key: cord-0849916-5n87rsus
authors: Hushmandi, Kiavash; Bokaie, Saied; Hashemi, Mehrdad; Moghadam, Ebrahim Rahmani; Raei, Mehdi; Hashemi, Farid; Bagheri, Mahdi; Habtemariam, Solomon; Nabavi, Seyed Mohammad
title: A review of medications used to control and improve the signs and symptoms of COVID-19 patients
date: 2020-09-19
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173568
sha: a1a0b8277739e71ac041cfb20f4a79d251e4b6a4
doc_id: 849916
cord_uid: 5n87rsus

In December 2019, an unprecedented outbreak of pneumonia associated with a novel coronavirus disease 2019 (COVID-19) emerged in Wuhan City, Hubei province, China. The virus that caused the disease was officially named by the World Health Organization (WHO) as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to the high transmission rate of SARS-CoV-2, it became a global pandemic and public health emergency within few months. Since SARS-CoV-2 is genetically 80% homologous with the SARS-CoVs family, it is hypothesized that medications developed for the treatment of SARS-CoVs may be useful in the control and management of SARS-CoV-2. In this regard, some medication being tested in clinical trials and in vitro studies include anti-viral RNA polymerase inhibitors, HIV-protease inhibitors, anti-inflammatory agents, angiotensin converting enzyme type 2 (ACE 2) blockers, and some other novel medications. In this communication, we reviewed the general characteristics of medications, medical usage, mechanism of action, as well as SARS-CoV-2 related trials.

COVID-19 is an emerging infection caused by a novelcoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cao et al., 2020c) . The virus was first detected in Wuhan, China, in December 2019, and soon affected a large number of people (Cao et al., 2020c; Lian et al., 2020) . The official total number of infected cases in China on April 15, 2020, reached 82,295, with 3,342 deaths (Azman and Luquero, 2020) . Since then, the virus has spread rapidly to other parts of the world, with a total of 23,130,443 infected cases and 803,374 deaths worldwide by August 22, 2020, 08:04 GMT (Khairat et al., 2020) .

Given the unknown biology of the virus and its high rate of transmission, there has been a concerted global effort to understand the various pathological dimensions of the disease (Shereen et al., 2020) . This include isolation of the virus, identification of its genetic sequence, and the search for appropriate pharmaceutical treatment options (Feng Tan, 2020) .

Other similar human coronaviruses previously identified in the last two decades are the Middle East Respiratory Syndrome Virus (MERS-CoV, 2015) and SARS-CoV (2003) (Rabaan et al., 2020) . The SARS-CoV was transmitted from an unknown host, perhaps a bat, to a civet cat, and then to a human, the first victim of which was reported in China (Kuehn, 2013; Lu et al., 2015) . These viruses target the lower respiratory system first by attaching to the pulmonary epithelial cells, and then delivering their nucleocapsid and stealing the cellular machinery to replicate in the cytoplasm (Lung et al., 2020) . The virus also affects other organs including the gastrointestinal tract , the brain , the kidney , the liver and the heart (Tan and Aboulhosn, 2020) .

Genetically, SARS-CoV and SARS-CoV-2 are 80% homologous (Yi et al., 2020) and they both belong to the Coronaviridae family with characteristic enveloped single-stranded and positive-strand ribonucleic acid (RNA) structure (Ciotti et al., 2020) .

The SARS family contains 14 binding amino acids residues, out of which 8 amino acids are specifically conserved for SARS-CoV-2. On this basis, it is believed that drugs used in the management of SARS-CoV patients may be somewhat effective in the management and treatment of COVID-19 patients. Hence, the main focus of COVID-19 therapy has so far has been based on drug repurposing strategy (Chatterjee et al., 2020) .

The SARS-CoV-2 replication cycle involves are six steps: viral entrance, replication machinery translation, replication, structural proteins translation, virion assembly and release. SARS-CoV-2 attaches to host cells via plasma membrane J o u r n a l P r e -p r o o f fusion and for this angiotensin-converting enzyme 2 (ACE2) is known to serve as a virion receptor. Some inhibitors such as griffithsin prevent the virus entry via binding to the receptor glycoproteins. SARS-CoV-2 can also be taken up into endosomes based on activation of spike proteins by cathepsin L. Lysosomotropic agents such as bafilomycin A1 or ammonium chloride which block the pH dependent cysteine protease could limit viral entry. Also, some the transmembrane serine protease 2 (TMPRSS2) which activates the spike proteins can be targeted by anti-TMPRSS2 antibody (Hoffmann et al., 2020; Shirato et al., 2018) . In the translation step, RNA-dependent RNA polymerase play an important role and can be targeted by drugs such as favipiravir. Furthermore, the virus RNA replication which is mediated by the kinase signaling pathway could be inhibited by saracatinib (Lin et al., 2017; Shin et al., 2018) . RNA-dependent RNA polymerase accounts for RNA replication of S1, S2, envelope and membrane structural proteins, and the RNAs translated by ribosomes on endoplasmic reticulum cytosolic surface. Then, nucleocapsids from genomic RNA, remain in the cytoplasm and fuse with virion precursor to be transported to the cell surface from the ER through the Golgi Apparatus in small vesicles. Virions are then released to infect other cells and induce the host inflammatory response (McKimm-Breschkin, 2013 ).

To date, the drugs used for COVID-19 include anti-viral RNA polymerase inhibitors (Shah et al., 2020) , HIV-protease inhibitors (Adepoju, 2020) , antiinflammatory agents (Russell et al., 2020) , angiotensin converting enzyme type 2 (ACE 2) blockers (Yang and Meng, 2020) , convalescent plasma (Roback and Guarner, 2020) , RNA antisense technologies (Xu et al., 2020b) , monoclonal antibodies (Shanmugaraj et al., 2020) and Chinese traditional medicines ).

Remdesivir is an antiviral drug of the nucleotide analogs class (Al-Tawfiq et al., 2020) . It is an analogue of adenosine, which disrupt the RNA chain of virus and causes termination in pre-mature form (Shannon et al., 2020) . The J o u r n a l P r e -p r o o f Gilead Sciences Company has been manufacturing it for treating Ebola virus and Marburg virus diseases (Grein et al., 2020) . Subsequent researches have shown that the drug is effective against other single stranded RNA viruses (Gordon et al., 2020) , including respiratory syncytial virus (Tchesnokov et al., 2019a) , Junin virus (De Clercq, 2019), Lassa fever virus (Shannon et al., 2020) , Nipah virus (Lo et al., 2019) , Hendra virus (Ko et al., 2020a) , and the coronaviruses (including MERS (de Wit et al., 2020) and SARS viruses (Ko et al., 2020b) ). Recent studies have been focusing on this drug to assess its effectiveness for SARS-CoV-2 infection. Based on its efficacy on patients infected with other coronaviruses (Agostini et al., 2018b) , it was provided to physicians for treating an American patient (Snohomish County, Washington, 2020) infected with SARS-CoV-2 and also submitted to China for more investigations in different phases of clinical tirals.

• SARS-CoV-2: The Gilead Company stated that remdesivir is already proven to be effective against SARS-CoV and MERS animal models.

On this basis, in January 2020, the Company started to test it against SARS-CoV-2 in a small group of infected patients in collaboration with Chinese medical authorities (Grein et al., 2020) .

J o u r n a l P r e -p r o o f • Veterinary applications: GS-441524, the active form of remdesivir, had been shown to be effective in coping with coronavirus caused feline infectious peritonitis. It has not been approved by FDA for this purpose, however, but has been available in social markets since 2019. It is claimed that a pill of the drug can eliminate feline coronavirus from infected cats (Pedersen et al., 2019) . Congolese health officials noticed that monoclonal antibody treatments such as mAb114 and REGN-EB3 was more effective in infected patients with Ebola virus. However, its safety as anti-Ebola therapy has been approved (Warren et al., 2016) .

Remdesivir is a prodrug and its active form, GS-441524, is a metabolic byproduct. GS-441524 as an adenosine nucleotide analog disrupts the J o u r n a l P r e -p r o o f activity of RNA-dependent RNA polymerase and escape of viral exoribonuclease. It also causes RNA chain termination, mutation and decline in RNA production of virus. Ebola virus RNA-dependent RNA polymerase is suppressed by the drug via RNA chain termination. In 2018, a report published that mutations in mouse hepatitis virus RNA replicase causes partial resistance to remdesivir, however, these mutations make the viruses less effective in pathogenicity (Agostini et al., 2018a; Tchesnokov et al., 2019b ).

Remdesivir had been administrated in a 35 years old male patient who was diagnosed with COVID-19 in Snohomish County, Washington. The patient suffered from developing pneumonia and persistent fever on seventh day of hospitalization. The next day after therapy, the patient showed clinical improvement with negative oropharyngeal swab, although nasopharyngeal swab persist positive. There was no side effect of remdesivir administration for this patient (Jacobs et al., 2016) . Also, previous case reports on the treatment of other viruses by remdesivir declare no side effects (Dörnemann et al., 2017) . Remdesivir had been prescribed for the first 12 patients in the United States (Kujawski et al., 2020) . All of them complained of transient 

J o u r n a l P r e -p r o o f

Favipiravir is an antiviral drug and also known as T-705, Avigan, Favipira and Favilavir. With activity against RNA viruses, it is being developed by Toyama Chemical (Japan) (Du and Chen, 2020; Shiraki and Daikoku, 2020) .

It is a derivative of pyrazinecarboxamide as well as other antiviral drugs

including T-1105 and T-1106 (Zhu et al., 2018) . Experimental studies had shown that favipiravir was effective against influenza viruses (Pascua et al., 2019) , yellow fever virus (Furuta et al., 2013) , foot and mouth disease virus (Furuta et al., 2009b) , West Nile virus (Escribano-Romero et al., 2017), arenaviruses (Veliziotis et al., 2020) , bunyaviruses (Scharton et al., 2014) and alphaviruses (Delang et al., 2014) , enteroviruses (Furuta et al., 2013) , Rift Valley fever (Borrego et al., 2019) and other flaviviruses (Segura Guerrero et al., 2018).

• Ebola virus: Some experimental studies are suggesting that favipiravir may be helpful for treating Ebola virus infected patients (Madelain et J o u r n a l P r e -p r o o f al., 2020). Its efficacy on Ebola infection in human is however not very clear (Bixler et al., 2018) . During west Africa Ebola virus outbreak, one study reported that favipiravir was effective in improvement of an Ebola infected nurse (Trompiz et al., 2014) . The results of a clinical trial that was conducted in Guéckédou, Guinea (December 2014) showed a decline in mortality rate in Ebola infected patients in low to moderate levels of the disease but with no effect on severe form (Fink, 2015; Grobusch-mp, 2015) .

• SARS-CoV-2: Since February 2020, favipiravir has been studied in drug repurposing program for the treatment of SARS-CoV-2 pandemic (Li and De Clercq, 2020) . The results showed that favipiravir seemed to be effective in improvement of COVID-19 patients (March 2020, Wuhan and Shenzhen, China). Then, one study conducted to compare favipiravir with lopinavir and found that it made reduction in viral clearance time to four days when compared to control group (eleven days) and improvement in CT scans result .

Favipiravir is a selective viral RNA-dependent RNA polymerase inhibitor.

Some studies demonstrated that favipiravir induces transcription mutations J o u r n a l P r e -p r o o f in RNA and lead to a lethal phenotype of virus. The active form of favipiravir, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), which is a metabolic byproduct, is also available as oral and intravenous formulations. Studies demonstrated that hypoxanthine guanine phosphoribosyltransferase (HGPRT) plays a key role in its activation. Also, it had been shown that favipiravir neither suppress the synthesis of RNA or DNA in mammalian cells, nor is toxic to them. Favipiravir was approved in Japan (2014) for its ability in coping with influenza pandemic. However, other studies did not support its effectiveness in human airway cells and this led to doubts about its effectiveness against influenza infections (Baranovich et al., 2013; Furuta et al., 2009a; Guedj et al., 2018; Jin et al., 2013; Naesens et al., 2013; Smee et al., 2009; Yoon et al., 2018 ).

Favipiravir was approved by China officials for the treatment of influenza on March 2020. Then, the drug was approved for use against SARS-CoV-2 infection in clinical trials (Baden and Rubin, 2020) . The first trial (NCT04310228) is a multicenter randomized trial that combines favipiravir (3200 mg/day) with tocilizumab (400 mg/day) and assesses the efficacy of the drug combination when compared with individual drugs alone. The primary outcome is defined as clinically cure rate. The second trial J o u r n a l P r e -p r o o f (NCT04336904) is a phase III clinical trial that was designed for evaluation of favipiravir safety in moderate type of SARS-CoV-2 infection. The third trial (NCT04303299) has similar design. The results of the investigations on 80 SARS-CoV-2 infected patients showed that favipiravir is the most potent antiviral agents when compared to other drugs in this group, and was without significant adverse effects on treated patients .

Ritonavir Lopinavir J o u r n a l P r e -p r o o f

Lopinavir/Ritonavir is an antiretroviral drug combination used to treat HIV/AIDS. Often ritonavir low dose is used as a part of highly active antiretroviral therapy. Lopinavir inhibit SARS-CoV replication via suppressing the main viral protease (Cao et al., 2020b) . Chu et al., investigated the effects of lopinavir (4 mg/ml) and ribavirin (50 mg/ml) on SARS-CoV (Chu et al., 2004) . They found that ribavirin along with lopinavir have more anti-retroviral effects on SARS-CoV when compared to each drug alone. They used combination lopinavir/ritonavir, ribavirin, and corticosteroids for SARS-CoV infected patients without acute respiratory distress syndrome (ARDS). Patients who received lopinavir/ritonavir were compared with patients receiving ribavirin and corticosteroids. The first group showed significant reduction in ARDS development or death at the 21th day of the medication. Another study in the same center showed significant reduction in intubation, steroid use and mortality in patients administered lopinavir/ritonavir when compared to patients not receiving the treatment. The result showed that lopinavir/ritonavir combination was beneficial when administrated at the time of SARS-CoV infection diagnosis (Que et al., 2003) . Also, one study showed that lopinavir had antiviral activity against SARS-CoV in vitro with the half maximal effective J o u r n a l P r e -p r o o f concentration in Vero E6 cells was close to that found in the serum of HIVinfected patients (Sheahan et al., 2020b) . A clinical trial evaluated the effects lopinavir/ritonavir in addition to interferon-β against MERS-CoV infected patients and showed no significant differences when compared to lopinavir/ritonavir alone (Chan et al., 2015) . In vitro studies further showed that lopinavir/ritonavir plus interferon-β did not have significant effects on virus titer and lung status in MERS-CoV infected mices (Sheahan et al., 2020a) . Animal studies found that lopinavir/ritonavir had beneficial effects on pathological and clinical features of MERS-CoV infection. Also, it is used for hepatitis C treatment (Molto et al., 2007) . Some of the reported side effects include gastrointestinal problems (nausea, vomiting, and diarrhea), loss of appetite, and in some serious cases, allergic reactions, arrythmias, pancreatitis, and liver problems (Bongiovanni et al., 2004 ).

• HIV/AIDS: Ritonavir is the second FDA approved drug for the treatment of HIV. It was originally designed to suppress HIV protease. Mechanistic studies found that ritonavir also inhibits CYP3A4 which is now known as the main mechanism of the drug's action. Currently, it is used in the treatment of HIV in a co-J o u r n a l P r e -p r o o f administration program of anti-retroviral drugs (Clevenbergh et al., 2002; Walmsley et al., 2002) .

• SARS-CoV-2: Even though there is no in vitro study that proved the efficacy of lopinavir/ritonavir for SARS-CoV-2, the persuasive results of studies on lopinavir/ritonavir effects on SARS-CoV and MERS-CoV led to the lopinavir/ritonavir consideration in SARS-CoV-2 treatment in China. The prescribed doses for adult and adolescent are 400 mg/day and 10 mg/kg body weight for no more than 10 days (Lim et al., 2020) .

Ritonavir is one the pseudo-C2-symmetric small molecule inhibitors family and act as a HIV protease inhibitor. Ritonavir specifically inhibits a metabolic enzyme, cytochrome P450-3A4 (CYP3A4). Mainly expressed in the intestine and liver, CYP3A4 metabolizes and removes protease inhibitors and xenobiotics (small and foreign molecules same as drugs or toxins) from the body. Ritonavir binds to CYP3A4 and inhibits it leading to a decrease in antiretroviral break down and increase in other antiretroviral drugs bioavailability and their serum levels (Zeldin and Petruschke, 2004 ).

One study reported the status of 6 infected patients with SARS-CoV-2 in Korea and China (Xu et al., 2020c) . The result showed that lopinavir/ritonavir led to a decrease in virus titer and improved clinical (Cao et al., 2020a) . The result showed no significant difference in clinical features, viral load and mortality rate of the two groups. Interpretation of the study results is difficult due to trials variation in medication type, medications initiation, different levels of disease severity and lack of control groups for comparison.

J o u r n a l P r e -p r o o f

Camostat is a serine protease inhibitor. Since serine protease enzymes play a variety of roles in the body, camostat has a diverse range of uses. Camostat was recognized as a protease inhibitor in the 1980s (Japan) and due to most of the data on it have been published in Japanese, very little information is available outside Japan. In Japan, camostat is used for chronic pancreatitis since 1985 in a dose of 600 mg/day.It has also been used in the treatment of postoperative reflux esophagitis since 1994 in a dose of 300 mg/day. In a trial with 900 mg/day, camostat showed edema and urticaria as side effects, while camostat therapy at a dose of 600 mg/day showed no significant side effects (Uno, 2020).

Camostat mesilate is a TMPRSS2 inhibitor that suppress the SARS-CoV spread and pathogenesis in an infected mouse model. Studies also showed that SARS-CoV-2 needs TMPRSS2 for entry into host cells (Bittmann et al., 2020) . In one study using SARS-CoV-2 isolated from infected patient, Camostat was shown to block the virus entry into lung cells (Bittmann et al., 2020) .

Camostat is used in the treatment of some cancers. Some studies also showed that camostat is effective against viral infections in addition to inhibiting fibrosis in the liver or kidney diseases or pancreatitis. (Midgley et al., 1994; Okuno et al., 2001) 

There are six clinical trials in phase I and II stages. One of these trials is designed to investigate the camostat mesylate effects on SARS-CoV-2 associated coagulopathy, myocardial injury, duration of hypoxia or intubation the length of intensive care unit and hospital stay, and mortality rates (NCT04435015). Another trial has bee designed to assess the effects of • SARS-CoV-2: Hyperinflammatory states such as elevated serum levels of IL-6, has been shown in severe SARS-CoV-2 infection and leads to increased mortality in patients. National Health Commission of China planned to use tocilizumab in the treatment of SARS-CoV-2 infected patients. China approved tocilizumab for its antiinflammatory effects in March 2020, however there is no data on its effectiveness or detail due to only 21 patients had been used in the study (Bennardo et al., 2020; Cellina et al., 2020; De Luna et al., 2020; Luo et al., 2020; Michot et al., 2020; Mihai et al., 2020; Zhang et al., 2020a; Zhang et al., 2020c) .

Tocilizumab as an anti-IL-6 receptor monoclonal antibody binds to both soluble and membrane-bound IL-6 receptors, and suppress the IL-6 associated pathways (Jones et al., 2010) .

One study employed 21 patients who were first under standard care program for a week and then under tocilizumab administration. At the end of the first week of standard care program, the IL-6 serum levels were 132.38 ± 278.54 pg/ml (normal < 7 pg/ml). After administration of tocilizumab, the results showed significant improvement of fever, C-reactive protein, lung opacities and decrease in mechanical ventilation requirement. At present, tocilizumab is one the most important medication options for severe condition of SARS-CoV-2 infection with elevated IL-6 serum levels. According to the 7th edition of the National Health Commission of the People's Republic of China COVID-19 Diagnosis and Treatment Guide, the recommended dose is 4-8 mg/kg or 400 mg standard dose twice a day. There are currently 14 clinical trials on this drug all over the world the result of which is yet to be published (Jones et al., 2010) . Another study with 89 patients showed lower mortality and rapid improvement in CRP and lymphocyte counts in addition to clinical indices (Formina et al., 2020) . 

Chloroquine is a 4-aminoquinoline class of drug and originally designed and used for the treatment of malaria. Also, it is used for amebiasis, rheumatoid arthritis, and lupus erythematosus due to its anti-inflammatory properties. At present, it is used for the treatment of SARS-CoV-2 infection. Chloroquine has some side effects including: appetite loss, muscle problems, skin rash, gastrointestinal problems, and in some cases serious side effects such as seizures, vision problems and muscle damages (Moore, 2020) . showed that chloroquine had better effect when compared to hydroxychloroquine with EC 50 of 6.5 ± 3.2 μM and 34 ± 5 μM, respectively. Physiologically based pharmacokinetic modelling J o u r n a l P r e -p r o o f showed a loading dose of hydroxychloroquine as 400 mg (Biot et al., 2006; Yao et al., 2020) .

antiviral effects of chloroquine may be related to its effects on endosomal and lysosomal pH. Since virus relase needs low pH, chloroquine consumption leads to impaired endosomal or lysosomal virus release. So, the virus cannot release its genetic material into the cell and replicate (Fredericksen et al., 2002; Savarino et al., 2003) .

Gautret et al. reported the initial results of their study on 200 mg hydroxychloroquine three times a day administration in SARS-CoV-2 infected patients (20 hydroxychloroquine and 16 control) (Gautret et al., 2001) . The results showed that hydroxychloroquine is significantly more effective to get rid of infection when compared to standard care protocol. Six patients also received a combination of hydroxychloroquine and azithromycin. The result showed that this combination is more effective than hydroxychloroquine alone. So, it seams that azithromycin may potentiate the effect of hydroxychloroquine against SARS-CoV-2 infection (Gautret et al., 2020) . Gao et al. , also reported significant improvement without adverse events for therapy with hydroxychloroquine . Another trial J o u r n a l P r e -p r o o f was conducted in Wuhan, China, on 62 patients with PCR-confirmed SARS-CoV-2 infection. Half of them were randomely assigned to receive 200 mg hydroxychloroquine sulfate orally and twice daily. The result showed that the time to clinical recovery was significantly reduced in hydroxychloroquine receiving group. Recently, some studies with inconsistent results were published. In a larg population trial in hospitalized patients, emergency use of chloroquine and hydroxychloroquine showed no benefitial effects on mortality, clinical signs and recovery speed (Boulware et al., 2020) . These controversial results made the US Food and Drug Administration (FDA) to withdraw the emergency use of chloroquine and hydroxychloroquine approve (Food and Administration, 2020) .

Angiotensin-converting enzyme 2 (ACE2) is a cell membrane's attached enzyme of the lungs, arteries, heart, kidney, and intestines celss. ACE2 catalyses the angiotensin II hydrolysis into angiotensin (1) (2) (3) (4) (5) (6) (7) . Recently, it was proven that ACE2 serves as the entry point into cells for some coronaviruses, including SARS-CoV, and SARS-CoV-2 .

• SARS-CoV-2: Several studies reported that SARS-CoV-2 entry into target cells utilise ACE2 receptors . There is also a significant correlation between SARS-CoV-2 infections with other co-morbidities including hypertension, cardiovascular disease, and diabetes . There is a hypothesis that medications that lead to increase in ACE2 expression could potentially increase susceptibility to SARS-CoV-2 infection. Also, ACE2 catalysis the conversion of angiotensin 2 to angiotensin 1-7 and vasodilates vessels and lowers angiotensin 2 receptor binding which leads to protect lungs from injury (Peng et al., 2005) .

In a study by Vaduganathan et al., it was found that ACE2 administration in patients with lung injury may be beneficial in SARS-CoV-2 infected patients with stable condition, and the use of it for patients with comorbidities in not J o u r n a l P r e -p r o o f recommended. On the other hand, some studies suggested that ACEIs increases the gene expression of ACE2, and other experimental studies vice versa. There are two clinical trials employed to evaluate the safety and efficacy of losartan in SARS-CoV-2 infected patients (Vaduganathan et al., 2020) .

Other potential medicactions for SARS-CoV-2 infection are listed in Table 1 .

Medicinal management of SARS-CoV-2 infected patients is conducting to control and treat infection and prevention of progression to critical illness. Each medication listed in the present review has beneficial effects along with some adverse effects and the results remain inconclusive due to daily changes in outcome. Due to the rapid progression of the disease and an increase in viral load, the authors suggest that rapid initiation of medication will be useful in high-risk patients. However, there is a concern about the unclear adverse effects of medications. In this regard, clinicians must follow releasing literature. So, authors suggest that clinicians and institutions release their experiences of treatment of COVID-19 to the medical community. Antibodies (Casadevall and Pirofski, 2020) Isolated more than 500 antibodies from SARS-CoV-2 infected patients for improvement of patients.

Anti-SARS-CoV-2 polyclonal hyperimmune globulin (Walls et al., 2020) Hypothesized the usefulness for severe infected patients.

J o u r n a l P r e -p r o o f Arbidol (Umifenovir) (Zhu et al., 2020) Antiviral drug for SARS-CoV-2 treatment without available clinical trial data.

Trials number: NCT04286503, NCT04260594, NCT04273763.

Aldose reductase inhibitor found to protect against oxidative damages.

Aviptadil (Jahangir et al.) A synthetic peptide that acts as vasoactivator and inhibits inflammatory cytokine such as IL-6 production.

Trials number: NCT04311697.

Baricitinib (Richardson et al., 2020) Inhibitor of janus kinase family enzyme.

Trials number: NCT04340232, NCT04320277, NCT04345289, NCT04321993.

Bevacizumab (Rosa and Santos, 2020) A monoclonal antibody that is human specific and synthetized by genetic engineering. Bevacizumab prevents the binding of vascular endothelial growth factor (VEGF) association with Flt-1 and KDR receptors. A type of immunotherapy by peptide technology of ligand antigen epitope presentation system for SARS-CoV-2 viral titer reduction.

CD24Fc (Jahangir et al.) A biological immunomodulator that reduces inflammatory cytokines.

Trials number: NCT04317040.

CM4620-IE An inhibitor of Calcium release-activated calcium channel and suppress the channel overactivation which can lead to pulmonary inflammatory J o u r n a l P r e -p r o o f

Identification of potent COVID-19 main protease (Mpro) inhibitors from natural polyphenols: An in silico strategy unveils a hope against CORONA

Tuberculosis and HIV responses threatened by COVID-19

Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Remdesivir as a possible therapeutic option for the COVID-19

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

Tocilizumab, a proposed therapy for the cachexia of Interleukin6-expressing lung cancer

From China: hope and lessons for COVID-19 control

Covid-19-the search for effective therapy

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro

New therapeutic opportunities for COVID-19 patients with Tocilizumab: Possible correlation of interleukin-6 receptor inhibitors with osteonecrosis of the jaws

Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities

TMPRSS2-Inhibitors Play a role in Cell Entry Mechanism of COVID-19: An Insight into Camostat and Nefamostat

Efficacy of favipiravir (T-705) in nonhuman primates infected with Ebola virus or Marburg virus

Lopinavir/ritonavir vs. indinavir/ritonavir in antiretroviral naive HIV-infected patients: immunovirological outcome and side effects

Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir

A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19

Experimental treatment with favipiravir for COVID-19: an open-label control study

Will Complement Inhibition be the New Target in Treating COVID-19 Related Systemic Thrombosis? Circulation

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Clinical Features and Shortterm Outcomes of 102 Patients with Corona Virus Disease

A new clinical trial to test high-dose vitamin C in patients with COVID-19

The convalescent sera option for containing COVID-19

Favorable changes of CT findings in a patient with COVID-19 pneumonia after treatment with tocilizumab

Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset

The 2019 novel coronavirus disease (COVID-19) pandemic: A review of the current evidence

Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

COVID-19 Outbreak: An Overview

Coronavirus disease 2019 (COVID-19) and cardiovascular disease. Circulation

Iatrogenic Cushing's syndrome in an HIV-infected patient treated with inhaled corticosteroids (fluticasone propionate) and low dose ritonavir enhanced PI containing regimen

Challenges in the treatment of rheumatoid arthritis

New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections

Rapid and Severe Covid-19 Pneumonia with Severe Acute Chest Syndrome in a Sickle Cell Patient Successfully Treated with Tocilizumab

Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral

Discovering drugs to treat coronavirus disease 2019 (COVID-19)

First newborn baby to receive experimental therapies survives Ebola virus disease

Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic

Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection

Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life sciences, 117477

Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sciences, 117592

Clinical Features of COVID-19-Related Liver Damage

Preventing the Transmission of COVID-19 Amongst Healthcare Workers

Ebola drug aids some in a study in West Africa

FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Food and Drug Administration

Temporal clinical and laboratory response to interleukin-6 receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 pneumonia

Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus

Favipiravir (T-705), a novel viral RNA polymerase inhibitor

T-705 (favipiravir) and related compounds: Novel broadspectrum inhibitors of RNA viral infections

T-705 (favipiravir) and related compounds: Novel broadspectrum inhibitors of RNA viral infections

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Short-term effect of chloroquine on the infectivity of Plasmodium chabaudi gametocytes

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Compassionate Use of Remdesivir for Patients with Severe Covid-19

COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission

Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Late Ebola virus relapse causing meningoencephalitis: a case report

Coronavirus (COVID-19): History, Current Knowledge and Pipeline Medications

The ambiguous base-pairing and high substrate efficiency of T-705 (favipiravir) ribofuranosyl 5′-triphosphate towards influenza A virus polymerase

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study

A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease

Interpreting COVID-19 and Virtual Care Trends: A Call for Action

Arguments in favour of remdesivir for treating SARS-CoV-2 infections

Arguments in favour of remdesivir for treating SARS-CoV-2 infections

Coronavirus breakthrough: dexamethasone is first drug shown to save lives

Current evidence and research prospects of Xuebijing injection in treating novel coronavirus-infected pneumonia (COVID-19)

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Traditional Chinese herbal medicine for treating novel coronavirus (COVID-19) pneumonia: protocol for a systematic review and meta-analysis

Analysis of Epidemiological and Clinical features in older patients with Corona Virus Disease

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

Effective inhibition of MERS-CoV infection by resveratrol

Critically ill patients with COVID-19 in Hong Kong: a multicentre retrospective observational cohort study

Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

Bat-to-human: spike features determining 'host jump'of coronaviruses SARS-CoV, MERS-CoV, and beyond

The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase

Tocilizumab treatment in COVID-19: a single center experience

Ribavirin does not potentiate favipiravir antiviral activity against Ebola virus in nonhuman primates

Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance

Tocilizumab, an anti-IL6 receptor antibody

Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration

COVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSc-ILD

Lopinavir/Ritonavir Pharmacokinetics in HIV and Hepatitis C Virus Co-Infected Patients without Liver Function Impairment

Chloroquine for COVID-19 Infection

Role of human hypoxanthine guanine phosphoribosyltransferase in activation of the antiviral agent T-705 (favipiravir)

Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-β

Optimizing T-705 (favipiravir) treatment of severe influenza B virus infection in the immunocompromised mouse model

Hydroxychloroquine and ivermectin: a synergistic combination for COVID-19 chemoprophylaxis and/or treatment?

Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis

COVID-19: Top 60 Drug Treatments in Development: The biopharma industry is ramping up the development of dozens of potential drug therapies and clinical testing in an all-hands effort to combat the pandemic

Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study

SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview

Baricitinib for COVID-19: a suitable treatment? -Authors' reply

Convalescent Plasma to Treat COVID-19: Possibilities and Challenges

Clinical trials on drug repositioning for COVID-19 treatment

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience 14, 1022

Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment

Coping with Covid-19 Coronavirus

Favipiravir inhibits in vitro Usutu virus replication and delays disease progression in an infection model in mice

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach

Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19)

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Saracatinib inhibits middle east respiratory syndrome-coronavirus replication in vitro

Wild-type human coronaviruses prefer cellsurface TMPRSS2 to endosomal cathepsins for cell entry

Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells

Benign COVID-19 in an immunocompromised cancer patient -the case of a married couple

COVID-19: Herd Immunity and Convalescent Plasma Transfer Therapy

The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease

Treatment for paraneoplastic neuromyelitis optica spectrum disorder (NMOsd): Probable effects of tocilizumab for both cancer and NMOsd

Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir

Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir

First French Ebola patient leaves hospital. Reuters. Uno, Y., 2020. Camostat mesilate therapy for COVID-19

Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19

The COVID-19 epidemic

Clinical Management of Argentine Hemorrhagic Fever using Ribavirin and Favipiravir

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection

IV anakinra for macrophage activation syndrome may hold lessons for treatment of cytokine storm in the setting of COVID19

Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Nervous system involvement after infection with COVID-19 and other coronaviruses

Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential

Factors associated with prolonged viral RNA

Clinical features and dynamics of viral load in imported and non-imported patients with COVID-19

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

More evidence is urgently needed to confirm the relation between angiotensin-converting enzyme inhibitors and COVID-19

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

COVID-19: what has been learned and to be learned about the novel coronavirus disease

Orally efficacious broad-spectrum ribonucleoside analog inhibitor of influenza and respiratory syncytial viruses

Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore

Clinical characteristics of Coronavirus Disease 2019 in Hangzhou, China: the combination of lopinavir/ritonavir, interferon, and arbidol may be a well choice for antiviral therapy in common cases

Pharmacological and therapeutic properties of ritonavirboosted protease inhibitor therapy in HIV-infected patients

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab

Successful treatment of Marburg virus with orally administrated T-705 (Favipiravir) in a mouse model

Arbidol Monotherapy is Superior to Lopinavir/ritonavir in Treating COVID-19

H1N1 influenza of infected patients who had recovered of infection were useful in prevention and treatment of infection. Effectiveness and safety of SARS-CoV infected patients' convalescent plasma is not clear yet

Steroid hormones excrete of adrenal cortex Trials number: NCT04345445, NCT04329650, NCT04273321

2020) HIV-1 protease inhibitor Trial numbers: NCT04252274

2020) Corticosteroid medication

Dong et A therapeutic agent that inhibits alcohol metabolism with demonstrated

Monoclonal IgG antibody of human that acts against membrane attack complex formation

Elfiky, 2020b) RNA polymerase inhibitor Nucleoside with antiviral activity that showed promising effects on Ebola and SARS-CoV

Monoclonal antibody with anti-inflammatory effects against GM-CSF production and may have favorable effects in SARS-CoV-2 treatment

2020) A protein derived of red algae with inhibitory effects on HIV action and SARS-CoV

Inhaled therapy Inhaled formulation of dry powder for improvement of respiratory complications of SARS-CoV-2 infection. Intranasal vazegepant Inhibitor of Calcitonin gene-related peptide receptor and down regulate the inflammatory status

Anti-parasite drug Trials number: NCT04343092

2020) Intravenous immunoglobulin

2020) Protease inhibitor of HIV

2020a) Bioavailable chlorinated salicylanilide, with anthelmintic and potential antineoplastic activity Trials number: NCT04345419 number: NCT04343248, NCT04345419, NCT04341493. Nitric oxide (Ling et al., 2020) Trials number: NCT04305457, NCT04337918, NCT04306393, NCT04312243, NCT03331445, NCT04285801

Antiviral medication Trials number: NCT04255017, NCT04261270, NCT04303299, NCT04338698. REGN3048 (Philippidis, 2020) Human specific monoclonal antibody and effective in MERS-CoV treatment

Antiviral agent against hepatitis C and some viral hemorrhagic fevers Trials number: NCT04276688. et al., 2020) Antiviral agent against HIV

2020) IL-6 receptor inhibitor for rheumatoid arthritis treatment

Sofosbuvir (Elfiky, 2020b) Antiviral drug against hepatitis C

2020) Cholesterol lowering drugs Trials number

TAK-888 (Schilling, 2020) SARS-CoV-2 antibody derived of infection recovered patients

TZLS-501 (Philippidis, 2020) Anti-IL6 receptor in human

Affects the angiopoietin-Tie2 pathway to improve endothelial function

Trials number: NCT04323514, NCT04335084, NCT04344184

Trials number: NCT04335084, NCT04344041, NCT04326725, NCT04334005

Chinese herbal medicine extract infusion formulation given at 100ml IV twice daily, suggested as a "may consider" treatment for severe and critical cases in the National Health Commission of the People's Republic of China: the COVID-19 Diagnosis and Treatment Guide

There are several medications suggested for SARS-CoV-2 treatment and/or controlling the symptoms

Each medications used up to now has beneficial and some adverse effects and the results remain inconclusive

Rapid onset of medication will be useful in high-risk patients to control the acute symptoms

There is a concern about the unclear long-term adverse effects of medications

All authors contributed equally to this work.

The authors state that there are no disclosures associated with this study.J o u r n a l P r e -p r o o f