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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 5  |  Page : 19-24

Supplementary medicines and antioxidants in viral infections: A review of proposed effects for COVID-19


Department of Pharmacy, Faculty of Pharmacy, Girne American University, Mersin 10, Turkey

Date of Submission10-Jun-2020
Date of Acceptance15-Jul-2020
Date of Web Publication13-Aug-2020

Correspondence Address:
Dr. Anmar Al-Taie
Department of Pharmacy, Faculty of Pharmacy, Girne American University, 99428 Kyrenia, North Cyprus, Mersin 10
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_132_20

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  Abstract 


The use of supplementary medicines and antioxidant drugs is not restricted to just preventing deficiencies or inhibiting the production of free radicals. There are a plethora of indications that supplements and antioxidants may suffice for and they include viral infections. Hence, the importance of understanding the potential efficacy and activity of supplements and antioxidants in the management of viral infections, specifically the coronavirus disease, cannot be overemphasized. This article aims to explain what supplements and antioxidants are, their proven efficacy in the management/treatment of the existing viral infections, and the possibility of their usefulness in the management/treatment of coronavirus disease. The coronavirus pandemic affected almost 10 million people worldwide and has contributed to hundreds of thousands of deaths, while research is ongoing for the development of a vaccine and if possible, a cure, it is important to explore every available option including traditional medicines, antioxidants, and complementary and supplementary medicines. A comprehensive review of this study was achieved by evaluating recent existing literature on the activity of supplements and antioxidants against viral infections and the coronavirus disease. It was discovered that although Vitamins C and D, zinc, and elderberry have antiviral properties and may be effective in managing preexisting viral infections, their activity against COVID-19 is still unknown and speculative. Therefore, there are no recent guidelines provided for the treatment of COVID-19 that recommend dietary supplements and/or antioxidants as pharmacological interventions.

Keywords: Antioxidants, COVID-19, SARS-CoV-2, supplementary medicines, viral infections


How to cite this article:
Al-Taie A, Victoria AO. Supplementary medicines and antioxidants in viral infections: A review of proposed effects for COVID-19. Biomed Biotechnol Res J 2020;4, Suppl S1:19-24

How to cite this URL:
Al-Taie A, Victoria AO. Supplementary medicines and antioxidants in viral infections: A review of proposed effects for COVID-19. Biomed Biotechnol Res J [serial online] 2020 [cited 2022 Oct 7];4, Suppl S1:19-24. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/19/292081




  Introduction Top


Clinical implications of human coronaviruses

Human coronaviruses (HCoVs) are considered inconsequential pathogens, widespread in humans and cause respiratory, enteric, hepatic, and neurologic diseases. They are large, enveloped, and positive-strand RNA viruses that can be divided into four genera: alpha, beta, delta, and gamma, of which alpha- and beta-CoVs are known to infect humans as surface spike (S) glycoprotein is critical for binding of host cell receptors and represent a key determinant of host range restriction.[1] These viruses account for 10%–30% of upper respiratory tract infections in adults, including the common cold. Coronaviruses are ecologically diverse with the greatest variety seen in bats, suggesting that they are the reservoirs for many of these viruses.[2] In the last two decades of the 21st century, two highly pathogenic HCoVs viruses were reported causing severe acute respiratory syndrome-coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 that emerged from animal reservoirs and causing global epidemics with high morbidity and mortality.[3]

Until recently, HCoVs received relatively little attention due to their mild phenotypes in humans. However, the new public health crises threatening the world was observed with the emergence and spread of 2019 novel coronavirus (2019-nCoV) or mentioned as the SARS-CoV-2, firstly detected in Wuhan, Hubei province, China, in late December 2019. The virus is suspected to originate in bats and is transmitted to humans through yet-unknown intermediary animals with consequent high fatality rates. SARS-CoV-2 appears to be much more transmissible than its two genomes SARS-CoV and MERS-CoV. The incubation period ranges from 2 to 14 days, and the virus persists for days on un-cleaned surfaces.[1],[4],[5],[6]

Transmission of the disease is by human-to-human transmission through inhalation or contact with infected droplets even in the presence of isolation efforts as in health-care settings.[7],[8],[9],[10] Fecal–oral transmission could be another mode of this viral infection as SARS-CoV-2 RNA was also detected and isolated in the stool specimen. Moreover, asymptomatic persons could also be considered potential sources of 2019-nCoV infection.[11],[12]

The cell entry and the predominant human receptor of this viral infection are via the angiotensin-converting enzyme 2 (ACE2) receptors which are found primarily in the lower respiratory tract, rather than in the upper airway. In this way, the SARS-CoV-2 first infects the lower airways and then binds to ACE2 on alveolar epithelial cells. It has been observed that SARS-CoV-2 is a potent inducer of inflammatory cytokine production, causing cytokine storm/cascade; activating immune cells; and inducing the secretion of inflammatory cytokines and chemokines into pulmonary vascular endothelial cells, which are considered the postulated mechanism for organ damage.[5],[13],[14]

Patients with SARS-CoV-2 most notably present with the clinical symptoms of dry cough, dyspnea, fever, sore throat, breathlessness, fatigue, malaise, and bilateral lung ground-glass opacity or filtrates on computed tomography imaging. A higher proportion of cases presented with gastrointestinal symptoms, including watery diarrhea and nausea. Cases could be progressed to pneumonia, acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, and shock. Older patients with medical comorbidities as a result of weaker immune function were the most susceptible to COVID-19 incidence and higher fatality rates compared to children who are infrequently affected and with no death cases.[4],[5],[15]

Effects of certain antioxidants on the pathogenesis of viral infections

N-Acetyl-l-cysteine

N-Acetyl-l-cysteine (NAC), the acetylated derivative of the amino acid l-cysteine, is considered a rich source of thiol groups. It is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers to attenuate reactive oxygen species production.[16] Furthermore, during influenza virus infection, it inhibits viral proliferation, induction of apoptosis, and gene expression for pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6, IL-8, RANTES, and interferon (INF)-inducing protein (IP)-10.[17],[18]

Earlier reports found that combined administration of NAC with antiviral drugs, such as oseltamivir or ribavirin, might synergistically be capable of reducing the lethal effect and mortality of influenza virus infection and could improve the treatment of influenza virus infections.[19] Meanwhile, administration of NAC appears to reduce symptomatic conditions associated with influenza virus infection. A study by De Flora et al.[20] found that administration of NAC (600 mg) orally twice daily for 6 months decreased both the incidence and severity of influenza-like episodes and the length of bed time and also significantly reduced the incidence of clinically apparent disease. In another clinical study by Lai et al.,[21] the authors reported that a combination treatment of continuous intravenous (IV) infusion of high-dose NAC at 100 mg/kg combined with oseltamivir improved viral pneumonia caused by the novel influenza A (H1N1) virus infection and septic shock. Reduced GSH displays anti-influenza activity in an experimental study through inhibition of viral macromolecule synthesis and proliferation resulting in a decreased viral titer in cultures of airway epithelial cells.[22] However, other studies still reported questionable antioxidant and antiviral activities of NAC to reduce viral load and inhibit viral replication against influenza A strains (H3N2 and H5N1) or as an antioxidant in influenza against other acute viral respiratory tract infections due to a weak protective effect of NAC alone. Moreover, high-dose NAC administration is not recommended in healthy populations as it might act as a pro-oxidant and might lower GSH and increase the amount of oxidized GSH, making hard to find a conclusion without larger trials.[18],[23]

Ascorbic acid

Ascorbic acid scavenges superoxide anion in high dosages. It has direct virucidal activities, inhibits the proliferation of influenza virus, and reduces the expression of viral antigens and the cellular viral load alongside restoring other cellular antioxidants, including tetrahydrobiopterin and α-tocopherol. Earlier studies also reported that ascorbic acid has immunomodulatory properties, concentrated in leukocytes, lymphocytes, and macrophages, which improve chemotaxis, enhance neutrophil phagocytic capacity and oxidative killing, and support lymphocyte proliferation and function. Ascorbic acid significantly recovered the diminished mitochondrial membrane potential and decreased the gene expression of pro-inflammatory cytokines.[24],[25]

Ascorbic acid appears to have clinical benefits in patients with acute viral infections, including HCoV, based on several physiological properties that make it an attractive option to both prevent viral infections and treat the resulting severe illness through its immune-modulating property related to the increased production of α/β INFs and downregulating the production of pro-inflammatory cytokines.[26],[27] A controlled trial found that ascorbic acid intake at a dose of 300 mg/day reduced the incidence of pneumonia and hospital stay compared to the control group, suggesting its possible beneficial role to ameliorate viral-induced oxidative injury and prevent influenza virus infection.[28] However, there is limited evidence-based clinical data to support the routine use of Vitamin C for the prevention of viral infections, including the common cold despite these theoretical benefits.[29] The therapeutic outcomes related to the use of ascorbic acid might be different for COVID-19 as it is caused by a novel different genome sequence.[30] On the other hand, recent clinical trials revealed that IV Vitamin C 50 mg/kg every 6 h for 96 h statistically showed a difference in 28-day all-cause mortality versus placebo.[31] Furthermore, a clinical study conducted in China on patients with moderate-to-severe COVID-19 found successful treatment with large doses of IV Vitamin C (10,000–20,000 mg/day), however, such kind of evidence is lacking more details and not fully reported due to several limitations, particularly related to the toxic effects of ascorbic acid on the stomach and kidneys.[32]

Effects of supplementary medicines on the pathogenesis of viral infections

Vitamin D

Vitamin D is a fat-soluble vitamin, found in foods and dietary supplements such as Vitamins D2 (ergocalciferol) and D3 (cholecalciferol). These two diverse kinds of Vitamin D require further metabolism into the active form, calcitriol.[33] The general metabolism and actions of Vitamin D are well known, but the idea which suggests its role in reducing the risk of microbial infections might be related to the fact that the peak influenza cases in the winter are associated with a reduced exposure to the sun, leading to reduced synthesis and serum levels of Vitamin D, which in turn affects immune function.[34]

The complex mechanisms by which Vitamin D supports immune function might include maintain cell physical barrier integrity, maintain tight junctions, gap junctions, adherens junctions and prevent disturbance of the junction integrity by the viruses and other infectious microorganisms. It also maintains cellular natural immunity and adaptive immunity by reducing the cytokine storm and suppressing responses mediated by the T helper cell type 1 (Th1) induced by the innate immune system that generates pro-inflammatory cytokines, such as tumor necrosis factor, IL-2, and INF-gamma, both are considered as potent predictors of poorer outcome in patients with severe viral infections, including COVID-19. Meanwhile, it increases the expression of anti-inflammatory cytokines by the T helper type 2 (Th2) cells, which helps enhance the indirect suppression of Th1 and promotes induction of the T regulatory cells. In addition, it enhances antimicrobial peptide expression including human cathelicidin, LL-37, and shifts response of cells involved with innate and adaptive immunity, such as dendritic and T-cells, toward a more anti-inflammatory behavior[35],[36],[37],[38],[39],[40] Moreover, the increased peptide induction of cathelicidins exhibits direct antimicrobial activities against enveloped and nonenveloped viruses and increases the microbial killing capacity by perturbing their cell membranes and neutralizing the biological activities of endotoxins.[41] Accordingly, the replication of many viruses is reduced, including influenza A virus and rotavirus.[42]

Earlier evidence showed that multiple factors could also contribute to low Vitamin D level, including advance age related to less time duration available for sun exposure and reduced production of Vitamin D as a result of lower levels of 7-dehydrocholesterol in the skin, thereby increasing case fatality rates with age by COVID-19. Besides, use of some medicines might reduce serum 25(OH)D levels by activating the pregnane-X receptors such as antiepileptics; antineoplastics; antibiotics; anti-inflammatory agents; and antihypertensive, antiretroviral, and endocrine drugs.[43],[44],[45] Additionally, earlier studies reported that acute viral respiratory infection, community-acquired pneumonia, and ARDS are associated with low Vitamin D levels.[46],[47] Accordingly, supplementation with 4000 IU/day of Vitamin D decreased dengue virus infection and reduced the risk of acute respiratory tract infections with little incidence of serious adverse events.[48],[49]

Several reports have proposed protective effects obtained from treatment with Vitamin D to reduce the risk of viral infection and aimed to evaluate the relationship between Vitamin D levels and COVID-19 prognosis. These effects might be related from enhancing the expression of genes related to antioxidation (GSH reductase and glutamate-cysteine ligase modifier subunit), thereby increasing the production of GSH alongside attenuating the immunological sequelae responsible for the fulminant respiratory effects from COVID-19 infection, such as prolonged INF-gamma response 4, and persistent IL-6 elevations.[50] Moreover, some reports claimed a very high prevalence of hypovitaminosis D in patients with COVID-19, suggesting the IV administration of calcitriol along with avoiding suboptimal sun exposure and food, or dietary supplementation, to ensure achieving adequate Vitamin D levels in COVID-19 management.[50] Nevertheless, these studies are still lacking definite therapeutic outcomes specific to COVID-19 infection, but could be of benefit regarding other respiratory tract infections.

For overall general health in the face of the impending COVID-19 epidemic and in the setting of a high prevalence of Vitamin D deficiency, patients should continue to follow recommendations for daily Vitamin D consumption particularly for vulnerable groups such as those with comorbid or compromised immune function and to be consistent with the recommended daily allowance, at the same time avoiding excessive doses of Vitamin D in hopes of preventing or treating COVID-19.

Zinc

Zinc is an important dietary trace mineral that can influence the functions of the immune cells.[51] It activates many enzymes and coenzymes that are involved in vital cellular functions, such as energy metabolism, DNA synthesis, RNA transcription, and many zinc-finger transcription factors.[52],[53],[54]

Earlier evidence suggests that the amount of ionic zinc present at the site of infection of the oral and nasal mucosa considerably correlated with the viral load. It inhibits viral replication and attachment to the nasopharyngeal mucous and modifies the effects of several respiratory pathogens, including rhinovirus, influenza virus, respiratory syncytial virus, and SARS-CoV.[55],[56],[57],[58],[59]

Meanwhile, zinc supplementation could increase CD4+ CD3+ cells in a higher proportion in the peripheral blood with enhanced T-cell-mediated immunity and increased monocyte resistance to apoptosis via suppressing the activation of caspase 3. It could also induce the production of antiviral INF which exerts antiviral effects and suppresses inflammatory events, including against H1N1 influenza virus infection.[60],[61],[62],[63]

Zinc supplementation reduces viral load in viral hepatitis C and enhances the response to antiviral treatment. In addition, it significantly improves both cutaneous and genital warts that are induced by human papillomavirus and also significantly reduces the prevalence of pneumonia.[64],[65],[66]

On the other hand, zinc deficiency can impair host-defense systems and increase the susceptibility to many different viral infections through reducing lymphocyte counts, impairing T and B lymphocyte functions with low IgG production, and lowering the phagocytic ability of macrophages, leading to an increased rate of infection.[51],[67],[68] Furthermore, genetic disorders related to zinc malabsorption are associated with immune system dysregulation and higher rate of severe viral infection.[69]

Recent reports related to the pandemic emergence of COVID-19 claimed a possible therapeutic role of zinc supplementation against this viral infection related to the aforementioned antiviral mechanisms of actions and proposed protection against the COVID-19 infection. This could be related to the fact that this viral infection also takes a similar route to get entry to the body, including the nasal cavity and other parts of the respiratory tract where the presence of a higher concentration of zinc at and around the site of infection would reduce the intensity of the COVID-19 infection.

Despite the lack of reputable data, in a pandemic situation, a courageous attempt for zinc supplementation to reduce viral disease burden is worth trying, and this kind of trial area needs further clinical validation suggesting zinc as part of a regimen to treat COVID-19.[70] More importantly, oral zinc supplementation is likely to be safe up to 40 mg/day in adults and less likely to induce human toxicity, but safety is less certain with greater doses that are implicated in common cold management, and higher doses above 200–400 have shown to induce adverse effects, including nausea, vomiting, epigastric pain, lethargy, and fatigue.[71]

Melatonin

Melatonin is a neurohormone primarily produced by the pineal gland secreted into the blood by the individual's rhythm dark–light cycle. Its peak plasma concentrations reach during the night time in the absence of light proportionally to the duration of darkness.[72] Melatonin has many antioxidant properties and binds up to ten free radicals per molecule, while its antioxidant effects are correlated with increased activity of superoxide dismutase, GSH peroxidase, reductase, and catalase.[73],[74] Recent reports have proposed that bats of the genus Rhinolophus could be the possible natural carriers of SARS-CoV-2 as it is 96% identical to another bat's coronavirus Bat-SARSr-CoV RaTG13, making the bats suffering minimal to no symptoms with mechanisms of antiviral resistance remaining mostly on the level of hypothesis.[13],[75],[76] The concentration of melatonin in bats is much higher reaching up to 500 pg/ml at the night time in comparison to humans. On the other hand, there is a daily variation in plasma melatonin concentrations in young compared to elderly populations (7 pg/ml vs. 2 pg/ml).[72],[77] Regarding the recent emergent pandemic SARS-CoV-2, this viral infection is age related, with few cases recorded in people under the age of 20. Accordingly, a hypothesis could be postulated that increased sensitivity to SARS-CoV-2 in the elderly populations is due to their reduced plasma melatonin concentrations, suggesting the possible administration of melatonin therapy to partially alleviate age-related comorbidities exacerbating SARS-CoV-2 infection and reducing its mortality rate. Recent evidence suggests that melatonin is reported as a pyroptosis inhibitor. This is attributed to the reports that SARS-CoV-2 causes severe lung pathology by inducing the production of pyroptosis, a highly inflammatory form of programmed cell death leading to lymphopenia which retards an effective immune response to the virus.[78],[79],[80] Moreover, the societal crisis related to SARS-CoV-2 produces massive and prolonged stress and anxiety, causing a severe negative effect on the immune system and reducing the number and activity of protective immune cells, stimulating immunosuppressive mechanisms, and suppressing the ability to resist this viral infection.[81]

Meanwhile, sleep deprivation and chronic insomnia significantly impaired the production of melatonin. This reduces the phagocyte activity and lymphocyte proliferation, reduces the levels of anti-inflammatory IL-10, reduces the levels of neutrophil phagocytosis, lowers the levels of NADPH oxidase and CD4+ T cells, and increases the number of pro-inflammatory cytokines and oxidative stress, which are correlated with the nocturnal peak level of melatonin and are necessary for anti-infective defense and proper vaccination response.[82],[83],[84]

In addition, during the crisis of SARS-CoV-2, melatonin could be used as an adjuvant to many drugs such as antiviral drugs to boost the pharmacological therapy and reduce their side effects as melatonin has been observed to reduce some of the side effects related to antiviral drugs.[85] Furthermore, another therapeutic benefit that emanates from melatonin application could be related in combination with methylprednisolone with greater efficacy to relieve edema, which contributes significantly to lung dysfunction and failure during the SARS-CoV-2 infection.[86] Nevertheless, there is still a need for clinical trials to verify the effectiveness of melatonin as an adjuvant therapy to be used in combination with other drugs for SARS-CoV-2 infection because the acute toxicity of melatonin even at high doses, such as 1–6.6 g/day administered for 30–45 days, is reported to be very low.[87]


  Conclusion Top


This review provides an insight into the current speculations on the effectiveness of supplements and antioxidants in the treatment of COVID-19. Literature relating to this topic is rapidly growing and hopefully, these would help in the discovery of ideal supplements and antioxidants that may be useful in pharmacotherapy. Hence, when the pandemic ends, access to viable vaccines and supplements would lead to positive health, social, and economic impact.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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