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Past, Present and Future of Remdesivir—Overview of a Most Popular Antiviral in Recent Times

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Past, Present and Future of Remdesivir—Overview of a Most Popular Antiviral in Recent Times DWAIPAYAN SARATHI CHAKRABORTY et al., JPRR, 2020;4:20 Research Article JPRR (2020) 4:20 Journal of Pharmaceutical Research and Reviews (ISSN:2576-8417) PAST, PRESENT AND FUTURE OF REMDESIVIR—OVERVIEW OF A MOST POPULAR ANTIVIRAL IN RECENT TIMES DWAIPAYAN SARATHI CHAKRABORTY*, SHOUVIK CHOUDHURY REGISTRAR, DEPARTMENT OF CARDIOLOGY, BELLE VUE CLINIC ABSTRACT Recent international epidemics of coronavirus-associated *Correspondence to Author: illnesses underscore the urgent medical and public health DWAIPAYAN SARATHI need for vaccine development and regulatory body approved CHAKRABORTY therapies. In particular, the current coronavirus disease REGISTRAR, DEPARTMENT OF 2019 (COVID-19) pandemic has quickly intensified interest in CARDIOLOGY, BELLE VUE CLIN- developing treatment options to mitigate impact on human life. IC Email: [email protected] Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being tested as a potential treatment for COVID-19 in How to cite this article: international, multi-site clinical trials. Currently available evidence DWAIPAYAN SARATHI about the antiviral effects of remdesivir against to accumulate CHAKRABORTY, SHOUVIK before the clinical trials are concluded. It is imperative for public CHOUDHURY. PAST, PRESENT health practitioners and the One Health community to stay up AND FUTURE OF REMDESIVIR— to date on the most promising potential therapeutic options OVERVIEW OF A MOST POP- that are under investigation. Thus, the purpose of this review ULAR ANTIVIRAL IN RECENT is to synthesize the knowledge to date about remdesivir as a TIMES. Journal of Pharmaceutical therapeutic option for coronaviruses, with a special focus on Research and Reviews, 2020; 4:20 information relevant to the One Health community eSciPub LLC, Houston, TX USA. Website: https://escipub.com/ JPRR: https://escipub.com/journal-of-pharmaceutical-research-and-reviews/ 1 DWAIPAYAN SARATHI CHAKRABORTY et al., JPRR, 2020;4:20 Among the myriad infectious disease threats bacterial agents discovered. The paucity of true humans face from bacteria, prions, parasites, broad-spectrum antiviral agents leaves a major protozoa, fungi, ectoparasites,and viruses, it is chasm in preparedness for viral infectious viral infections that arguably constitute the disease emergencies. The current antiviral biggest pandemic threat in the modern era. The discovery process and strategy is driven by an replication rates and transmissibility of viruses overarching aim of finding treatments for specific are two major factors that underlie this threat. individual viruses of concern and not against However, at least one additional factor plays an viral families, let alone larger groupings of essential role: the lack of ‘broad-spectrum’ viruses akin to grampositiven or gram-negative antiviral agents. Indeed, while bacteria can still spectrum antibacterial agents. When an cause substantial epidemics in parts of the world emerging infectious disease or pandemic where access to clean water and/ or strikes, if it is of bacterial or fungal origin it could antimicrobials is limited, the pandemic threats be almost assured that clinicians, posed by bacteria, such as from the plague- microbiologists, and pharmacologists could craft causing Yersinia pestis, has been substantially an effective regimen from amongst existing diminished in the antibiotic era [1]. For viruses antimicrobials. By contrast, nearly every novel that pose epidemic risks, on the other hand, viral epidemic of regional or global importance current therapeutic options are more limited. has been characterized by the common refrain Viruses, by their obligate parasitical nature, must that supportive care is the mainstay of therapy use host cell machinery for many functions. with drug trials coming, for the most part, post- Thus, antiviral strategies must be directed at the outbreak. If we look back into the history of virus specifically with care to avoid interfering pandemics in last 100 yrs the notorius bugs with host cellular function. As such, the number those have affected the whole world severely of clear targets per virus may be limited. By belongs to the group of viruses. So development contrast, bacterial protein synthesis, for of antiviral drugs and their uses in those example, occurs via ribosomes that belong to pandemics times were always a major concern the bacteria and are disparate enough from in treatment aspect. human ribosomes in identity that specific Remdesivir is an investigational antibiotics can be deployed to target only monophosphoramidate prodrug of an adenosine bacterial protein synthesis. This unique feature analog that was developed by Gilead Sciences, of viruses, which derives from their very nature, Inc. in response to the Ebola outbreak in serves to delimit antiviral therapies in a manner WestAfrica from 2014 to 2016. As a nucleoside not applicable to antibacterial therapies. analog, remdesivir acts as a RNA-dependent Additionally, other characteristics of viruses RNA polymerase (RdRp) inhibitor, targeting the serve as obstacles to broad-spectrum antiviral viral genome replication process. After the host agents. These include differences between RNA metabolizes remdesivir into active nucleoside and DNA viruses, vastly different virally encoded triphosphate (NTP), the metabolite competes proteins across viral families, single or double with adenosine triphosphate (ATP; the natural strand genomic structure, cytoplasmic or nuclear nucleotide normally used in this process) for replications cycles, and degree of reliance on incorporation into the nascent RNA strand.[2] host proteins. The existing armamentarium of The incorporation of this substitute into the new antiviral drugs is rapidly expanding and now strand results in premature termination of RNA covers several viral families.However, very few synthesis, halting the growth of the RNA strand existing antiviral agents have spectrums of after a few more nucleotides are added. Once activity that even slightly measure up to the remdesivir added into the growing chain (i spectrum of penicillin or sulfa, the first anti- position), it cannot cause an immediate stop. On JPRR: https://escipub.com/journal-of-pharmaceutical-research-and-reviews/ 2 DWAIPAYAN SARATHI CHAKRABORTY et al., JPRR, 2020;4:20 the contrary, it will continue to extend three more human endothelial cells, with low half-maximal nucleotides down to stop the strand at (i + 3) effective concentration (EC 50 ) values of 0.06– position.[3] This drug is widely distributed in the 0.14 μM [10] . In addition, remdesivir was body with a predominant accumulation in reported to exhibit antiviral activity in vitro bladder, kidneys, liver, prostate gland, salivary against Marburg virus [10] , Paramyxoviridae gland (mandibular), pancreas,Seminal vesicle, (such as parainfluenza type 3 virus, Nipah virus, epididymis and testes. Half life of the drug is Hendra virus, and measles and mumps viruses) 0.84-1.04 hr.It gets elimintated majorly by renal and Pneumoviridae (such as respiratory route (63%) and too some extent by billiary syncytial virus) [11] excretion (27.8%).It poorly crosses blood-brain Early clinical experience of remdesivir therapy in barrier. Remdesivir is at least partially a female nurse from Scotland with Ebola metabolized by the cytochrome P450 enzymes meningoencephalitis, which was supported by CYP2C8, CYP2D6, and the detection of Ebola virus RNA in plasma and CYP3A4.[4] Blood plasma concentrations of cerebrospinal fluid, its first use for Ebola virus remdesivir are expected to decrease if it is infection in humans, was reported in 2016. She administered was successfully treated with highdose corticosteroids and 14 days of remdesivir together with cytochrome P450 inducers such as therapy (once-daily rifampicin, carbamazepine, phenobarbital, infusion of 150 mg over 2 h for 2 days, and then phenytoin, primidone, and St John's wort.[5] daily 225 mg for another 12 days). No serious The therapeutic efficacy of remdesivir was first clinical or biochemical events occurred except a described in an animal model against Ebola transient rise of serum amylase level. [12] among infected rhesus monkeys in which once- Remdesivir was rapidly pushed through clinical daily dosing resulted in suppression of viral trials due to the West African Ebola virus replication and protection from lethal disease.[6] epidemic of 2013–2016, eventually being used Besides, in a mouse model of SARS-CoV in people with the disease. Preliminary results infection, prophylactic and early therapeutic were promising; it was used in the emergency dosing of remdesivir effectively decreased the setting during the Kivu Ebola epidemic that viral load in the lungs and improved pulmonary started in 2018, along with further clinical trials, function.[7] Efficacy studies in mice showed that until August 2019, when Congolese health remdesivir had therapeutic efficacy against officials announced that it was significantly less Severe Acute Respiratory Syndrome (SARS)- effective than monoclonal antibody treatments CoV and Middle East Respiratory Syndrome such as mAb114 and REGN-EB3. The trials, coronavirus (MERS-CoV) in Ces1c−/− mice.[8] however, established its safety Efficacy of this drug was tested against Nipah profile.[13,14.15,16,17,18,19]. Phase II clinical virus Bangladesh genotype in African green trials were conducted in Ebola virus-infected monkeys which showed in contrast to control patients.In clinical trials of anti-Ebola drugs, the animals, which all succumbed to the infection, all fatality
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