
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12019-1
10.1016/j.heliyon.2024.e35988
e35988
Review Article
Repurposing existing drugs for the treatment ofCOVID-19/SARS-CoV-2: A review of pharmacological effects and mechanism of action
Liang Yutong liangyutongllg@163.com
a
Quan Xiaoxiao ab
Gu Ruolan a
Meng Zhiyun a
Gan Hui a
Wu Zhuona a
Sun Yunbo a
Pan Huajie c
Han Peng a
Liu Shuchen liusc118@sohu.com
a⁎
Dou Guifang dougf@bmi.ac.cn
a⁎⁎
a Beijing Institute of Radiation Medicine, Beijing, China
b Scientific Experimental Center of Guangxi University of Chinese Medicine, Nanning, China
c General Internal Medicine Department, Jingnan Medical District, PLA General Hospital, Beijing, China
⁎ Corresponding author. liusc118@sohu.com
⁎⁎ Corresponding author. dougf@bmi.ac.cn
11 8 2024
30 8 2024
11 8 2024
10 16 e3598826 2 2024
5 8 2024
7 8 2024
© 2024 The Authors. Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.

Keywords

Severe acute respiratory syndrome coronavirus type 2
Drug repositioning
Clinical trials
Pharmacological effects
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pmc1 Introduction

In December 2019, the coronavirus disease-2019 (COVID-19) pandemic began, becoming the most urgent global public health emergency. Severe acute respiratory syndrome coronavirus type 2 (Sars-CoV-2) is the causative agent of COVID-19 and belongs to the coronavirus family of single-stranded RNA viruses, whose coronal structure depends on the spatial conformation of the “spike” protein [1]. The S protein is the most researched part of the Sars-CoV-2 viral genome. Because it recognizes angiotensin-converting enzyme 2 (ACE2) on the cell surface, it is directed by transmembrane serine 2 protease (cleavage of the spiked protein) as a part of fusion with the cell membrane and internalized, thereby infecting normal cells in the body [2]. ACE2 internalizes and activates the immune system triggering lung inflammation characterized by elevated levels of proinflammatory markers such as interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor (TNF), and C-reactive protein (CRP) [3] (Fig. 1).Fig. 1 Description of the structure and invasion pathway of the virus.

Fig. 1

To date, few drugs have proven effective against SARS-CoV-2. Severe illness and death have been reported in patients with pre-existing diabetes mellitus [4], chronic obstructive pulmonary disease [5,6], hypertension, heart and kidney disease [7], cancer [8], and polycystic ovary syndrome [9]. Several studies [10,11]have shown that a few patients taking drugs for chronic diseases are not infected with SARS-CoV-2. James Black, the Scottish pharmacologist, suggested that the best method to discover a new drug is to begin with an old one [12]. This article will discuss how prior indications are related to the dosage of repurposed drugs used in COVID-19, or how the severity of the patient's condition affects the choice of repurposed drug or its dosing regimen, and also discusses in detail the difficulty of investigating these drug candidates in clinical trials involving patients with COVID-19.

2 Drug repositioning strategies and challenges

Currently, there are two main orientations—targeted and untargeted positioning. In targeted drug repositioning, the biological target is known for the original indication. However, it is for a different disease, and the known pharmacological mechanisms apply to the new indication. In untargeted drug repositioning, the pharmacological mechanisms remain unknown. Drugs and drug candidates act on new targets beyond the original range for new therapeutic indications. Therefore, the targets and indications are novel. Two different strategies [13] were explored to identify Mpro inhibitors based on structures within a mega-chemical library by docking. Two separate focused screens were implemented; the first-screened molecules that matched the active site of Mpro were selected as the top-ranked compounds for experimental evaluation. The secondary screen optimized the fragments identified in the crystallographic screen by building a focused library containing numerous compounds. The most promising lead compounds were compared with previously identified Mpro inhibitors. Compared with the drug-directed approaches, this approach resulted in a higher success rate of drug discovery because most biological targets are representative of disease pathways/mechanisms [14]. Currently, additional targets, receptors, and related mechanisms are being identified. It is advantageous for drug repurposing to construct disease-specific networks, characterize genetic expression, consider key targets, and identify disease-causing protein molecules associated with cells and metabolic pathways of interest in disease models [15] (Table 1.).Table 1 Clinical trials of drug repositioning.

Table 1Drug name	Broad mechanism of action	Status	Phase	Purpose	NCT	
Favipiravir	Antiviral drug	Recruiting	Phase Ⅳ	Treatment	NCT05502081	
FNC	Anti-HIV infection drugs	Recruiting	Phase Ⅳ	Treatment	NCT05697055	
FNC	Anti-HIV infection drugs	Completed	Phase Ⅲ	Treatment	NCT05033145; NCT04668235	
RV	Synthetic nucleoside drugs	Unknown Status	Phase Ⅲ	Treatment	NCT04392427	
Oseltamivir	Anti-influenza drug	Completed	Phase Ⅳ	Treatment	NCT02780622	
Oseltamivir	Anti-influenza drug	Recruiting	Phase Ⅳ	Treatment	NCT04973462	
Colchicine	Gout anti-inflammatory and analgesic drugs	Completed	Phase Ⅳ	Treatment	NCT05246072	
Colchicine	Gout anti-inflammatory and analgesic drugs	Completed	Phase Ⅲ	Treatment	NCT04472611; NCT04667780; NCT04724629;
NCT04350320; NCT04328480	
Colchicine	Gout anti-inflammatory and analgesic drugs	Recruiting	Phase Ⅲ	Prevention	NCT04416334	
Tocilizumab	IL-6 receptor antagonists	Completed	Phase Ⅳ	Treatment	NCT04730323	
Tocilizumab	IL-6 receptor antagonists	Recruiting	Phase Ⅳ	Treatment	NCT04779047	
Tocilizumab	IL-6 receptor antagonists	Completed	Phase Ⅲ	Treatment	NCT04356937; NCT04600141; NCT04577534; NCT04330638	
Interferon Lambda	Innate immune defense drugs	Completed	Phase Ⅱ	Treatment	NCT04354259	
Dexamethasone	Glucocorticoids	Active Not Recruiting	Phase Ⅳ	Treatment	NCT04530409	
Dexamethasone	Glucocorticoids	Completed	Phase Ⅳ	Treatment	NCT05004753; NCT04707534	
Dexamethasone	Glucocorticoids	Recruiting	Phase Ⅳ	Treatment	NCT05062681	
Dexamethasone	Glucocorticoids	Completed	Phase Ⅲ	Treatment	NCT04603729; NCT04909918; NCT04834375; NCT04640168	
Tamoxifen	Nonsteroidal anti-estrogens	Not Yet Recruiting	Phase Ⅱ	Treatment	NCT04389580	
Raloxifene	SERM	Completed	Phase Ⅱ/Ⅲ	Treatment	NCT05172050	
UDCA	Choleretic	Recruiting	Phase Ⅳ	Prevention	NCT05690646	
AZM	Macrolide antibiotics	Completed	Phase Ⅳ	Treatment	NCT04370782	
AZM	Macrolide antibiotics	Recruiting	Phase Ⅳ	Treatment	NCT04715295	
AZM	Macrolide antibiotics	Completed	Phase Ⅲ	Prevention	NCT04344379	
AZM	Macrolide antibiotics	Completed	Phase Ⅲ	Treatment	NCT04338698;
NCT04673214;
NCT04646109;
NCT04530422;
NCT04381962;
NCT04358081	
Doxycycline	Nonconventional antibiotics	Completed	Phase Ⅳ	Treatment	NCT04370782	
Doxycycline	Nonconventional antibiotics	Recruiting	Phase Ⅳ	Prevention	NCT05072093	
Doxycycline	Nonconventional antibiotics	Recruiting	Phase Ⅳ	Treatment	NCT04729140; NCT04715295	
CEP	Anti-inflammatory and antioxidant	Completed	Phase Ⅱ	Treatment	NCT05398705	
Metformin	Biguanide antihyperglycemic agents	Active Not Recruiting	Phase Ⅲ	Treatment	NCT04510194	
Metformin	Biguanide antihyperglycemic agents	Not Yet Recruiting	Phase Ⅳ	Treatment	NCT02915198	
Azvudine: FNC; Ribavirin: RV; SERMs: Selective estrogen receptor modulators; UDCA: Ursodeoxycholic acid; AZM: Azithromycin; CEP: Cepharanthine.

However, changes to their original use have only occasionally been successful. It must be acknowledged that several drugs, primarily in phase III or phase IV clinical trials, prove to be ineffective or exhibit grave side effects. Drug repositioning strategies face some challenges, especially with quantification. One of the main challenges of starting the development of a drug in this type of indications is that the patient populations quickly evolve and change over time (Fig. 2). At the beginning of the pandemic, the majority of patients were dealing with severe COVID, and not all drug candidates were efficacious at the tested doses for these patients. Patients quickly evolved to a moderate population of the disease with a different disease progression and even response to intervention, especially for completely new and unknown viruses， making conclusions regarding the effectiveness of the candidate products very challenging.Fig. 2 Description of the different stages of the disease.

Fig. 2

3 Existing candidates

Over the past few years, clinical trials and drug repositioning studies have been conducted at different stages. Several studies are underway to select novel drugs to control the epidemic and to conduct in vitro, in vivo, and human clinical trials. Antivirals, immune boosters, anti-inflammatory agents, immunomodulators, antiparasitic agents, and endocrine system drugs are available, demonstrating a different role. The trials have led to the discovery of more potential pharmacological effects. A wide range of these drugs with multiple mechanisms of action have been selected as potential candidates for treating patients with SARS-CoV-2(Table 2.).Table 2 Description of drug candidates and structure.

Table 2Generic Name	Structure	
Favipiravir	Image 1	
Azvudine	Image 2	
Raloxifene	Image 3	
Oseltamivir	Image 4	
Colchicine	Image 5	
Tamoxifen	Image 6	
Dexamethasone	Image 7	
Raloxfene	Image 8	
UDCA	Image 9	
Dexamethasone	Image 10	
Cepharanthine	Image 11	
Metformin	Image 12	

3.1 Antiviral therapy

Antivirals inhibit viral multiplication, provide time for the host immune system, ward off the viral attack, and repair damaged tissues, thereby moderating the disease [16]. Most mechanisms for inhibiting SARS-CoV-2 involve inhibiting viral replication via different approaches and reducing the damage caused by the inflammatory cytokine storm. Mixed results were obtained when several antiviral drugs were subjected to extensive in vivo and in vitro trials at the beginning of the outbreak.

3.1.1 Favipiravir

Favipiravir is an antiviral drug [17]that selectively and effectively inhibits RNA-dependent RNA polymerase (RdRp, nsp12) in RNA viruses. It is effective in animal models with lethal RNA viruses. The drug treats life-threatening human infections such as Ebola virus disease, Lassa fever, rabies, and severe fever with thrombocytopenia syndrome. In 2014, favipiravir was approved in Japan for treating influenza cases that are nonresponsive to conventional treatment [18]. Currently, researchers have conducted studies to treat novel viruses, including Ebola and SARS-CoV-2 [[19], [20], [21], [22], [23], [24]]. The researchers affirmatively confirmed the efficacy of the combination or individual administration of the antiviral favipiravir.

The RdRp activity of SARS-CoV-2 was 10-fold higher than that of other viral RdRp [25,26]. In addition, the mechanism of action of favipiravir involving the direct inhibition of viral replication and transcription is unique among anti-influenza drugs. Because human cells do not contain the RdRp structural domain and possess a conserved RdRp catalytic structural domain, the broad-spectrum coverage of favipiravir renders it a promising candidate.

In mice infected with influenza virus, Favipiravir (200 mg/kg/day) protected mice from death by influenza virus infection. In mice artificially infected with the Ebola virus, Favipiravir effectively blocked virus production, achieving 95 % and 99.6 % antiviral efficacy after 2 and 6 days of treatment initiation, respectively. In vitro studies have demonstrated the antiviral activity of favipiravir (concentration: 0.25–3 mg mL−1) on the Vero-E6 cell line infected with SARS-CoV-2 using a real-time cell analyzer. In vitro, at an optimum concentration of 2 mg/mL, the lowest toxicity and sufficient antiviral activity were observed [27]. In vivo, studies revealed that high favipiravir doses significantly reduced pulmonary infectious virus titration and improved pulmonary histopathology in hamsters infected with SARS-CoV-2. Furthermore, high favipiravir doses were found to reduce the transmission of the virus in direct contact [28]. The bioavailability of favipiravir was approximately 97.6 %. The mean Cmax of the recommended dosing regimen is 51.5 μg/mL [29]. The research findings demonstrated that favipiravir was safe and outperformed controls in reducing the duration of viral shedding in post-discharge recurrence-positive patients who were with SARS-CoV-2 RNA [30].

Among hospitalized patients, compared with standard treatment, favipiravir [31] exhibited higher viral clearance on day 5, higher fever remission rates on days 3–4, significant improvement in chest radiology, and lesser duration for clinical improvement. Regarding adverse events, the favipiravir group showed a higher incidence of hyperuricemia and elevated alanine aminotransferase but a lower incidence of nausea and vomiting. The severe adverse events of this drug have not been studied. If pregnancy is confirmed or suspected, favipiravir in women should be avoided [32]. Phase IV clinical trials of favipiravir for COVID-19 have been completed, and treatment has been approved for marketing by the Central Drugs Standard Control Organization.

3.1.2 Azvudine

Azvudine (FNC) represents a novel nucleoside reverse transcriptase inhibitor with antiviral activity against HIV, hepatitis B virus, and hepatitis C virus [33]. Developed initially as an anti-HIV infection drug, a viral infectivity factor inhibitor, and an HIV-1 reverse transcriptase inhibitor, FNC received National Medical Products Administration approval from the State Drug Administration of China on July 20, 2021, for treating HIV infection as an oral tablet. In research on the COVID-19 virus, single-cell sequencing in rhesus monkeys and thymus homing characteristics in rats suggested that FNC promoted thymic function [34]. A randomized, open-label, controlled clinical trial of FNC tablets for mild and frequent COVID-19 showed that compared with standard antiviral therapy, FNC treatment resulted in a mean reduction in nucleic acid-negative conversion time of 4.5 days [35].

Moreover, FNC treatment accelerated viral elimination (virus clearance time of approximately 5 days) and improved lung function. In patients with moderate COVID-19, it maintained vital signs and significantly reduced the time for symptom improvement. The oral administration of FNC tablets in rhesus monkeys with SARSCoV-2 infection and patients with COVID-19 reduced viral load, inflammation, and organ damage [34]. The drug showed no adverse events in patients with COVID-19 [36]. The drug was thus used to treat patients with COVID-19. A clinical trial (NCT05033145) using FNC demonstrated that the drug reduced viral load, inflammation, and organ damage. It is worth mentioning that Multiple clinical trials are ongoing (NCT05697055) based on small dosages (5 mg/day, for up to 14 days), rapid viral decline. Over 800 patients with mild, moderate, and severe disease have been enrolled in a phase III clinical trial (CXHL2000162), with viral load and clinical benefit as evaluation indicators, which are highly conducive to a comprehensive and integrated assessment of drug efficacy.

3.1.3 Ribavirin

Ribavirin (RV), a synthetic guanosine nucleoside, is intended for treating some forms of hepatitis C. RV represents a noninterferon–inducing viral inhibitor chemotherapeutic agent with broad-spectrum activity against several RNA and DNA viruses; it interferes with the synthesis of viral mRNA.The FDA gives dosing guidance for ribavirin tablets, capsules, or oral solution for one indication: that is, in combination with interferon alpha-2b for the treatment of chronic hepatitis C (CHC) [37,38],and only in patients 3 years of age and older (note: ribavirin alone is not effective for the treatment of CHC). In October 2016, the FDA approved Navinta's ribavirin inhaler for treating severe lower respiratory tract infections in hospitalized infants and children with respiratory syncytial virus (RSV) infection [39,40]. RV posed significant dose-limiting toxicities, such as hemolytic anemia, with reduced hemoglobin levels within the first 1–2 weeks of treatment [41]. Clinical studies demonstrate that RV has a significant therapeutic effect in the early stages of SARS-CoV-2 pathogenesis [42,43]. Numerous clinical studies conducted to date have shown no serious adverse effects. The dose used in the treatment of viral hepatitis C is the same as that used in the treatment of SARS-CoV-2 (500 mg/day), and the dose used in the treatment of viral respiratory tract infections is 450 mg/day.

3.1.4 Oseltamivir

Oseltamivir, a neuraminidase inhibitor, is used for preventing and treating influenza. It prevents and treats influenza A virus (including the H1N1 pandemic) and influenza B virus infections [44]. Oseltamivir exerts its antiviral activity by inhibiting the activity of viral neuraminidase found on the surface of the virus, thereby preventing host cell outgrowth, viral replication, and infectivity. Tan et al. [45] used computer evaluation and molecular docking analysis techniques to demonstrate that oseltamivir carboxylic acid was more conducive to effective binding to the active site of 3-chymotrypsin-like protease (3CLpro), thereby blocking viral replication. In a single-center retrospective cohort study, the administration of oseltamivir was associated with shorter hospital stays, earlier recovery and discharge, and lower mortality [46]. In vitro and retrospective studies found that oseltamivir was ineffective against SARS-CoV-2 in vitro and that its clinical use failed to improve the signs and symptoms of patients or delay the disease progression [45]. Notably, gastrointestinal symptoms can affect a small proportion of patients with COVID-19 [47]; a systematic assessment of oseltamivir (Influenza) showed a reduction in the proportion of diarrhea [48].

Therefore, it is speculated that there would be an additional benefit if oseltamivir is used for treating SARS-CoV-2 infection. The results are optimistic when the drug is combined with some antiviral agents.

3.2 Anti-inflammatory drugs and immunotherapy

SARS-CoV-2 triggered the proliferation of mast cells in the submucosa of the respiratory tract [49], thereby activating the NF-kB pathway and increasing the inflammatory responses. Consequently, there is a higher risk of inflammation-associated cytokine storms following viral infection [50]. In addition, T cell reduction and functional failures have been observed in patients with COVID-19 [51]. Therefore, particularly in critically ill patients infected with SARS-CoV-2, blocking the overactive inflammatory response, thereby activating innate and adaptive immune responses, could be an effective strategy for treating COVID-19. Researchers are currently targeting anti-inflammatory drug repositioning that cures or prevents multiorgan dysfunction and lung injury caused by infection-related inflammation[[52], [53], [54]]. Researchers are actively investigating immunotherapy, including but not limited to recovery plasma, mesenchymal stem cells, and monoclonal antibodies. Monoclonal antibodies are proteins synthesized in the laboratory to help the immune system fight viruses. Currently, monoclonal antibodies, such as Tocilizumab[[55], [56], [57]], and Bebtelovimab [58,59] are being widely and extensively tested in phase III/IV clinical trials.

3.2.1 Colchicine

Colchicine is derived from colchicum or autumn saffron, a plant in the lily family [60]. It is used as an alkaloid to relieve the painful symptoms of gout attacks and remedy the inflammatory symptoms of familial Mediterranean fever, an inherited auto-inflammatory disease [61,62]. Colchicine disrupts cell division by inhibiting the inflammatory response triggered by microtubulin. Specifically, Colchicine disrupts the inflammatory vesicle complex in the monocytes and neutrophils, activating interleukin-1 (IL-1) and IL-18 [63]. Cytokines are associated with the severity of COVID-19 by inhibiting the release of IL-1β [64].

In an experimental model of acute respiratory distress syndrome (ARDS), colchicine reduced inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment [65]. SARS-CoV-2 activates the inflammatory process by activating protein 3 of the pyrin structural domain (NLRP3); specifically, NLRP3 activation occurs early in SARS-CoV-2 infection and triggers a cytokine storm. Colchicine can target NLRP3 inflammatory vesicles to reduce excessive inflammation.

Simultaneously, a phase III, randomized, double-blind, adaptive, placebo-controlled, multicenter trial was conducted in Brazil, Canada, Greece, South Africa, Spain, and the USA. In patients with PCR-confirmed COVID-19, colchicine resulted in lower mortality or hospitalization rates than placebo. The control group received medication according to the COVID-19 routine (protocol), and patients in the intervention group received a loading dose of colchicine 1.5 mg on top of the usual treatment, followed by 0.5 mg 60 min later if no gastrointestinal adverse effects were observed. a single dose of 1.0 mg colchicine was given in the context of coadministration of azithromycin. Maintenance doses were all 0.5 mg colchicine twice daily (once daily for patients weighing <60 kg). The 10-day cumulative event-free survival rates were 83 % and 97 % in the control and colchicine groups, respectively (P = 0.03). Available clinical trials have proven that High Doses of Colchicine significantly improve or clear SARS-CoV-2 [66,67], only improving the time to clinical deterioration relative to mild to moderate patients.

3.2.2 Tocilizumab

Tocilizumab is an IL-6 receptor antagonist used for treating rheumatoid arthritis [68], cytokine release syndrome (CRS), systemic juvenile idiopathic arthritis [69], and giant cell arteritis [70] and is administered by an intravenous and/or subcutaneous injection. IL-6 is a cytokine produced by T cells, B cells, lymphocytes, monocytes, and fibroblasts. IL-6 evokes antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation [71]. Tocilizumab binds to soluble and membrane-bound IL-6 receptors and prevents IL–6–mediated inflammation. Tocilizumab has been investigated as a possible treatment for severe COVID-19 in 2019. Despite the lack of direct antiviral effects, tocilizumab reduced immune-induced organ damage caused by severe SARS-CoV2 infection [72].

The pooled risk ratio estimates indicated that tocilizumab treatment predicted better overall survival in patients with COVID-19, particularly in severe cases [73]. A systematic evaluation and meta-analysis documented an even stronger association of tocilizumab treatment with good prognosis in patients with COVID-19 requiring mechanical ventilation, despite a higher incidence of secondary infections [74]. A phase IV clinical trial (NCT04730323) using tocilizumab in patients with COVID19-associated CRS claimed that this drug is an effective treatment option for critically ill patients with COVID-19, substantially reducing their oxygen requirements and thereby reducing ICU stay duration, the median length of stay, and mortality [56]. Clinical trials have also shown that Tocilizumab treats patients with mild-to-moderate COVID-19 who are at a high risk of developing severe COVID-19 [55,74,75]. The drug significantly reduces the probability of COVID-19 patients developing serious illness [56,72].

3.2.3 Dexamethasone

Dexamethasone is a glucocorticoid with potent anti-inflammatory properties used for treating various inflammatory diseases, including bronchial asthma and endocrine and rheumatic diseases; it is commonly intramuscularly and intravenously administered. Apart from binding to specific nuclear steroid receptors, dexamethasone interferes with NF-kB activation and apoptotic pathways. This drug upregulates CTLA-8 mRNA and protein in CD4 and CD4 T cells and blocks CD28-mediated cell cycle entry and differentiation [76]. Lower corticosteroid doses possess anti-inflammatory effects and promote anti-inflammatory genes, such as IL-10, whereas higher doses exert immunosuppressive effects [77]. A randomized clinical trial indicated that dexamethasone caused a significant increase in the number of days of survival and prevented the need for mechanical ventilation in patients with moderate or severe COVID-19.

A phase IV clinical study (NCT04530409) demonstrated that the timing of corticosteroid administration is vital for recovery and reducing mortality in COVID-19. Patients with the most severe form of COVID-19 experience a hyperinflammatory state (cytokine storm) that shares features with a rare blood disorder called hemophagocytic lymph histiocytosis. Immunosuppression can help these patients. By contrast, immunosuppression in the early stages of viral infection may increase viral replication and exacerbate the disease. A multicenter randomized controlled trial in Spain [78] demonstrated that the early administration of dexamethasone reduced the duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS.

The timing of dexamethasone use is critical for treating SARS-CoV-2 infection; moreover, its combination with other drugs has the potential for therapeutic advances. A prospective controlled nonrandomized study [79] indicated that treatment with raltegravir/dexamethasone significantly reduced mortality and length of hospital stay and accelerated SARS-CoV-2 clearance compared with dexamethasone alone. Regarding treatment, the safety assessments of systemic corticosteroids compared with low-dose (6 mg–8 mg) dexamethasone suggested a reduction in all-cause mortality after 30 days with high-dose (12 mg or higher) dexamethasone [80]; The role of glucocorticoids in improving survival in patients with severe SARS-CoV-2 is primarily established, with excellent anti-inflammatory effects. Glucocorticoids are currently not recommended in mildly ill patients; prolonged use of broad-spectrum antibiotics should be avoided.

3.2.4 Poly (ADP-ribose) polymerase 1 inhibitor

Future research directions should focus on selecting different types of hormones, a more refined population of beneficiaries and the exploration of dosing. The activation of poly (ADP-ribose) polymerase 1 (PARP1), a post-translational modifying enzyme, has proven to be associated with several inflammatory and viral diseases [81]. PARP1 inhibits viral growth by suppressing viral replication and blocking the binding of nucleocapsid proteins to viral RNA [82]. PARP1 inhibitors are used in clinical practice for treating certain cancers, such as breast, ovarian, and pancreatic cancers. The mechanism of its inhibition of SARS-CoV-2 may involve an essential RNA-binding protein—HuR—that interacts with PARP1 and is hetero-protonated by PARP1 [83]. HuR influences the expression levels of target genes in cells by modulating the stability and translation efficiency of target mRNAs, which comprise cytokines/chemokines and proinflammatory factors. Chemokines play an important role in adaptive immune response [84,85]. The interaction between PARP-1 and the nuclear factor-κB (NF-κB) pathway promotes the production of proinflammatory cytokines, such as TNF-α, IL-6, INF-γ, E-selectin, and ICAM-1 and the expression of nitric oxide synthase[[86], [87], [88]]. The PARP inhibitor PJ34 significantly inhibited lipopolysaccharide (LPS)-induced lung inflammation in mice [83]. Several in vitro studies revealed that negative PARP inhibitors can significantly block SARS-CoV-2 virus replication, suggesting a potential therapeutic approach to PARP inhibitors against COVID-19 or its variants [81,89]. Notably, the theoretical aspects of PARP as a therapeutic option are currently well established. Clinical trials are expected to be conducted to prove its feasibility.

3.3 Selective estrogen receptor modulator

COVID-19 pandemic data indicated sex differences in morbidity and mortality, with men showing a higher likelihood of experiencing complications from SARS-CoV-2 infection and, in particular, middle-aged and older men having a much higher risk of mortality and severe illness compared with women [90]. Women, particularly premenopausal women, were protected [91]. Immune reactivity surrounding ovulation correlates with high estradiol concentrations. Postmenopausal hormone replacement therapy (HRT) and combined contraceptive use produced side effects similar to an effective immune response and protection against viral infection [92]. Therefore, selective estrogen modulators (SERMs) are the primary determinant of sex differences; the immunomodulatory role of estrogen in SARS-CoV-2 infection is of greater interest as it may explain the male morbidity, mortality, and susceptibility to the severity of this disease. It is widely known is that estrogen exerts significant anti-inflammatory and immunomodulatory effects in COVID-19 [92,93]. Recent studies have shown that SARS-CoV-2 S proteins bind to and regulate estrogen receptors. Estrogen reduces SARS-CoV-2 infectivity by modulating proinflammatory signaling pathways [[94], [95], [96]]. Owing to the off-target effects of HRT, new nonhormonal agents, such as raloxifene and tamoxifen, have been developed via the evaluation of selective pharmacological effects on tissue-specific therapeutic targets to reduce adverse events.

3.3.1 Tamoxifen

Tamoxifen is a nonsteroidal antiestrogen used for treating estrogen receptor-positive breast cancer and preventing the incidence of breast cancer in high-risk groups [96,97]. The antiviral rationale may be related to viral entry and replication inhibition and cytopathic effects (CPEs). Tamoxifen interferes with SARS-CoV-2 entry by promoting endolysosomal alkalinization, altering endolysosomal kinetics, and directly inhibiting androgen receptor signaling via three approaches [98]. Zu et al. evaluated the antiviral activity of two drugs [99] and found that tamoxifen demonstrated potent antiviral activity. Tamoxifen inhibited SARS-CoV-2 infection in Caco-2 cells in a dose-dependent manner and this drug strongly antagonized SARS-CoV-2 infection in vitro. Correlative studies supported the immunomodulatory role of estrogen, which plays an acute role in viral infection and wound repair and reduces the devastating effects of the virus on the lungs and the severity of symptoms. The combination of isotretinoin and tamoxifen being evaluated in another trial (NCT04389580) is expected by researchers to treat or remit adult patients with severe SARS-COV-2. Although in vitro efficacy evidence is clear [99,100], limited clinical evidence supports its antiviral efficacy.

In addition, raloxifene counteracted the spike-mediated activation of ADAM17 in human lung cells. In a multicenter, double-blind, parallel-group phase II/III trial, raloxifene was investigated for treating adult patients with early mild-to-moderate COVID-19; the findings demonstrated a reduced time to viral elimination and a safety profile consistent with other reports. Imamura et al. showed synergistic antiviral effects of raloxifene and pioglitazone via induced pluripotent stem cell screening.

3.3.2 Raloxifene

Raloxifene, being a selective estrogen receptor modulator (SERM), binds to estrogen receptors [101]. Iaconis et al. [102]claimed that raloxifene as a potential pharmacological agent against SARS-CoV-2. Iaconis et al. tested the drug using the most common SARS-CoV-2 variant and found its ability to contrast viral CPEs superior. As predicted by computational studies, tamoxifen treatment did not directly affect spike/ACE2 interactions or viral internalization in infected cell lines. The validation of the hypothesis that raloxifene and tamoxifen are both effective will set the foundation for further research into estrogen receptor modulation as a therapeutic tool for treating other infectious diseases.

3.4 Miscellaneous

3.4.1 Ursodeoxycholic acid

UDCA is frequently prescribed for treating steroidal gallbladder stones, biliary depression, and bile-depleted liver diseases [103,104]. An overdose occurs as a result of diarrhea. Typically, overdose is a rare event owing to poor absorption of UDCA at higher doses and excessive elimination in feces. Computational analysis revealed that UDCA is membrane-bound and reduces the internalization of SARS-Cov2 in host cells [105]. Studies [106,107] have revealed that UDCA inhibits ACE2 expression in human nasal epithelium and contributes to the inhibition of abnormal airway epithelial cell migration. Therefore, UDCA has been shown to “target” SARS-CoV-2's passage into human cells at a receptor on the cell surface called ACE2. Because the drug targets the host cell rather than the virus, it can prevent infection by the new coronavirus and may have the ability to prevent infection by future mutants of the new coronavirus. Moreover, UDCA increases alveolar fluid clearance in ARDS [108]. Hence, preventing SARS-CoV-2 infection may be achieved by inhibiting cytokine storm syndrome. UDCA therapy may be beneficial in reducing COVID-19 infection risk, alleviating symptoms, and shortening the recovery time in patients with chronic liver disease [109]. However, there is too little data from clinical studies on UDCA, and UDCA treatment does not appear to have significant effects on the outcome of COVID-19. Specially designed prospective studies are needed to evaluate efficacy in preventing infection and severe disease [110].

3.4.2 Doxycycline

Doxycycline is a nontraditional broad-spectrum antibiotic synthesized from hygromycin with a proven safety profile. Indicated for treating a wide range of infections with gram-positive and gram-negative bacteria, aerobic and anaerobic bacteria, and other types of bacteria [111], doxycycline plays a considerable role for treating pneumonia and has several advantages, including cardiac safety, easy lung tissue accessibility, and potential antiviral and immunomodulatory effects exerted via various mechanisms [112]. Mahmud et al. demonstrated that patients with mild-to-moderate COVID-19 infection treated with ivermectin and doxycycline recovered earlier and were less likely to be exacerbated [113]. Stambouli [114]conducted a phase IV clinical trial (NCT04370782) with doxycycline and zinc prophylaxis in patients with reduced risk of SARS-CoV-2. Clinical trials have shown that doxycycline alone can significantly improve symptoms in patients at a high risk of severe disease [115].

Doxycycline 100 mg twice daily for seven days proved to be safe and non-inferior in terms of efficacy when compared to hydroxychloroquine-azithromycin for preventing clinical worsening of mild symptomatic or asymptomatic COVID-19 and achieving virological suppression [116]. Regarding clinical data performance, doxycycline is a potential and promising clinical drug candidate, particularly for patients at a high risk of severe pulmonary disease, but not for conventional therapy [117]. However, in vitro experiments with Doxycycline have inadequate data to support this. Caution should be exercised that any imbalance caused by inappropriate or indiscriminate use of repurposed drugs leads to a catastrophic increase in antimicrobial resistance.

3.4.3 Cepharanthine

Cepharanthine (CEP), with its naturally occurring alkaloid origin from Stephania cepharantha Hayata, has demonstrated unique anti-inflammatory, antioxidant, immunomodulatory, antiparasitic, and antiviral properties [118]. The analysis of CEP by transcriptomics effectively reversed most dysregulated genes and pathways in infected cells [119], including the endoplasmic reticulum stress/unfolded protein response and heat shock factor-mediated heat shock response. These are genomic expressions of viral disruptions and genes associated with cellular stress responses. CEP inhibits NF-κB activation, lipid peroxidation, nitric oxide production, cytokine production, and cyclooxygenase expression [120]. The anti–COVID–19 activity of CEP has been demonstrated in in vitro assays [121]. Currently, many in vitro experiments have demonstrated the antiviral efficacy of CEP against SARS-CoV-2 [[122], [123], [124], [125], [126]]. A new study analyses the broad-spectrum anti–COVID–19 activity of a series of metabolites in the natural biosynthetic pathway of CEP [127]. All these findings are critical for viral replication and inflammatory responses. Currently, Cepharanthine is a promising drug; however, several in vivo or clinical trials are required to validate its safety and reliability for robustness and adaptability of clinical treatment.

3.4.4 Metformin

Metformin, a biguanide antihyperglycemic drug, is the first-line therapy used for treating type II diabetes mellitus (T2DM) [128,129]. Moreover, it is used for treating insulin resistance in polycystic ovary syndrome [130]. The precise mechanism of action of metformin has extensively been studied in recent years[[131], [132], [133]]. Because metformin exerts multiple actions in addition to hypoglycemic effects, including anti-inflammatory effects, it can be speculated that it may positively influence the prognosis of T2DM patients with COVID-19 [134]. In a zebrafish model, metformin alleviated cytokine storms, reduced viral entry into cells, and prevented microvascular damage and secondary fibrosis [135]. An intriguing point is regarding its unique microcirculatory protective effect because the deterioration of COVID-19 disease largely occurs owing to severe defects in microvascular structure and function [136]. Metformin inhibits NLRP3 inflammatory vesicle activation and IL-1β production in cultured and alveolar macrophages as well as inhibits nondependent IL-6 secretion by inflammatory vesicles, resulting in the attenuation of LPS- and SARS-CoV-2–induced acute respiratory distress syndrome (ARDS) [137]. In addition, the safety of metformin as a first-line antihyperglycemic agent is unquestionable. Clinical and preclinical data suggest that metformin provides cardiopulmonary protection against COVID-19 by enhancing ACE2 expression [138,139]. In clinical trials, a further apparent benefit of metformin use observed before diagnosis [140,141]may be owing to the inhibition of neutrophil extracellular trap formation by this drug during infection and periods of disease exposure with SARS-CoV-2, rather than its anti-inflammatory activity. A related meta-analysis showed that mortality and severity in patients with T2DM were attenuated by the effects of metformin treatment [142]. Particular attention is required for the indicated population; however, reports of increased acidosis and lactic acidosis in patients with more severe COVID-19 caution that metformin should be discontinued in patients with hypoxemia or acute renal disease. A multicenter, quad-blind, parallel randomized phase III clinical trial proves that a 42 % reduction in the risk of developing long SARS-CoV-2 infection was observed when metformin was orally administered for 14 days and followed up to 300 days post-infection and a 63 % reduction in the risk of developing long SARS-CoV-2 infection was observed when metformin was used within 4 days of symptom onset [143]. Another clinical [144]demonstrated that metformin treatment reduced hospitalization, emergency room risk, and mortality due to new coronavirus infections by about 40 %. Therefore, metformin can alleviate SARS-CoV-2 infection in patients with T2DM and is promising for long SARS-CoV-2 infection. However, prospective studies on the clinical and metabolic role of metformin in COVID-19 are required [139].

4 Discussion

Drug repositioning represents an attractive approach to address an unsatisfied clinical need in infectious diseases. Looking for relationships between new coronaviruses and chronic diseases, metabolic diseases, and cancerous tumors. Interestingly, adult patients with underlying diseases are more or less symptomatically distinct, and the severity of SARS-CoV-2 is low in patients who are taking drugs for chronic diseases. In addition, we considered whether the medications typically taken by patients with chronic or metabolic diseases might affect this. In addition, we have to consider repurposing drug dosing regimens, as different indications with different disease stages require different doses. The fact that some drugs only work in the early stages or in mild-to-moderate patients, and that comorbidities, age of the population to be treated, etc., change rapidly,and even response to interventions, makes conclusions about the efficacy of a product candidate very challenging.

Despite the superior results in in vitro and in vivo trials, several drugs tested in extensive clinical trials (Table 3.), such as favipiravir,do not support routine clinical use owing to side effects. Oseltamivir, tamoxifen, and dexamethasone are more suitable for clinical use in combination for treating patients with severe SARS-CoV-2 infection. Tamoxifen and dexamethasone are more suitable for clinical combination therapy in patients with mild or severe Sars-CoV-2 infection. Notably, FNC and raloxifene can act against mutated Sars-CoV-2 infection. In contrast to other repurposed antirheumatic drugs used in patients with COVID-19, colchicine possesses multiple antiviral and anti-inflammatory capacities and exerts multiple effects on the inflammatory cascade response. Despite its lower potency compared with glucocorticoids (particularly dexamethasone), colchicine is available for oral administration. Additional time and research will be needed to verify these exciting new findings and possible new effects.Table 3 Mechanisms, targets, and clinical side effects of the candidates.

Table 3Drug name	Target	Mechanism	In vitro data supports (or does not support) efficacy	clinical side effect	
Favipiravir	RdRp	Blocking virus transcription and replication	Support	A higher incidence of hyperuricemia and elevated alanine aminotransferase	
Azvudine	RdRp	Blocking virus transcription and replication; Promotes thymic function	Support	No side effects	
Ribavirin	RNA polymerase	Blocking virus transcription and replication;	Support	No side effects	
Oseltamivir	3CLpro	Binding the active site of 3CLpro	Not Support	No side effects	
Colchicine	NLRP3	Reducing cytokine storms; Interferes with leukocyte activation	Support	Abdominal pain, nausea, vomiting, diarrhea, and hypovolemia, multiorgan failure	
Tocilizumab	IL-6	Reducing cytokine storms; Inhibits the production of fibronectin, albumin, and transferrin	Support	No side effects	
PARP1	HuR	Interacts with PARP1 and is hetero-protonated by PARP1	Support	N/A	
Dexamethasone	Inflammatory cytokines	Reducing cytokine storms;	Support	Glaucoma, cataracts, fluid retention, high blood pressure, psychological effects，weight gain or increased risk of infections and osteoporosis	
Tamoxifen	lysosome	Altered endolysosomal kinetics; Promotion of endolysosomal alkalinization; Direct inhibition of AR signaling	Support	N/A	
Raloxifene	ADAM17	Counteracting Spike-mediated activation of ADAM17 in human lung cells	Support	No side effects	
Ursodeoxycholic acid	FXR	Blocking FXR proteins directly reduces the amount of ACE2	Support	N/A	
Doxycycline	3CLpro	Regulation of 3CLpro; down-regulation of inflammatory factors	Not Support	Antibiotic-resistant	
Cepharanthine	NSP13	Reversal of most dysregulated genes and pathways in infected cells; Inhibition of expression of relevant inflammatory factors	Support	N/A	
Metformin	IL-6	Enhanced ACE2 expression; down-regulation of inflammatory factors	Support	Acidosis and lactic acidosis	

We must find effective ways to prevent infection, severe disease, and long-term sequelae, thereby solving this challenging issue that plagues the world. Simultaneously, we ought to be aware that several drugs exert many potential multiple effects but this does not mean they will definitively affect the patients with mutated SARS-CoV-2 infection or endangered patients. Further, we reiterate that most drugs are prescribed and should not be taken by individuals with no indications or for preventing Sars-CoV-2 and that blind use increases the risk of adverse events.

From a historical point of view, the strategy of drug repositioning has solved numerous diseases that were challenging[[144], [145], [146], [147], [148]]. In the face of the current pandemic crisis, this strategy is undoubtedly one of the most substantial contributors to the fight against viruses in the past and the future.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The authors declare that this study received funding from Chinese Biosafety Construction Project (145AHQ080014008X-12-02 ). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Data availability statement

Data availability does not apply to this article as no new data were created or analyzed in this study.

CRediT authorship contribution statement

Yutong Liang: Writing – review & editing, Writing – original draft, Conceptualization. Xiaoxiao Quan: Resources. Ruolan Gu: Formal analysis. Zhiyun Meng: Writing – review & editing. Hui Gan: Methodology. Zhuona Wu: Funding acquisition. Yunbo Sun: Methodology. Huajie Pan: Resources. Peng Han: Funding acquisition. Shuchen Liu: Writing – review & editing. Guifang Dou: Writing – review & editing.

Declaration of competing interest

I also certify that I have disclosed any financial or non-financial relationships that may be interpreted as constituting a conflict of interest about this manuscript. I understand that this information will be subject to peer review, and I am willing to provide further information or clarification if required.

I confirm that I have no known conflicts of interest that would influence the results or interpretation of the data presented in this manuscript, and I understand that failure to disclose a conflict of interest is unethical and may result in sanctioning imposed on me.

Acknowledgments

Thanks to the help of Shuchen Liu, Guifang Dou in paper submission; Ruolan Gu, Zhiyun Meng, Hui Gan, Wenzhong Sun, Zhuona Wu, Yunbo Sun, Peng Han, Huajie Pan, Chunbo Ge helped with essay writing and language.
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References

1 V’kovski P. Kratzel A. Steiner S. Stalder H. Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2 Nat. Rev. Microbiol. 19 2021 155 170 10.1038/s41579-020-00468-6 33116300
2 Hu B. Guo H. Zhou P. Shi Z.-L. Characteristics of SARS-CoV-2 and COVID-19 Nat. Rev. Microbiol. 19 2021 141 154 10.1038/s41579-020-00459-7 33024307
3 Barnes C.O. Jette C.A. Abernathy M.E. Dam K.-M.A. Esswein S.R. Gristick H.B. Malyutin A.G. Sharaf N.G. Huey-Tubman K.E. Lee Y.E. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies Nature 588 2020 682 687 10.1038/s41586-020-2852-1 33045718
4 Wu J. Zhang J. Sun X. Wang L. Xu Y. Zhang Y. Liu X. Dong C. Influence of diabetes mellitus on the severity and fatality of SARS-CoV-2 (COVID-19) infection Diabetes Obes. Metabol. 22 2020 1907 1914 10.1111/dom.14105
5 Halpin D.M.G. Faner R. Sibila O. Badia J.R. Agusti A. Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection? Lancet Respir. Med. 8 2020 436 438 10.1016/S2213-2600(20)30167-3 32251625
6 Milne S. Li X. Yang C.X. Leitao Filho F.S. Hernández Cordero A.I. Yang C.W.T. Shaipanich T. van Eeden S.F. Leung J.M. Lam S. Inhaled corticosteroids downregulate SARS-CoV-2-related genes in COPD: results from a randomised controlled trial Eur. Respir. J. 58 2021 2100130 10.1183/13993003.00130-2021
7 Gasmi A. Peana M. Pivina L. Srinath S. Gasmi Benahmed A. Semenova Y. Menzel A. Dadar M. Bjørklund G. Interrelations between COVID-19 and other disorders Clin. Immunol. 224 2021 108651 10.1016/j.clim.2020.108651
8 Kakkassery H. Carpenter E. Patten P.E.M. Irshad S. Immunogenicity of SARS-CoV-2 vaccines in patients with cancer Trends Mol. Med. 28 2022 1082 1099 10.1016/j.molmed.2022.07.006 35999131
9 Alur-Gupta S. Boland M.R. Dokras A. N3C consortium risk of SARS-CoV-2 infection among women with polycystic ovary syndrome Fertil. Steril. S0015–0282 23 2023 63 68 10.1016/j.fertnstert.2023.01.025
10 Ts H. COVID-19 therapeutics why not angiotensin receptor blockers (ARBs)? J. Assoc. Phys. India 71 2023 10.59556/japi.71.0393
11 Ct B. Kb B. T M. Ab K. Dj O. Cj T. Jb B. Dm J. Rhb W. Jj D. Favorable antiviral effect of metformin on severe acute respiratory syndrome coronavirus 2 viral load in a randomized, placebo-controlled clinical trial of coronavirus disease 2019 Clin. Infect. Dis. : an official publication of the Infectious Diseases Society of America 2024 10.1093/cid/ciae159
12 Chen H. Wu J. Gao Y. Chen H. Zhou J. Scaffold repurposing of old drugs towards new cancer drug discovery Curr. Top. Med. Chem. 16 2016 2107 2114 10.2174/1568026616666160216155556 26881709
13 Luttens A. Gullberg H. Abdurakhmanov E. Vo D.D. Akaberi D. Talibov V.O. Nekhotiaeva N. Vangeel L. De Jonghe S. Jochmans D. Ultralarge virtual screening identifies SARS-CoV-2 main protease inhibitors with broad-spectrum activity against coronaviruses J. Am. Chem. Soc. 144 2022 2905 2920 10.1021/jacs.1c08402 35142215
14 Vincent F. Nueda A. Lee J. Schenone M. Prunotto M. Mercola M. Phenotypic drug discovery: recent successes, lessons learned and new directions Nat. Rev. Drug Discov. 21 2022 899 914 10.1038/s41573-022-00472-w 35637317
15 Wong A.K. Sealfon R.S.G. Theesfeld C.L. Troyanskaya O.G. Decoding disease: from genomes to networks to phenotypes Nat. Rev. Genet. 22 2021 774 790 10.1038/s41576-021-00389-x 34341555
16 Villa T.G. Feijoo-Siota L. Rama J.L.R. Ageitos J.M. Antivirals against animal viruses Biochem. Pharmacol. 133 2017 97 116 10.1016/j.bcp.2016.09.029 27697545
17 Shiraki K. Daikoku T. Favipiravir An anti-influenza drug against life-threatening RNA virus infections Pharmacol. Ther. 209 2020 107512 10.1016/j.pharmthera.2020.107512
18 Tsuzuki S. Hayakawa K. Doi Y. Shinozaki T. Uemura Y. Matsunaga N. Terada M. Suzuki S. Asai Y. Yamada G. Effectiveness of favipiravir on nonsevere, early-stage COVID-19 in Japan: a large observational study using the COVID-19 registry Japan Infect. Dis. Ther. 11 2022 1075 1087 10.1007/s40121-022-00617-9 35307811
19 Hayden F.G. Shindo N. Influenza virus polymerase inhibitors in clinical development Curr. Opin. Infect. Dis. 32 2019 176 186 10.1097/QCO.0000000000000532 30724789
20 Furuta Y. Komeno T. Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93 2017 449 463 10.2183/pjab.93.027
21 Madelain V. Nguyen T.H.T. Olivo A. de Lamballerie X. Guedj J. Taburet A.-M. Mentré F. Ebola virus infection: review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials Clin. Pharmacokinet. 55 2016 907 923 10.1007/s40262-015-0364-1 26798032
22 C L. Do T. A G. Assessing the impact of antiviral drugs commonly utilized during the COVID-19 pandemic on the embryonic development of Xenopus laevis J. Hazard Mater. 472 2024 10.1016/j.jhazmat.2024.134462
23 Vv S. Tv B. Aa C. Ef K. Le A. Pharmacogenomic studies of antiviral drug favipiravir Pharmaceutics 16 2024 10.3390/pharmaceutics16040503
24 R Z. Q J. S G. H Z. Q X. B L. J Z. H J. R Z. H D. Favipiravir ameliorates bleomycin-induced pulmonary fibrosis by reprogramming M1/M2 macrophage polarization Int. Immunopharm. 131 2024 10.1016/j.intimp.2024.111774
25 Park G.J. Osinski A. Hernandez G. Eitson J.L. Majumdar A. Tonelli M. Henzler-Wildman K. Pawłowski K. Chen Z. Li Y. The mechanism of RNA capping by SARS-CoV-2 Nature 609 2022 793 800 10.1038/s41586-022-05185-z 35944563
26 Stevens L.J. Pruijssers A.J. Lee H.W. Gordon C.J. Tchesnokov E.P. Gribble J. George A.S. Hughes T.M. Lu X. Li J. Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms Sci. Transl. Med. 14 2022 eabo0718 10.1126/scitranslmed.abo0718
27 Yildiz Pekoz A. Akbal Dagistan O. Fael H. Culha M. Erturk A. Basarir N.S. Sahin G. Serhatli M. Cakirca G. Tekin S. Pulmonary delivery of favipiravir inhalation solution for COVID-19 treatment: in vitro characterization, stability, in vitro cytotoxicity, and antiviral activity using real time cell analysis Drug Deliv. 29 2022 2846 2854 10.1080/10717544.2022.2118398 36062490
28 Kaptein S.J.F. Jacobs S. Langendries L. Seldeslachts L. Ter Horst S. Liesenborghs L. Hens B. Vergote V. Heylen E. Barthelemy K. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity Proc. Natl. Acad. Sci. U. S. A. 117 2020 26955 26965 10.1073/pnas.2014441117 33037151
29 S B. D A. Z S. S B. C S. M G. F A. A O. C G.H.S. Favipiravir-induced inflammatory and hydropic degenerative liver injury in rats Adv. Clin. Exp. Med. : official organ Wroclaw Medical University 32 2023 10.17219/acem/159089
30 Zhao H. Zhang C. Zhu Q. Chen X. Chen G. Sun W. Xiao Z. Du W. Yao J. Li G. Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: a multicenter, open-label, randomized trial Int. Immunopharm. 97 2021 107702 10.1016/j.intimp.2021.107702
31 Hung D.T. Ghula S. Aziz J.M.A. Makram A.M. Tawfik G.M. Abozaid A.A.-F. Pancharatnam R.A. Ibrahim A.M. Shabouk M.B. Turnage M. The efficacy and adverse effects of favipiravir on patients with COVID-19: a systematic review and meta-analysis of published clinical trials and observational studies Int. J. Infect. Dis. 120 2022 217 227 10.1016/j.ijid.2022.04.035 35470021
32 Delang L. Abdelnabi R. Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses Antivir. Res. 153 2018 85 94 10.1016/j.antiviral.2018.03.003 29524445
33 Wang R.-R. Yang Q.-H. Luo R.-H. Peng Y.-M. Dai S.-X. Zhang X.-J. Chen H. Cui X.-Q. Liu Y.-J. Huang J.-F. Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro PLoS One 9 2014 e105617 10.1371/journal.pone.0105617
34 Zhang J.-L. Li Y.-H. Wang L.-L. Liu H.-Q. Lu S.-Y. Liu Y. Li K. Liu B. Li S.-Y. Shao F.-M. Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients Signal Transduct. Targeted Ther. 6 2021 414 10.1038/s41392-021-00835-6
35 Ren Z. Luo H. Yu Z. Song J. Liang L. Wang L. Wang H. Cui G. Liu Y. Wang J. A randomized, open-label, controlled clinical trial of azvudine tablets in the treatment of mild and common COVID-19, a pilot study Adv. Sci. 7 2020 e2001435 10.1002/advs.202001435
36 Kale A. Shelke V. Dagar N. Anders H.-J. Gaikwad A.B. How to use COVID-19 antiviral drugs in patients with chronic kidney disease Front. Pharmacol. 14 2023 1053814 10.3389/fphar.2023.1053814
37 Fernandez H. Banks G. Smith R. Ribavirin A clinical overview Eur. J. Epidemiol. 2 1986 1 14 10.1007/BF00152711 3021519
38 Kesselheim A.S. Sinha M.S. Campbell E.G. Schneeweiss S. Rausch P. Lappin B.M. Zhou E.H. Avorn J. Dal Pan G.J. Multimodal analysis of FDA drug safety communications: lessons from zolpidem Drug Saf. 42 2019 1287 1295 10.1007/s40264-019-00849-8 31302895
39 Inhibition of respiratory syncytial virus replication and suppression of RSV-induced airway inflammation in neonatal Rats by Colchicine - PubMed Available online: https://yc.mlpla.mil.cn/s/gov/nih/nlm/ncbi/pubmed/G https/31656730/
40 Buchwald A.G. Graham B.S. Traore A. Haidara F.C. Chen M. Morabito K. Lin B.C. Sow S.O. Levine M.M. Pasetti M.F. Respiratory syncytial virus (RSV) neutralizing antibodies at birth predict protection from RSV illness in infants in the first 3 Months of life Clin. Infect. Dis. 73 2021 e4421 e4427 10.1093/cid/ciaa648 32463443
41 Shields W.W. Pockros P.J. Ribavirin analogs Clin. Liver Dis. 13 2009 419 427 10.1016/j.cld.2009.05.006 19628158
42 Wong C.K.H. Wan E.Y.F. Luo S. Ding Y. Lau E.H.Y. Ling P. Hu X. Lau E.C.H. Wong J. Zheng X. Clinical outcomes of different therapeutic options for COVID-19 in two Chinese case cohorts: a propensity-score analysis eClinicalMedicine 32 2021 10.1016/j.eclinm.2021.100743
43 Ckh W. Eyf W. S L. Y D. Ehy L. P L. X H. Ech L. J W. X Z. Clinical outcomes of different therapeutic options for COVID-19 in two Chinese case cohorts: a propensity-score analysis EClinicalMedicine 32 2021 10.1016/j.eclinm.2021.100743
44 Kumar S. Goicoechea S. Kumar S. Pearce C.M. Durvasula R. Kempaiah P. Rathi B. Poonam, null oseltamivir analogs with potent anti-influenza virus activity Drug Discov. Today 25 2020 1389 1402 10.1016/j.drudis.2020.06.004 32554062
45 Tan Q. Duan L. Ma Y. Wu F. Huang Q. Mao K. Xiao W. Xia H. Zhang S. Zhou E. Is oseltamivir suitable for fighting against COVID-19: in silico assessment, in vitro and retrospective study Bioorg. Chem. 104 2020 104257 10.1016/j.bioorg.2020.104257
46 Zendehdel A. Bidkhori M. Ansari M. Jamalimoghaddamsiyahkali S. Asoodeh A. Efficacy of oseltamivir in the treatment of patients infected with covid-19 Ann Med Surg (Lond) 77 2022 103679 10.1016/j.amsu.2022.103679
47 Poudel A.N. Zhu S. Cooper N. Roderick P. Alwan N. Tarrant C. Ziauddeen N. Yao G.L. Impact of covid-19 on health-related quality of life of patients: a structured review PLoS One 16 2021 e0259164 10.1371/journal.pone.0259164
48 Lin L. Jiang X. Zhang Z. Huang S. Zhang Z. Fang Z. Gu Z. Gao L. Shi H. Mai L. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection Gut 69 2020 997 1001 10.1136/gutjnl-2020-321013 32241899
49 Trivedi N. Verma A. Kumar D. Possible treatment and strategies for COVID-19: review and assessment Eur. Rev. Med. Pharmacol. Sci. 24 2020 12593 12608 10.26355/eurrev_202012_24057 33336780
50 Ye Q. Wang B. Mao J. The pathogenesis and treatment of the Cytokine storm’ in COVID-19 J. Infect. 80 2020 607 613 10.1016/j.jinf.2020.03.037 32283152
51 Mangalmurti N. Hunter C.A. Cytokine storms: understanding COVID-19 Immunity 53 2020 19 25 10.1016/j.immuni.2020.06.017 32610079
52 I J. Na N. None Y. Ma H. Za M.-H. Mr M.A.R. Af S.M. Kw L. S I. Inhibitory effect of food-functioned phytochemicals on dysregulated inflammatory pathways triggered by SARS-CoV-2: a mechanistic review Crit. Rev. Food Sci. Nutr. 2024 10.1080/10408398.2024.2341266
53 A G. Y J. A K.-S. C P. Pf D. Hydrocortisone rapidly and significantly reduces the IL-6 level in blood and lungs of patients with COVID-19-related ARDS Crit. Care 28 2024 10.1186/s13054-024-04887-2
54 Z C. J W. X L. Y L. F L. M L. S C. X J. Helminth alleviates COVID-19-related cytokine storm in an IL-9-dependent way mBio 2024 10.1128/mbio.00905-24
55 Rm S. Hs H. Ae A.W. Mm S.-B. F S. Sa A. Ym M. Ms B. Efficacy of the early treatment with tocilizumab-hydroxychloroquine and tocilizumab-remdesivir in severe COVID-19 patients Journal of infection and public health 15 2022 10.1016/j.jiph.2021.10.024
56 Chachar A.Z.K. Khan K.A. Iqbal J. Shahid A.H. Asif M. Fatima S.A. Khan A.A. Younis B.B. Tocilizumab-an option for patients with COVID-19 associated cytokine release syndrome: a single center experience a Retrospective Study-Original Article. Ann Med Surg (Lond) 63 2021 102165 10.1016/j.amsu.2021.02.011
57 Repurposed tocilizumab in patients with severe COVID-19 - PubMed Available online: https://pubmed.ncbi.nlm.nih.gov/33298617/
58 Luo J. Li T. Liu C. Wang Y. Tran C. Ao G. The effect of Bebtelovimab on clinical outcomes in patients with COVID-19: a meta-analysis J. Infect. 87 2023 68 71 10.1016/j.jinf.2023.04.010 37085048
59 McCreary E.K. Kip K.E. Collins K. Minnier T.E. Snyder G.M. Steiner A. Meyers R. Borneman T. Adam M. Thurau L. Evaluation of Bebtelovimab for treatment of covid-19 during the SARS-CoV-2 omicron variant era Open Forum Infect. Dis. 9 2022 ofac517 10.1093/ofid/ofac517 36324319
60 Angelidis C. Kotsialou Z. Kossyvakis C. Vrettou A.-R. Zacharoulis A. Kolokathis F. Kekeris V. Giannopoulos G. Colchicine pharmacokinetics and mechanism of action Curr. Pharmaceut. Des. 24 2018 659 663 10.2174/1381612824666180123110042
61 Sönmez H.E. Batu E.D. Özen S. Familial mediterranean fever: current perspectives J. Inflamm. Res. 9 2016 13 20 10.2147/JIR.S91352 27051312
62 Leung Y.Y. Yao Hui L.L. Kraus V.B. Colchicine--Update on mechanisms of action and therapeutic uses Semin. Arthritis Rheum. 45 2015 341 350 10.1016/j.semarthrit.2015.06.013 26228647
63 Dalbeth N. Lauterio T.J. Wolfe H.R. Mechanism of action of colchicine in the treatment of gout Clin. Therapeut. 36 2014 1465 1479 10.1016/j.clinthera.2014.07.017
64 Tardif J.-C. Bouabdallaoui N. L'Allier P.L. Gaudet D. Shah B. Pillinger M.H. Lopez-Sendon J. da Luz P. Verret L. Audet S. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial Lancet Respir. Med. 9 2021 924 932 10.1016/S2213-2600(21)00222-8 34051877
65 Dupuis J. Sirois M.G. Rhéaume E. Nguyen Q.T. Clavet-Lanthier M.-É. Brand G. Mihalache-Avram T. Théberge-Julien G. Charpentier D. Rhainds D. Colchicine reduces lung injury in experimental acute respiratory distress syndrome PLoS One 15 2020 e0242318 10.1371/journal.pone.0242318
66 A L. K P. V M. High doses of colchicine act as “silver bullets” against severe COVID-19 Cureus 16 2024 10.7759/cureus.54441
67 K E. Gee A. Mn F. R S. Mf A. The role of colchicine in the management of COVID-19: a meta-analysis BMC Pulm. Med. 24 2024 10.1186/s12890-024-03001-0
68 Scott L.J. Tocilizumab: a review in rheumatoid arthritis Drugs 77 2017 1865 1879 10.1007/s40265-017-0829-7 29094311
69 Sheppard M. Laskou F. Stapleton P.P. Hadavi S. Dasgupta B. Tocilizumab (actemra) Hum. Vaccines Immunother. 13 2017 1972 1988 10.1080/21645515.2017.1316909
70 Stone J.H. Tuckwell K. Dimonaco S. Klearman M. Aringer M. Blockmans D. Brouwer E. Cid M.C. Dasgupta B. Rech J. Trial of tocilizumab in giant-cell arteritis N. Engl. J. Med. 377 2017 317 328 10.1056/NEJMoa1613849 28745999
71 Tanaka T. Narazaki M. Kishimoto T. IL-6 in inflammation, immunity, and disease Cold Spring Harbor Perspect. Biol. 6 2014 a016295 10.1101/cshperspect.a016295
72 Raiteri A. Piscaglia F. Granito A. Tovoli F. Tocilizumab: from rheumatic diseases to COVID-19 Curr. Pharmaceut. Des. 27 2021 1597 1607 10.2174/1381612827666210311141512
73 Wei Q. Lin H. Wei R.-G. Chen N. He F. Zou D.-H. Wei J.-R. Tocilizumab treatment for COVID-19 patients: a systematic review and meta-analysis Infect Dis Poverty 10 2021 71 10.1186/s40249-021-00857-w 34001244
74 Somers E.C. Eschenauer G.A. Troost J.P. Golob J.L. Gandhi T.N. Wang L. Zhou N. Petty L.A. Baang J.H. Dillman N.O. Tocilizumab for treatment of mechanically ventilated patients with COVID-19 Clin. Infect. Dis. 73 2021 e445 e454 10.1093/cid/ciaa954 32651997
75 Oksi J. COVID-19: Salvage TOcilizumab as a Rescue Measure. Use of Tocilizumab in the Inflammatory Phase of COVID-19/New Coronavirus Disease 2021 clinicaltrials.gov
76 Giles A.J. Hutchinson M.-K.N.D. Sonnemann H.M. Jung J. Fecci P.E. Ratnam N.M. Zhang W. Song H. Bailey R. Davis D. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy J Immunother Cancer 6 2018 51 10.1186/s40425-018-0371-5 29891009
77 Tomazini B.M. Maia I.S. Cavalcanti A.B. Berwanger O. Rosa R.G. Veiga V.C. Avezum A. Lopes R.D. Bueno F.R. Silva M.V.A.O. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial JAMA 324 2020 1307 1316 10.1001/jama.2020.17021 32876695
78 Villar J. Ferrando C. Martínez D. Ambrós A. Muñoz T. Soler J.A. Aguilar G. Alba F. González-Higueras E. Conesa L.A. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial Lancet Respir. Med. 8 2020 267 276 10.1016/S2213-2600(19)30417-5 32043986
79 Marrone A. Nevola R. Sellitto A. Cozzolino D. Romano C. Cuomo G. Aprea C. Schwartzbaum M.X.P. Ricozzi C. Imbriani S. Remdesivir plus dexamethasone versus dexamethasone alone for the treatment of coronavirus disease 2019 (COVID-19) patients requiring supplemental O2 therapy: a prospective controlled nonrandomized study Clin. Infect. Dis. 75 2022 e403 e409 10.1093/cid/ciac014 35084022
80 Wagner C. Griesel M. Mikolajewska A. Metzendorf M.-I. Fischer A.-L. Stegemann M. Spagl M. Nair A.A. Daniel J. Fichtner F. Systemic corticosteroids for the treatment of COVID-19: equity-related analyses and update on evidence Cochrane Database Syst. Rev. 11 2022 CD014963 10.1002/14651858.CD014963.pub2 36385229
81 Rajawat J. Chandra A. Role of poly(ADP-ribose) polymerase (PARP1) in viral infection and its implication in SARS-CoV-2 pathogenesis Curr. Drug Targets 22 2021 1477 1484 10.2174/1389450122666210120142746 33494667
82 Zhu H. Wei M. Xu J. Hua J. Liang C. Meng Q. Zhang Y. Liu J. Zhang B. Yu X. PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications Mol. Cancer 19 2020 49 10.1186/s12943-020-01167-9 32122376
83 Ke Y. Han Y. Guo X. Wen J. Wang K. Jiang X. Tian X. Ba X. Boldogh I. Zeng X. Erratum PARP1 promotes gene expression at the post-transcriptional level by modulating the RNA-binding protein HuR Nat. Commun. 8 2017 15191 10.1038/ncomms15191
84 Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation N. Engl. J. Med. 354 2006 610 621 10.1056/NEJMra052723 16467548
85 Glass C.K. Olefsky J.M. Inflammation and lipid signaling in the etiology of insulin resistance Cell Metabol. 15 2012 635 645 10.1016/j.cmet.2012.04.001
86 Naura A.S. Datta R. Hans C.P. Zerfaoui M. Rezk B.M. Errami Y. Oumouna M. Matrougui K. Boulares A.H. Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia Eur. Respir. J. 33 2009 252 262 10.1183/09031936.00089008 18829681
87 Haddad M. Rhinn H. Bloquel C. Coqueran B. Szabó C. Plotkine M. Scherman D. Margaill I. Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice Br. J. Pharmacol. 149 2006 23 30 10.1038/sj.bjp.0706837 16865091
88 Jijon H.B. Churchill T. Malfair D. Wessler A. Jewell L.D. Parsons H.G. Madsen K.L. Inhibition of poly(ADP-ribose) polymerase attenuates inflammation in a model of chronic colitis Am. J. Physiol. Gastrointest. Liver Physiol. 279 2000 G641 G651 10.1152/ajpgi.2000.279.3.G641 10960365
89 Stone N.E. Jaramillo S.A. Jones A.N. Vazquez A.J. Martz M. Versluis L.M. Raniere M.O. Nunnally H.E. Zarn K.E. Nottingham R. Stenoparib, an inhibitor of cellular poly(ADP-ribose) polymerase, blocks replication of the SARS-CoV-2 and HCoV-NL63 human coronaviruses in vitro mBio 12 2021 e03495 10.1128/mBio.03495-20 20
90 Di Vincenzo A. Andrisani A. Vettor R. Rossato M. Estrogen and COVID-19: friend or foe? Ann. Oncol. 32 2021 933 934 10.1016/j.annonc.2021.03.201
91 Brandi M.L. Are sex hormones promising candidates to explain sex disparities in the COVID-19 pandemic? Rev. Endocr. Metab. Disord. 23 2022 171 183 10.1007/s11154-021-09692-8 34761329
92 Al-Kuraishy H.M. Al-Gareeb A.I. Faidah H. Al-Maiahy T.J. Cruz-Martins N. Batiha G.E.-S. The looming effects of estrogen in covid-19: a rocky rollout Front. Nutr. 8 2021 649128 10.3389/fnut.2021.649128
93 Jafari A. Esmaeilzadeh Z. Khezri M.R. Ghasemnejad-Berenji H. Pashapour S. Sadeghpour S. Ghasemnejad-Berenji M. An overview of possible pivotal mechanisms of genistein as a potential phytochemical against SARS-CoV-2 infection: a hypothesis J. Food Biochem. 46 2022 e14345 10.1111/jfbc.14345
94 Mateus D. Sebastião A.I. Carrascal M.A. Carmo A. do Matos A.M. Cruz M.T. Crosstalk between estrogen, dendritic cells, and SARS-CoV-2 infection Rev. Med. Virol. 32 2022 e2290 10.1002/rmv.2290
95 Allegretti M. Cesta M.C. Zippoli M. Beccari A. Talarico C. Mantelli F. Bucci E.M. Scorzolini L. Nicastri E. Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection Cell Death Differ. 29 2022 156 166 10.1038/s41418-021-00844-6 34404919
96 Fourteenth Gaddum Memorial Lecture A current view of tamoxifen for the treatment and prevention of breast cancer - PubMed available online https://pubmed.ncbi.nlm.nih.gov/8242225/
97 Arora S. Narayan P. Osgood C.L. Wedam S. Prowell T.M. Gao J.J. Shah M. Krol D. Wahby S. Royce M. U.S. FDA drug approvals for breast cancer: a decade in review Clin. Cancer Res. 28 2022 1072 1086 10.1158/1078-0432.CCR-21-2600 34711632
98 S B. E F. M T. D A. G M. F N. P P. M M. Estrogen and androgen receptor inhibitors: unexpected allies in the fight against COVID-19 Cell Transplant. 30 2021 10.1177/0963689721991477
99 Zu S. Luo D. Li L. Ye Q. Li R.-T. Wang Y. Gao M. Yang H. Deng Y.-Q. Cheng G. Tamoxifen and clomiphene inhibit SARS-CoV-2 infection by suppressing viral entry Signal Transduct. Targeted Ther. 6 2021 435 10.1038/s41392-021-00853-4
100 G M. H P. H T. Y L. X Z. B L. L J. W T. Y H. Y L. Antiviral efficacy of selective estrogen receptor modulators against SARS-CoV-2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor J. Med. Virol. 94 2022 10.1002/jmv.27951
101 Heringa M. Review on raloxifene: profile of a selective estrogen receptor modulator Int. J. Clin. Pharmacol. Therapeut. 41 2003 331 345 10.5414/cpp41331
102 Iaconis D. Bordi L. Matusali G. Talarico C. Manelfi C. Cesta M.C. Zippoli M. Caccuri F. Bugatti A. Zani A. Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants Cell Death Dis. 13 2022 498 10.1038/s41419-022-04961-z 35614039
103 Goossens J.-F. Bailly C. Ursodeoxycholic acid and cancer: from chemoprevention to chemotherapy Pharmacol. Ther. 203 2019 107396 10.1016/j.pharmthera.2019.107396
104 Kotb M.A. Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode Int. J. Mol. Sci. 13 2012 8882 8914 10.3390/ijms13078882 22942741
105 Rodal Canales F.J. Pérez-Campos Mayoral L. Hernández-Huerta M.T. Sánchez Navarro L.M. Matias-Cervantes C.A. Martínez Cruz M. Cruz Parada E. Zenteno E. Ramos-Martínez E.G. Pérez-Campos Mayoral E. Interaction of spike protein and lipid membrane of SARS-CoV-2 with ursodeoxycholic acid, an in-silico analysis Sci. Rep. 11 2021 22288 10.1038/s41598-021-01705-5
106 Brevini T. Maes M. Webb G.J. John B.V. Fuchs C.D. Buescher G. Wang L. Griffiths C. Brown M.L. Scott W.E. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2 Nature 615 2023 134 142 10.1038/s41586-022-05594-0 36470304
107 Thuy P.X. Bao T.D.D. Moon E.-Y. Ursodeoxycholic acid ameliorates cell migration retarded by the SARS-CoV-2 spike protein in BEAS-2B human bronchial epithelial cells Biomed. Pharmacother. 150 2022 113021 10.1016/j.biopha.2022.113021
108 M H. H N. T H. M I. J U. T M. K K. Y T. K O. Intestinal collinsella may mitigate infection and exacerbation of COVID-19 by producing ursodeoxycholate PLoS One 16 2021 10.1371/journal.pone.0260451
109 Y L. N Z. X C. Y L. X L. Protective effect of ursodeoxycholic acid on COVID-19 in patients with chronic liver disease Front. Cell. Infect. Microbiol. 13 2023 10.3389/fcimb.2023.1178590
110 G M. M C. G M. A P. A A. A N. R M. M P. A G. F F. Ursodeoxycholic acid does not affect the clinical outcome of SARS-CoV-2 infection: a retrospective study of propensity score-matched cohorts Liver Int. : official journal of the International Association for the Study of the Liver 44 2024 10.1111/liv.15736
111 Chopra I. Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance Microbiol. Mol. Biol. Rev. 65 2001 232 260 10.1128/MMBR.65.2.232-260.2001 ; second page, table of contents 11381101
112 Ali A.S. Asattar M.A. Karim S. Kutbi D. Aljohani H. Bakhshwin D. Alsieni M. Alkreathy H.M. Pharmacological basis for the potential role of azithromycin and doxycycline in management of COVID-19 Arab. J. Chem. 14 2021 102983 10.1016/j.arabjc.2020.102983
113 Mahmud R. Rahman M.M. Alam I. Ahmed K.G.U. Kabir A.K.M.H. Sayeed S.K.J.B. Rassel M.A. Monayem F.B. Islam M.S. Islam M.M. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial J. Int. Med. Res. 49 2021 3000605211013550 10.1177/03000605211013550
114 Stambouli N. Driss A. Gargouri F. Bahrini K. Arfaoui B. Abid R. Taamallah K. Hannachi S. Boughariou S. Rebai A. COVID-19 prophylaxis with doxycycline and zinc in health care workers: a prospective, randomized, double-blind clinical trial Int. J. Infect. Dis. 122 2022 553 558 10.1016/j.ijid.2022.06.016 35724828
115 Yates P.A. Newman S.A. Oshry L.J. Glassman R.H. Leone A.M. Reichel E. Doxycycline treatment of high-risk COVID-19-positive patients with comorbid pulmonary disease Ther. Adv. Respir. Dis. 14 2020 1753466620951053 10.1177/1753466620951053
116 E S. S Z. M G. Jc K. C K. L M. A Z. Y W. A N.A. A N.M. Doxycycline vs hydroxychloroquine + azithromycin in the management of COVID-19 patients: an open-label randomized clinical trial in sub-saharan Africa (DOXYCOV) Cureus 15 2023 10.7759/cureus.45619
117 Butler C.C. Yu L.-M. Dorward J. Gbinigie O. Hayward G. Saville B.R. Van Hecke O. Berry N. Detry M.A. Saunders C. Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (principle): a randomised, controlled, open-label, adaptive platform trial Lancet Respir. Med. 9 2021 1010 1020 10.1016/S2213-2600(21)00310-6 34329624
118 M R. R D. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions Pharmacol. Rep. : PRO 2011 63 10.1016/s1734-1140(11)70500-x
119 Li S. Liu W. Chen Y. Wang L. An W. An X. Song L. Tong Y. Fan H. Lu C. Transcriptome analysis of cepharanthine against a SARS-CoV-2-related coronavirus Briefings Bioinf. 22 2021 1378 1386 10.1093/bib/bbaa387
120 Rogosnitzky M. Okediji P. Koman I. Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19 Pharmacol. Rep. 72 2020 1509 1516 10.1007/s43440-020-00132-z 32700247
121 Ma W. W L. X C. Discovery of COVID-19 inhibitors targeting the SARS-CoV-2 Nsp13 helicase J. Phys. Chem. Lett. 11 2020 10.1021/acs.jpclett.0c02421
122 Liang D. Li Q. Du L. Dou G. Pharmacological effects and clinical prospects of cepharanthine Molecules 27 2022 8933 10.3390/molecules27248933 36558061
123 G C. J L. H L. H Z. M L. D L. Z M. H G. Z W. X Z. Cepharanthine ameliorates pulmonary fibrosis by inhibiting the NF-κB/NLRP3 pathway, fibroblast-to-myofibroblast transition and inflammation Molecules 28 2023 10.3390/molecules28020753
124 Xia B. Zheng L. Li Y. Sun W. Liu Y. Li L. Pang J. Chen J. Li J. Cheng H. The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19 Front. Pharmacol. 14 2023 1098972 10.3389/fphar.2023.1098972
125 An W. Tian F. Li J. Chen J. Tong Y. N-glycoproteomic profiling revealing novel coronavirus therapeutic targets potentially involved in cepharanthine's intervention Med Nov Technol Devices 16 2022 100156 10.1016/j.medntd.2022.100156
126 Cz C. M X. M P. K G. Jd P. Mr S. W Z. P S. H G. M S. Identifying SARS-CoV-2 entry inhibitors through drug repurposing screens of SARS-S and MERS-S pseudotyped particles ACS Pharmacol. Transl. Sci. 3 2020 10.1021/acsptsci.0c00112
127 L L. Z X. B H. B Z. Y T. C W. L Y. Z Z. L L. K L. Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery Nat. Commun. 15 2024 10.1038/s41467-024-45690-5
128 Ungar G. Freedman L. Shapiro S.L. Pharmacological studies of a new oral hypoglycemic drug Proc Soc Exp Biol Med 95 1957 190 192 10.3181/00379727-95-23163 13432032
129 Dhillon S. Dapagliflozin: a review in type 2 diabetes Drugs 79 2019 1135 1146 10.1007/s40265-019-01148-3 31236801
130 Naderpoor N. Shorakae S. de Courten B. Misso M.L. Moran L.J. Teede H.J. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis Hum. Reprod. Update 21 2015 560 574 10.1093/humupd/dmv025 26060208
131 Madiraju A.K. Qiu Y. Perry R.J. Rahimi Y. Zhang X.-M. Zhang D. Camporez J.-P.G. Cline G.W. Butrico G.M. Kemp B.E. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo Nat. Med. 24 2018 1384 1394 10.1038/s41591-018-0125-4 30038219
132 Cameron A.R. Logie L. Patel K. Erhardt S. Bacon S. Middleton P. Harthill J. Forteath C. Coats J.T. Kerr C. Metformin selectively targets redox control of complex I energy transduction Redox Biol. 14 2018 187 197 10.1016/j.redox.2017.08.018 28942196
133 Madiraju A.K. Erion D.M. Rahimi Y. Zhang X.-M. Braddock D.T. Albright R.A. Prigaro B.J. Wood J.L. Bhanot S. MacDonald M.J. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase Nature 510 2014 542 546 10.1038/nature13270 24847880
134 Scheen A.J. Metformin and COVID-19: from cellular mechanisms to reduced mortality Diabetes Metab. 46 2020 423 426 10.1016/j.diabet.2020.07.006 32750451
135 Rosa I.F. Peçanha A.P.B. Carvalho T.R.B. Alexandre L.S. Ferreira V.G. Doretto L.B. Souza B.M. Nakajima R.T. da Silva P. Barbosa A.P. Photobiomodulation reduces the cytokine storm syndrome associated with COVID-19 in the zebrafish model Int. J. Mol. Sci. 24 2023 6104 10.3390/ijms24076104 37047078
136 Wiernsperger N. Al-Salameh A. Cariou B. Lalau J.-D. Protection by metformin against severe covid-19: an in-depth mechanistic analysis Diabetes Metab. 48 2022 101359 10.1016/j.diabet.2022.101359
137 Xian H. Liu Y. Rundberg Nilsson A. Gatchalian R. Crother T.R. Tourtellotte W.G. Zhang Y. Aleman-Muench G.R. Lewis G. Chen W. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation Immunity 54 2021 1463 1477.e11 10.1016/j.immuni.2021.05.004 34115964
138 Malhotra A. Hepokoski M. McCowen K.C. Shyy Y.-J. J. ACE2, metformin, and COVID-19 iScience 23 2020 101425 10.1016/j.isci.2020.101425
139 Diabetes Metformin and the clinical course of covid-19: outcomes, mechanisms and suggestions on the therapeutic use of metformin - PubMed available online https://pubmed.ncbi.nlm.nih.gov/35370738/
140 Usman A. Bliden K.P. Cho A. Walia N. Jerjian C. Singh A. Kundan P. Duhan S. Tantry U.S. Gurbel P.A. Metformin use in patients hospitalized with COVID-19: lower inflammation, oxidative stress, and thrombotic risk markers and better clinical outcomes J. Thromb. Thrombolysis 53 2022 363 371 10.1007/s11239-022-02631-7 35041121
141 Kow C.S. Hasan S.S. Mortality risk with preadmission metformin use in patients with COVID-19 and diabetes: a meta-analysis J. Med. Virol. 93 2021 695 697 10.1002/jmv.26498 32902868
142 Yang W. Sun X. Zhang J. Zhang K. The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus Diabetes Res. Clin. Pract. 178 2021 108977 10.1016/j.diabres.2021.108977
143 Ct B. Jb B. D L. J N. Ma P. K C. H B. B A. Jd H. C T. Outpatient treatment of covid-19 with metformin, ivermectin, and fluvoxamine and the development of long covid over 10-month follow-up medRxiv : the preprint server for health sciences 2022 10.1101/2022.12.21.22283753
144 Bramante C.T. Huling J.D. Tignanelli C.J. Buse J.B. Liebovitz D.M. Nicklas J.M. Cohen K. Puskarich M.A. Belani H.K. Proper J.L. Randomized trial of metformin, ivermectin, and fluvoxamine for covid-19 N. Engl. J. Med. 387 2022 599 610 10.1056/NEJMoa2201662 36070710
145 Mast N. Anderson K.W. Johnson K.M. Phan T.T.N. Guengerich F.P. Pikuleva I.A. In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds J. Biol. Chem. 292 2017 12934 12946 10.1074/jbc.M117.794909 28642370
146 Franks M.E. Macpherson G.R. Figg W.D. Thalidomide Lancet 363 2004 1802 1811 10.1016/S0140-6736(04)16308-3 15172781
147 Cheung K.S. Chan E.W. Seto W.K. Wong I.C.K. Leung W.K. ACE (Angiotensin-Converting enzyme) inhibitors/angiotensin receptor blockers are associated with lower colorectal cancer risk: a territory-wide study with propensity score analysis Hypertension 76 2020 968 975 10.1161/HYPERTENSIONAHA.120.15317 32623923
148 Perry J.M. Tao F. Roy A. Lin T. He X.C. Chen S. Lu X. Nemechek J. Ruan L. Yu X. Overcoming wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells Nat. Cell Biol. 22 2020 689 700 10.1038/s41556-020-0507-y 32313104
