Current clinical anticipation of Arbidol against COVID-19: Possibilities
Ramana Hechhu1, Rangapuram Vasanthi2*, Tamrat Balcha Balla1, Kaliaperumal J1
1School of Pharmacy, College of Health Sciences and Medicine, Wolaita Sodo University, Ethiopia.
2GITAM School of Pharmacy, GITAM Deemed to be University, Hyderabad, Telangana State, India.
World Health Organization (WHO) has assessed that coronavirus disease 2019 (COVID-19) as an epidemic. However, an effective antiviral for COVID-19 is still uncertain. Since the onset of the outbreak, the scientific and clinical community keep proposing many agents that would have efficacy against COVID-19. Arbidol is an indole core with proven effectiveness against influenza over the past few years apart from critics. The concrete hypothesis of arbidol interaction with spike glycoprotein prevents the entry of virus. Further, demonstrated clinical efficiency of arbidol against RNA virus and broad-spectrum inhibition of influenza A and B virus, adenovirus, and other viruses, including hepatitis C virus, drives us to seek more understating of the molecule and its clinical possibilities. In this review, we attempt to describe the many possible hypotheses of arbidol against Covid-19.
The world witnessed several respiratory infectious diseases include the severe acute respiratory syndrome corona virus (SARS-CoV) in 2003 and, Middle East respiratory syndrome corona virus (MERS-CoV) in 2012, presently, 2019 novel corona virus (later World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019) in December 2019 were the three unidentified possess a positive-sense single-stranded RNA genome of corona viruses of the twenty-first centuries has showed the emergence and epidemic. The high recombination rate, and significant genetic variability of COVID-19 evidenced an easy transmission of the virus in human and animals, which are great epidemiologically challenging.1
SARS-CoV-2 is one among seven sorts of a corona virus2 including those that cause severe respiratory diseases. Corona viruses are an oversized family of viruses which can cause illness in animals and humans as well. In humans, several corona viruses are known to cause respiratory infections ranging from the common cold to a severe respiratory distress including Middle East respiratory syndrome (MERS) and Severe-acute respiratory syndrome (SARS) etc. A corona virus is a kind of a common virus that can affect an upper respiratory tract or a lower respiratory tract.3 The SARS-CoV-2 virus causes COVID-19 with varying symptoms which includes dry cough, fever, joint pain, difficulty in breathing, multiple organ failure due to sPo2 starving, etc. led long term morbidity.4
Most of the recently infected people are asymptomatic so, it’s a really crucial challenge to diagnose the patients with no symptoms but infected by this disease. COVID-19 is principally considered a respiratory disease, but some infected people’s experience non-respiratory symptoms, such as stroke. 5,6
In a short span, it has captured global consciousness by significantly affecting the day-to-day life of human beings. Currently, as a worldwide pandemic, COVID-19 poses major challenges. The World Health Organization has called this as a Public health emergency of International Concern.7 SARS-COV2 is a single stranded RNA enveloped virus, target cells through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2(ACE2) receptor.8
Severe acute respiratory infection (SARI) is the most the of viral infections that cause generalized clinical symptoms that cannot be easily differentiated from other respiratory infections. Monitoring SARI cases of influenza strains like H1N1 and Sars-Cov-2. Confirmed novel corona virus (nCoV) cases are clinically managed by immediate implementation of appropriate infection prevention and control (IPC) measures, such as early supportive therapy and monitoring, management of hypoxemic respiratory failure, management of septic shock and specific anti-Novel-CoV. treatments.9
As of Oct 14th 2020, WHO reported 38,435,977 confirmed cases with nearly 4% (1,092,124) of mortality rate in 216 countries across the world.10 On other hand, intense research on both vaccines and medicines to treat or prevent Covid-19 is being administered by different research groups within the worldwide.
Herbal Pharmaceuticals play a role in reducing the spread or complications of COVID-19 an infection within the body of individuals. The mixture of a conventional therapy and herbal medicines for the treatment of patients infected with COVID-19 have been proven a higher degree of the rate of recovery, because, of medicines of a plant origin a wide use, abundance high efficacy and lack of secondary effects.11 COV- 2 main protease contains a non-structural protein (PDB ID: 6LU7) which functions the potential target for the studies. Terpenoids (Clerodol) can inhibit the COVID-19 main protease that present within the Corona virus which is a crucial viral enzyme.12 Transfusion of convalescent blood products (CBP), especially convalescent plasma (CP) used as a passive immunization therapy to treat COVID-19.13
Arbidol (ARB) is an unapproved molecule except for China and Russia, which is being clinically hypothesised for its treatment of RNA viral infections and potential role in controlling SARS-CoV-2. ARB, namely umifenovir, inhibits viral replication for SARS coronaviruses which was obtained from its experimental data which is promising.14 ARB also showed dam virus replication by inhibiting the fusion of influenza virus lipid membranes with host cells.15 ARB is the most generally used of antiviral. However, no randomized comparative study data point out that one antiviral is the best than another for SARS-CoV-2. The safety and efficacy profile of chloroquine phosphate, human interferon alpha-2b and ARB are under investigation for treatment of COVID-19.16
ARB has been administered since 2007 in Russia and China against influenza, with no significant adverse effects reported. However, ARB is seriously criticized by the Russian Academy of Medical Sciences. Its vast potential as a broad-spectrum antiviral, defined through in vitro and in vivo studies, lends hope for its clinical use against various infectious diseases that are at present not therapeutically controlled. ARB shows promising in vitro inhibitory activity against the hepatitis C virus (HCV), the hepatitis B virus (HBV), reovirus, chikungunya virus (CHIKV), Hantaan virus, and coxsackie virus B5, additionally to influenza and pathogenic human respiratory viruses.
2. CURRENT CLINICAL POSSIBILITIES:
ARB (Umifenovir-Trade name) ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylsulfanyl)methyl]-1H-indole-3-carboxylate hydrochloride monohydrate could also be a derivative of indole carboxylic acids, was developed by a joint consortium of Russian scientists from the Centre for Drug Chemistry, Moscow, the Medical Radiology Scientific Research Institute, Obninsk, and the Pasteur Scientific Research Institute for Epidemiology and Microbiology, St.Petersburg17,18 for the proposed broad-spectrum antiviral compound that blocks viralfusion.19-22 Umifenovir manufactured in both Russia and China, where it had been licensed to be used for the prophylaxis and treatment of influenza A and B infections. Experimental studies on its mechanism of action against the influenza virus showed that umifenovir falls within a category of inhibitors that interact with hemagglutinin (HA) to stabilize it against the low pH transition to its fusogenic state; consequently, it inhibits HA-mediated membrane fusion during influenza virus infection.20,21 Umifenovir showed strong antiviral activity against both influenza A and B viruses in cell culture and in virus-infected mice.23-25 Clinical trials conducted on quite 30,000 patients showed that umifenovir is well tolerated, and no side effects are revealed.17,18 ARB resistant mutants are generated in cell culture,22 but thus far, ARB-resistant viruses haven't been isolated from humans. there's also no evidence of present resistance to umifenovir in any influenza virus isolates.26,27
Later on, umifenovir demonstrated in vitro antiviral efficacy in widely spreading virus strains, just like the Ebola virus, human herpesvirus 8 (HHV-8), hepatitis C virus (HCV), and Tacaribe arenavirus.28
In recent years, many studies have revealed the effectiveness of ARB against both SARS-CoV and MERS-CoV by blocking viral entry due to the interaction with spike protein. Molecular dynamics and structural analysis also strongly support interaction with spike proteins with Nsp7_Nsp8 complex, Nsp14, Nsp15, E-channel, or Spike with the mfScores of 136.087, 118.253, 118.253, 117.879, and 145.125, respectively. Further, preclinical studies have shown untreated ARB can effectively inhibit coronavirus up to 60 times at a degree of 10 to 30 mmol/L, and significantly inhibit the virus’s pathological effects on cells.29 Further, a retrospective cohort study that matches ARB and lopinavir/ritonavir (LPV/r) treatment for patients with COVID-19 with LPV/r only shown 69% favourable response with ARB monotherapy which is highly promising.30
3. RECENT CLINICAL USAGES:
Recent multicentric open-labeled randomized superiority clinical test conducted in Wuhan, China of favipiravir (116 patients) vs ARB (120 patients) for COVID-19 patients revealed that in patients with moderate COVID-19 infections (who had not received any prior antivirals), favipiravir showed superior efficacy regarding the speed of clinical recovery at day 7 and a reduced the incidence of fever and cough. The clinical recovery rate at day 7 was 55.8% within the ARB group and 71.4% within the favipiravir group. All patients were eighteen years or older, and therefore the dose of favipiravir used was 1600 mg twice daily on day one then 600 mg twice daily for an extra 7 to 10 days on the same side the adverse effect profile of favipiravir was reported as manageable.31
Luminol system + kinetic chemiluminescence with the two, 2′-azobis (2-amidinopropane) dihydrochloride aided antioxidant quantification of ARB reveals with a higher degree of significance with Trolox upon oral administration. Further, the same study also shown ARB scavenges free radicals in two, latent steps. Perhaps this process can significantly contribute to the compensation of oxidative stress caused by a viral disease and, therefore, the therapeutic effect of the drug.32
The effectiveness of ARB against SARS-CoV-2 in clinical practice remains controversial. However, the study conducted on COVID-19 patients with lopinavir/ritonavir and arbidol reveals that ARB monotherapy provided a promising superior effect. However, the phenomena and RNA load remain the same.33
M. Tobaiqy et al.34 reviewed the four hundred and forty-nine articles within the literature search; of those, only 41 studies were eligible for inclusion, most of which were conducted in China of which only three were clinical trials. They reported that, the utilization of lopinavir, an antiviral HIV medication (N=21)- together with ritonavir (N=18) or alone (N=3)- oseltamivir (N=16) and arbidol hydrochloride (N¼8) for the treatment of COVID-19 alongside corticosteroids. However, no conclusive evidence of its efficacy in patients with COVID-19 was reported in associated with arbidol hydrochloride. But it had been reported alongside favipiravir, which was approved for the treatment of novel influenza on 15th February, 2020 in China.
A recent study by Naveen Vankadari 35 reported that the potential drug target and mechanism of ARB action to treat COVID-19. The molecular dynamics and structural analysis reveal ARB targets on SARS-CoV-2 spike glycoprotein interference on cell adhesion to the host which is indicating the potential of ARB to treat COVID-19. It had been provided information that the potential drug target and mechanism of action of ARB is going to be helped within the development of the latest therapeutics for SARS-CoV-2.
The recent reports evaluated the treatment efficacy of selected antiviral medications on mortality and lesion absorption supported chest CT scan by the study of assembled a cohort consisting of 504 hospitalized COVID-19. The general death rate was 15.67% within the cohort. Older age, lower SpO2 level, bigger lesion, early admission data, and therefore, the presence of pre-existing conditions were related to higher mortality. Which concluded ARB is in a position to substantially related to a discount in mortality among hospitalized COVID-19 patients. The mixture of ARB and Oseltamivir may further relate to a discount in mortality. In all analyses, the treatment effect of ARB on reducing mortality among hospitalized COVID-19 patients is robust. The combined use of ARB and oseltamivir appears to be ready to further is related to a discount within the mortality. Additionally, patients taking ARB shows faster lesion absorption, which is according to its effect on mortality.36
The safety and efficacy retrospective study on ARB provided and it won’t improve the prognosis or accelerate SARS-CoV-2 clearance in non-ICU patients.37
Xi Wang et al.38 evaluated six currently available and licensed anti-influenza drugs against SARS-CoV-2 includes ARB, oseltamivir, peramivir etc. Additionally, arbidol, an anti-influenza drug targeting the viral hemagglutinin (HA) is getting used during a clinical trial against COVID-19 (ChiCTR2000029573) and has been recently added to the principles in China. A recent retrospective study suggested that arbidol treatment showed tendency to enhance the discharging rate and reduce the death rate of COVID-19 patients.
Renyi Wu et al.39 reviewed the papers and presented the information about the ARB major mechanism of action is to dam the virus-cell membrane fusion also as virus-endosome fusion through incorporation into cell membranes and interference with the hydrogen bonding network of phospholipids.40 In the influenza virus, it's been shown to directly interact with virus particles to stabilize hemagglutinin (HA), reducing the likelihood of reaching the low pH threshold required for conformational transition into functional fusogenic HA.41
More recently James M. Sanders & colleagues 42 reported that, the present status of the treatment of COVID-19 by using the chosen Repurposed Drugs and other agents. During which ARB may be a brighter repurposed antiviral with a singular mechanism of action targeting the S protein/ACE2 interaction and inhibiting membrane fusion of the viral envelope. A nonrandomized study of 67 patients with COVID-19 showed that treatment with ARB for a median duration of 9 days was related to lower mortality rates (0% [0/36]vs 16% [5/31]) and better discharge rates compared with patients who didn't receive the agent. This observational data cannot establish the efficacy of ARB for COVID-19, but ongoing RCTs in China are further evaluating this agent.
Ping Xu a 43 carried out a multicentre retrospective cohort study of patients with laboratory-confirmed COVID-19 infection pneumonia from 3 hospitals in Hubei and Guangdong, 141 adults (aged 18 years) without ventilation were included. Combined group patients got arbidol and IFN-alpha 2b, monotherapy group patients inhaled IFN- alpha 2b for 10 to 14 days. Of 141 COVID-19 patients, baseline clinical and laboratory characteristics were similar between the combined group and monotherapy group, that 30% of the patient’s leucocytes counts were below the normal range and 36.4% of the patients experienced lymphocytopenia. The duration of viral RNA of the tract within the monotherapy group wasn't longer than that within the combined therapy group. There have been no significant differences between the two groups. The absorption of pneumonia within the combined group was faster than that within the monotherapy group. We inferred that arbidol/IFN - 2 b therapy is usually used as an efficient method to reinforce the COVID-19 pneumonia of mild patients, although it helpless with accelerating the virus clearance. These results should be verified during a wider prospective randomized environment.
Further, recent literature on COVID-19 concerning human controlled treatment trails for medications including lopinavir/ritonavir, ARB, hydroxychloroquine and dexamethasone suggested moderated clinical clearance with remdesvir and ARB.
Juan A. Siordia Jr 44 performed statistical analyses for typical viral clearance showed significant with 95% CI 0.76–3.50 and 0.35–83.30 on the seventh and 14th day respectively further ARB showed significant relief in fever and cough and less increment on gastric acids.
The efficiency of ARB compared with chloroquine phosphate on non-severe, hospitalised COVID-19 patients. For that, they retrospectively analysed the hospitalised, laboratory-confirmed COVID-19 patients, treated with antiviral monotherapies at Huizhou Municipal Central Hospital between Jan 19 and Mar 16, 2020. Demographic and clinical data was extracted from electronic medical records. The first outcome of the study was the viral shedding interval.
Here, twenty-seven patients with COVID-19 were included in the study with 10 receiving chloroquine phosphate, 11 receiving arbidol, and 6 receiving lopinavir/ritonavir. Baseline demographics and clinical data were similar between groups revealed that chloroquine and arbidol couldn't only shorten the viral shedding interval, but also decreased the hospitalization duration and hospitalization expenses.45
Jinnong ZhANG et al.46 postulated that post-exposure prophylaxis (PEP) using arbidol is related to decreased infection among individuals exposed to confirmed cases of COVID-19 infection. They conducted a retrospective case-control study on relations and healthcare workers exposed to patients confirmed to possess SARS-CoV-2 infection by real-time RT-PCR and Chest CT from January. They collected demographic information, work location of exposure, post-exposure prophylaxis information, and symptoms, if any, 24 days after exposure. The ampule number of close contact possibilities were undergone the study. There have been no differences in age, profession and sex distribution within the two groups with different post-exposure prophylaxis. Logistic regression supported the information of the relations and health care workers with arbidol or oseltamivir prophylaxis showed that arbidol PEP was a robust protective factor against the event of COVID-19. Here the findings suggest arbidol could reduce the infection the risk of the novel coronavirus in hospital and family settings. This treatment should be promoted for PEP use and will be the topic of further investigation.
Recently, In India, the CSIR constituent lab CSIR-Central Drug Research Institute (CDRI) Lucknow 47 have received permission for completing phase III clinical trial randomized, double-blind, placebo-controlled trial of efficacy, safety, and tolerability of antiviral umifenovir. The phase III clinical trials are going to be administered at King George’s Medical University (KGMU), Dr Ram Manohar Lohia Institute of Medical Sciences (RMLIMS) and ERA’s Lucknow Medical College & Hospital, Lucknow. ARB reveals promising for COVID-19. Umifenovir is primarily used for treatment of influenza and is out there in China and Russia. It has recently inherited prominence thanks to its potential use for COVID-19 patients. To gauge its efficacy in Indian patients, CSIR-CDRI has haunted the clinical test. Medizest Pharmaceutical, Goa, indeed developing technology for manufacturing ARB have been already received test license from Drugs controller general of India (DCGI).
The COVID-19 pandemic represents the best global public health crisis within the past 100 years. The spread of COVID-19 is accelerating. At present, there is no specific antiviral drugs for COVID-19 outbreak.
Hopefully vaccines and or specific therapeutic drugs targeting SARSCoV-2 are going to be made available within the next few months or years. With the speed, and volume of basic and clinical COVID-19/ SARS-CoV-2 research to develop potential drugs and therapies for this disease, our hope is going to be on the horizon. ARB's broad-spectrum activity may arise through the duality of function: a capacity to interact with both membranes and with viral and cellular proteins. These interactions would impede cellular processes and pathways that are hijacked by several viruses to infect their host cells. ARB also inhibits HCV replication, which can arise via alteration of intracellular membrane-protein structures essential for intracellular trafficking (e.g., clathrin coat components, elements of the cytoskeleton) and virus replication (e.g., membranous web), and will hinder membrane rearrangements necessary for the budding viral step. Within the present state of our knowledge, ARB could therefore constitute an economic pharmacological approach, affordable for emerging countries in urgent need of effective antiviral therapies.
A number of studies are still recruiting patients, and different results on arbidol's utilization in COVID-19 patients are anticipated to be released sooner end of this year.
5. CONFLICTS OF INTEREST:
The authors declare no conflict of interest.
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Accepted on 07.06.2021 © RJPT All right reserved
Research J. Pharm.and Tech 2022; 15(4):1653-1658.