The recent announcement by President Trump about a drug with “tremendous promise” in combating COVID-19 sent people hunting through pharmacies and physicians. Trump was referencing hydroxychloroquine, an anti-malarial medication first synthesized in 1946 that has also proved useful treating lupus and rheumatoid arthritis, often in combination with other drugs. Hydroxychloroquine is classified as a disease-modifying antirheumatic drug (DMARD) and is a safer, more potent derivative of chloroquine (4,12).

The announcement by the President came after a small French study(1,2) found evidence that the DMARD may help with the novel virus. The test has since fallen under scrutiny because the small sample size failed to be randomized or blinded; however, 13 clinical trials around the world are now studying hydroxychloroquine as a CVD-19 treatment. The FDA has not yet approved it for treatment or prevention of COVID-19 in the United States, where it is marketed under brand name Plaquenil®.

While waiting on the results of the trials, the FDA lifted years-old restrictions placed on India-based Ipca Laboratories, a manufacturer of hydroxychloroquine and chloroquine, in a bid to get more of the medication. If studies show promise the agency wants to make sure the public can actually access it. This medication is not going to be a miracle cure and does come with plenty of safety precautions. Adverse reactions can occur with just a single dose (most common in higher doses).

“Given the uncertainty around COVID-19, we understand that people are trying to find new ways to prevent or treat this virus, but self-medicating is not the way to do so.”

– Dr. Daniel Brooks

Side Effects of Hydroxychloroquine

 There have been several reports of persons over-dosing and even self-medicating with forms of chloroquine used for aquariums. Don’t do that. This drug should never be used without first consulting your doctor and is not recommended for persons with liver and/or kidney issues. The most common side effect is dizziness, and others may include:

  • headaches
  • seizures
  • nausea, vomitting, stomach pain
  • loss of appetitte, weight loss
  • pyschiatric changes, anxiety, nightmares
  • hair loss
  • slowed heart rate with QT elongation

Taking the medication with food or milk improves absorption and minimizes certain side effects. Hydroxychloroquine should never be consumed with alcohol.

 

How Does Chloroquine / Hydroxychloroquine Work?

Acids and Bases

These drugs have interesting biochemical properties that may also be effective against other viral infections. Viruses are sensitive to pH changes, and the antiviral effects of inhibiting pH-dependent steps (increasing endosomal, virus vacuole pH) required for viral replication is one mechanism of their action. Trials of several viruses including flaviviruses, retroviruses, and coronaviruses have been successful using this approach (8,9).

When a Coronavirus infects the cell, it injects a messenger RNA into the cell for ribosomes to translate it. These ribosomes will translate RNA into a protein called RNA-dependent RNA polymerase. This enzyme is inhibited by high intracellular levels of zinc . This is the hypothesized mechanism as to which zinc ionophores, such as hydroxychloroquine and natural alternatives, work to prevent the widespread replication of COVID-19.

Zinc Ionophore

Chloroquine is also a zinc ionophore (10). An ionophore chauffeurs zinc in and out of the cell. Zinc is known to inhibit viral RNA polymerase (13). It essentially limits the ability of the virus to replicate itself and overwhelm the cell. Zinc is not a novel substance that only comes into play with COVID-19, but rather an essential mineral integral to cellular processes throughout the body. The National Institutes of Health (NIH) states:

“Zinc is involved in numerous aspects of cellular metabolism. It is required for the catalytic activity of approximately 100 enzymes [1,2] and it plays a role in immune function [3,4], protein synthesis [4], wound healing [5], DNA synthesis [2,4], and cell division [4]. Zinc also supports normal growth and development during pregnancy, childhood, and adolescence [6-8] and is required for proper sense of taste and smell [9].”

 

Figure 1: Zinc passing through lipid membrane of cell with ionophore

Natural Alternatives to Hydroxychloroquine

If hydroxychloroquine / chloroquine in vitro could stop the virus, was this because the medications act as zinc ionophores? If so, its begs the question, “Do other zinc ionophores do the same thing?”

Quercetin

Dietary Sources

Quercetins are naturally occurring flavonoids. These flavonoids are found in a variety of foods, including vegetables such as onions, garlic, brassica, mustard greens, and ginger; fruit such as apples, berries, and grapes; and many seeds, nuts, flowers bark and tea leaves (17). I have personally been using quercetin for years with my patients in my functional medicine program that suffer from allergies, mitochondrial disease and for cardioprotective reasons (15,16,17,18).

Quercetin as a Zinc Ionophore

Quercetin is a zinc ionophore (13). A 2015 study found that that Quercetin shows inhibitory activity in the early stages of a wide range of influenza viruses, including H1N1 and H5N1 (14). Although influenza is not in the same family of viruses as the coronavirus, it’s plausible that a similar mechanism could apply here. There is actually some evidence that Quercetin has already proven effective at treating Ebola and Zika viruses.

Quercetin Dosage

Studies are currently being done to determine effective doses. At this time, I recommend 400mg up to twice per day.

 

Figure 2: Effect of QCT, EGCG, and CQ on the uptake of zinc cations by liposomes. Zinc-dependent fluorescence emission of FluoZin-3 encapsulated within liposomes treated with zinc cations, polyphenols, and CQ.

Epigallocatechin 3-Gallate (EGCG)

EGCG is a catechin found primarily in green tea and touted as the most effective chemopreventive polyphenol (19). A recent study found EGCG amplified the effectiveness of Quercetin as a zinc ionophore (13). This suggests that ECGC and Quercetin provide a synergistic effect with enhanced bioavailability

EGCG Dosage

There are no studies to evaluate effective doses. Until there are, I recommend 200mg to 400mg 2x/day taken with Quercetin.

A common question, “Will drinking green tea provide enough ECGC?” No, you cannot get enough only from drinking green tea. Get your hands on the standardized supplement form.

Zinc

This trace element is essential to to cell function and involved in over 100 enzymes. Zinc has long been tauted for it’s potential to support the immune system(5,6), but also plays an important role in wound healing, fertility, preventing and treating pneumonia and preserving community between neurons (memory)(7,8,9).

Zinc Format and Dosage

I recommend the zinc salt of gluconic acid in combination with the above zinc ionophores, however supply is currently limited. Other formats include glycinate and picolinate. Most people do not lack an intake of zinc, but in this case I tend to error on the side of caution and ensure and adequate supply with supplementation. I recommend 25mg 2x/day. 

Preparing Your Body is Key

Currently, there is a national shortage of ventilators and a high death rate of those that actually need to intubated. We need to take steps to prepare our body for the eventual infection of COVID-19, be prepared to reduce the ability of the virus to replicate before our immune system is overwhelmed by the pathogen.

I am in full agreement with following the guidelines as established by the CDC for primary prevention of the novel coronavirus. Until further research informs us of best practices to fight this virus, do everything possible from a biochemical standpoint to arm your body with the tools necessary to fight this pandemic with the least amount of side effects. Many of these medicines are natural, organic compounds with a high degree of safety. As I have discussed in this article, the combination of Quercetin and ECGC offer a high virus inhibiting potential with a valuable degree of safety at a time of great uncertainty. I wish you all the best.

Where Can I Buy These Products?

Quality products manufactured in a certified GMP facility should be the most important factor in influencing your purchasing decision. Although Amazon does offer some of these products, the legitimacy has been called into question. Two of my favorite brands include Xymogen and Orthomolecular Products because they adhere to the highest standards. Since there is a very high demand for the nutrients at this time, it may be quite difficult to find the recommendations above. If you are interested to purchase or prefer to use my recommendations you can email me at drbrady@viorlife.com where I can recommend my preferred products that you can purchase online available at this time.

 

References

  1. Gautret, P., et. Al, (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Jounral of Antimicrobial Agents. Accessed March 27, 2020. https://doi.org/10.1016/j.ijantimicag.2020.105949
  2. Colson, P., Rolain, JM., Raoult, D., (2020). Chloroquine for the 2019 novel coronavirus SARS-CoV-2. International Journal of Antimicrobial Agents. Volume 5, Issue 3. https://doi.org/10.1016/j.ijantimicag.2020.105923
  3. Xue, J., Moyer, A., Peng, B., Wu, J., Hannafon, B. N., & Ding, W. Q. (2014). Chloroquine is a zinc ionophore. PloS one9(10), e109180. https://doi.org/10.1371/journal.pone.0109180
  4. Xueting Yao, Fei Ye, Miao Zhang, Cheng Cui, Baoying Huang, Peihua Niu, Xu Liu, Li Zhao, Erdan Dong, Chunli Song, Siyan Zhan, Roujian Lu, Haiyan Li, Wenjie Tan, Dongyang Liu, In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clinical Infectious Diseases, , ciaa237,
  5. Shankar, A., Prasad AS (1998). Zinc and immune function: the biological basis of altered resistance to infection. AM J Clin Nutr. Aug;68(2 Suppl):447S-463S
  6. Chasapis, CT., et al. (2012). Zinc and Human Health: An Update. Arch Toxicol 2012 Apr;86(4):521-34
  7. Dardenne, M. (2002). Zinc and Immune Function. European Journal of Clinical Nutrition. 2002 Aug;56 Suppl 3:S20-3.
  8. Savarino, Adrea et al. Effects of chloroquine on viral infections: an old drug against today’s diseases. The Lancet Infectious Diseases, Volume 3, Issue 11, 722 – 727
  9. Bangdong L. Wei, Paul W. Denton, Eduardo O’Neill, Tianci Luo, John L. Foster, J. Victor Garcia. Inhibition of Lysosome and Proteasome Function Enhances Human Immunodeficiency Virus Type 1 Infection
    Journal of Virology Apr 2005, 79 (9) 5705-5712;
  10. Xue, J., Moyer, A., Peng, B., Wu, J., Hannafon, B. N., & Ding, W. Q. (2014). Chloroquine is a zinc ionophore. PloS one9(10), e109180. https://doi.org/10.1371/journal.pone.0109180
  11. Denison, M., et al (1992). Intracellular processing of the N-terminal ORF 1a proteins of the coronavirus MHV-A59 requires multiple proteolytic events. Virology Volume 189, Issue 1, July 1992, Pages 274-284
  12. Yao, X., et al (2020). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).  2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237
  13. 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 Chem2014 Aug 13;62(32):8085-93doi: 10.1021/jf5014633. Epub 2014 Jul 31. PubMed PMID: 25050823.
  14. Wu, W., Li, R., Li, X., He, J., Jiang, S., Liu, S., & Yang, J. (2015). Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry. Viruses8(1), 6. https://doi.org/10.3390/v8010006
  15. Otsuka H, Inaba M. Fujikura T, Kunitomo M (1995). Histochemical  and functional characteristics of metachromatic cells in the nasal epithelium in allergic rhinitis: studies of nasal scrapings and their dispersed cells.  1995 Oct;96(4):528-36.
  16. Haggag EG, Abou-Moustafa MA, Boucher W (2003). The effect of a herbal water-extract on histamine release from mast cells and on allergic asthma.  2003;3(4):41-54.
  17. Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M. T., Wang, S., Liu, H., & Yin, Y. (2016). Quercetin, Inflammation and Immunity. Nutrients8(3), 167. https://doi.org/10.3390/nu803016
  18. Patel RV., et al (2018). Therapeutic potential of quercetin as a cardiovascular agent.  2018 Jul 15;155:889-904. doi: 10.1016/j.ejmech.2018.06.053. Epub 2018 Jun 27.
  19. Du, G. J., Zhang, Z., Wen, X. D., Yu, C., Calway, T., Yuan, C. S., & Wang, C. Z. (2012). Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients4(11), 1679–1691. https://doi.org/10.3390/nu4111679

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