Research Proposal
DOI:10.6084/m9.figshare.15153186 License CC BY 4.0
Authors and Affiliation:
Amr Kamel Khalil Ahmed - Director of the tuberculosis program Ghubera, public health department, First health cluster, Ministry of Health, Riyadh, Saudi Arabia
ORCiD: https://orcid.org/0000-0003-3477-236X
Mahmoud Elkazzaz - Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt
ORCiD: https://orcid.org/0000-0003-3703-520X
Michelle Carole Orzechowski - CEO of Coronavirus Corporation Epidemiology, Research, and Development, - Vaccines/Medications/Lab Testing, Lutz, United States of America
ORCiD: https://orcid.org/0000-0002-8541-8726
Project Title: The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C and Vitamin D for the potential Symptom Reducer, Prevention, and Treatment for Coronavirus Disease 2019 (COVID-19)
These products are unapproved new drugs not being sold in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 2pt1 U.S.C. § 355(a). Furthermore, these products are not misbranded drugs under section 502 of the FD&C Act, 21 U.S.C. § 352. The introduction or delivery for introduction of these products into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act, 21 U.S.C. § 331(a) and (d). [1]
Hypotheses:
The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C, and Vitamin D when taken together may Inhibit the Viral Replication of Anti-Cytokine Storm and an Antiviral against RNA Viruses like Coronavirus Disease 2019 (COVID-19) by using the formulations including Zinc; Zinc Ionophores (Quercetin); Bromelain, EGCG, Retinoic Acid, Vitamin C and Vitamin D. Zinc Ionophores possibly enhance transport of Zinc into the Cells to effect Intra-Cellular Zinc levels and potentially impair intracellular replication of Coronavirus Disease 2019 (COVID-19). [12]
Zinc regulates Adaptive Immune Cell Functions with High levels of Intracellular pH as RNA-dependent and RNA polymerase decreases the replication of RNA viruses like COVID-19.
Quercetin has chelate Zinc Ions and acts as a Zinc Ionophore.
Bromelain activates Natural Killer Cells and the production of Granulocyte-Macrophage Colony Stimulating Factor, Interleukin-2, and Interleukin-6 decreases the activation of T-helper cells.
EGCG can suppress ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2, which mediate cell entry of the virus.
Retinoic Acid has a characteristic of antiviral, Immunity induction, ACE2 upregulation or downregulation, and anti-clotting.
Vitamin C has Enzymatic Co-Factor for Hormone Production, Collagen Synthesis, and Immune Potentiation.
Vitamin D regulates the Inflammatory Cytokine Response. Vitamin D deficiency has been associated with increased COVID-19 mortality and is commonly confounded by increasing age, obesity, diabetes, darker skin tones, and lack of fitness.
Introduction:
Zinc alone is a potent inhibitor of viral replication. Zinc in the combination with Quercetin potentially synergistic in reducing viral replication since Quercetin is potentially a Zinc Ionophore facilitating intracellular entry and inhibition of intracellular viral replication.
Zinc in the combination with Quercetin can access the DNA cellular layer and stop SARS-CoV-2 from replicating RNA cells, potentially resetting replicated cells, Treating the Coronavirus disease 2019 (COVID-19).
Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily as supplements for 3 to 5 days were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis through restraining from hyper-inflammation and cytokine storm. Randomized clinical trials are needed in the future to ensure the efficacy of quercetin, bromelain, zinc, and ascorbic acid combination. [11.2]
In addition to proper PPE and the COVID-19 vaccination, The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C, and Vitamin D may be an effective Symptom Reducer for Coronavirus Disease 2019 (COVID-19) [14]
On 09/30/2021 The Center for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee will meet. [15]
The pathogen, a novel coronavirus (SARS-CoV-2), was identified by local hospitals using a surveillance mechanism for "pneumonia of unknown etiology" that was established in the wake of the 2003 SARS outbreak to allow timely identification of novel pathogens. The immune system plays a critical role in protecting the human body from infectious diseases. T-cell counts are reduced significantly in COVID-19 patients, and the surviving T-cells appear functionally exhausted. Non-ICU patients with total T cell counts lower than 800/μ L may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition. Further research on the severity of comorbidities and all medication received by the patients is mandatory to shed light on these associations. [11]
The Role of Zinc
Since the discovery of the first reported case with zinc - deficiency in Iran by Prasad et al. in 1961 we have learned a lot about Zinc, and we have much more left to learn. Zinc is the second most abundant common trace mineral in the human body, with vital biological functions from cell growth and development to cell homeostasis and immune response. Mechanical ventilation is a necessary intervention to support patients with lung injury and acute respiratory distress syndrome (ARDS) but can also exacerbate injury through mechanical stress-activated signaling pathways. It is shown that stretch applied to cultured human lung cells, and mouse lungs in vivo induce robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by injurious mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF- We further show that dietary zinc- deficiency in mice potentiates ventilator-induced lung injury, and that plasma zinc levels were significantly reduced in human patients with ARDS compared to healthy and non-ARDS ICU controls. [11]
Zinc sulfate 220 mg (50 mg elemental zinc) can be taken orally per day. [3]
Zinc: It May have some anti-viral properties. Doses of 15-30 mg of zinc per day are presumed to be safe, short-term, for one to two weeks. Zinc can interact with other medications (antibiotics and antivirals), and long-term use of high doses of zinc can cause copper deficiency. [13]
The Role of Quercetin
A natural flavonoid molecule that is distributed broadly in many fruits and vegetables including red onion, cranberry, kale, tomatoes, Hungarian wax, and watercress. It was revealed in previous studies that quercetin has an anti-inflammatory and anti-hypersensitivity effect by preventing pro-inflammatory prostaglandins and leukotrienes through inhibiting cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, therefore; quercetin was used as an extract in various trials to treat different infectious and non-infectious diseases. In addition, quercetin showed to reduce tumor necrosis factor-alpha (TNF-α) production with chronic inflammation. Reduction in the ratio of CD4 + CD8 + T cells and suppression of macrophages, dendritic, mast cells, and interleukin-6 (IL-6) levels were revealed after a specific tissue was treated with quercetin in pre-clinical studies. Besides, quercetin is expected to have antiviral activity by acting as a zinc chelator and as a zinc ionophore as well. However, because most of these studies were done by using quercetin in-vitro with high concentration and in-vivo studies cannot use the same doses; it's showed minimum effect during clinical trials. The available data clarifies that quercetin is a very safe molecule and used as a nutritional supplement with a dose reached 1500 mg divided per day. [11.2]
Quercetin (also known as 3,5,7,3',4' pentahydroxyflavone, is a widely distributed plant flavonoid, found in several vegetables, leaves, seeds, and grains, where it is conjugated with residual sugars to form Que glycosides. Studies suggest that Quercetin supplementation may promote antioxidant, anti-inflammatory, antiviral, and immune protective effects. Quercetin has been studied in various types and models of viral infection due to its promising antiviral effects in inhibiting polymerases, proteases, reverse transcriptase, suppressing DNA gyrase, and binding viral capsid proteins. Recently, Quercetin has been shown to inhibit in vitro production of cyclooxygenase (COX) and lipoxygenase (LOX) which are typically induced by inflammation. The anti-inflammatory effect has been supported by in vivo experiments as well. Examples of Quercetins inhibitory qualities include the significant blocking of pro-inflammatory cytokines in cultured fibroblasts. 10 𝜇M Quercetin downregulated the production of COX-2, the Nuclear Factor kappa B (NF-𝜅B), and NO. 10–25 𝜇M Quercetin inhibited the level of NO and TNF-𝛼. Other properties of 50 and 100 𝜇M Quercetin include reducing the secretion of IL6 and TNF-𝛼 in LPS-stimulated RAW 264.7 microphages, while at 25 and 50 𝜇M it proved to be the most efficient blocker of TNF-𝛼 secretion in macrophages. Finally, at low concentrations, Quercetin (less than 50 𝜇M) also stimulated anti-inflammatory cytokine IL-10. Similarly, 25𝜇M Quercetin blocked IL-1𝛽, IL-6, IFN-𝛾, and TNF-𝛼 secretion in human whole blood induced by LPS. Quercetin can also inhibit pro-inflammatory cytokines. A six-week regiment of 150 milligrams of Quercetin taken daily by human subjects significantly lowered cytokine TNF-𝛼 serum concentrations. Quercetin effectively inhibited LPS-induced DC activation by reducing the production of pro-inflammatory cytokines/chemokines and the expression levels of MHC class II and costimulatory molecules. In addition, Quercetin uniquely blocked endocytosis by Dendritic Cells DCs, and the LPS-induced DC migration was diminished by Quercetin treatment. Quercetin has been shown clinically to block human mast cell cytokine release, possibly inhibiting the clinical manifestation of a cytokine storm. Severe COVID-19 disease progression is associated with increased levels of C-Reactive protein, D-Dimer, Ferritin, IL-2, and IL-6. Quercetin has been shown in studies to reduce all these markers. Balancing systemic iron levels within narrow limits is critical for maintaining human health. There are no known pathways to eliminate the excess iron from the body and therefore iron homeostasis is maintained by modifying dietary absorption so that it matches daily obligatory losses. Several dietary factors can modify iron absorption. Polyphenols are plentiful in the human diet and many compounds, including Quercetin's most abundant dietary polyphenol, are potent iron chelates. Quercetin is a zinc ionophore and could have a similar antiviral activity to chloroquine but is described as a safe choice in the treatment of viral infections. [11.3]
Quercetin is a polyphenol that has a theoretical mechanism of action that could reduce the activity of a SARS-CoV-2 entry through the ACE2 receptor, inhibit viral proteases via conveyance of Zinc, and attenuate inflammatory responses mediated through interleukin-6. The mechanisms of action favorably affect viral replication and immune response, so it is conceivable that this agent taken in combination with others discussed could play an assistive role in reducing early viral amplification and tissue damage. The suggested dose of quercetin is 500 mg BID. [10]
Quercetin: A naturally occurring antioxidant/flavonoid that may have benefits for allergic rhinitis and possibly in exercise-induced respiratory infections. Quercetin may interact with some antibiotics known as fluoroquinolones (ciprofloxacin, levofloxacin) and could also interact with other medications that are metabolized through your liver system known as the cytochrome p450 enzyme system (3A4 and 2C9). These drugs may include warfarin, midazolam, cyclosporine, drugs known as the "statins" (atorvastatin, pravastatin, rosuvastatin, simvastatin), medications known as non-steroidal anti-inflammatory drugs (ibuprofen, diclofenac, naproxen), tamoxifen, and possibly losartan. There is also a possibility it may interact in those individuals with hypothyroidism. Use caution in these patients. Doses of 500 mg twice daily have been studied and shown to be possibly safe for up to twelve weeks. [13]
The Role of Bromelain
Protein enzyme is found mainly in the stem of the pineapple plant. The bioavailability of bromelain was high through the oral route and was safe even when consumed more than 11 grams per day. In vitro studies showed that bromelain exerts anti-inflammatory effects through reducing bradykinin serum and modulating the expression of some genes related to inflammation. Three genes related to inflammation including TLR4, TNF-α, and IL-8 were found to be less expressed after bromelain treatment. On the other hand, PPARγ gene expression was elevated after treatment with bromelain. Therefore, bromelain may have a role in reducing inflammations during various disorders and may be used in combination with other analgesics and anti-inflammatory drugs. Since the inflammatory status of patients during COVID-19 may lead to severe consequences and even death if not prevented or treated adequately; it is important to ensure high-quality care to patients and provide evidence-based prophylaxis and treatment. [11.2]
Bromelain activates the inflammatory mediators, including interleukin (IL)-1β, IL-6, interferon (INF)-γ, and tumor necrosis factor (TNF)-α in mouse macrophage and human peripheral blood mononuclear cells (PBMC) (Barth). These results indicated that bromelain potentially activates the healthy immune system in association with the rapid response to cellular stress. Conversely, bromelain reduces IL-1β, IL-6, and TNF-α secretion when immune cells are already stimulated in the condition of inflammation-induced overproduction of cytokines. It was also found that bromelain upregulated p53 and Bax with consequent activation of Caspase 3 and Caspase 9 with a concomitant decrease in BCL2. Marked inhibition of cyclooxygenase 2 (COX2) expression with inactivation of NF Kappa B by blocking phosphorylation and degradation of IK B α were blocked by bromelain. Furthermore, bromelain ameliorated extracellular signal of regulated protein kinase ERK1/2, P38 mitogen-activated protein kinase MAPK and Akt activity. So, it modulated defective cellular signaling cascades. Bromelain prevents or minimizes the severity of angina pectoris and transient ischemic attack (TIA). It is useful in the prevention and treatment of thrombophlebitis. It may also break down cholesterol plaques and exert a potent fibrinolytic activity. A combination of bromelain and other nutrients protects against ischemia/reperfusion injury in skeletal muscle. Bromelain influences blood coagulation by increasing the serum fibrinolytic ability and by inhibiting the synthesis of fibrin, a protein involved in blood clotting. [11.3]
Bromelain: An enzyme that comes from the stalk of the pineapple. It has been shown to have some activity in reducing symptoms for acute sinusitis2. It can, however, interact with blood thinners such as warfarin, and also certain antibiotics such as tetracyclines. Use with caution for these agents [13]
The Role of EGCG
Via activating Nrf2, can suppress ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2, which mediate cell entry of the virus. Through inhibition of SARS-CoV-2 main protease, EGCG may inhibit viral reproduction. EGCG via its broad antioxidant activity may protect against SARS-CoV-2 evoked mitochondrial ROS (which promote SARS-CoV-2 replication) and against ROS burst inflicted by neutrophil extracellular traps. By suppressing ER-resident GRP78 activity and expression, EGCG can potentially inhibit the SARS-CoV-2 life cycle. EGCG also shows protective effects against 1) cytokine storm-associated acute lung injury/acute respiratory distress syndrome, 2) thrombosis via suppressing tissue factors and activating platelets, 3) sepsis by inactivating redox-sensitive HMGB1, and 4) lung fibrosis through augmenting Nrf2 and suppressing NF-κB. These activities remain to be further substantiated in animals and humans. The possible concerted actions of EGCG suggest the importance of further studies on the prevention and treatment of COVID-19 in humans. These results also call for epidemiological studies on the potential preventive effects of green tea drinking on COVID-19. [12]
The Role of Retinoic Acid
Angiotensin-converting enzyme (ACE2) protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells. Viral spike protein-binding with ACE2 down-regulates it. As ACE2 is known to protect the lung from injuries, SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage. In this Review, we use established and emerging evidence based on the findings of previous studies and researches to propose a testable hypothesis that a Combination of chemopreventive agents (All-Trans Retinoic acid and Tamoxifen) can be tested to prevent inflammatory complications in severe acute respiratory syndrome coronavirus 2 infections via two mechanisms by inhibiting bradykinin B1, B2 receptors expression and upregulating the depleted ACE2 in COVID-19. Bradykinin B1 receptors are not expressed under physiological conditions but are induced under inflammatory conditions. Here we hypothesize that permanent attack and invasion of COVID-19 to lung epithelial cells via binding to ACE2 leads to tissue injury and inflammation and that increases BK levels and BK-B2-receptor (B2R) stimulation A study reported that tissue injury and inflammation increases BK levels and BK-B2-receptor (B2R) stimulation. We suggest that Bradykinin mediates and induces lung injury, pro-inflammatory cytokines, and inflammation likely precipitates life-threatening respiratory complications in COVID-19. Further experiments showed that BK treatment stimulated IL-6 production On the other hand a study reported that cells treated with Retinoic acid and Tamoxifen for 48 h significantly decreased the BK-B2 receptor protein levels (70.3 ± 0.6% vs. 100% of control, P < 0.05). Retinoids inhibit bradykinin B1 receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects. In addition, retinoic acid is known to possess in vivo anti-inflammatory, antiplatelet and fibrinolytic activities. A study investigated the in vitro thrombin and platelet aggregation inhibitory activities of retinoic acid and retinaldehyde. Retinoic acid, retinaldehyde, and retinol exhibited potent inhibition of thrombin, with IC50 values of 67μg/ml, 74μg/ml and 152μg/ml, respectively for the inhibition of thrombin (Sigma); and 49μg/ml, 74μg/ml and 178μg/ml, respectively for the inhibition of thrombin (plasma). Amongst vitamin A and its derivatives, retinoic acid showed the highest inhibition of both forms of thrombin. Besides the effectiveness of TAM on cancer cells, it also has other effects on numerous microbes including parasites, fungi, bacteria, and some viruses such as the Ebola virus and human immunodeficiency virus (HIV). Furthermore, Tamoxifen can block the action of interleukin 6 and inhibit neutrophils. A study demonstrated that tamoxifen has side effects associated with neutropenia. Since tamoxifen can cause neutropenia and subsequently influence the neutrophil-to-lymphocyte ratio (NLR) value In addition it has an anti-malarial effect similar to chloroquine In conclusion. [16]
The Role of Vitamin C
Exerts its antiviral properties by supporting lymphocyte activity, increasing interferon-α production, modulating cytokines, reducing inflammation, improving endothelial dysfunction, and restoring mitochondrial function. There are also suggestions that Vitamin C may be directly viricidal. The in vitro effects constitute a reflection of both the supra-physiological concentrations of ascorbate and the interaction between Vitamin C and metal-containing culture media - both of which are pro-oxidant, generating reactive oxygen species. [11]
Vitamin C has been used in a variety of viral infections and could be useful in combination with other supplements in COVID19 [10]
Vitamin C: may help reduce the severity and duration of a cold, especially if you start taking Vitamin C before feeling ill. 500 mg- 1000 mg of Vitamin C twice a day is a typical starting dose to try to help boost immunity. People with kidney issues should use it with caution as Vitamin C is eliminated by the kidneys. [13]
The Role of Vitamin D
Coronavirus disease 2019 (COVID-19) has caused global disruption and a significant loss of life. Existing treatments that can be repurposed as prophylactic and therapeutic agents could reduce the pandemic's devastation. Emerging evidence of potential applications in other therapeutic contexts has led to the investigation of dietary supplements and nutraceuticals for COVID-19. Such products include Quercetin, Bromelain, Zinc, EGCG, Vitamin C, and Vitamin D; all of which are currently under clinical investigation. In this review, we critically appraise the evidence surrounding dietary supplements and nutraceuticals for the prophylaxis and treatment of COVID-19. Overall, further study is required before evidence-based recommendations can be formulated, but nutritional status plays a significant role in patient outcomes, and these products could help alleviate deficiencies. For example, evidence indicates that vitamin D deficiency may be associated with a greater incidence of infection and severity of COVID-19, suggesting that vitamin D supplementation may hold prophylactic or therapeutic value. A growing number of scientific organizations are now considering recommending vitamin D supplementation to those at high risk of COVID-19. Because research in vitamin D and other nutraceuticals and supplements is preliminary, here we evaluate the extent to which these nutraceutical and dietary supplements hold potential in the COVID-19 crisis. [12.23]
Vitamin D: May help reduces the number of respiratory illnesses, especially for those who are deficient. Supplementing with 1,000-2,000 international units per day may be beneficial. Vitamin D levels can be monitored, it is recommended to not exceed blood levels of 50 nanograms/ milliliter of Vitamin D. [13]
Background:
Milan, Italy had the first specimen detect SARS-CoV-2 from the specimen source: Oropharyngeal Swab, collected on 2019-12-05 but was submission received was reported on 2020-11-30. Wuhan, China, however, had the first specimen identified SARS-CoV-2 from the specimen source: Bronchoalveolar lavage, collected on 2019-12-24 and submission received was reported first on 2020-01-11. Reported submissions of SARS-CoV-2 globally in Humans, Animals, and the Environment. Currently, 9 different Variants are emerging from SARS-CoV-2 including Alpha, Beta, Gamma, Delta, Eta, Iota, Kappa, Lambda, and Mu that have been reported as of 01-Sep-2021. There have been over 1,200 reported cases of SARS-CoV-2 in the following submitted specimens for 14 different Animals including Dog, Cat, Hamster, Mouse, Otter, Monkey, Gorilla, Anteater, Mink, Lion, Tiger, Leopard, Snow Leopard, and Bat. There have been over 1,200 reported cases of SARS-CoV-2 in the Environment from the following samples: Sewer and Wastewater. [0]
There is currently a global outbreak of respiratory disease caused by a novel coronavirus that has been named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). The disease caused by the virus has been named "Coronavirus Disease 2019" (COVID-19). On January 31, 2020, the Department of Health and Human Services (HHS) issued a declaration of a public health emergency related to COVID-19 and mobilized the Operating Divisions of HHS. In addition, on March 13, 2020, there was a Presidential declaration of a national emergency in response to COVID-19. Therefore, FDA is taking urgent measures to protect consumers from certain products that, without approval or authorization by FDA, claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. [1]
At the Pharmacy Compounding Advisory Committee on September 12, 2018, the FDA was proposing that quercetin dihydrate NOT be included on the 503A Bulks List. The Vote Result proposing if quercetin dihydrate should be placed on the list was: YES: 0 NO: 11 ABSTAIN: 0. The Meeting Committee Discussion for the Vote was that: The committee unanimously agreed that quercetin dihydrate NOT be included on the 503A Bulks List. Many committee members expressed concerns with the lack of reasonable data supporting the use of quercetin dehydrate in its proposed indications, the number of known drug interactions with this product, and the number of products that are currently available for these conditions are already proven to be safe and efficacious. Several committee members also noted that the product is widely available over-the-counter as an oral dietary supplement, and in the future, more substantial data would be needed to consider an IV formulation. Please note that one committee member was not present for the vote. Please see the transcript for details of the committee discussion. [2]
Discussion:
There are an overwhelming amount of Abstracts currently for Coronavirus Disease 2019 (COVID-19) using either Quercetin, Bromelain, Zinc, EGCG, Vitamin C, or Vitamin D as a Symptom Reducer, Prevention and/or treatment. [12]
There is only ONE study currently on https://clinicaltrials.gov for Quercetin and Bromelain with Zinc and Vitamin C for Coronavirus Disease 2019 (COVID-19) [11]
There are ZERO studies on https://clinicaltrials.gov for Quercetin and Bromelain with Zinc, EGCG, Vitamin C, and Vitamin D for Coronavirus Disease 2019 (COVID-19) [12]
Limitations:
There is a lack of research conducted for Quercetin and the FDA voted not to during Evaluation and Research on 09/2018 [2], The FDA decreased the daily dose of Zinc, Vitamin C, and Vitamin D on 03/2020 [3], A 02/2021 FDA warning letter issued regarding Zinc, Vitamin C and Vitamin D stating without approval or authorization by FDA to claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. [1]
On 11-FEB-2021 the COVID-19 Treatment Guidelines Panel Voted as followed and was published for the 25-AUG-2021 COVID-19 Treatment Guidelines: [15]
Vitamin C - There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19.
Vitamin D - There is insufficient evidence for the Panel to recommend either for or against the use of vitamin D for the treatment of COVID-19.
Zinc - There is insufficient evidence for the Panel to recommend either for or against the use of zinc for the treatment of COVID-19. • The Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).
In addition to the antiviral medications and the immune-based therapies that are discussed elsewhere in the COVID-19 Treatment Guidelines, adjunctive therapies are frequently used in the prevention and/or treatment of COVID-19 or its complications. Some of these agents are being studied in clinical trials. Some clinicians advocate for the use of vitamin and mineral supplements to treat respiratory viral infections. Ongoing studies are evaluating the use of vitamin and mineral supplements for both the treatment and prevention of SARS-CoV-2 infection. [15]
The Food and Drug Administration, Center for Drug Evaluation and Research on 12-Sep-2018 unanimously voted not to research quercetin dihydrate for the indications: Asthma, allergy, cancer prevention and treatment, and hypertension. Many committee members expressed concerns with the lack of reasonable data supporting the use of quercetin dehydrate in its proposed indications, the number of known drug interactions with this product, and the number of products that are currently available for these conditions Also, that are already proven to be safe and efficacious. the product is widely available over-the-counter as an oral dietary supplement [2] On 18-Feb-2021 the FDA took urgent measures to protect consumers from certain products that, without approval or authorization by FDA, claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. [1] With changes on March 2020 for the Daily Value and Percent Daily Value: Changes on the New Nutrition and Supplement Facts Labels. FDA suggested doses as of 03/2020 are as followed: [3]
Zinc - 11 mg QD - FDA suggested dose Before 03/2020 Zinc 15 mg QD [1]
Vitamin A – 900 mcg QD - FDA suggested dose Before 03/2020 5,000 IU QD [1]
Vitamin C - 90 mg QD - FDA suggested dose Before 03/2020 60 mg QD [1]
Vitamin D - 20 mcg QD - FDA suggested dose Before 03/2020 400 IU QD [1]
Significance:
The Counter use of Quercetin and Bromelain is available for ages Two Years Old and older at a Maximum Suggested Dose of Quercetin 800 mg, and Bromelain 200 mg. [6.3] [7.5]
Conclusion:
Over the Counter Quercetin 800 mg QD, Bromelain 200 mg QD, Zinc 11mg QD, Vitamin A 900 mcg QD, Vitamin C 90 mg QD, and Vitamin D 20 mcg QD taken in combination together with Green Tea is potentially safe together for reducing the severity of symptoms in COVID-19 infection from ages Two Years Old and Older. The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C, and Vitamin D might help reduce the COVID-19 vaccine symptoms and would potentially be a promising addition to proper PPE with COVID-19 Vaccinations to help combat the fight on Coronavirus Disease 2019 (COVID-19). This combination is available online and in stores around the world. [17]
Conflict of Interest:
The Authors have no Conflict of Interest.
Funding: N/A
Authors:
Dr. Amr Ahmed - Ministry of Health - Saudi Arabia
Dr. Abdullah Al.Kattan - King Faisal University - Saudi Arabia
Mahmoud Elkazzaz - Biochemistry Master Degree – Kafr Elksheikh University, Egypt
Michelle C. Orzechowski - Certified Clinical Research Coordinator – United States of America
Correspondence to:
Author/Abstract Writer: Michelle C. Orzechowski, CCRC
Email: Morzechowski4122014@Gmail.com
Keywords:
Quercetin Intake, Bromelain Treatment, Zinc Chelating Strategies, EGCG, Retinoic Acid, Vitamin C Effect, Vitamin D Acts
References:
[0]
Evidence of SARS-CoV-2 RNA in an Oropharyngeal Swab Specimen, Milan, Italy, Early December 2019 https://wwwnc.cdc.gov/eid/article/27/2/20-4632_article GISAID
[1]
Secretary of Health and Human Services, Determination that a Public Health Emergency Exists (originally issued Jan. 31, 2020, and subsequently renewed), available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.
Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak (Mar. 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamationdeclaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.
As explained in the next paragraph, there is currently an outbreak of a respiratory disease named "Coronavirus Disease 2019" (COVID-19) https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/mercolacom-llc-607133-02182021
[2]
Food and Drug Administration Center for Drug Evaluation and Research Summary Minutes of the Pharmacy Compounding Advisory Committee Meeting September 12, 2018, https://www.fda.gov/media/121380/download
https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503a-fdc-act
[3]
Daily Value and Percent Daily Value: Changes on the New Nutrition and Supplement Facts Labels https://www.fda.gov/media/135301/download
[4] Zinc
https://www.drugs.com/npp/zinc.html
https://www.drbvitamins.com/shop/zinc-90-veggiecap
Zinc and SARS‑CoV‑2: A molecular modeling study of Zn interactions with RNA‑dependent RNA‑polymerase and 3C‑like proteinase enzymes Link: https://www.spandidos-publications.com/10.3892/ijmm.2020.4790
[5] EGCG
https://www.drugs.com/npp/green-tea.html
https://www.nowfoods.com/supplements/egcg-green-tea-extract-400-mg-veg-capsules
[6] Quercetin
https://www.drugs.com/npp/quercetin.html
https://www.drbvitamins.com/shop/quercetin-bromelain-veggiecap
https://reddremedies.com/products/childrens-sinus-support
https://www.nowfoods.com/supplements/quercetin-bromelain-veg-capsules
[7] Bromelain
https://www.drugs.com/npp/pineapple.html
https://www.drbvitamins.com/shop/quercetin-bromelain-veggiecap
https://www.fda.gov/food/generally-recognized-safe-gras/enzyme-preparations-used-food-partial-list
https://rd.springer.com/content/pdf/10.1007/PL00000936.pdf
https://creeksidenaturals.com/product/snifflex/
https://www.nowfoods.com/supplements/quercetin-bromelain-veg-capsules
[8] Vitamin C
https://www.drugs.com/mtm/vitamin-c.html
https://www.drbvitamins.com/shop/vitamin-c-1000mg-360-veggiecaps
https://www.nowfoods.com/supplements/c-1000-zinc-immune-veg-capsules
[9] Vitamin D
https://www.drugs.com/pro/vitamin-d-ergocalciferol.html
https://www.drbvitamins.com/shop/vitamin-d-5000iu-360-softgel
https://www.nowfoods.com/supplements/vitamin-d-3-5000-iu-softgels
[10] Sabine Hazan, M.D
A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection (HELPCOVID-19) https://clinicaltrials.gov/ct2/show/NCT04335084
Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19) Link: https://dx.doi.org/10.31083/j.rcm.2020.04.264
Detection of SARS‑CoV‑2 from patient fecal samples by whole genome sequencing Link: https://dx.doi.org/10.1186/s13099-021-00398-5
[11] Dr. Abdullah Al.Kattan & Dr. Amr Ahmed
The Study of Quadruple Therapy Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected With COVID-19 Link: https://clinicaltrials.gov/ct2/show/NCT04468139
Ahmed, Amr & Abdelseed, Heba & Albalawi, Yousef & Aslsalameen, Eman & Almutairi, Yousef & Alkattan, Abdullah & Arabia, Saudi. (2020). Evaluation of the Effect of Zinc, Quercetin, Bromelain, and Vitamin C on COVID-19 Patients. 10.1101/2020.12.22.20245993. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new strain of coronavirus. There are three phases of COVID-19: early infection stage, pulmonary stage, and hyper-inflammation stage respectively. It is important to prevent lung or other organs injuries by preventing phase-II and phase-III via pharmacological or non-pharmacological treatments. This was a case series study done on twenty-two patients confirmed to be infected with SARS-CoV-2 and diagnosed with COVID-19. Patients in this study have been using quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg, and ascorbic acid 1 g once daily as supplements for 3 to 5 days during SARS-CoV-2 infection. This study aims to evaluate the safety and efficacy of quercetin, bromelain, zinc, and ascorbic acid combination supplements on patients with COVID-19. The mean levels of WBC, ANC, ALC, AMC, and AST were normal among all included patients before and after taking quercetin, bromelain, zinc, and ascorbic acid supplements (P-value > 0.05). Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg, and ascorbic acid 1 g once daily supplements were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis. Randomized clinical trials are needed in the future to ensure the efficacy of quercetin, bromelain, zinc, and vitamin c combination.
Research References: Evaluation of the Effect of Zinc, Quercetin, Bromelain and Vitamin C on COVID-19 Patients December 2020 https://dx.doi.org/10.1101/2020.12.22.20245993
Sadeghi Dousari, Amin et al. "COVID-19 (Coronavirus Disease 2019): A New Coronavirus Disease." Infection and drug resistance vol. 13 2819-2828. 12 Aug. 2020, Link: https://dx.doi.org/10.2147/IDR.S259279
Kaur, Supreet et al. "The looming storm: Blood and cytokines in COVID-19." Blood reviews, 100743. 18 Aug. 2020, Link: https://dx.doi.org/10.1016/j.blre.2020.100743
Valentini M, Zmerly H. Antirheumatic drugs for COVID-19 treatment based on the phases of the disease: Current concept. J Popul Ther Clin Pharmacol. 2020 Jun 27;27(S Pt 1):e14-e25. PMID: 32650355 Link: https://dx.doi.org/:10.15586/jptcp.v27iSP1.689
Anand David, Alexander Victor et al. "Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid." Pharmacognosy reviews vol. 10,20 (2016): 84-89. Link: https://dx.doi.org/10.4103/0973- 7847.194044
Mlcek, Jiri et al. "Quercetin and Its Anti-Allergic Immune Response." Molecules (Basel, Switzerland) vol. 21,5 623. 12 May. 2016, Link: https://dx.doi.org/10.3390/molecules21050623
Nair, Madhavan P, et al. "The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor-alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system." Clinical and vaccine immunology: CVI vol. 13,3
(2006): 319-28. Link: https://dx.doi.org/10.1128/CVI.13.3.319-328.2006
Kobori, Masuko et al. "Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice." Molecular nutrition & food research vol. 60,2 (2016): 300-12. Link: https://doi:10.1002/mnfr.201500595
Gang Xiong, Wansheng Ji, Fei Wang, Fengxiang Zhang, Peng Xue, Min Cheng, Yanshun Sun, Xia Wang, Tianliang Zhang, "Quercetin Inhibits Inflammatory Response Induced by LPS from Porphyromonas gingivalis in Human Gingival Fibroblasts via Suppressing NF-κB Signaling Pathway", BioMed Research International, vol. 2019, Article ID 6282635, 10 pages, 2019 Link: https://dx.doi.org/10.1155/2019/6282635
Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O'Sullivan CK, Fernández-Larrea JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014 Aug 13;62(32):8085-93..Epub 2014 Jul 31. Link: https://dx.doi.org/10.1021/jf5014633
Larson, Abigail J et al. "Quercetin: A Treatment for Hypertension?-A Review of Efficacy and Mechanisms." Pharmaceuticals (Basel, Switzerland) vol. 3,1 237-250. 19 Jan. 2010, Link: https://dx.doi.org/10.3390/ph3010237
Pavan, Rajendra et al. "Properties and therapeutic application of bromelain: a review." Biotechnology research international vol. 2012 (2012): 976203. Link: https://dx.doi.org/10.1155/2012/976203
Lotz-Winter H. On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects. Planta Med. 1990 Jun;56(3):249-53. PMID: 2203073 Link: https://dx.doi.org/10.1055/s-2006-960949
Rathnavelu, Vidhya et al. "Potential role of bromelain in clinical and therapeutic applications." Biomedical reports vol. 5,3 (2016): 283-288. Link: https://dx.doi.org/10.1007/s12250-017-4057-9doi:10.3892/br.2016.720
Verma N, Meena NK, Majumdar I, Paul J (2017) Role of Bromelain as Herbal AntiInflammatory Compound Using In Vitro and In Vivo Model of Colitis. J Autoimmune Disord Vol 3:52. 15
Wong G, He S, Siragam V, Bi Y, Mbikay M, Chretien M, Qiu X. Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection. Virol Sin. 2017 Dec;32(6):545-547. PMID: 28884445; PMCID: PMC6598929 Link: https://dx.doi.org/10.1007/s12250-017-4057-9
Qiu, Xiangguo, et al. "Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection." Antimicrobial agents and chemotherapy vol. 60,9 5182-8. 22 Aug. 2016, Link: https://dx.doi.org/10.1128/AAC.00307-16
Chiow, K H et al. "Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection." Asian Pacific journal of tropical medicine vol. 9,1 (2016): 1-7. Link: https://dx.doi.org/10.1016/j.apjtm.2015.12.002
Jasso-Miranda, Carolina, et al. "Antiviral and immunomodulatory effects of polyphenols on macrophages infected with dengue virus serotypes 2 and 3 enhanced or not with antibodies." Infection and drug resistance vol. 12 1833-1852. 1 Jul. 2019, Link: https://dx.doi.org/10.2147/IDR.S210890
Aucoin, Monique et al. "The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review." Advances in integrative medicine, 10.1016/j.aimed.2020.07.007. 30 Jul. 2020, Link: https://dx.doi.org/10.1016/j.aimed.2020.07.007
Wu, Wenjiao et al. "Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry." Viruses vol. 8,1 6. 25 Dec. 2015, Link: https://dx.doi.org/10.3390/v8010006
Ahmed, Amr & Albalawi, Yousef & Shora, Hassan & Abdelseed, Hiba & Al-Kattan, Abdulla. (2020). Effects of Quadruple Therapy: Zinc, Quercetin, Bromelain, and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. 10.37179/rijed.000005. ABSTRACT COVID-19 emerged in Wuhan, China in December 2019, reached epidemic proportions, and spread globally as a serious life-threatening pandemic. SARS- Cov-2 is the causative virus that causes severe acute respiratory distress, pneumonia, respiratory failure, and septic shock leading to increased mortality. High-risk patients include those with chronic non-communicable diseases such as diabetes, hypertension, coronary heart disease, and cancers. No specific treatment is available and supportive care is all that could be done to rescue patients. Quadruple therapy consisting of Zinc, Quercetin, Bromelain, and Vitamin C showed promising results in improving clinical outcomes among COVID-19 patients. Keywords: COVID-19, Cytokines, zinc, Quercetin, Bromelain, Vitamin C.
Research References: Effects of Quadruple Therapy: Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19 https://dx.doi.org/10.37179/rijed.000005
Haibo Z, Josef MP, Yimin Li, Nanshan Z, Arthur SS (2020) Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target Intensive Care Med 46:586-590. Link: https://bit.ly/3lrcRu5
Halpin DMG, Faner R, Sibila O, Badia JR, Agusti A (2020) Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection? Lancet Respir Med 8: 436-438. Link: https://bit.ly/3bgv8FX
Qun Li, Xuhua G, Peng W, Xiaoye W, Lei Z, et al. (2020) Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 382: 1199-1207. Link: https://bit.ly/3jnQ4gK
Aysooda H, Omid S, Akram NB, Sepideh S, Gabriel SB, et al. (2019) Immunomodulatory Effects of Flavonoids: Possible Induction of T CD4+ Regulatory Cells Through Suppression of mTOR Pathway Signaling Activity. Front Immunol 10: 51. Link: https://bit.ly/3lnEMem
Diao B, Wang C, Tan Y, Xiewan C, Ying Liu, et al. (2020) Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19) Front. Immunol 11: 827. Link: https://bit.ly/3gFYAWK
PRASAD AS, HALSTED JA, NADIMI M (1961) Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism, and geophagia. Am. J. Med 31: 532–546. Link: https://bit.ly/3hD2fWz
Roohani N, Hurrell R, Kelishadi R, Schulin R (2013) Zinc and its importance for human health: An integrative review. J. Res. Med. Sci 18: 144–157. Link: https://bit.ly/2QB4LRa
Englert J, Boudreault F, Pinilla-Vera M, Alvin TK, Colleen I, et al. (2016) ID: 60 Zinc deficiency primes the lung for ventilator-induced injury. Journal of Investigative Medicine 64: 973. Link: https://bit.ly/2Qx0hLx
Carr AC, Maggini S (2017) Vitamin C, and Immune Function. Nutrients.9: 1211. Link: https://bit.ly/31CvDGM
Furuya A, Uzaki M, Yamasaki H, Arakawa T, Arita Koyama MAH (2008) Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med. 22: 541–545. Link: https://bit.ly/31yX98d
Colunga BRML, Berrill M, Catravas JD, Marik PE (2020) Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Frontiers in Immunology 11: 1451. Link: https://bit.ly/2QxVppr
Chen S, Jiang H, Wu X, Fang J (2016) Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. Mediators Inflamm 2016: 9340637. Link: https://bit.ly/2EzcZaf
Huang RY, Yu YL, Cheng WC, OuYang CN, Fu E, et al. (2010) Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immunol. 184: 6815-6821. Link: https://bit.ly/3jzRh51
Zuyi W, Bodi Z, Shahrzad A, Nikolaos S, Alan Butcher, et al. (2012) Quercetin Is More Effective than Cromolyn in Blocking Human Figure 2: Quercetin and bromelain for blocking the interleukin. Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.1(1): 018-021. DOI: 10.37179/rijed.000005 Re Int Jou of end and dia 021 Volume 1 Issue 1 – 1005 Photosensitivity in Humans. PLoS One 7: e33805. Link: https://bit.ly/32wunUZ
Lesjak M, Rukshana H, Sara B, Vernon S, Edward S, et al. (2014) Quercetin Inhibits Intestinal Iron Absorption and Ferroportin Transporter ExpressionIn Vivo and In Vitro. PLoS ONE 9: e102900. Link: https://bit.ly/2YI9SUu
Dabbagh-Bazarbachi H, Gael C, Isabel MQ, Mayreli O, Ciara KOH, et al. (2014) "Zinc ionophore activity of quercetin and e-epigallocatechin gallate: from Hepa 1-6 cells to a liposome model." J Agric Food Chem. 62: 8085-8093. Link: https://bit.ly/2EzfuJF
Onken JE, Greer PK, Calingaert B, Hale LP (2008) Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 126: 345-352. Link: https://bit.ly/3gCCrsz
Pavan R, Jain S, Shraddha, Kumar A (2012) Properties and therapeutic application of bromelain: a review. Biotechnol Res Int. 2012: 976203. Link: https://bit.ly/3b4COdY
Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R (2016) Potential role of bromelain in clinical and therapeutic applications (Review) Biomed. Reports 5: 283-288. Link: https://bit.ly/3hDc0UO
Hu PA, Chen CH, Guo BC, Kou YR, Lee TS (2020) Bromelain Confers Protection against the Non-Alcoholic Fatty Liver Disease in Male C57BL/6 Mice. Nutrients. 12: 1458. Link: https://bit.ly/3gCeGRh
[12] Abstract References:
The combination of Quercetin and Bromelain with Zinc, Vitamin C, and Vitamin D, when taken together, may inhibit the viral replication of antiviral and Anti-Cytokine Storm by restraining Hyper-Inflammation and Cytokine Storm An Antiviral against RNA viruses like COVID-19 using the combination of Zinc with a Zinc Ionophore Acidifies parts of Cellular Milieu and increase Metallothioneins. Link: https://dx.doi.org/10.6084/m9.figshare.15153186
Dietary Supplements for COVID-19 Chapter May 2021Advances in Experimental Medicine and Biology Gerard E. MullinBerkeley LimektkaiLin Wang[...]Edward Giovannucci 1 Citation Link: https://dx.doi.org/10.1007/978-3-030-63761-3_29
Zinc supplementation and COVID-19 pandemic Preprint Full-text availableJul 2021 Mohammad Sarwar MirAbas Khan Link: https://dx.doi.org/10.13140/RG.2.2.24657.45922
Zinc supplementation and COVID-19 Article Full-text available 2020 Abas KhanMohammad Sarwar Mir Link: http://jmcrr.info/index.php/jmcrr
Dietary Supplements and Nutrcaceutical Remedies for COVID-19ArticleFull-text availableMay 2021Poshadri AchinnaH.W. Deshpande Link: https://www.agricosemagazine.com
Is nutraceutical supplementation appropriate for COVID-19 management? Article Apr 2021Allergy and Asthma Proceedings Michele PiazzaAttilio L BonerSandro Girotto[...]Joseph A. Bellanti Link: https://dx.doi.org/10.2500/aap.2021.42.210030
Zinc Supplements in COVID-19 Pathogenesis-Current Perspectives Article Full-text availableMay 2021 Muhammed MajeedChavez MKalyanam NagabhushanamLakshmi Mundkur Link: https://dx.doi.org/10.26420/austinjnutrmetab.2021.1107
Authors' response: Ethnicity and vitamin D supplementations for COVID-19 ArticleFull-text availableJul 2021Reviews in Medical Virology Timotius Ivan HariyantoDenny IntanJoshua Edward Hananto[...]Andree Kurniawan Link: https://dx.doi.org/10.1002/rmv.2280
Vitamin D supplementation for COVID-19: is it necessary? Article Full-text available 2020MEDISAINS Agus Santosa Link: https://dx.doi.org/10.30595
Vitamin D and COVID 19 Preprint Full-text availableJul 2021 Mohammad Sarwar MirAbas Khan Link: https://dx.doi.org/10.13140/RG.2.2.17946.57287
Prophylactic and Therapeutic Role of Vitamin D Supplementation in COVID-19: A Review Article Jul 2021European Journal of Medical and Health Sciences Mehrie Harshad PatelSakshi MishraKetul Barot[...]Luis Del Prado 21 Citations Link: https://dx.doi.org/10.24018/ejmed.2021.3.4.943
The prophylaxis and treatment potential of supplements for COVID-19 Article Full-text availableAug 2020European Journal of Pharmacology Adeleh SahebnasaghFatemeh SaghafiRazieh Avan[...]Seyed Mohammad Nabavi Link: https://dx.doi.org/10.1016/j.ejphar.2020.173530
Supplementation with vitamin D in the COVID-19 pandemic? Article Full-text available Jul 2020Nutrition Reviews Fatemeh Hadizadeh 12 Citations Link: https://dx.doi.org/10.1093/nutrit/nuaa081
Should we supplement zinc in COVID-19 patients? Evidence from meta-analysis Article Full-text availableJun 2021Polskie Archiwum Medycyny Wewnȩtrznej Łukasz SzarpakMichał PrucAleksandra Gasecka[...]Krzysztof J Filipiak 2 Citations Link: https://dx.doi.org/10.20452/pamw.16048
Vitamin D and COVID-19: Evidence and recommendations for supplementation Article Full-text available Nov 2020Royal Society Open Science George E GriffinMartin HewisonJulian Hopkin[...]D. Thickett 6 Citations Link: https://dx.doi.org/10.1098/rsos.201912rsos201912
Vitamin D and COVID-19: evidence and recommendations for supplementation Article Full-text availableNov 2020Royal Society Open Science George E GriffinMartin HewisonJulian Hopkin[...]David Thickett 15 Citations Link: https://dx.doi.org/10.1098/rsos.201912
Vitamin D supplementation in the COVID-19 pandemic Article May 2020Mayo Clinic Proceedings Darko SiukaMarija PfeiferBojana Pinter 19 Citations Link: https://dx.doi.org/10.1016/j.mayocp.2020.05.036
Dietary Supplements and Nutraceuticals under Investigation for COVID-19 Prevention and Treatment Article Full-text available May 2021 m Systems Ronan Lordan Halie M Rando Casey S Greene 5 Citations Link: https://dx.doi.org/10.1128/mSystems.00122-21
The Role of Diet and Supplementation of Natural Products in COVID-19 Prevention Article Full-text available Feb 2021Biological Trace Element Research Amin GasmiChirumbolo SalvatoreMassimiliano Peana[...]Geir Bjorklund 5 Citations Link: https://dx.doi.org/10.1007/s12011-021-02623-3
Recommendations for High dose Vitamin D Supplementation to help Fight the COVID-19 Pandemic and its Inclusion in National COVID-19 Management Guidelines Article Full-text availableJul 2021 Jugal KishoreDavid S GrimesDavid C Anderson[...]Monika Sahoo Link: https://dx.doi.org/10.24321/2455.7048.202104
Role of dietary supplements in treatment and prophylaxis of COVID-19: A Systematic Review Article Full-text availableMay 2021 Fourrages Hafiza Sobia Link: May 2021Fourrages 246(5):100-118
A secondary approach with conventional medicines and supplements to recuperate current COVID-19 status Article Full-text availableJun 2021Biomedicine & Pharmacotherapy Apu ChowdhuryMuhammad SajidNabila Jahan[...]Sicen Wang Link: https://dx.doi.org/10.1016/j.biopha.2021.111956
Active vitamin D supplementation and COVID-19 infections: review Article Jan 2021 Irish Journal of Medical Science Farid NakhoulRola NakhoulElias A.T. KochNakhoul Nakhoul 1 Citation Link: https://dx.doi.org/10.1007/s11845-020-02452-8
Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment Preprint Feb 2021 Ronan LordanHalie M RandoCovid-Review ConsortiumCasey S Greene Link: https://dx.doi.org/10.1128/mSystems.00122-21
"Vitamin D supplementation and COVID-19 treatment: A systematic review and meta-analysis" Article Jun 2021Diabetes and Metabolic Syndrome Clinical Research and Reviews Dimple RawatAvishek RoySouvik Maitra[...]Dalim Kumar Baidya 1 Citation Link: https://dx.doi.org/10.1016/j.dsx.2021.102189
Vitamin D supplementation and COVID-19: Expert consensus and guidelines Article Dec 2020Geriatrie et Psychologie Neuropsychiatrie du Vieillissement Cédric AnnweilerJean-Claude Souberbielle Link: https://dx.doi.org/10.1684/pnv.2020.0907
Vitamin supplementation as a potential adjunctive therapeutic approach for COVID-19: biological and clinical plausibility Article Aug 2021 Journal of Basic and Clinical Physiology and Pharmacology Amin SorkhabiAila SarkeshAlireza Daei Sorkhabi[...]Hossein Bannazadeh Baghi Link: https://dx.doi.org/10.1515/jbcpp-2021-0111
Adherence to COVID-19 Nutrition Guidelines Is Associated with Better Nutritional Management Behaviors of Hospitalized COVID-19 Patients Article Full-text availableJun 2021Nutrients Amelia FaradinaSung Hui TsengNgan Dang Khanh Ho[...]Jung-Su Chang Link: https://dx.doi.org/10.3390/nu13061918
The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis Article Full-text availableJun 2020Frontiers in Immunology Inga WesselsBenjamin RollesLothar Rink 90 Citations Link: https://dx.doi.org/10.3389/fimmu.2020.01712
Vitamin D supplementation for the treatment of COVID-19: Summary of a living Cochrane review Article May 2021EXPLORE L. Susan Wieland https://dx.doi.org/10.1016/j.explore.2021.06.004
Vitamin D Supplementation in Influenza and COVID-19 Infections Article Full-text availableMay 2020Nutrients Kow Chia SiangMuhammad Abdul HadiSyed Shahzad Hasan 11 Citations Link: https://dx.doi.org/10.3390/nu12061626
COVID-19 and nutriceutical therapies, especially using zinc to supplement antimicrobials Article Publisher preview available Jan 2021 Inflammo pharmacology Desley ButtersMichael Whitehouse 3 Citations Link: https://dx.doi.org/10.1007/s10787-020-00774-8
Vitamin D and COVID-19: A Physiological Perspective Article Full-text availableMay 2021Biomedical Research and Therapy Pendhamma Sindhusen Link: https://dx.doi.org/10.15419/bmrat.v8i5.674
Safety of COVID-19 Vaccination in Immune-Deficient Patients Receiving Supplemental Immunoglobulin Therapies ArticleJun 2021 Journal of Clinical Immunology Jacqueline D. SquireAvni Y. Joshi Link: https://dx.doi.org/10.1007/s10875-021-01101-8
Vitamin D supplementation, COVID-19 & Disease Severity: A meta-analysis Article Jan 2021QJM: monthly journal of the Association of Physicians Komal ShahDeepak SaxenaDileep Mavalankar 13 Citations Link: https://dx.doi.org/10.1093/qjmed/hcab009
Potential health benefits of zinc supplementation for the management of COVID‐19 pandemic Article Full-text availableJan 2021Journal of Food Biochemistry Ademola OyagbemiTemitayo AjibadeYapo Guillaume Aboua[...]Momoh A Yakubu 3 Citations Link: https://dx.doi.org/10.1111/jfbc.13604
Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis Article Full-text availableJun 2021Journal of Endocrinological Investigation Rimesh PalMainak BanerjeeSanjay Bhadada[...]Abhinav Vyas 2 Citations Link: https://dx.doi.org/10.1007/s40618-021-01614-4
Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS Article Full-text availableJun 2021Nutrients Quirin NotzJohannes HerrmannTobias Schlesinger[...]Christian Stoppe 1 Citation Link: https://dx.doi.org/10.3390/nu13062113
Dietary Intake and Supplement Use Among Saudi Residents during COVID-19 Lockdown Article Full-text availableJun 2021International Journal of Environmental Research and Public Health Hanan A AlfawazNasiruddin KhanGhadah A. Aljumah[...]Nasser M Al-Daghri Link: https://dx.doi.org/10.1016/j.cmi.2021.01.013DOI:10.3390/ijerph18126435
Prophylaxis for COVID-19: a systematic review January 2021Clinical Microbiology and Infection 27(4) Link: https://dx.doi.org/10.1016/j.cmi.2021.01.013
The suggested role of Vitamin D supplementation in COVID-19 severity Article Aug 2020 Journal of Contemporary Medical Sciences Parviz AfsharMohammad GhaffaripourHamid Sajjadi Link: https://dx.doi.org/10.22317/jcms.v6i4.822
Adjunctive Nutraceutical Therapies for COVID-19 Article Full-text availableFeb 2021International Journal of Molecular Sciences Lalita SubediStephanie TchenBhakta Prasad Gaire[...]Kurt Hu 3 Citations Link: https://dx.doi.org/10.3390/ijms22041963
Dietary supplements and herbal medicine for COVID-19: A systematic review of randomized control trials Article Full-text availableMay 2021Clinical Nutrition ESPEN Zitong FengJuan YangMingzhu Xu[...]Shaoyang Cui Link: https://dx.doi.org/10.1016/j.clnesp.2021.05.018
Role of Vitamin D Supplementation in Prevention and Treatment of COVID-19 Article Full-text availableJul 2020Indian Journal of Clinical Biochemistry Aakriti KhemkaArpita SuriNaveen Kumar SinghSanjiv Kumar Bansal 3 Citations Link: https://dx.doi.org/:10.1007/s12291-020-00908-3
For people with moderate to severe COVID-19, what are the benefits and harms of vitamin D supplementation? Article May 2021 Sera TortJane Burch Link: https://dx.doi.org/10.1002/cca.3689
Patients' Behavior Regarding Dietary or Herbal Supplements Before and During COVID-19 in Saudi Arabia Article Full-text availableMay 2021 International Journal of Environmental Research and Public Health Leen A AldwihiShahd I. KhanFaisal Fahad Alamri[...]Omar A. Almohammed 1 Citation Link: https://dx.doi.org/10.3390/ijerph18105086
Prophylaxis for COVID-19: a systematic review Article Full-text availableJan 2021Clinical Microbiology and Infection Mikaela SmitAnnalisa MarinosciThomas Agoritsas[...]Alexandra Calmy 3 Citations Link: https://dx.doi.org/10.1016/j.cmi.2021.01.013
Use Of Vitamin C, Vitamin D, and Zinc Supplements To Avoid COVID-19 In Article Full-text available Mar 2021 Ebru Kuyumcu Savan Link: https://dx.doi.org/10.19070/2379-1586-2100038
Role of adjunctive vitamin C supplement therapy in combating COVID-19 Article Full-text availableNov 2020International Journal of Basic & Clinical Pharmacology Gnaneswari Regati Link: https://dx.doi.org/10.18203/2319-2003.ijbcp20205135
Vitamin D supplementation as a rational pharmacological approach in the COVID-19 pandemic Article Full-text availableNov 2020AJP Lung Cellular and Molecular Physiology Leon FerderVirna Margarita Martín GiménezFelipe Inserra[...]Walter Manucha 10 Citations Link: https://dx.doi.org/10.1152/ajplung.00186.2020
Vitamin C and D to decrease the risk and severity of COVID 19 symptoms. Is cortisol reduction the mechanism behind lowering the severity of COVID 19 symptoms? Article Full-text availableJul 2021Food and Nutrition Adrian Isaza Link: https://dx.doi.org/10.33425/2641-4295.1043
The Covid-19 infection: An opportunity to develop systematic vitamin D supplementation in psychiatry Article Feb 2021 L Encéphale Guillaume FondMarc MassonRaphaelle Richieri[...]Laurent Boyer Link: https://dx.doi.org/10.1016/j.encep.2021.02.002
Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445,850 users of the COVID Symptom Study app Article Full-text availableMar 2021BMJ Nutrition Prevention & Health Panayiotis LoucaBenjamin MurrayKerstin Klaser[...]Cristina Menni 5 Citations Link: https://dx.doi.org/10.1136/bmjnph-2021-000250
Vitamin C and D supplementation and the severity of COVID-19: A protocol for systematic review and meta-analysis Article Full-text availableJul 2021Medicine Gislani Acásia da Silva ToscanoIvani Iasmin de AraújoTalita Araujo de Souza[...]Gilson De Vasconcelos Torres COVID-19 and Dentistry Article Full-text availableJun 2021 Hugh DevlinParisa SoltaniStephen Bustin Link: https://dx.doi.org/10.1097/MD.0000000000026427
Clinical Effects of Zinc Supplementation in Patients Hospitalized with COVID-19: A Systematic Review and Meta-analysis Article Jun 2021Korean Journal of Clinical Pharmacy Hye Won ParkSo Yeon LeeSook Hee An Link: https://dx.doi.org/10.24304/kjcp.2021.31.2.136
Vitamin D supplementation to mitigate COVID-19 morbidity in the vulnerable Article Full-text availableJun 2020 Koenraad Van den AbbeelePeter A.M. de Beer Link: https://nutrition.bmj.com/content/3/1/67.responses
Potential role of Zinc supplement in CVD and COVID-19 co- morbidity Preprint Full-text availableNov 2020 Muhammad Manjurul KarimShahnaz SultanaRokaia SultanaMohammad Tariqur Rahman Link: https://dx.doi.org/10.14293/S2199-1006.1.SOR-.PP3ZKDJ.v1
Effect of COVID‑19 on Awareness and Consumption of Dietary Supplements in Saudi Arabia JNatSciMed42190-5118721 141307 Article Full-text availableJun 2021 Sulaiman A Alshammari Link: https://dx.doi.org/10.4103/jnsm.jnsm_156_20
The fight against COVID-19 the role of drugs and food supplements Article Full-text availableJun 2020 Dario RuscianoRoberta GaleazziPaola Bagnoli 7 Citations
Link: file:///C:/Users/ne113669/Downloads/ThefightagainstCOVID19theroleofdrugsandfoodsupplements.pdf
Vitamin D supplementation and Covid-19 outcomes: A systematic review, meta-analysis, and meta-regression Article Full-text availableJun 2021 Reviews in Medical Virology Timotius Ivan HariyantoDenny IntanJoshua Edward Hananto[...]Andree Kurniawan 1 Citation Link: https://dx.doi.org/10.1002/rmv.2269
COVID-19 and vitamin D supplementation: Is there any evidence-based to reduce the risk? Article Full-text available Jan 2021 Amina Chentouf Link: https://dx.doi.org/10.51745/najfnr.4.10.S19-S24
A TGF - beta2 enriched formula as an oral nutritional supplement for hospitalized COVID-19 patients Article Apr 2021 I. GrandoneMassimiliano CavalloLuisa Barana[...]Gaetano Vaudo Link: https://dx.doi.org/10.23736/S2724-5985.21.02820-8
Potential Role of Zinc Supplementation in Prophylaxis and Treatment of COVID-19 Article Apr 2020Medical Hypotheses Amit KumarYuichi KubotaMikhail ChernovHidetoshi Kasuya 83 Citations Link: https://dx.doi.org/10.1016/j.mehy.2020.109848
Vitamin D supplementation: a potential approach for COVID-19 therapeutics? Preprint Apr 2020 John ArboledaSilvio Urcuqui-Inchima 7 Citations Link: https://dx.doi.org/10.31219/osf.io/cgd4t
Adjuvant therapy with Serratiopeptidase and Vitamin D for COVID-19 patients: A new perspective Article Full-text available May 2021 Kuldeep Kumar GuptaAdil RahmanAjai Kumar[...]Priyanka Asia Link: https://www.ijmscr.com
Bromelain: A Review on its Potential as a Therapy for the Management of Covid-19 June 2020Nigerian journal of physiological sciences: official publication of the Physiological Society of Nigeria 35(1):10-19 Link: https://www.bioline.org.br/np
Bromelain and its potential therapeutic effects in COVID-19-induced respiratory complications December 2020 Link: https://dx.doi.org/10.31254/jmr.2020.6614
Bromelain: A potential therapeutic application in SARS- CoV-2 infected patients June 2021 Link: https://dx.doi.org/10.17352/aaa.000011
Bromelain Inhibits SARS-CoV-2 Infection in VeroE6 Cells September 2020 Link: https://dx.doi.org/10.1101/2020.09.16.297366
The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19 November 2020Metabolism Open Link: https://dx.doi.org/10.1016/j.metop.2020.100066
Potential protective mechanisms of green tea polyphenol EGCG against COVID-19 Author Zhichao Zhang, Xiangchun Zhang, Keyi Bi, Yufeng He, Wangjun Yan Chung S.Yang, Jinsong Zhang Link: https://dx.doi.org/10.1016/j.tifs.2021.05.023
[13] Northwell Health COVID-19 Supplements Sheet
https://www.northwell.edu/sites/northwell.edu/files/2020-10/covidsupplementonesheet.pdf
https://naturalmeds@vivohealthpharmacy.com
[14]
https://www.nbcnews.com/nightly-news/video/inside-tampa-icu-seeing-spike-in-covid-cases-119375941724
[15]
https://www.covid19treatmentguidelines.nih.gov/
https://www.fda.gov/advisory-committees/advisory-committee-calendar
[16] Mahmoud Elkazzaz, Biochemistry Master Degree – Kafr Elksheikh University, Egypt
Assessment of the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 ( Isotretinoin in Treatment of COVID-19) (Randomized) (Isotretinoin) Link: https://clinicaltrials.gov/ct2/show/NCT04353180
Combination of Chemopreventive Agents (All-Trans Retinoic Acid and Tamoxifen) as Potential Treatment for the Lung Complication of COVID-19 Link: https://clinicaltrials.gov/ct2/show/NCT04568096
In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) Protein ion channel inhibitor Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574788/
All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity Link: https://doi.org/10.3390/v13081669
[17] Online Store Reviews
https://www.amazon.com/gp/aw/reviews/B08CBBHPTF/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B089XTSC1K/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B08MV751Y5/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B08DG8LQ19/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B08FGVQRV2/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B08WM4D4RG/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B089NKZT59/ref=cm_cr_dp_mb_top?ie=UTF8
https://www.amazon.com/gp/aw/reviews/B08J9X5H1N/ref=cm_cr_dp_mb_top?ie=UTF8