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FOCUS ON COVID-19

Current drugs with potential for coronavirus disease 2019 therapy: a literature review

Alihosseini, Samina; Leylabadlo, Hamed Ebrahimzadeha,b; Parsaei, Mahdic,d; Sarafraz, Nazilac; Ghanbarov, Khudaverdie; Esposito, Silvanof; Kafil, Hossein S.g

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Reviews and Research in Medical Microbiology: January 2022 - Volume 33 - Issue 1 - p e148-e160
doi: 10.1097/MRM.0000000000000258
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Abstract

Introduction

Coronavirus disease 2019 (COVID-19), which was declared as a pandemic by WHO on 11 March 2020, has estimated to infect more than 3 million cases confirmed worldwide by WHO, a number that seems to be underestimated because of asymptomatic carrier's existence [1,2]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2: formerly 2019-nCoV) has high homology to other pathogenic coronaviruses, such as those originating from bat-related zoonosis (SARS-CoV), which caused approximately 646 deaths in China at the start of the past decade. Coronaviruses, like influenza viruses, circulate in nature in various animal species [3]. Alpha-coronaviruses and beta-coronaviruses can infect mammals and gamma-coronaviruses and delta-coronaviruses tend to infect birds, but some of them can also be transmitted to mammals. Although still preliminary, current data suggest that bats are the most probable initial source of the current COVID-19 outbreak, that begun on December 2019 in Wuhan, China, apparently spreading from a ‘wet market’ to multiple cities and provinces in China [4].

This enveloped RNA betacoronavirus called SARS-CoV-2 (formerly 2019-nCoV), has a spectrum of mild, self-limiting upper respiratory tract infection to severe progressive pneumonia and multiorgan failure, with a mortality rate estimated about 2–2.5%, increasing with age and underlying disease [5,6]. Thus far, there is not a specific, approved pharmacologic therapeutic agent for coronavirus infection [7]. In the case of an emerging disease, medical teams and scientists try to focus on repurposing US Food and Drug Administration (FDA)-approved drugs to treat the most severe cases of infection. Here, we review the repurposing drugs for prophylaxis and treatment of COVID-19 patients.

Drugs currently used for treatment of coronavirus disease 2019

Prophylaxis

To date, no specific drug or vaccine has been confirmed for COVID-19 chemoprevention, so prevention of exposure is the best recommendation [8]. Vaccine preparation will cost lots of dollars and maybe as much as 12 months away from availability. The most commonly used drug in COVID-19 chemoprevention up to now is chloroquine, which was introduced as well known and safe drug used for the prevention and treatment of malaria. Chloroquine has proposed to have a direct and indirect antiviral mechanisms of action. Impeding virus attachment to the cell surface and virus envelope maturation disturbance are two direct inhibitory mechanisms of chloroquine [9].

Interfering with terminal glycosylation of angiotensin-converting enzyme 2 (ACE2) which is a cellular receptor involved in the entry of SARS-CoV-19, is an example of indirect action of decreasing virus receptor binding [10]. Wang et al.[11] showed that chloroquine can function at both entry and postentry stages of 2019-nCoV infection in Vero E6 cells. This group also demonstrated that hydroxychloroquine (HCQ), a less toxic derivative of chloroquine, shows effective therapeutic potentials in suppressing SARS-CoV-2 infection in vitro, and inhibits entry and postentry stages of SARS-CoV-2 [12]. Chang et al.[13] recommend two prophylactic schedules against COVID-19 prophylaxis with chloroquine. However, there is very limited evidence for chloroquine and HCQ usage in COVID-19 prevention. Some people started to self-medicate these drugs by themselves, without paying attention to serious harms of these agents in case of not being monitored. WHO stopped HCQ arm of the Solidarity Trial, which is an international clinical trial investigating an effective treatment for COVID-19, launched by the WHO and partners. The reason was HCQ inefficiency in decreasing COVID-19 mortality in hospitalized patients in comparison with standard of care (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments). WHO also suspended the Welcome-funded COPCOV study, which is a prophylaxis study on HCQ and chloroquine efficacy, because of health concerns of these drugs (https://wellcome.ac.uk/news/can-chloroquine-prevent-coronavirus-disease-only-research-will-give-us-answer). Several further studies declined any effect by chloroquine and FDA disapproved this drug from prophylaxis or treatment strategies. Their initial suggestion was chloroquine usage under Monitored Emergency Use of Unregistered Interventions framework or an ethically approved trial by WHO [14]. As there is no approved drug for the prevention of COVID-19, general hand hygiene may be the best choice for disease spreading prevention. WHO recommends regular hand wash with water and soap or cleaning them with alcohol-based hand rubs.

Treatment

There is an urgent need for pharmacologic agents confirmed for COVID-19 treatment; however, there is no definite line of treatment for this lethal disease. One of the strategies used in such conditions is repurposing and off-label use of formerly approved drugs. There are numerous therapeutics applied for disease control till now, the efficacy of which needs to be more precisely studied. The latest edition (6th) of Guidelines for the Prevention, Diagnosis, and Treatment of Novel Coronavirus-induced Pneumonia issued by the National Health Commission for experimental treatment of COVID-19, was published on 18 February 2020. Antivirals used in the 6th Guideline include interferon (IFN)-α, Lopinavir/ritonavir, Ribavirin, Chloroquine phosphate, and Arbidol [15]. Clinical trials investigating these drugs are summarized in Table 1.

Table 1 - Recently registered trials on drugs against coronavirus disease 2019.
Drugs/Product Study identifier Sponsor Study design Primary outcome Status of trial
Chloroquine NCT04303507 University of Oxford Double-blind, randomized, placebo-controlled trial N = 10000, healthcare workers, or other individuals at significant risk of COVID-19 randomized to chloroquine or placebo Number of symptomatic COVID-19 infections Not yet recruiting
Hydroxychloroquine sulfate NCT04316377 University Hospital, Akershus Phase 4, pragmatic randomized controlled trial N = 202, COVID-19 in need of hospital admission randomized to standard of care or standard of care with the addition of therapy with chloroquine Rate of decline in SARS-CoV-2 viral load Not yet recruiting
Hydroxychloroquine NCT0426151 7 Shanghai Public Health Clinical Center Phase 3, randomized, open label N = 30, treatment of pneumonia caused by COVID-19 randomized to hydroxychloroquine and conventional treatments or conventional treatments Virological clearance, mortality rate Completed
Chloroquine phosphate NCT04286503 Beijing YouAn Hospital Phase 4, multicenter, randomized, open-controlled N = 520, COVID-19 treatment with carrimycin and lopinavir/ritonavir or arbidol or chloroquine phosphate Fever to normal time (day), pulmonary inflammation resolution time, negative conversion (%) of 2019-nCOVRNA Not yet recruiting
Chloroquine NCT04304053 Fundacio Lluita Contra la SIDA Phase 3, cluster randomized clinical trial N = 3040, treatment of nonsevere confirmed cases of COVID-19 and chemoprophylaxis of their contacts as prevention strategy Effectiveness of chemoprophylaxis assessed by incidence of secondary COVID-19 cases Recruiting
Hydroxychloroquine NCT04321278 Hospital Israelita Albert Einstein Phase 3, randomized open label N = 440, treatment of patients hospitalized with pneumonia with hydroxychloroquine and azithromycin compared with hydroxychloroquine Evaluation of the clinical status of patients Not yet recruiting
Hydroxychloroquine sulfate vs. Lopinavir/ritonavir NCT04307693 Asan Medical Center Phase 2, open-labeled, randomized N = 150, treatment of patients with mild COVID-19 with lopinavir/ritonavir, hydroxychloroquine, or control arm Viral load Recruiting
Lopinavir/ritonavir NCT04321174 Darrell Tan Phase 3, cluster randomized controlled trial N = 1220, Postexposure prophylaxis of COVID-19 Microbiologic evidence of infection Not yet recruiting
Lopinavir/ritonavir vs. ASC09/ritonavir NCT04261907 First Affiliated Hospital of Zhejiang University Not applicable randomized, open-label, multicenter, clinical trial N = 160, treatment of patients with 2019-nCoV pneumonia with ASC09/ritonavir or lopinavir/ritonavir The incidence of composite adverse outcome Not yet recruiting
Lopinavir/Ritonavir vs. oseltamivir vs. abidol hydrochloride NCT0425501 7 Tongji Hospital Phase 4, open, prospective/retrospective, randomized controlled cohort study N = 400, treatment of 2019-nCoV pneumonia with abidol hydrochloride, oseltamivir and lopinavir/ritonavir Rate of disease remission, Time for lung recovery Recruiting
Lopinavir/Ritonavir, remdesivir, lopinavir/ ritonavir and IFN-β-1a+hydroxychloroquine NCT04315948 Institut National de la Sante Et de la Recherche Medicale, France Phase 3, multicentre, adaptive, randomized, open clinical trialN = 3100, treatments for COVID-19 in hospitalized adults Percentage of patients reporting each severity rating on a 7-point ordinal scale Recruiting
Lopinavir/Ritonavir, ribavirin and IFN-β-1b combination vs. lopinavir/ritonavir alone NCT04276688 The University of Hong Kong Phase 2, open-label randomized controlled trial N = 70, patients with 2019-nCoV infection Time to negative nasopharyngeal swab 2019-nCoV RT-PCR Recruiting
Lopinavir/Ritonavir, alpha-interferon nebulization NCT04275388 Jiangxi Qingfeng Pharmaceutical Co. Ltd. Not Applicable, randomized, open-label trial N = 348, patients with 2019-nCoV pneumonia Clinical recovery time Not yet recruiting
Lopinavir/Ritonavir vs. alfa interferon NCT04251871 Beijing 302 Hospital Not applicable, randomized, open label N = 150, pneumonia caused by human coronavirus Time to complete remission Recruiting
Remdesivir (GS-5734) NCT04292899 Gilead Sciences Phase 3, randomized, open label N = 400, patients with severe COVID-19 Proportion of participants with normalization of fever and oxygen saturation Recruiting
Remdesivir (GS-5734) NCT04292730 Gilead Sciences Phase 3, randomized, open label N = 600, patients with moderate COVID-19 Proportion of participants discharged by day 14 Recruiting
Remdesivir NCT04252664 Capital Medical University Phase 3, randomized, controlled, double blind trial N = 308, patients hospitalized with mild or moderate COVID-19 Time to clinical recovery Recruiting
Remdesivir NCT04257656 Capital Medical University Phase 3, randomized, controlled, double blind trial N = 453, patients hospitalized with severe COVID-19 Time to clinical improvement Recruiting
Remdesivir, hydroxychloroquine NCT04321616 Oslo University Hospital Phase 3, open randomized adaptive controlled trial N = 700, COVID-19 patients with hydroxychloroquine, remdesivir and standard of care In-hospital mortality Not yet recruiting
Remdesivir NCT04280705 NIAID Phase 3, adaptive, randomized, double-blind, placebo-controlled trial N = 440, COVID-19 patients Percentage of subjects reporting each severity rating on an 8-point ordinal scale Recruiting
Remdesivir NCT04302766 U.S. Army Medical Research and Development Command Expanded Access Available
Arbidol NCT04260594 Jieming QU Phase 4, randomized, open label N = 380, 2019-nCoV-infected pneumonia Virus negative conversion rate in the first week Not yet recruiting
Arbidol hydrochloride granules NCT04273763 Second Affiliated Hospital of Wenzhou Medical University Not applicable, randomized, open label N = 60, patients with suspected and mild, or common COVID-19 Time to clinical recovery after treatment Enrolling by invitation
Abidol hydrochloride combined with interferon atomization NCT04254874 Tongji Hospital Phase 4, open, prospective/retrospective, randomized controlled cohort study N = 100, treatment of 2019-nCoV viral pneumonia Rate of disease remission, Time for lung recovery Recruiting
Recombinant human IFN-α-1b NCT04320238 Shanghai Jiao Tong University School of Medicine Phase 3, non-randomized, open label N = 2944, preventive effect of recombinant human IFN-α on COVID-19 in medical staff New-onset COVID-19 Recruiting
Recombinant human IFN-α1β NCT04293887 Tongji Hospital Early Phase 1, multicenter, randomized, open, blank-controlled, multistage clinical study The incidence of side effects Not yet recruiting
N = 328, patients with COVID-19 in Wuhan with recombinant human IFN α1β
Tocilizumab NCT04317092 National Cancer Institute, Naples Phase 2, multicenter, single-arm, open-label One-month mortality rate Recruiting
N = 330, Patients with COVID-19 pneumonia
Tocilizumab NCT04320615 Hoffmann-La Roche Phase 3, randomized, double-blind, placebo-controlled, multicenter study Clinical Status Assessed Using a 7-Category Ordinal Scale Not yet recruiting
Tocilizumab combined with favipiravir NCT04310228 Peking University First Hospital Not applicable, three arms, multicenter, randomized and controlled N = 150, treatment of COVID-19 Clinical cure rate Recruiting
Tocilizumab NCT04306705 Tongji Hospital Retrospective cohort N = 120, management of cytokine release syndrome triggered by COVID-19 Proportion of participants with normalization of fever and oxygen saturation through day 14 Recruiting
Tocilizumab NCT04315480 Università Politecnica delle Marche Phase 2, single group assignment N = 30, patients affected by severe multifocal interstitial pneumonia correlated to COVID-19 Arrest in deterioration of pulmonary function, improving in pulmonary function Not yet recruiting
Convalescent plasma NCT04292340 Shanghai Public Health Clinical Center observational study N = 15, COVID-19 patients using anti-2019-nCoV inactivated convalescent plasma The virological clearance rate Recruiting
COVID-19, coronavirus disease 2019; NIAID, National Institute of Allergy and Infectious Diseases; RT, real time; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Chloroquine and hydroxychloroquine

Initial studies from china have shown that chloroquine has an antiviral effects. By activating anti-SARS-CoV-2 CD8+ T-cells, this drug has reported indirect antiviral features [16]. The State Council of China on 17 February 2020, demonstrated significant efficacy and acceptable safety for chloroquine in treating COVID-19 associated pneumonia in multicenter clinical trials conducted in China [17]. Trials conducted on more than 100 Chinese patients have reported that chloroquine has a superior benefit to control and has efficacy in the improvement of pneumonia and lung imaging findings, conversion to virus-negative state and shortening the course of the disease, with no severe adverse reactions [18]. Since no available data has been provided up to now to support this outcome, chloroquine have been used cautiously [19]. An expert consensus on chloroquine for the treatment of COVID-19 pneumonia by multicenter collaboration group of the department of science and technology and health commission of Guangdong province, recommends chloroquine tablet 500 mg twice daily for 10 days in mild, moderate, and severe cases of COVID-19 pneumonia who have not chloroquine contraindication [20,21]. Zhou et al. proposed that HCQ could be a better therapeutic alternative for chloroquine, as chloroquine can cause severe side effects like retinopathy, circular defects, diametric defects in the retina, and cardiomyop-athy [22]. This drug has been reported with teratogenic effects and can cause fetal development disorders. Thus, HCQ was reported as a better choice and similar pre and postinfection antiviral effects like chloroquine. This drug is cheaper, applicable in pregnant women, and attenuates severe progression of COVID-19 [22]. A French group of confirmed COVID-19 patients was treated with HCQ, and azithromycin was added depending on the patient's clinical presentation. The authors report reduced viral load/disappearance in COVID-19 patients, reinforced by azithromycin addition [23]. In a systematic review and meta-analysis conducted for assessing the safety profiles of these medications, it has been shown that the rate of adverse effects in patients taking chloroquine and HCQ is higher those taking placebo, recommending more precaution when administering these agents [24]. After initial reports, several studies rose against effect of chloroquine or HCQ in outcome of Covid-19 and no significant effect observed. To prevent any adverse effect it was disapproved and currently it is not recommended to be used in any form of Covid-19 patients.

Lopinavir/ritonavir (Kaletra, AbbVie)

Both approved as anti-HIV drugs [25], these protease inhibitors combination have shown anti SARS-CoV-2 effects. Chu et al.[26] found that these agents have anti-SARS-CoVactivity in vitro. In the first case of COVID-19 presentation in Korea, Korean researchers prescribed lopinavir 400 mg/Ritonavir 100 mg from 4th day of illness. On 11th day, the fever began to subside and by 14th day, dyspnea began to improve [27]. Another Korean group reported reduced viral loads with symptoms improvement in the third patient diagnosed with COVID-19 in Korea [28]. Liu et al.[29] reported the beneficial effects of lopinavir in a group of ten hospitalized patients from 22 January 2020 until 11 February 2020 in China, advising more researches on large scales to verify these findings. However, in a Chinese study recently published in New England Journal of Medicine, no benefit was observed in 199 COVID-19 hospitalized adult patients with severe disease compared with standard care alone. No difference was seen in the time to clinical improvement, 28 days’ mortality and detectable viral RNA between two groups [30].

In a combination therapy for five severe COVID-19 pneumonia cases, three antiviral drugs including lopinavir/ritonavir, HCQ, and IFN-β-1b was administered to the patients and clinical symptoms improvement was monitored. In each five patients, respiratory manifestations resolved completely and all were discharged from the hospital. Most of the adverse reactions were minor and medications could be maintained without any deterioration [31]. In a retrospective cohort study, it was shown that patients treated with lopinavir/ritonavir, had more rapid viral clearance than HCQ in mild-to-moderate COVID-19 patients, which is recommended to be confirmed in randomized, controlled trials [32]. Based on importance of liver biomarkers, initial consideration of these biomarkers are recommended [33].

Angiotensin-converting enzyme inhibitors

It's been suggested that ACE inhibitor (ACEI) and angiotensin II type I receptor inhibitors could be used in patients with COVID-19 [34]. However, Diaz [35] hypothesized that taking ACEI and angiotensin receptor blocker (ARB) can lead to upregulated ACE2 receptors in the cardiopulmonary circulation, which serves as an attachment site for SARS-CoV-2 virions in the respiratory system, therefore leading to COVID-19 severe outcomes. Kuster et al.[36] demonstrates that ACEI and ARB should be initiated/continued in patients with cardiovascular disease such as heart failure, hypertension, and myocardial infarction, as withdrawal or changing to other drugs could result in enhanced cardiovascular mortality in severely ill COVID-19 patients.

Remdesivir

Being a nucleoside analogue, this drug is clustered in antiviral category. Functioning at a post virus entry stage, it blocks virus infection at low concentrations in vitro [11]. Treatment with this novel prodrug was done on the first case of COVID-19 in the USA, with no adverse effects. Patient felt better and needed no more supplemental oxygen the next day [37]. FDA granted Emergency Use Authorization to this drug On 1 May 2020.

In a compassionate use of Remdesivir for patients with severe COVID-19, clinical improvement was seen in 68% of patients, which was improvement in oxygen-support class, 47% discharged and 57% of patients under mechanical ventilation were extubated [38].

Arbidol (Umifenovir) and Favipiravir

A broad-spectrum antiviral agent, arbidol has shown anti-SARS-CoV activity in vitro[39]. Recently arbidol has been investigated for postexposure prophylaxis and could reduce the infection risk of the COVID-19 in hospital and family settings [40]. In a retrospective cohort study in China, 49 patients with novel coronavirus-infected pneumonia were treated with arbidol and 62 patients were controlled by empirical regimens. Arbidol groups were better in viral clearance, imaging findings improvement, and oxygen demand, especially in patients with mild illness at admission [41]. Similar results were not reported in other studies investigating arbidol efficacy in COVID-19 combined with lopinavir/ritonavir [42] or IFN-α2b [43]. Favipiravir is a new type of RNA-dependent RNA polymerase inhibitor. There is a study comparing efficacy and safety of arbidol with favipiravir, on 240 Chinese patients, admitted to 3 hospitals from 20 February 2020 to 12 March 2020. Time to fever and cough relief was shorter than the favipiravir group, but no significant difference was observed for auxiliary oxygen therapy or noninvasive mechanical ventilation rate. Favipiravir is recommended for ordinary COVID-19 patients untreated with antiviral previously [44]. In another study published on 18 March 2020, the efficacy of favipinavir and lopinavir/ritonavir was compared. Viral clearance time was shorter in the favipinavir group. Chest imaging improvement was also higher (91.43 vs. 62.22%, respectively), with fewer adverse reactions [45]. This drug seems safe in shorter term usage, but for longer period of time, it may show some adverse reactions, such as hyperuricaemia, teratogenicity, and corrected QT interval prolongation, which has not yet been adequately studied [46].

Ivermectin

Ivermectin is a medication used to treat many types of parasite infestations. Previously FDA approved as an antiparasitic drug against strongyloidiasis, head lice, scabies, and other diseases caused by roundworms and whipworms. Recently, Caly et al. demonstrated that ivermectin promising effects against SARS-CoV-2 in vitro and shows strong antiviral effects in infected cultured cells by nuclear transport inhibitory activity. After 24 h of the addition of 5 μmol/l ivermectin, a 93% reduction in viral RNA of infected cells was reported. This effect was also continued until 48 h and no further decrease was observed after 72 h. At any of the time points, there wasn’t any toxicity of ivermectin. The study suggests that ivermectin can be a safe repurposing drug that reduces the virus RNA load to approximately 5000 fold in vitro and may be a worthy choice of further investigation in the future [47]. However, in previous studies concerning the effectiveness of ivermectin in Zika virus-infected mice, or in a clinical trial against the dengue virus, no clinical benefit was observed [47,48].

Human recombinant soluble angiotensin-converting enzyme 2

ACE2 gene is expressed in alveolar epithelial type II cells, which acts as a potential receptor of the Spike protein of SARS-CoV-2. These cells secrete surfactant and promote alveolar expansion and ease the respiratory process. Hoffmann et al.[49] could show that soluble ACE2 can bind and neutralize an S protein expressing the Pseudovirus of SARS-CoV-2. Human recombinant soluble ACE2 (hrsACE2) is a recent point of attention. It was shown that this agent can reduce SARS-CoV-2 viral growth in vitro by inhibiting viral attachment to cell surfaces. As ACE2 is expressed in multiple sites of the body including kidney and blood vessels, hrsACE2 has been examined in the engineered human blood vessel and kidney organoids infected with SARS-CoV-2. This agent could inhibit the early stages of SARS-CoV-2 infection in these cells, too [50].

Interferons

IFNs are sort of cytokines communicating between cells against pathogens and have a critical role in the immune system. There are 3 classes of IFNs which act against viral infections: I (such as IFN-α and IFN-β), II (IFN-γ), and III. In SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) disease, IFN I production is decreased and reaction to viral infections is suppressed [51,52]. Pretreatment of cells infected by SARS-CoV with small amounts of IFN-α improves the decreased IFN production [53]. Bijlenga et al. showed that administration of pegylated recombinant IFN-α2b in monkeys (macaques), could protect type 1 pneumocytes against SARS-CoV [54]. These advantageous effects are seen whenever IFNs are administered at early stage of infection. The delayed application could result in worsening the cytokine storm and inflammation deterioration [55]. Clinical trials are going on to examine the approved anti-hepatitis C virus combination of pegylated IFN and ribavirin (ChiCTR2000029387) and favipiravir and IFN-α (ChiCTR2000029600). IFN-α atomization inhalation was recommended in 5 million units per time for adults in sterile injection water, twice daily as an antiviral treatment in COVID-19 [56].

In a retrospective case series of the 238 consecutive hospitalized COVID-19 confirmed patients in China, Arbitol and IFN showed significant discharge beneficial than Lopinavir/Ritonavir alone treatment in total patients [hazard ratios (95% confidence interval (CI)) = 2.50 (1.07, 5.83), P = 0.03] [57]. In another study to evaluate therapeutic impacts of IFN-β-1a administration in COVID-19, Dastan et al. revealed beneficial effects of IFN-β-1a in combination with HCQ and lopinavir/ritonavir in the management of COVID-19. Fever and other disease symptoms resolved within 1 week or so after the treatment. In 10 days, there was a great virological clearance outcome, and imaging findings resolved after 14 days in all patients. Most important of all, there was no adverse reactions or death during the 14-day period of treatment [58]. The same results were seen in the case series of five severe COVID-19 pneumonia patients who received lopinavir/ritonavir, HCQ, and IFN-β-1b. To control excessive inflammation, low-dose, short-term corticosteroids was administered. The study offers triple antiviral combination therapy in some of the critically ill COVID-19 patients [31].

It has recently been proposed that, using IFNs alone or in combination with other antiviral agents, could elicit an underlying vulnerability to depression or trigger a de-novo episode of depression, because of reduction in tryptophan (TRP) levels. Using foods or supplements that can boost TRP levels in hospitalized COVID-19 patients, or considering selective serotonin reuptake inhibitors are two possible ways of controlling depressive symptoms [59].

Ribavirin

First marketed in 1980 for the respiratory syncytial virus treatment in children, ribavirin is a nucleoside analog with a broad-spectrum of antiviral effects. Promising results were obtained in ribavirin and IFNα-2b combination for a MERS-CoV rhesus macaque model, this combination didn’t result in favorite outcomes for MERS-CoV patients [60]. By reducing concentration, ribavirin would not be a logical choice in respiratory disorders, as it's not recommended in Massachusetts General Hospital COVID-19 Treatment Guidance published on 3 March 2020.

In a phase 2 trial of 127 patients admitted to six hospitals in Hong Kong, a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of IFN-β-1b on alternate days, were compared with the control group of 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h. Combination therapy showed superior results in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 [61].

Tocilizumab (Actemra)

An important reason of a life-threatening COVID-19 pneumonia that occurs in 5% of these patients is increased inflammation or ‘cytokine storm’. Anticytokine treatments seem a therapeutic approach in this setting. Tocilizumab is an IL-6 receptor mAb that is currently used for rheumatoid arthritis [62]. Xu et al. investigated tocilizumab in a number of severely ill COVID-19 patients. A few days after injection, fever, and other clinical symptoms returned to normal. 75% of patients had decreased oxygen demand and one patient need no oxygen support. Lymphopenia returned to normal 5 days after treatment in 52.6% of patients. 84.2% of patients with an elevated C-reactive protein levels experienced a decreased level to normal. Authors suggest tocilizumab as an effective treatment in severe patients of COVID-19 and a new therapeutic strategy [63].

In a cohort of mechanically ventilated COVID-19 patients, effectiveness, and safety of tocilizumab was assessed in 154 patients requiring mechanical ventilation. Tocilizumab was associated with less hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. This agent was associated with more likelihood of superinfections (54 vs. 26%; P < 0.001), but 28-day case fatality rate wasn’t different between the two groups [64]. These results were repeated in other studies, but requiring randomized, placebo-controlled clinical trials [65,66].

The important thing in tocilizumab usage in COVID-19 patients, is the proper time to its administer. Tocilizumab is effective in preventing the use of invasive ventilation when used early in confirmed cytokine storm syndrome, bilateral lung infiltrates and severe hypoxemia [67].

Convalescent plasma

One of the ways for immediate immunotherapy for susceptible people is the application of passive antibody. The mechanism behind this approach is neutralizing antibodies, that bind to viral antigens and renders them ineffective in the cellular attachment. Arabi et al.[68] found that convalescent sera had an immunotherapeutic potential for the treatment of MERS-CoV infection. Receiving convalescent plasma in SARS patients from recovered ones resulted in appropriate clinical outcomes [69]. Because of a longtime history of administration without specific reported side effects, its worthy to test convalescent plasma efficacy in COVID-19 patients, as a comment in The Lancet[70].

In a large cohort of COVID-19 patients receiving COVID-19 convalescent plasma, it has been shown that convalescent plasma administration even after 2 weeks of symptom onset, would result in decreased symptoms and mortality in severe or critical COVID-19 patients, including reduced amount of viral loads and C-reactive protein concentration, increase in percentage of lymphocytes and radiological improvements within 14 days after COVID-19 convalescent plasma usage. The median time from treatment to clinical improvements in patients who received convalescent plasma within 7 weeks after symptom onset was approximately 10 days, but in cases who received plasma later than 7 weeks of symptoms onset, time to recovery was significantly prolonged [71].

Supplementary treatment and nutritional interventions

There are some recommended foods, fruits, and supplements commonly known for immunity boosting and body defense enhancement against viral infections. Some of the supplements suggested or used for COVID-19 patients are listed below:

Vitamin C

This water-soluble vitamin supports the immune system and has shown protective effects against coronavirus [72]. Having antihistamine effects, this agent leads in flu-like symptoms improvements such as sneezing and runny nose [73]. Under certain conditions, this vitamin may prevent the susceptibility of lower respiratory tract infection [74], so vitamin C supplementation may prevent pneumonia of COVID-19. Erol suggests that high-dose intravenous vitamin C treatment would suppress immune effector cells mediated in lung injury after COVID-19 pneumonia, so vitamin C could be a good choice in the early stages of this disease [75].

Vitamin A

Vitamin A-deficient children represent a very severe form of measles and vitamin A supplementation reduces morbidity and mortality of these patients [76,77]. This vitamin makes the uninfected cells refractory to replicating viruses [78]. The severity of infection with a kind of coronaviruses was more in vitamin A deficient chickens than in those fed a diet adequate in vitamin A [79]. This vitamin, therefore, is a potent supplement in COVID-19 patients.

Vitamin D

Both observational and clinical trial data have suggested a link between low levels of serum 25-hydroxyvitamin D and increased rates of respiratory tract infections [80,81]. In addition to the morbidity they cause, upper respiratory tract infections have a remarkable economic burden on healthcare systems and societies [82]. Moreover, despite conflicting reports and heterogeneity within studies, a recent systematic review encompassing 10 933 participants in 25 randomized controlled trials concluded that vitamin D supplementation reduced the risk of acute respiratory infection, with stronger protective effects in patients with baseline 25 hydroxy vitamin D levels less than 25 nmol/l [83]. In a recently published article by Grant et al., it was demonstrated that the reason of high rate of COVID-19 cases in China and Korea is vitamin D deficiency during winter. Authors believe that by vitamin D supplementation, incidence, severity and death rate of COVID-19 will decrease [84]. A reduced level of vitamin D results in infection with bovine coronavirus in cattle, so proper supplementation lead in immune system resistance to SARS-CoV-2 [85].

Selenium

Animal and epidemiological studies in people indicate that a low level of selenium could increase genetic mutations and virulence of some viruses, such as coxsackievirus, poliovirus, and murine influenza [86]. It has been reported that selenium in combination with ginseng stem-leaf saponins stimulates immune system response against live bivalent infectious bronchitis coronavirus vaccine in chickens [87].

Zinc

As a trace nutritional element, zinc plays an important role in both innate and adaptive immune system development [88]. It helps in humoral and cell-mediated immunity and reduces susceptibility to infections [89]. It has been shown that zinc inhibits the replication of SARS coronavirus (SARS-CoV) in the combination with pyrithione [90].

Systemic corticosteroids

Corticosteroids were widely used during the outbreaks of SARS-CoV and MERS-CoV however, these patients experienced more complications than other patients. Delayed viral shedding [91,92], psychosis, diabetes and vascular necrosis in survivors [93–95] were all seen as outcomes of corticosteroid therapy. In a Comment in The Lancet, corticosteroids use is not recommended in COVID-19-related lung injury or shock treatment, outside of a clinical trial [96]. Recently, Chinese researchers in Wuhan evaluated the efficacy and safety of treatment of severe COVID-19 pneumonia with methyl-prednisolone. Patients receiving the treatment had a shorter time for fever back to normal, faster improvement of oxygen saturation and a better absorption degree of the focus in chest computed tomography (CT). They conclude that early, low-dose and short-term (1–2 mg/ kg/day for 5–7 days) application of corticosteroid in a severe form of COVID-19 pneumonia would result in faster improvement of disease [97]. In another study, all patients that had been treated with a combination of a low-dose corticosteroid (methylprednisolone 40–80 mg/day) and immunoglobulin (10 g/day), had shown deteriorating conditions in symptoms and chest CT findings. Treatment was then revised to a short-term moderate-dose cortico-steroid (methylprednisolone 160 mg/day) and immuno-globulin (20 g/day). After a while, patients gradually recovered, without need to tracheal intubation or invasive mechanical ventilation. These data indicate that short-term moderate-dose corticosteroid and immunoglobulin after a combination of unresponded low-dose therapy could reverse COVID-19 patient's conditions [98].

In a case series of seven mechanically ventilated COVID-19 acute respiratory distress syndrome patients, early treatment with high-dose, short-term methylprednisolone intravenously, enabled extubation of the patients within 7 days without critical side effects of corticosteroids [99].

A randomized, controlled clinical trial in the United Kingdom, called the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial, was conducted to test a range of potential treatments for COVID-19, including low-dose dexamethasone. It has been shown that a 10-day dexamethasone 6 mg daily (orally or by intravenous injection) administration decreases deaths by one-third in ventilated patients [rate ratio 0.65 (95% CI 0.48–0.88); P = 0.0003] and by one-fifth in other patients receiving oxygen only [0.80 (0.67–0.96); P = 0.0021] (http://www.ox.ac.uk/news/2020-06-16-low-cost-dexamethasone-reduces-death-one-third-hospitalised-patients-severe), which was welcomed by WHO (https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients).

Conclusion

Nowadays, the COVID-19 epidemic has caused lots of problems for the health system, especially because of the high rate of transmission and being no confirmed therapeutic agent available to fight against it. Here we have reviewed up to now the most recent published data concerning the repurposing formerly approved drugs to induce prophylaxis and treatment of COVID-19. Moreover, there is numerous therapeutics applied for disease control till now, the efficacy of which needs to be more precisely studied. Here, we evaluated the last data about efficacy and safety of chloroquine, HCQ, lopinavir / ritonavir, remdesivir, arbidol, IFNs, tocilizumab, convalescent plasma, and systemic corticosteroids in this regard. Information of drugs recently used for COVID-19 treatment, are summarized in Table 2. The efforts toward developing an effective anti-SARS-CoV-2 vaccine have been ignited, and it's hoped to resolve problems regarding these drugs. However, we are probably at least 1 year to 18 months away from substantial vaccine production. In the end, we hope that with international collaboration, this global dilemma will end as soon as possible with the least burden of disease.

Table 2 - Information of drugs recently used for coronavirus disease 2019 treatment.
Agent Dosing Monitoring Drug–drug Interactions Contraindications Reference
Chloroquine phosphate 500 mg BD for 10 days in mild, moderate, and severe cases Complete blood count: risk of myelosuppression Caution with: Known hypersensitivity [100]
ECG: risk of QTc prolongation Concomitant QTc prolonging agents Amiodarone (increased risk of ventricular arrhythmia) [101]
Blood glucose: risk of hypoglycemia Anticonvulsants [102]
Epilepsy: risk of lower seizure threshold G6PD: risk of hemolysisa Aminoglycoside antibiotics [103]
Hydroxychloroquine phosphate hypersensitivity Day 1: 400 mg BD, Days 2–5: 200 mg BD (total duration 5 days) [100] Complete blood count: risk of myelosuppression Caution with: Known
ECG: risk of QTc prolongation Concomitant QTc prolonging agents Known hypersensitivity to 4-aminoquinoline compounds [101]
Blood glucose: risk of hypoglycemia Anticonvulsants Preexisting maculopathy of the eye [102]
Epilepsy: risk of lower seizure threshold Aminoglycoside antibiotics Pregnancy [103]
G6PD: risk of hemolysisa Retinal toxicity inducing drugs Children aged <6 years of age
Retinal toxicityb Concomitant with medicines causing adverse ocular or skin reactions Lactase deficiency or glucose-galactose malabsorption
Lopinavir/ ritonavir (Kaletra) 400mg-100 mg BID, for up to 14 days Liver function test: before and during treatment Concomitant with medicines primarily metabolized by CYP3A Known hypersensitivity [100]
Alternative and herbal medicines Severe hepatic insufficiency [101]
Concomitant with medicines primarily metabolized by CYP3A for clearance that elevated level cause [102]
Serious and/or life threatening events Children <14 days Pregnant womenPatients with hepatic or renal failure Patients treated with disulfiram or metronidazole [103]
Remdesivir 200 mg IV day 1, 100 mg IV daily, up to 10 days Investigational drug, see: Investigational drug, see: Investigational drug, see: [100,102,103]
https://rdvcu.gilead.com/ https://rdvcu.gilead.com/ https://rdvcu.gilead.com/ [101]
Arbidol 200 mg TDS, 5–10 days Possible drug interactions between arbidol and CYP3A4 inhibitors and inducers Known hypersensitivity [40]
Children under 2 years
IFN-β-B1 (Betaseron) Dosing for progressive COVID to be determined Injection site reaction [102]
Flu like syndrome
Tocilizumab 50–59 kg: 400 mg IV Liver function test Pregnancy [102]
60–85 kg: 600 mg IV May be harmful to newborns [103]
>85kg: 800 mg IV, For one dosec Mothers should stop breastfeeding if receiving tocilizumab [101]
COVID, coronavirus disease; IV, intravenous.
aDo not delay initiation of treatment in the context of moderate or severe COVID-19 if status unknown.
bOphthalmological examination not required in context of COVID-19 infection in recommended dose and duration of treatment.
cIn absence or with poor clinical improvement, a second dose should be administered after 8–12 h.

Acknowledgements

We acknowledge the help of Dr MH Soroush for his comments.

Authors’ contributions: all authors contributed in data collection, article writing and final proof of the study.

Compliance with ethical standards.

The current work was supported by Tabriz University of Medical Sciences.

Ethical approval: Local ethics committee of Tabriz University of Medical Sciences approved this study.

Informed consent: not applicable.

Conflicts of interest

The authors declare that they have no conflicts of interest.

References

1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506.
2. Ozma MA, Maroufi P, Khodadadi E, Köse Ş, Esposito I, Ganbarov K, et al. Clinical manifestation, diagnosis, prevention and control of SARS-CoV-2 (Covid-19) during the outbreak period. Infez Med 2020; 28:153–165.
3. Faezi NA, Bialvaei AZ, Leylabadlo HE, Soleimani H, Yousefi M, Kafil HS. Viral infections in patients with acute respiratory infection in Northwest of Iran. Mol Genet Microbiol Virol 2016; 31:163–167.
4. Rodriguez-Morales AJ, Bonilla-Aldana DK, Balbin-Ramon GJ, Rabaan AA, Sah R, Paniz-Mondolfi A, et al. History is repeating itself: probable zoonotic spillover as the cause of the 2019 novel coronavirus epidemic. Infez Med 2020; 28:3–5.
5. Baron SA, Devaux C, Colson P, Raoult D, Rolain JM. Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19? Int J Antimicrob Agents 2020; 55:105944.
6. Khodadadi E, Maroufi P, Khodadadi E, Esposito I, Ganbarov K, Espsoito S, et al. Study of combining virtual screening and antiviral treatments of the Sars-CoV-2 (Covid-19). Microb Pathog 2020; 146:104241.
7. Fathizadeh H, Maroufi P, Momen-Heravi M, Dao S, Köse Ş, Ganbarov K, et al. Protection and disinfection policies against SARS-CoV-2 (COVID-19). Infez Med 2020; 28:185–191.
8. Fathizadeh H, Taghizadeh S, Safari R, Khiabani SS, Babak B, Hamzavi F, et al. Study presence of COVID-19 (SARS-CoV-2) in the sweat of patients infected with Covid-19. Microb Pathog 2020; 149:104556–1104556.
9. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases. Lancet Infect Dis 2003; 3:722–727.
10. Liu YZ, Hou FQ, Ding P, Ren YY, Li SH, Wang GQ. Pegylated interferon-α enhances recovery of memory T cells in e antigen positive chronic hepatitis B patients. Virol J 2012; 9:274.
11. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30:269–271.
12. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydro-xychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6:1–4.
13. Chang R, Sun WZ. Repositioning chloroquine as antiviral prophylaxis against COVID-19: potential and challenges.Drug Discov Today 2020 Jul 3:S1359-6446(20)30258-0. doi: 10.1016/j.drudis.2020.06.030. Epub ahead of print.
14. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020; 57:279–283.
15. Guidelines for the prevention, diagnosis, and treatment of novel coronavirus-induced pneumonia, the 6th ed. http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2/files/b218cfeb1bc54639af227f922bf6b817.pdf. [Accessed 23 February 2020]. (in Chinese).
16. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020; 55:105938.
17. Audio transcript of the news briefing heldby the State Council of China on February 17, 2020. The National Health Commission of the People's Republic of China. http://www.nhc.gov.cn/xcs/yqfkdt/202002/f12a62d10c2a48c6895cedf2faea6e1f.shtml. [Accessed 18 February 2020]. (in Chinese).
18. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends 2020; 14:72–73.
19. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020; 177:104762.
20. Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia. Expert consensus on chlor-oquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua jie he he hu xi za zhi 2020; 43:185–188.
21. Schrezenmeier E, Dörner T. Mechanisms of action of hydro-xychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020; 16:155–166.
22. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother 2020; 75:1667–1670.
23. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial. Int J Antimicrob Agents 2020; 56:105949.
24. Ren L, Xu W, Overton JL, Yu S, Chiamvimonvat N, Thai PN. Assessment of hydroxychloroquine and chloroquine safety profiles-a systematic review and meta-analysis. medRxiv 2020; preprint.
25. Singh J, Chhikara BS. Comparative global epidemiology of HIV infections and status of current progress in treatment. Chem Biol Lett 2014; 1:14–32.
26. Chu C, Cheng V, Hung I, Wong M, Chan K, Chan K, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial viro-logical and clinical findings. Thorax 2004; 59:252–256.
27. Kim JY, Choe PG, Oh Y, Oh KJ, Kim J, Park SJ, et al. The first case of 2019 novel coronavirus pneumonia imported into Korea from Wuhan, China: implication for infection prevention and control measures. J Korean Med Sci 2020; 35:e61.
28. Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, et al. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR. J Korean Med Sci 2020; 35:e79.
29. Liu F, Xu A, Zhang Y, Xuan W, Yan T, Pan K, et al. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int J Infect Dis 2020; 95:183–191.
30. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787–1799.
31. Hong SI, Ryu BH, Chong YP, Lee S, Kim S, Kim HC, et al. Five severe COVID-19 pneumonia patients treated with triple combination therapy with lopinavir/ritonavir, hydroxychloroquine, and interferon β-1b. Int J Antimicrob Agents 2020; 56:106052.
32. Kim JW, Kim EJ, Kwon HH, Jung CY, Kim KC, Choe JY, et al. Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019.Korean J Intern Med 2020 Jun 16. doi: 10.3904/kjim.2020.224. Epub ahead of print.
33. Gholizadeh P, Safari R, Marofi P, Zeinalzadeh E, Pagliano P, Ganbarov K, et al. Alteration of liver biomarkers in patients with SARS-CoV-2 (COVID-19). J Inflamm Res 2020; 13:285–292.
34. Sun M, Yang J, Sun Y, Su G. Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43:E014.
35. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med 2020; 27:
36. Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: should inhibitors of the renin-angioten-sin system be withdrawn in patients with COVID-19? Eur Heart J 2020; 41:1801–1803.
37. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382:929–936.
38. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; 382:2327–2336.
39. Ji XG, Zhao YH, Zhang M, Zhao JH, Wang JY. The experimental study of the anti-SARS-CoV effect of arbidole. Pharm J Chin PLA 2004; 20:274–276.
40. Zhang J, Wang W, Peng B, Peng W, Zhang Y, Wang Y, et al. Potential of arbidol for postexposure prophylaxis of COVID-19 transmission-preliminary report of a retrospective case-control study. Curr Med Sci 2020; 40:480–485.
41. Xu KC, Yuan YF, Yi J, Ding P, Wu C, Li WR, et al., Clinical efficacy of arbidol in patients with 2019 novel coronavirus-infected pneumonia: a retrospective cohort study (12 February 2020). Available at SSRN: https://ssrn.com/abstract=3542148 or http://dx.doi.org/10.2139/ssrn.3542148.
42. Wen C, Xie Z, Li Y, Deng X, Chen X, Cao Y, et al. Real-world efficacy and safety of lopinavir/ritonavir and arbidol in treating with COVID-19: an observational cohort study. Zhonghua Nei Ke Za Zhi 2020; 59:E012.
43. Xu P, Huang J, Fan Z, Huang W, Qi M, Lin X, et al. Arbidol/IFN-α2b therapy for patients with corona virus disease 2019: a retrospective multicenter cohort study. Microbes Infect 2020; 22:200–205.
44. Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv 2020; Preprint.
45. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing) 2020 Mar 18. doi: 10.1016/j.eng.2020.03.007. Epub ahead of print.
46. Pilkington V, Pepperrell T, Hill A. A review of the safety of favipiravir-a potential treatment in the COVID-19 pandemic? J Virus Erad 2020; 6:45.
47. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178:104787.
48. Ketkar H, Yang L, Wormser GP, Wang P. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis 2019; 95:38–40.
49. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181:271–280.e8.
50. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020; 181:905–913.e7.
51. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev 2001; 14:778–809.
52. Dandekar AA, Perlman S. Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol 2005; 5:917–927.
53. Kuri T, Zhang X, Habjan M, Martínez-Sobrido L, García-Sastre A, Yuan Z, et al. Interferon priming enables cells to partially overturn the SARS coronavirus-induced block in innate immune activation. J Gen Virol 2009; 90 (Pt 11):2686.
54. Bijlenga G. Proposal for vaccination against SARS coronavirus using avian infectious bronchitis virus strain H from The Netherlands. J Infect 2005; 51:263–265.
55. Yuen KS, Ye ZW, Fung SY, Chan CP, Jin DY. SARS-CoV-2 and COVID-19: the most important research questions. Cell Biosci 2020; 10:1–5.
56. Jin YH, Cai L, Cheng ZS, Cheng H, Deng T, Fan YP, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-CoV) infected pneumonia (standard version). Mil Med Res 2020; 7:4.
57. Huang Y, Cai C, Zang J, Xie J, Xu D, Zheng F, et al. Treatment strategies of hospitalized patients with coronavirus disease-19. Aging 2020; 12:11224–11237.
58. Dastan F, Nadji SA, Saffaei A, Marjani M, Moniri A, Jamaati H, et al. Subcutaneous administration of Interferon beta-1a for COVID-19: a noncontrolled prospective trial. Int Immuno-pharmacol 2020; 85:106688.
59. Shader RI. COVID-19, interferons, and depression: a commentary. Psychiatry Res 2020; 291:113198.
60. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother 2020; 64:
61. Hung IFN, Lung KC, Tso EYK, Liu R, Chung TWH, Chu MY, et al. Triple combination of interferon beta-1b, lopinavir- ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 2020; 395:1695–1704.
62. Kaly L, Rosner I. Tocilizumab - a novel therapy for nonorgan-specific autoimmune diseases. Best Pract Res Clin Rheumatol 2012; 26:157–165.
63. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020; 117:10970–10975.
64. Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. medRxiv 2020; preprint.
65. Jordan SC, Zakowski P, Tran HP, Smith EA, Gaultier C, Marks G, et al. Compassionate use of tocilizumab for treatment of SARS-CoV-2 pneumonia. Clin Infect Dis 2020; ciaa812 [Online ahead of print].
66. Lohse A, Klopfenstein T, Balblanc JC, Royer PY, Bossert M, Gendrin V, et al. Predictive factors of mortality in patients treated with tocilizumab for acute respiratory distress syndrome related to coronavirus disease 2019 (COVID-19). Microbes Infect 2020; 22:500–503.
67. Andrianopoulos I, Papathanasiou A, Papathanakos G, Chaidos A, Koulouras V. Tocilizumab's efficacy in patients with Coronavirus Disease 2019 (COVID-19) is determined by the presence of cytokine storm.J Med Virol 2020 Jun 22:10.1002/jmv.26209. doi: 10.1002/jmv.26209. Epub ahead of print.
68. Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus 2015; 4:1–8.
69. Cheng Y, Wong R, Soo Y, Wong W, Lee C, Ng M, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis 2005; 24:44–46.
70. Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis 2020; 20:398–400.
71. Xia X, Li K, Wu L, Wang Z, Zhu M, Huang B, et al. Improved clinical symptoms and mortality on severe/critical Covid-19 patients utilizing convalescent plasma transfusion. Blood 2020; 136:755–759.
72. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). 2020 Jun 19;11:1451.
73. Field CJ, Johnson IR, Schley PD. Nutrients and their role in host resistance to infection. J Leukocyte Biol 2002; 71:16–32.
74. Hemilä H. Vitamin C intake and susceptibility to pneumonia. Pediatr Infect Dis J 1997; 16:836–837.
75. Erol A. High-dose intravenous vitamin C treatment for COVID-19. (26 February 2020). https://doi.org/10.31219/osf.io/p7ex8.
76. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc 1999; 58:719–727.
77. Villamor E, Mbise R, Spiegelman D, Hertzmark E, Fataki M, Peterson KE, et al. Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth. Pediatrics 2002; 109:e6–e16.
78. Trottier C, Colombo M, Mann KK, Miller WH Jr, Ward BJ. Retinoids inhibit measles virus through a type I IFN-dependent bystander effect. FASEB J 2009; 23:3203–3212.
79. West CE, Sijtsma SR, Kouwenhoven B, Rombout JH, van der Zijpp AJ. Epithelia-damaging virus infections affect vitamin A status in chickens. J Nutr 1992; 122:333–339.
80. Bergman P, Lindh ÅU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2013; 8:e65835.
81. Charan J, Goyal JP, Saxena D, Yadav P. Vitamin D for prevention of respiratory tract infections: a systematic review and meta-analysis. J Pharmacol Pharmacother 2012; 3:300.
82. Fendrick AM, Monto AS, Nightengale B, Sarnes M. The economic burden of non-influenza-related viral respiratory tract infection in the United States. Arch Intern Med 2003; 163:487–494.
83. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-ana-lysis of individual participant data. BMJ 2017; 356:i6583.
84. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020; 12:988.
85. Nonnecke B, McGill J, Ridpath J, Sacco R, Lippolis J, Reinhardt T. Acute phase response elicited by experimental bovine diarrhea virus (BVDV) infection is associated with decreased vitamin D and E status of vitamin-replete preruminant calves. J Dairy Sci 2014; 97:5566–5579.
86. Beck MA, Levander OA, Handy J. Selenium deficiency and viral infection. J Nutr 2003; 133:1463S–1467S.
87. Ma X, Bi S, Wang Y, Chi X, Hu S. Combined adjuvant effect of ginseng stem-leaf saponins and selenium on immune responses to a live bivalent vaccine of Newcastle disease virus and infectious bronchitis virus in chickens. Poult Sci 2019; 98:3548–3556.
88. Maares M, Haase H. Zinc and immunity: an essential interrelation. Arch Biochem Biophys 2016; 611:58–65.
89. Tuerk MJ, Fazel N. Zinc deficiency. Curr Opin Gastroenterol 2009; 25:136–143.
90. Te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog 2010; 6:e1001176.
91. Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018; 197:757–767.
92. Lee N, Chan KA, Hui DS, Ng EK, Wu A, Chiu RW, et al. Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol 2004; 31:304–309.
93. Lee DT, Wing Y, Leung HC, Sung JJ, Ng Y, Yiu G, et al. Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study. Clin Infect Dis 2004; 39:1247–1249.
94. Xiao J, Ma L, Gao J, Yang Z, Xing X, Zhao H, et al. Glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy. Zhonghua Nei Ke Za Zhi 2004; 43:179–182.
95. Li Y, Wang S, Gao H, Wang J, Wei C, Chen L, et al. Factors of avascular necrosis of femoral head and osteoporosis in SARS patients’ convalescence. Zhonghua Yi Xue Za Zhi 2004; 84:1348–1353.
96. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395:473–475.
97. Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: singlecenter experience from Wuhan, China. medRxiv 2020; preprint.
98. Zhou ZG, Xie SM, Zhang J, Zheng F, Liu JH, Cai CL, et al. Short-term moderate-dose corticosteroid plus immunoglobulin effectively reverses COVID-19 patients who have failed low-dose therapy. 2020. preprint.
99. So C, Ro S, Murakami M, Imai R, Jinta T. High-dose, short-term corticosteroids for ARDS caused by COVID-19: a case series. Respirol Case Rep 2020; 8:e00596.
100. Bergin C, Philbin M, Gilvarry P, O’Connor M, King F. Specific antiviral therapy in the clinical management of acute respiratory infection with SARS-CoV-2 (COVID-19). 2020.
    101. Nicastri E, Petrosillo N, Ippolito G, D’Offizi G, Marchioni L, Bartoli TA, et al. National institute for the infectious diseases ‘L. Spallanzani’ IRCCS. Recommendations for COVID-19 clinical management. Infect Dis Rep 2020; 12:
      102. UoM Guideline. Inpatients guidline for treatment of Covid-19 in adults and children. Internal guidline of Michigan medicine. Arbor, Michigan: University of Michigan; 2020, 1–9.
        103. Members M. Massachusetts general hospital COVID-19 treatment guidance. Mass Gen Hosp 2020; 2020:1–10.
          Keywords:

          coronavirus; coronavirus disease 2019; drugs; severe acute respiratory syndrome coronavirus 2; therapy

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