DSC, TGA-FTIR and FTIR Assisted by Chemometric Factor Analysis and PXRD in Assessing the Incompatibility of the Antiviral Drug Arbidol Hydrochloride with Pharmaceutical Excipients.

Arbidol hydrochloride is an antiviral product widely used in Russia and China for the treatment of, among other diseases, influenza. In recent years, it has turned out to be highly effective against COVID-19. However, there is little knowledge about its physicochemical properties and its behavior in the presence of various pharmaceutical excipients, which could be useful in the development of new preparations by increasing its solubility and bioavailability. For this reason, binary mixtures composed of arbidol hydrochloride and selected pharmaceutical excipients such as chitosan, polyvinylpyrrolione K-30 and magnesium stearate were prepared and subjected to differential scanning calorimetry (DSC), thermogravimetry combined with Fourier transform infrared spectrometry (TGA-FTIR) and Fourier transform infrared spectrometry (FTIR) analyses. In order to obtain clarity in the interpretation of the outcomes, chemometric calculations with factor analysis (FA) were used. Additionally, a powder X-ray diffraction (PXRD) and an intrinsic dissolution rate study were performed for arbidol hydrochloride itself and in the presence of excipients. As a result of the study, it was revealed that arbidol hydrochloride may undergo polymorphic transformations and be incompatible with chitosan and magnesium stearate. However, mixing arbidol hydrochloride with polyvinylpyrrolidone K-30 guarantees the obtaining of durable and safe pharmaceutical preparations.

Glycomic Analysis Reveals That Sialyltransferase Inhibition Is Involved in the Antiviral Effects of Arbidol.

Due to the high mutation rate of influenza virus and the rapid increase of drug resistance, it is imperative to discover host-targeting antiviral agents with broad-spectrum antiviral activity. Considering the discrepancy between the urgent demand of antiviral drugs during an influenza pandemic and the long-term process of drug discovery and development, it is feasible to explore host-based antiviral agents and strategies from antiviral drugs on the market. In the current study, the antiviral mechanism of arbidol (ARB), a broad-spectrum antiviral drug with potent activity at early stages of viral replication, was investigated from the aspect of hemagglutinin (HA) receptors of host cells. N-glycans that act as the potential binding receptors of HA on 16-human bronchial epithelial (16-HBE) cells were comprehensively profiled for the first time by using an in-depth glycomic approach based on TiO2-PGC chip-Q-TOF MS. Their relative levels upon the treatment of ARB and virus were carefully examined by employing an ultra-high sensitive qualitative method based on Chip LC-QQQ MS, showing that ARB treatment led to significant and extensive decrease of sialic acid (SA)-linked N-glycans (SA receptors), and thereby impaired the virus utilization on SA receptors for rolling and entry. The SA-decreasing effect of ARB was demonstrated to result from its inhibitory effect on sialyltransferases (ST), ST3GAL4 and ST6GAL1 of 16-HBE cells. Silence of STs, natural ST inhibitors, as well as sialidase treatment of 16-HBE cells, resulted in similar potent antiviral activity, whereas ST-inducing agent led to the diminished antiviral effect of ARB. These observations collectively suggesting the involvement of ST inhibition in the antiviral effect of ARB. IMPORTANCE This study revealed, for the first time, that ST inhibition and the resulted destruction of SA receptors of host cells may be an underlying mechanism for the antiviral activity of ARB. ST inhibition has been proposed as a novel host-targeting antiviral approach recently and several compounds are currently under exploration. ARB is the first antiviral drug on the market that was found to possess ST inhibiting function. This will provide crucial evidence for the clinical usages of ARB, such as in combination with neuraminidase (NA) inhibitors to exert optimized antiviral effect, etc. More importantly, as an agent that can inhibit the expression of STs, ARB can serve as a novel lead compound for the discovery and development of host-targeting antiviral drugs.

Arbidol increases the survival rate by mitigating inflammation in suckling mice infected with human coronavirus OC43 virus.

Human coronavirus OC43 (HCoV-OC43) often causes common cold and is able to neuroinvasive, but it can also induce lower respiratory tract infections (LRTI) especially in children and the elderly adults with underlying diseases. HCoV-OC43 infections currently have no approved antiviral treatment. Arbidol (ARB) is a broad-spectrum antiviral and is an antiviral medication for the treatment of influenza used in Russia and China. Due to its multiple mechanisms of action, such as inhibition of viral fusion and entry, immunomodulation, and modulation of host cell signaling pathways, ARB has the potential to be an effective treatment option for viral infections. Therefore, the study aims to investigate the activities of ARB against HCoV-OC43 infections. Suckling mice were infected with HCoV-OC43 and treated with ARB (50, 25 and 12.5 mg/kg/d) by gavage once daily for 4 days. the survival rates and body weight were recorded, the viral titer was measured by real-time quantitative polymerase chain reaction, cytokine levels were measured by Bio-Plex assays. Histopathological changes of the lungs and brain were analyzed. Our results show ARB increased the survival rate, reduced viral copy numbers in the lung, mitigated pro-inflammatory cytokine production, and improved brain and lung histopathology significantly without any significant toxicity or side effects in vivo. Our results suggest ARB could be a promising approach for the prevention and treatment of HCoV-OC43 while further studies are needed to address these possibilities and the underlying mechanism.

Multicenter, randomized controlled, open label evaluation of the efficacy and safety of arbidol hydrochloride tablets in the treatment of influenza-like cases.

OBJECTIVE: To study the efficacy and safety of arbidol hydrochloride tablets as a treatment for influenza-like diseases. METHODS: In this multicenter, randomized, controlled, open label study, a total of 412 influenza-like cases were collected from 14 hospitals in seven regions of Hebei Province from September 2021 to March 2022. Patients were randomly divided into two groups. The control group (n = 207) were administered oseltamivir phosphate capsules for five days and the experimental group (n = 205) were administered arbidol hydrochloride tablets for five days. The primary endpoint was the time to normal body temperature, and the secondary endpoints included the time to remission of influenza symptoms, incidence of influenza-like complications, and incidence of adverse reactions. RESULTS: Before treatment, there was no significant difference between the two groups in general conditions, blood routine, body temperature, or symptom severity. After treatment, there was no significant difference between the groups in the mean time to fever remission (59.24 h ± 25.21 vs. 61.05 h ± 29.47) or the mean time to remission of influenza symptoms (57.31 h ± 30.19 vs. 62.02 h ± 32.08). Survival analyses using Log-rank and Wilcoxon bilateral tests showed that there was no significant difference in fever relief time or influenza symptom relief time between the two groups. Regarding the incidence of complications and adverse events, there was only one case of tracheitis, one case of nausea, one case of vomiting, and one case of dizziness in the control group. In the experimental group, there was one case of nausea, one case of vomiting, and one case of drowsiness. In addition, one patient in the control group was hospitalized for urinary calculi. CONCLUSION: There was no significant difference between the patients with influenza-like cases treated with arbidol hydrochloride tablets and those treated with oseltamivir phosphate capsules. Further, the patients treated with arbidol hydrochloride tablets had fewer adverse reactions, and thus, the tablets were safe to use.

Sunlight-induced degradation of COVID-19 antivirals arbidol in natural aquatic environments: Mechanisms, pathways and toxicity.

Insights into COVID-19 antivirals' environmental fate and ecological risk are urgently required due to their increasing concentrations in aquatic environments, which have rarely been studied. Herein, we first investigated the photochemical transformation and the resulting alterations in toxicity of arbidol, an antiviral drug with relatively higher toxicity. The photolysis of arbidol was rapid with a rate constant of 0.106 min-1 due to its superior ultraviolet light absorption, in which the direct photolysis was predominated with a contribution of 91.5%. Despite its substantial photolysis, only 14.45% of arbidol was mineralized after 100 min, implying that arbidol and its products might have a long-term impact on aquatic environment. It was inferred that arbidol was photolyzed mainly via the loss of thiophenol, bromine, and alkylamine, based on twelve photolytic products identified. Notably, the experimental results demonstrated that the photolysis process increased the acute toxicity of arbidol, and the toxicity prediction indicated that the ecotoxicity of two photolytic products was very high with LC50 values below 0.1 mg/L. Due to the co-effect of multiple constituents, the photolytic rate observed in wastewater treatment plant effluent and in river water was comparable to that in ultra-pure water, while it was slightly enhanced in lake water. The presence of dissolved organic matter suppressed arbidol photolysis, while NO3- exhibited a promotion effect. These results would be of great significance to assess the fate and risk of COVID-19 antivirals in natural aquatic environments.

Meta-analysis of arbidol versus lopinavir/ritonavir in the treatment of coronavirus disease 2019.

OBJECTIVES: To systematically evaluate the efficacy and safety of arbidol and lopinavir/ritonavir (LPV/r) in the treatment of coronavirus disease 2019 (COVID-19) using a meta-analysis method. METHODS: The China Knowledge Network, VIP database, WanFang database PubMed database, Embase database, and Cochrane Library were searched for a collection of comparative studies on arbidol and lopinavir/ritonavir in the treatment of COVID-19. Meta-analysis was used to evaluate the efficacy and safety of Arbidol and lopinavir/ritonavir in the treatment of COVID-19. RESULTS: The results of the systematic review indicated that Arbidol had a higher positive-to-negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid on Day 7 (p = 0.03), a higher positive-to-negative conversion rate of SARS-CoV-2 nucleic acid on Day 14 (p = 0.006), a higher improvement rate of chest computed tomography on Day 14 (p = 0.02), a lower incidence of adverse reactions (p = 0.002) and lower rate of mortality (p = 0.007). There was no difference in the rate of cough disappearance on Day 14 (p = 0.24) or the rate of severe/critical illness (p = 0.07) between the two groups. CONCLUSIONS: Arbidol may be superior to lopinavir/ritonavir in the treatment of COVID-19. However, due to the small number of included studies and the number of patients, high-quality multicenter large-sample randomized double-blind controlled trials are still needed for verification.

Pharmacokinetic comparison of four arbidol hydrochloride preparations in beagle dogs.

This study aimed to compare the pharmacokinetic properties of four preparations (dispersible tablets, ordinary tablets, capsules and granules) of arbidol hydrochloride, a broad-spectrum antiviral drug, in beagle dogs. Briefly, a single dose of 100 mg of the four preparations of arbidol hydrochloride was orally administered to dogs; blood was then collected from the veins of the foreleg at different times after administration to prepare plasma samples. The plasma concentration of arbidol hydrochloride was measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that when orally administered with dispersible tablets, ordinary tablets, capsules and granules suspended with water, there were no significant differences in the pharmacokinetic parameters (including peak time, peak concentration, elimination half-life, area under the curve (AUC0-t ), and mean retention time) of arbidol hydrochloride. However, in the case of the dispersible tablets, the pharmacokinetics of arbidol hydrochloride was significantly affected by the mode of administration. Compared with direct feeding, peak time [0.50 (0.13, 0.50) vs. 1.00 (0.50, 2.00)] was significantly shortened (P = 0.033) and the AUC0-48 h (8726.5 ± 2509.3 vs. 3650.8 ± 1536.9 ng h/ml) was significantly increased (P = 0.012) when the dispersible tablets were orally administered as water dispersion. In conclusion, the pharmacokinetics of four preparations of arbidol hydrochloride were not significant different in beagle dogs. However, compared with direct feeding, the absorption of arbidol hydrochloride was faster and the bioavailability was better when the dispersible tablets were orally administered as water dispersion.

Optimal Drug Regimen and Combined Drug Therapy and Its Efficacy in the Treatment of COVID-19: A Within-Host Modeling Study.

The COVID-19 pandemic has resulted in more than 524 million cases and 6 million deaths worldwide. Various drug interventions targeting multiple stages of COVID-19 pathogenesis can significantly reduce infection-related mortality. The current within-host mathematical modeling study addresses the optimal drug regimen and efficacy of combination therapies in the treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Interferon (INF) and Lopinavir/Ritonavir. It is concluded that these drugs, when administered singly or in combination, reduce the number of infected cells and viral load. Four scenarios dealing with the administration of a single drug, two drugs, three drugs and all four are discussed. In all these scenarios, the optimal drug regimen is proposed based on two methods. In the first method, these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem are formulated. In this framework, the optimal drug regimen is derived. Later, using the comparative effectiveness method, the optimal drug regimen is derived based on the basic reproduction number and viral load. The average number of infected cells and viral load decreased the most when all four drugs were used together. On the other hand, the average number of susceptible cells decreased the most when Arbidol was administered alone. The basic reproduction number and viral load decreased the most when all four interventions were used together, confirming the previously obtained finding of the optimal control problem. The results of this study can help physicians make decisions about the treatment of the life-threatening COVID-19 infection.

Effective degradation of COVID-19 related drugs by biochar-supported red mud catalyst activated persulfate process: Mechanism and pathway.

With the global spread of the COVID-19 pandemic, the water pollution caused by extensive production and application of COVID-19 related drugs has aroused growing attention. Herein, a novel biochar-supported red mud catalyst (RM-BC) containing abundant free hydroxyl groups was synthesized. The RM-BC activated persulfate process was firstly put forward to degrade COVID-19 related drugs, including arbidol (ARB), chloroquine phosphate, hydroxychloroquine sulfate, and acyclovir. Highly effective removal of these pharmaceuticals was achieved and even 100% of ARB was removed within 12 min at optimum conditions. Mechanism study indicated that SO4 •- and HO• were the predominant radicals, and these radicals were responsible for the formation of DMPOX in electron spin resonance experiments. Fe species (Fe0 and Fe3O4) and oxygen-containing functional groups in RM-BC played crucial roles in the elimination of ARB. Effects of degradation conditions and several common water matrices were also investigated. Finally, the degradation products of ARB were identified by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and possible degradation pathways were proposed. This study demonstrated that RM-BC/PS system would have great potential for the removal of COVID-19 related drug residues in water by the catalyst synthesized from the solid waste.

Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs.

Neglected diseases caused by arenaviruses such as Lassa virus (LASV) and filoviruses like Ebola virus (EBOV) primarily afflict resource-limited countries, where antiviral drug development is often minimal. Previous studies have shown that many approved drugs developed for other clinical indications inhibit EBOV and LASV and that combinations of these drugs provide synergistic suppression of EBOV, often by blocking discrete steps in virus entry. We hypothesize that repurposing of combinations of orally administered approved drugs provides effective suppression of arenaviruses. In this report, we demonstrate that arbidol, an approved influenza antiviral previously shown to inhibit EBOV, LASV, and many other viruses, inhibits murine leukemia virus (MLV) reporter viruses pseudotyped with the fusion glycoproteins (GPs) of other arenaviruses (Junin virus [JUNV], lymphocytic choriomeningitis virus [LCMV], and Pichinde virus [PICV]). Arbidol and other approved drugs, including aripiprazole, amodiaquine, sertraline, and niclosamide, also inhibit infection of cells by infectious PICV, and arbidol, sertraline, and niclosamide inhibit infectious LASV. Combining arbidol with aripiprazole or sertraline results in the synergistic suppression of LASV and JUNV GP-bearing pseudoviruses. This proof-of-concept study shows that arenavirus infection in vitro can be synergistically inhibited by combinations of approved drugs. This approach may lead to a proactive strategy with which to prepare for and control known and new arenavirus outbreaks.

Clinical efficacy of methylprednisolone and the combined use of lopinavir/ritonavir with arbidol in treatment of coronavirus disease 2019.

This study aims to comparatively analyze the therapeutic efficacy upon multiple medication plans over lopinavir/ritonavir (LPV/r), arbidol (ARB), and methylprednisolone on patients with coronavirus disease 2019 (COVID-19). Totally, 75 COVID-19 patients admitted to The First Affiliated Hospital, Zhejiang University School of Medicine from January 22, 2020 to February 29, 2020 were recruited and grouped based on whether or not LPV/r and ARB were jointly used and whether or not methylprednisolone was used. Indexes including body temperature, time for nucleic acid negative conversion, hospital stays, and laboratory indexes were examined and compared. For all patients, there were no significant differences in the change of body temperature, the time for negative conversion, and hospital stays whether LPV/r and ARB were jointly used or not. While for severe and critically severe patients, methylprednisolone noticeably reduced the time for negative conversion. Meanwhile, the clinical efficacy was superior on patients receiving methylprednisolone within 3 days upon admission, and the duration of hospital stays was much shorter when methylprednisolone was given at a total dose of 0-400 mg than a higher dose of >400 mg if all patients received a similar dose per day. Nonetheless, no significant changes across hepatic, renal, and myocardial function indexes were observed. LPV/r combined with ARB produced no noticeably better effect on COVID-19 patients relative to the single-agent treatment. Additionally, methylprednisolone was efficient in severe and critically severe cases, and superior efficacy could be realized upon its early, appropriate, and short-term application.

Antiviral drugs arbidol and interferon alpha-1b contribute to reducing the severity of COVID-19 patients: a retrospective cohort study.

OBJECTIVES: The aim of this study was to evaluate the role of antiviral drugs in reducing the risk of developing severe illness in patients with moderate COVID-19 pneumonia. METHODS: This retrospective cohort study included 403 adult patients with moderate COVID-19 pneumonia who were admitted to Shenzhen Third People's Hospital, China. The antiviral drugs arbidol, interferon alpha-1b, lopinavir-ritonavir and ribavirin were distributed to the patients for treatment. The primary endpoint of this study was the time to develop severe illness. RESULTS: Of the 462 patients admitted, 403 had moderate COVID-19 symptoms at hospital admission and were included in this study. 90 of the 403 (22.3%) patients progressed to severe illness. The use of arbidol was associated with a lower severity rate 3.5% compared to control group 30.5%, p-value < 0.0001; the adjusted hazard ratio was 0.28 (95% CI: 0.084-0.90, p = 0.033). The use of interferon alpha-1b was associated with a lower severity rate 15.5% compared to control group 29.3%, with p-value < 0.0001; the adjusted hazard ratio was 0.30 (95% CI: 0.15-0.58, p =  0.0005). The use of lopinavir-itonavir and ribavirin did not show significant differences in adjusted regression models. Early use of arbidol within 7 days of symptom onset was significantly associated with a reduced recovery time of - 5.2 days (IQR - 3.0 to - 7.5, p = 4e-06) compared with the control group. CONCLUSION: Treatment with arbidol and interferon alpha-1b contributes to reducing the severity of illness in patients with moderate COVID-19 pneumonia. Early use of arbidol may reduce patients' recovery time.

Comparative effectiveness of Lopinavir/Ritonavir-based regimens in COVID-19.

The coronavirus disease 2019 (COVID-19) is an epidemic disease caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and spreading throughout the world rapidly. Here we evaluated the efficacy of the Lopinavir/Ritonavir (LPV/r) and its combination with other drugs in the treatment of COVID-19. We included 170 confirmed COVID-19 patients who had been cured and discharged. Their antiviral therapies were LPV/r alone or combinations with interferon (IFN), Novaferon and Arbidol. We evaluated the medication efficacy by comparing the time of the negative nucleic acid conversion and the length of hospitalization mainly. The LPV/r + Novaferon [6.00 (4.00-8.00) and 7.50 (5.00-10.00) days] had shorter time of the negative nucleic acid conversion (P = .0036) and shorter time of hospitalization (P < .001) compared with LPV/r alone [9.00 (5.00-12.00) and 12.00 (11.00-15.00) days] and LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days]. On the contrary, LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days] had shorter time of the negative nucleic acid conversion (P = .031) and shorter time of hospitalization (P < .001) compared with LPV/r + IFN +Novaferon [10.00 (8.00-11.25) and 13.50 (11.50-17.00) days] and LPV/r + IFN +Arbidol [14.00 (9.75-19.00) and 19.50 (13.25-24.00) days]. In conclusion, the combination of LPV/r and Novaferon may have better efficacy against COVID-19. However, adding IFN based on LPV/r + Novaferon or adding Arbidol based on LPV/r + IFN may not improve the efficacy.

A study on clinical effect of Arbidol combined with adjuvant therapy on COVID-19.

This study aims to explore the clinical effect of Arbidol (ARB) combined with adjuvant therapy on patients with coronavirus disease 2019 (COVID-19). The study included 62 patients with COVID-19 admitted to the First Hospital of Jiaxing from January to March 2020, and all patients were divided into the test group and the control group according to whether they received ARB during hospitalization. Various indexes in the two groups before and after treatment were observed and recorded, including fever, cough, hypodynamia, nasal obstruction, nasal discharge, diarrhea, C-reactive protein (CRP), procalcitonin (PCT), blood routine indexes, blood biochemical indexes, time to achieve negative virus nucleic acid, and so on. The fever and cough in the test group were relieved markedly faster than those in the control group (P < .05); there was no obvious difference between the two groups concerning the percentage of patients with abnormal CRP, PCT, blood routine indexes, aspartate aminotransferase, and alanine aminotransferase (P > .05); the time for two consecutive negative nucleic acid tests in the test group were shorter than that in the control group; the hospitalization period of the patients in the test group and control group were (16.5 ± 7.14) days and (18.55 ± 7.52) days, respectively. ARB combined with adjuvant therapy might be able to relieve the fever of COVID-19 sufferers faster and accelerate the cure time to some degree, hence it's recommended for further research clinically.

Clinical features and efficacy of antiviral drug, Arbidol in 220 nonemergency COVID-19 patients from East-West-Lake Shelter Hospital in Wuhan: a retrospective case series.

OBJECTIVE: We aimed to describe the features of 220 nonemergency (mild or common type) COVID-19 patients from a shelter hospital, as well as evaluate the efficiency of antiviral drug, Arbidol in their disease progressions. METHODS: Basic clinical characteristics were described and the efficacy of Arbidol was evaluated based on gender, age, maximum body temperature of the patients. RESULTS: Basically, males had a higher risk of fever and more onset symptoms than females. Arbidol could accelerate fever recovery and viral clearance in respiratory specimens, particularly in males. Arbidol also contributed to shorter hospital stay without obvious adverse reactions. CONCLUSIONS: In the retrospective COVID-19 cohort, gender was one of the important factors affecting patient's conditions. Arbidol showed several beneficial effects in these patients, especially in males. This study brought more researches enlightenment in understanding the emerging infectious disease.

Candidate drugs against SARS-CoV-2 and COVID-19.

Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial.

BACKGROUND: Treatment of patients with COVID-19 has included supportive care to mainly relief symptoms of the disease. Although World Health Organization (WHO) has not recommended any effective treatments for COVID-19, there are some reports about use of antiviral drugs. The aim of this study is to determine the effect of Arbidol (ARB) on COVID-19 disease. METHODS: Using an open-label randomized controlled trial, we examined the efficacy of ARB in patients with COVID-19 in a teaching hospital. One hundred eligible patients with diagnosis of COVID-19 were recruited in the study and assigned randomly to two groups of either hydroxychloroquine followed by KALETRA (Lopinavir/ritonavir) or hydroxychloroquine followed by ARB. The primary outcome was hospitalization duration and clinical improvement 7 days after admission. The criteria of improvement were relief of cough, dyspnea, and fever. Time to relief from fever was also assessed across the two groups. Without any dropouts, 100 patients were entered into the study for the final analysis at significance level of 0.05. RESULTS: The mean age of patients was 56.6 (17.8) years and 56.2 (14.8) years in ARB and KALETRA groups, respectively. Majority of patients were male across two groups (66 and 54%). The duration of hospitalization in ARB group was significantly less than KALETRA arm (7.2 versus 9.6 days; P = 0.02). Time to relief fever was almost similar across two groups (2.7 versus 3.1 days in ARB and KALETRA arms, respectively). Peripheral oxygen saturation rate was significantly different after 7 days of admission across two groups (94% versus 92% in ARB and KALETRA groups respectively) (P = 0.02). Based on multiple linear regression analysis, IHD, Na level, and oxygen saturation at the time of admission and type of therapy were the independent adjusted variables that determined the duration of hospitalization in patients with COVID-19. CONCLUSION: Our findings showed that Arbidol, compared to KALETRA, significantly contributes to clinical and laboratory improvements, including peripheral oxygen saturation, requiring ICU admissions, duration of hospitalization, chest CT involvements, WBC, and ESR. We suggest further studies on ARB against COVID-19 using larger sample size and multicenter design. TRIAL REGISTRATION: IRCT20180725040596N2 on 18 April 2020.

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol.

The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ∼16 Šfrom the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.

[The efficacy and safety of lopinavir/ritonavir and arbidol in patients with coronavirus disease 2019].

Objective: To evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) and arbidol in treating patients with coronavirus disease 2019 (COVID-19) in the real world. Methods: The clinical data of 178 patients diagnosed with COVID-19 admitted to Guangzhou Eighth People's Hospital from January 20 to February 10, 2020 were retrospectively analyzed. According to patient's antiviral treatment regimens, 178 patients were divided into 4 groups including LPV/r group (59 patients), arbidol group (36 patients), LPV/r plus arbidol combination group (25 patients) and the supportive care group without any antiviral treatment (58 patients). The primary end point was the negative conversion time of nucleic acid of 2019 novel coronavirus (2019-nCoV) by pharyngeal swab. Results: The baseline parameters of 4 groups before treatment was comparable. The negative conversion time of viral nucleic acid was (10.20±3.49), (10.11±4.68), (10.86±4.74), (8.44±3.51) days in LPV/r group, arbidol group, combination group, and supportive care group respectively (F=2.556, P=0.058). There was also no significant difference in negative conversion rate of 2019-nCoV nucleic acid, the improvement of clinical symptoms, and the improvement of pulmonary infections by CT scan (P>0.05). However, a statistically significant difference was found in the changing rates from mild/moderate to severe/critical type at day 7 (χ(2)=9.311, P=0.017), which were 24%(6/25) in combination group, 16.7%(6/36) in arbidol group, 5.4%(3/56) in LPV/r group and 5.2%(3/58) in supportive care group. Moreover, the incidence of adverse reactions in three antiviral groups was significantly higher than that in supportive care group (χ(2)=14.875, P=0.002). Conclusions: Antiviral treatment including LPV/r or arbidol or combination does not shorten the negative conversion time of 2019-nCoV nucleic acid nor improve clinical symptoms. Moreover, these antiviral drugs cause more adverse reactions which should be paid careful attention during the treatment.

How do arbidol and its analogs inhibit the SARS-CoV-2?

BACKGROUND: COVID-19 is not fully known and causes severe inflammation and cytokine storm. It has many symptoms, such as: fever, sore throat, headache, dyspnoea, and diarrhoea. Arbidol was used in the treatment of COVID19, which was the most critical health problem in the world. However, the desired recovery was not achieved with Arbidol. Many countries still use this drug in the treatment of COVID19. AIM: We aimed to determine whether Arbidol, the hemagglutinin esterase inhibitor used in the treatment of COVID-19, was effective against SARS Cov-2 in silico. RESULTS AND CONCLUSION: The similarity between hemagglutinin and spike proteins were reported due to the fact that inhibition properties of Arbidol and its 39 analogues were examined in detail against hemagglutinin esterase and spike glycoproteins. CID 1070884 and CID 1207786 were found to be more active against hemagglutinin esterase than in Arbidol, while these compounds were inactive against spike glycoproteins. The interaction mechanism was clarified between arbidol and spike proteins. Phenylalanine, tyrosine, glycine, lysine, and aspartic acid were found to be the headliner amino acids in the interactions between Arbidol and binding domains of spike glycoproteins in the SARS-CoV2 (Tab. 3, Fig. 8, Ref. 28).