Postulated Adjuvant Therapeutic Strategies for COVID-19
Abstract
:1. Introduction
2. SARS-CoV-2 and COVID-19
2.1. Clinical Features of the SARS-CoV-2 Infection
2.2. COVID-19 Stages
2.3. Complications Associated with COVID-19
2.3.1. Hyperinflammation Due to Immune System Overresponse (Cytokine Storm)
2.3.2. Immune Dysregulation
2.3.3. Antibody Profile
2.3.4. Hematologic Consequences
2.3.5. Endotheliitis
3. Therapies for Potential Prevention and Improvement of the Associated Symptoms
3.1. Transfer Factors
3.2. Anti-Inflammatory Natural Blend
3.3. Potential Activities of the Ingredients in COVID-19 Pathophysiology
3.3.1. Regulation of the Immune System
Macrophage Activation (Box #1)
Activation of NK Cells (Box #4)
Increasing T Cells Functions (Box #2)
CD4+ Cells Activation (Box #5)
IFN-γ Production (Box #3 and #6)
Antibodies Production (Box #8)
Development and Function of Neutrophils (Box #9)
Improving Tissue Barrier Function on Innate Immunity
3.3.2. Support on Avoidance of Virus Entrance in the Cell
Reducing the Virus Entrance in the Cell (DPP4R Inhibitory Effect, ACE2 Blocker Effect) (Box #10)
3.3.3. Support on Decrease of Virus Replication
Increasing Intracellular Zinc Level and Synergistic Effect of Resveratrol (Box #12 and #16)
TLR7 Activation/Boosting Interferon Type 1 Response (Box #17 and #19)
3.3.4. Support on Control of Hyperinflammation
Lymphocytes B Proliferation and Differentiation (Box #7)
Inhibition of TL4 (Box #11)
Inflammatory Interleukine-6 Inhibition (Box #13 and #20)
Inhibition of TNF-α and NF-kB Activation (Box # 14, #15, # 18 and #21)
Interleukin-7 Regulation and Lymphopoietic Stimulation
3.3.5. Support on Reduction of Oxidative Stress
3.3.6. Potential Antithrombotic Effect
3.3.7. Potential Protection of Endothelial Barrier
3.4. Safety Considerations
- Contraindications: In case of use of immunosuppressants, they have antagonistic effects (Imuno TF® regulates the immune system, increasing Th1 response)”. There is not enough information about the use of the transfer factor during pregnancy and breastfeeding. Avoid use during this period [173].
- Drug interaction: The effects of transfer factors can be reduced with the use of corticosteroids.
- Adverse effects: Rare. Occasionally, when the patient starts TF treatment, typical flu symptoms, fever episode, nausea, and gastrointestinal symptoms may occur. These symptoms are usually classified as Jarisch–Herxheimer reactions and are probably related to a direct reaction of TF in the intestine or systemic pathogens [174].
- Safety: Miodesin® does not induce changes in DNA [61]. Uncaria tomentosa (Willd.) DC. and Haematococcus pluvialis (astaxanthin esters) are classified by the Dietary Supplements Information Expert Committee (DSI-EC) of the United States Pharmacopeial Convention as Class A, which indicates that the available evidence does not indicate a serious risk to health – this substance has a monograph in United States Pharmacopeia and National Formulary (USP–NF). Preliminary studies with Endopleura uchi (Huber) Cuatrec. (Humiriaceae) did not reveal any toxicity [175,176].
- Contraindications: Active ingredients included in Miodesin® are contraindicated for patients with rheumatism and patients who will undergo or have had an organ transplantation. The use of Miodesin® during pregnancy and lactation should be discussed with the prescriber [111].
- Drug interaction: Miodesin® is contraindicated for concomitant use with immunosuppressants due to its immunostimulant effect. Drug interactions may occur with warfarin, estrogens, theophylline, ginger and drugs metabolized by the cytochrome P-450 route. In patients taking these medicines, Miodesin® should be administered under medical supervision [177]. Miodesin® may also potentiate the action of antihypertensive drugs [178].
- Adverse effects: active ingredients of Miodesin® may cause fatigue, fever, diarrhea and constipation [177].
- Safety: United States Pharmacopeia provides monograph for this substance as a pharmaceutical ingredient (as gluconate).
- Contraindications: Iron and copper deficiency [179].
- Drug interaction: concurrent administration of zinc salts may diminish the absorption of tetracycline [180]. Large doses inhibit iron and copper absorption [179]. Amiloride reduces zinc excretion, leading to its accumulation in the body [181]. Consumption of fiber-containing foods inhibit absorption of zinc, then take the medicine an hour before, or two hours after, consumption of food high in fiber [182].
- Adverse effects: Side effects of zinc salts are abdominal pain, dyspepsia and diarrhea [183]. No effects have been reported for fertility, pregnancy and lactation [184]. Zinc accumulation in the body could lead to toxic side effects, such as metallic taste sensation, vomiting, and stomach problems [185].
- Contraindications: In cases of selenium poisoning or hypersensitivity to products containing selenium. Pregnancy: there are no data from the use of selenium in pregnant women; selenium is excreted in human milk, but at therapeutic doses, no effects are anticipated in newborn/lactating infants. Selenium can be used during lactation. There are no data on fertility with the use of selenium in humans; selenium did not affect male fertility in rats and the effects of selenium on female fertility in rodents were only observed at very high doses. In general, doses to correct selenium deficiency are not expected to have adverse effects on fertility [188].
- Drug interaction: Major interaction with the drug eltrombopag; do not use both substances simultaneously [189]. Selenium is generally incompatible with high concentrations of ascorbic acid (reduction of selenite to elemental selenium which is not soluble and not available as a nutritional source of selenium) [188].
- Adverse effects: Gastrointestinal upset. Very high selenium dosages (above 850 µg daily) are known to cause selenium toxicity, whose signs include depression, nervousness, emotional instability, nausea, vomiting, and in some cases loss of hair and fingernails [185].
- Safety: United States Pharmacopeia has provided a monograph for this substance as a pharmaceutical ingredient. The reports of vitamin D toxicity show that hypercalcemia involve serum 25(OH)D concentrations when it is greatly above 200 nmol/L. To achieve this level, a daily intake higher than 40,000 IU would be required—then, this value could be considered as the lowest observed adverse effect level (LOAEL) for vitamin D [190].
- Drug interaction: Vitamin D is a chemical structure similar to calcitriol; do not use medications containing calcitriol while using vitamin D. Vitamin D3 may interfere with cholesterol laboratory tests, possibly causing false test results [191].
- Adverse effects: Vitamin D at normal doses usually has no side effects. At high doses, it can occur gastrointestinal (nausea and vomiting), metabolic (hypercalcemia), renal (hypercalciuria) and dermatological (pruritus, urticaria) effects [191].
- Safety: United States Pharmacopeia has provided a monograph for this substance as a pharmaceutical ingredient.
- Contraindications: G6PDH deficiency [193]. Nephrolithiasis patients or with history of nephrolithiasis; hyperoxaluria; patients with severe kidney failure or kidney failure; hemochromatosis [194]. There are no controlled studies regarding the use of ascorbic acid in pregnant women; ingestion of high doses of the vitamin in pregnant women can produce scurvy in the newborn. Ascorbic acid is excreted in breast milk; there is insufficient data on the effects of ascorbic acid supplementation in newborns. The product should only be administered during pregnancy or lactation when considered essential by the doctor. The recommended dose should not be exceeded, as chronic overdose can be harmful to the fetus and newborn. There is no evidence to suggest that normal endogenous levels of ascorbic acid cause adverse reproductive effects in humans [194].
- Drug interaction: Oral anticoagulants such as warfarin and acenocoumarol: their action could be modified by ascorbic acid in large doses. Deferoxamine: concurrent use with high doses of ascorbic acid may potentiate iron tissue toxicity, with impaired cardiac function, causing cardiac decompensation; ascorbic acid should not be administered during the first month of deferoxamine treatment. Cyanocobalamin (vitamin B12): ascorbic acid in large doses may reduce the amounts of cyanocobalamin available in serum and reserves; ascorbic acid is recommended to be administered at least 2 h after meals. Indinavir (protease inhibitors): high doses of ascorbic acid significantly decrease the plasma concentration of indinavir, with a probable reduction in its efficacy. Cyclosporine: limited data suggests that antioxidant supplements like ascorbic acid may lower cyclosporine blood levels. Disulfiram: chronic or high doses of ascorbic acid can interfere with the effectiveness of disulfiram. Iron: ascorbic acid can increase iron absorption, especially in people with iron deficiency; small incremental increases in iron may be important in subjects with conditions such as hereditary hemochromatosis or in subjects who are heterozygous for this condition, as it may exacerbate iron overload [194].
- Adverse effects: Metabolism and nutrition disorders: in especially predisposed patients, gouty arthritis may occur, and uric acid stones may form. Nervous system disorders: headache, insomnia. Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal and gastrointestinal pain. Renal and urinary disorders: the administration of ascorbic acid in individuals predisposed to increased stone formation has been associated with the production of oxalate, urate or cystine stones, or precipitation of drugs in the urinary tract; subjects with the highest risks are those with renal impairment [194].
- Contraindications: The safety of ferulic acid in children, pregnant women, or nursing mothers has not been established, therefore precaution is to be taken for these groups [195].
- Drug interaction: One animal study (mice) showed that ferulic acid increases the blood levels of the anticoagulant clopidogrel, increasing the risk of bleeding and bruising, but this was yet not confirmed in humans [197].
- Adverse effects: Not currently reported for humans by oral route.
- Safety: EFSA has provided safety evaluation on resveratrol (safe up to 150 mg/day) [198].
- Contraindications: Resveratrol might slow blood clotting and increase the risk of bleeding in people with bleeding disorders. Resveratrol might have estrogen-like actions—if the patient has any condition that might be made worse by exposure to estrogen, use is not recommended [199].
- Drug interaction: Resveratrol may interact with carbamazepine and other substrates of CYP3A4 [200].
- Adverse effects: Not currently reported [199].
- Safety: Spirulina maxima is classified by the Dietary Supplements Information Expert Committee (DSI-EC) of the United States Pharmacopeial Convention as Class A, which indicates that the available evidence does not indicate a serious risk to health, and permits this substance has a monograph in United States Pharmacopeia and National Formulary (USP–NF) [201].
- Contraindications: Phenylketonuria (cyanobacteria may contain the amino acid phenylalanine) [202]. Information regarding safety and efficacy in pregnancy and lactation are currently not available, then spirulina should be avoided during this period [203,204]. Patients with autoimmune disorders may present adverse reactions when consuming immunostimulatory herbal preparations [205].
- Drug interaction: No interaction currently documented in vivo. Antiplatelet action was demonstrated in vitro [206].
- Safety: United States Pharmacopeia provides monograph for this substance as a pharmaceutical ingredient.
- Contraindications: This drug crosses the placenta and was measurable in the serum of infants. Use is not recommended during pregnancy unless clearly needed [212].
- Drug interaction: May alter the absorption of inhaled human insulin [212].
- Adverse effects: The most common adverse events are anaphylactoid reaction, nausea, vomiting, flushing, and skin rash [212].
- Safety: The oral LD50 for glucosamine has been estimated to be >8000 mg/kg body weight in rats and mice and >6000 mg/kg in rabbits [213].
- Contraindications: There is not enough data showing if glucosamine sulfate is safe to be used during pregnancy or while breast-feeding. Avoid use during this period. There are preliminary reports suggesting that glucosamine sulfate can increase insulin levels, which could cause an increase in cholesterol—then, the cholesterol levels should be monitored if the patient is taking glucosamine and has high cholesterol [214].
- Drug interaction: Warfarin (increases the effect, slowing blood clotting) and antineoplastic drugs such as etoposide, teniposide and doxorubicin (antagonist effect on cell division) [214].
- Adverse effects: Glucosamine sulfate can cause some mild side effects including nausea, heartburn, diarrhea, and constipation. Rare side effects are drowsiness, skin reactions, and headache [214].
- Contraindications: In case of silicon poisoning or hypersensitivity to products containing silicon [217]. There is no information available on the use of silicon during pregnancy or while breastfeeding. Avoid use during this period.
- Drug interaction: Silicon has no known severe, serious, moderate, or mild interactions with other drugs [217].
- Adverse effects: There are no known side effects associated with using silicon up to date; silicon is present in neurofibrillary tangles in Alzheimer’s disease [217].
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Glossary
C3a and C5a | complement components C3a and C5a; anaphylatoxins |
CD4+ | T helper/amplifier cells |
CD8+ | cytotoxic subpopulation of T cells |
CLR | C-type lectin receptors |
CoV | a family of viruses in which the SARS-CoV-2 strain is included |
COVID-19 | coronavirus disease 2019 |
DPP4 | dipeptidyl peptidase-4 |
dsRNA | double stranded RNA viruses |
IFN | interferon (IFN-α, IFN-γ) |
Ig | immunoglobulin (IgA, IgD, IgE, IgG, IgM) |
IKK | IκB kinase |
IL | interleukin (IL-1, IL-2, IL-6, IL-8, IL-21, etc) |
IRAK4 | interleukin-1 receptor-associated kinase-4 |
IRFs | interferon regulatory factors |
JAK-STAT | Janus kinase/signal transducers and activators of transcription |
MAD-5 | melanoma differentiation-associated protein 5 |
MAPK | mitogen-activated protein kinase |
MAVS | mitochondrial antiviral-signaling protein |
MCP-1 | membrane cofactor protein 1 |
MyD88 | myeloid differentiation primary response 88 |
NEMO | nuclear factor-kappa B essential modulator |
NF-κB | nuclear factor-κB |
NK cells | natural killer cells |
PAMPs | pathogen-associated molecular patterns |
PKCs | protein kinase C |
PPRs | pattern recognition receptors |
RIG-I | retinoic acid-inducible gene I |
S protein | spike protein |
SARS-CoV-2 | severe acute respiratory syndrome coronavirus 2 |
ssRNA | single stranded RNA viruses |
Th cells | T helper cells (Th1, Th2, Th17) |
TIRAP | toll-interleukin 1 receptor (TIR) domain-containing adapter protein |
TLR | toll-like receptors (TLR3, TLR4, TLR7) |
TNF | tumor necrosis factor (TNF-α, TNF-β) |
TRAF6 | tumor necrosis factor receptor associated factor 6 |
TRAM | TRIF-related adaptor molecule |
TRIF | TIR-domain-containing adapter-inducing interferon-β |
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Ingredients | Suggested Quantity | Action and Use (Key Points) |
---|---|---|
Transfer factors (oligo- and polypeptides from porcine spleen, ultrafiltered at < 10 kDa; Imuno TF®) | 100 mg | Immunoregulator. It can enhance the antigenic stimulus, making CD4+ Th1 cells to produce IFN-γ, IL-1 and TNF-α. It can also modulate the response to the recognition of microorganism via activation of TLR4-MD2 complex and can increase innate defense against invasive microbial/viral infection and inflammation in not previously immunized patients. It has shown a potential to decrease the level of proinflammatory IL-6, and to stimulate the release of IL-10, a cytokine that inhibits Th2 cells, thus playing a role avoiding immune hyperresponsiveness and hyperinflammatory condition [55,56,57,58]. |
Anti-inflammatory blend of natural extracts from Uncaria tomentosa, Endopleura uchi and Haematoccocus pluvialis (Miodesin®) | 800 mg | Presents anti-inflammatory properties, as it inhibits the release of cytokines (IL-1β, IL-6, IL-8, and TNF-α) and chemokines (CCL2, CCL3, and CCL5) and the expression of NF-κβ, inflammatory enzymes (COX-1, COX-2, PLA2, iNOS), and chemokines (CCL2, CCL3, and CCL5) [59,60,61]. The alkaloidal fraction of its composition (oxindoles) can play a role in immunoregulation, while triterpenoid alkaloids and quinovic acid glycosides present in the product may inhibit some DNA and RNA viruses [62]. It can also contribute to reducing the oxidative stress and to enhance phagocytosis (glycosides) [63,64]. |
Zinc (as orotate or gluconate) | 60 mg | Supports the effective function and proliferation of numerous immune cells, such as neutrophils and NK cells, as well as the humoral immune response [65,66]. Increasing concentration of intracellular zinc inhibits the replication of SARS coronavirus (SARS-CoV) and other viruses [67]. |
Selenium yeast | 48 mg (equivalent to 96 µg of Se) | Important element for optimal innate and adaptative immune response, as it stimulates T helper lymphocytes, cytotoxic T and NK cells, and macrophage phagocytosis. Deficiency of selenium induces impairment of the host’s immune system and mutation of benign variants of RNA viruses to virulence. It also has potential to help in the prevention and control of RNA viruses by amplifying the signaling functions of TLR7 [3,68,69]. |
Ascorbic acid (Vitamin C) | 300 mg | Remarkable antioxidant [70]. It can improve the functionality of immune system, reducing the severity of infections and its symptoms through the enhancement of T-cell and NK cell function and proliferation [68,71,72,73]. |
Cholecalciferol (Vitamin D3) | 20,000 IU | Possesses immunoregulatory effect that can prevent hyperinflammatory response caused by respiratory tract infections, as it increases lymphocytes T and B proliferation and maturation, as well as immunoglobulins production [68,74,75,76]. It presents antiviral and antibacterial effects [77]. The restoration of Vitamin D normal levels reduces the rates of C-reactive protein, which is estimated to reduce in nearly 15% the severe COVID-19 cases [78]. |
Trans-resveratrol | 90 mg | Potent antioxidant. It can activate NK cells, suppress TLR4 and proinflammatory genes’ expression, and reduce NF-kB, with decrease in the expression of TNF-α, IL-1, IL-6, metalloproteases (MMP-1 and MMP3) and Cox-2 [79,80,81,82]. It also presents potential to reduce virus entrance in the cells, and can act synergistically with zinc to decrease the virus replication rate [83,84]. |
Ferulic acid | 480 mg | Participates in the activation of TLR7, induction of heme oxygenase-1 (HO-1) activity, and prevention and control of RNA virus infections by amplifying the signaling functions of TLR7 and MAVS [3]. |
Spirulina (Spirulina máxima) | 800 mg | Possesses a direct effect on both innate (activation of macrophage and NK cells) and specific immunities (regulation of T cells and increased production of antibodies) [68,85,86]. Phycocyanobilins present in spirulina may have potential for boosting type 1 IFN response in the context of RNA virus infection [3]. |
N-Acetylcysteine | 560 mg | Helps to prevent and control RNA virus infections by amplifying functions of TLR7 and mitochondrial antiviral-signaling protein (MAVS) in evoking type 1 IFN production [3]. |
Glucosamine sulfate potassium chloride | 610 mg | May upregulate MAVS activation, therefore it may play a role in the prevention and the control of RNA virus infections [3]. |
Maltodextrin-stabilized orthosilicic acid (SiliciuMax®) | 400 mg (equivalent to ≡ 6 mg of Si) | Silicon can potentially provide a net increase in circulating lymphocytes and immunoglobulins (especially IgG) [87]. |
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Ferreira, A.O.; Polonini, H.C.; Dijkers, E.C.F. Postulated Adjuvant Therapeutic Strategies for COVID-19. J. Pers. Med. 2020, 10, 80. https://doi.org/10.3390/jpm10030080
Ferreira AO, Polonini HC, Dijkers ECF. Postulated Adjuvant Therapeutic Strategies for COVID-19. Journal of Personalized Medicine. 2020; 10(3):80. https://doi.org/10.3390/jpm10030080
Chicago/Turabian StyleFerreira, Anderson O., Hudson C. Polonini, and Eli C. F. Dijkers. 2020. "Postulated Adjuvant Therapeutic Strategies for COVID-19" Journal of Personalized Medicine 10, no. 3: 80. https://doi.org/10.3390/jpm10030080