodeficiency virus (HIV) Favipiravir (T-705) which is guanine base molecule reverse transcriptase inhibitor. It has broad-spectrum accepted for management of influenza and effectively activity in contradiction of RNA viruses such as inhibit the RNA (Ribonucleic acid) -dependent RNA SARS and MERS through in-vivo and in-vitro polymerase of RNA viruses such as Ebola, Influenza, evaluation and tested for Ebola in clinical trials. The yellow fever, enterovirus, chikungunya and norovirus adenine or guanine base nucleotide analogues act and a recently reported for its activity against COVID [13] through the RNA-dependent RNA polymerase and -19 with EC50 value is 61.88 μM in Vero E6 cells . inhibiting the synthesis of viral RNA in a broad Ribavirin is also guanine derivative permitted for spectrum of RNA viruses, including human corona management of respiratory syncytial virus (RSV) and viruses. United States Food and Drugs Human Viral Challenge(HVC) that has been Administration (USFDA) approved this drug for the investigated in patients with Severe Acute management of COVID-19 and it has EC50 value Respiratory Syndrome (SARS), and Middle East 0.77 μM in Vero E6 cells. It is one of the fastest Respiratory Syndrome (MERS), but its side effects approvals given by USFDA. Marketing authorization like as anemia may be severe at high doses and was given to Gilead Sciences[14, 16]. whether it deals adequate effectiveness against [14, 15] Galidesivir is an adenosine derivative that COVID-19 is unknown . approved for HCV and is currently under clinical 2.1.2. Experimental Nucleoside Analogues: studies for evaluation its safety in in fine fettle

Table 1: Some drugs used for COVID-19 through Drug repurposing

Candidate MOA/ Indication Status clinical trials Sponser/ Producer Kaletra (lopinavir/ >10 latest stages clinical studies ritonavir) HIV Protease inhibitor (Including combination with AbbVie Combinational HIV-1 Infection other drugs) therapy Prevent SARS-CoV-2 Nafamostat mesylate Spike Protein originated Accomplished preclinical University of Tokyo (Fusan) membranefusion acute studyin Japan pancreatitis Prevent SARS-CoV-2 Camostat mesylate Phase 1, 2 Clinical study University of Aarhus Spike Protein initiated (Foypan) inGermany made in Japan membranefusion Endosomal acidification Medical institutions Chloroquine fusion inhibitor Clinical investigation in china worldwide anti-malarial Endosomal acidification Hydroxy-chloroquine fusion inhibitor, Medical institutions Clinical studies in china (Plaquenil) antimalarila, Rheumatoid worldwide arthritis subjects and its efficacy in contradiction of yellow Pegylated interferon α-2a and α-2b applied for the fever, and has shown antiviral activities in preclinical management of HBV and HCV and applied to investigations in contradiction of numerous RNA stimulate innate antiviral results in patients who are viruses, as well as SARS and MERS2[11, 17]. infected with COVID-19. The clinical trials of 2.2 The spike glycoprotein is promising interferons already initiated, in which tests the inhibitors official anti-HCV combination of a pegylated interferon plus ribavirin, but till date it is not sure Griffithsin is a red-alga-derived lectin which fixes to whether combination of pegylated interferon and a oligosaccharides on the surface of different viral nucleoside compound shows synergistic action glycoproteins which includes SARS-CoV spike against COVID-19[23]. glycoprotein and HIV glycoprotein 120[18, 19]. It has been tested against HIV prevention in phase I Nitazoxanide is the accepted for tretament of studies in the form of gel or enema, but the potency diarrheal condition and recently reported it also and delivery systems of spike inhibitors should be inhibiting coronavirus with EC50 value of 2.12 μM evaluated again for the treatment or prevention of in Vero E6 cells. Nitazoxanide, conventionally an COVID-19 [11, 20]. antihelminthic agent, has wide-ranging antiviral activity and are natively auspicious safety profile. 2.3 Protease Inhibitors Nitazoxanide has established in-vitro antiviral Ritonavir, Disulfiram and lopinavir these are reported activity in contradiction of MERS and SARS-CoV-2 approved protease inhibitors which are to be active in Awaiting further suggestion, the antiviral activity, contradiction of MERS and SARS[13]. immunomodulatory properties, and safety profile of nitazoxanide permit its advance study as a Ritonavir and lopinavir were primarily designated management option for SARS-CoV-2[17, 24]. for inhibition of 3-chymotrypsin-like protease of MERS and SARS, and emerging with better clinical 2.5 Prophylaxis Treatment : results of COVID-19 patients in a non-randomized Chloroquine/ hydroxychloroquine, a front-line drug open- label trial[18]. applied in the management and prophylaxis of Disulfiram is a accepted drug for treatment of malaria. These are also used in management of alcohol dependence and recently reported for COVID autoimmune disease act by inhibiting the replication of deoxyribonucleic acid (DNA) and RNA viruses -19 to prevent the papain-like protease of SARS and [25] MERS in in-vitro testing, but lacking of clinical which includes most of human corona viruses . evidence [1, 21, 22]. Recently, chloroquine was establish to prevent SARS -CoV-2 in vitro and its hydroxylated form has been 2.4 Host targeted agents : suggested as a probable treatment to treat patients diseased with SARS-CoV-2 [26-28].

2.6 Glycopeptide inhibitors : Monoclonal antibodies focused in contradiction of Glycopeptide antibiotic, teicoplanin is applied in the key inflammatory cytokines or other features of the management of bacterial infection and recently instinctive immune response signify alternative reported that it was active in vitro against SARS-CoV potential class of adjunctive treatments for COVID- and added in the library of molecules that could be 19. The reasoning for their application is that the used as therapeutic arsenal beside COVID-19[29]. This fundamental pathophysiology of important organ antibiotic, presently used in the management of Gram impairment in the lungs and supplementary organs is -positive bacterial infection, especially in triggered by an augmented immune response and Staphylococcal infections, has previously showed cytokine release, or “cytokine storm.” IL-6 seems to efficacy in contradiction ofnumerous viruses such as be a crucial driver of this dysregulated inflammation Influenza virus, ebola, flavivirus, HIV virus, hepatitis constructed on primary case sequence from China. C virus and on corona virus such as SARS-CoV and Consequently, monoclonal antibodies in MERS-CoV Camostat mesylate, an official contradiction of IL-6 could hypothetically dampen (approved) medicine in Japan for the management of this process and improve clinical outcomes. pancreatitis, inhibits nCoV cell entrance in-vitro via Tocilizumab, a monoclonal antibody IL-6 receptor prevent of the hostserine protease, TMPRSS2. This antagonist, is FDA permitted to treat RA and newer mechanism delivers an supplementary drug cytokine release syndrome following chimeric target for forthcoming investigation[7, 30]. antigen receptor T-cell therapy. Given this experience, tocilizumab has been applied in small 2.7 Adjunctive therapies : series of severe COVID-19 cases with initial At existing in the nonexistence of established intelligences of success. The lack of a comparator treatment for SARS-CoV-2, the foundation group bounds the understanding of the drug specific stoneofattentionforpatientswithCOVID-19 rests effect and warrants caution until more rigorous data supportive caution, going from symptomatic type are available. Numerous RCT soft ocilizumab, only patient treatment to complete exhaustive care or in amalgamation, in patients withCOVID-1 by backing. Though, 3 adjunctive treatments that means of severe pneumonia are ongoing in China authorization special reference are corticosteroids, (NCT04310228, ChiCTR200002976), and it is comprised in the existing Chinese national anticytokine or immunomodulatory drugs, and [36] immunoglobulin treatment[31, 32]. management guidelines . 2.7.1 Corticosteroids : Sarilumab, alternative IL-6 receptor antagonist permitted for RA, is actuality studied in a multi- The rationale for the application of corticosteroids is center, double-blind, and phase 2/3 trial for to reduction the host inflammatory replies in the hospitalized patients by means of severe COVID-19 lungs, which may lead to acute lung damage and (NCT04315298). Another monoclonal antibody or acute respiratory distress syndrome (ARDS). immune modulatory agents in clinical trials in China However, this advantage may be compensated by or existing for prolonged admittance in the US adverse effects, comprising delayed viral clearance comprise bevacizumab (anti–vascular endothelial and improved risk of secondary infection. Though growth factor medication; NCT04275414), direct confirmation for corticosteroids in COVID-19 fingolimod (immune modulator approved for is inadequate, reviews of conclusions in other viral multiple sclerosis; NCT04280588), and eculizumab pneumonias are edifying. Remarkable investigations (antibody inhibiting terminal complement; in patients with SARS and MERS informed no NCT04288713)[37] relations of corticosteroids with enhanced survival, but established an relationship with hindered viral 2.7.3 Immunoglobulin therapy : clearance from the respiratory tract and blood and Alternative potential adjunctive treatment for COVID elevated rate of difficulties comprising -19 is the applied of convalescent plasma or hyper hyperglycemia, psychosis, and a vascular necrosis[33, immune immunoglobulins. The validation for this 34]. Therefore, the probable harms and lack of management is that antibodies from improved demonstrated advantage for corticosteroids cautions patients may benefit with both free virus and diseased in contradiction of their routine applications in cell immune clearance. Anecdotal accounts or patients with COVID-19 external an RCT except an procedures for convalescent plasma treatment have affiliated compelling suggestion, such as chronic been described as rescue therapy in SARS and obstructive pulmonary disease exacerbation or MERS. A 2009 potential investigational study in 93 refractory shock exists[35]. disapprovingly unwell patients with H1N1 influenza 2.7.2 Anticytokine or immunomodulatory Drugs : A, 20 of them received convalescent plasma, reported that received of convalescent plasma vs. non

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