By Deborah Clark, BSPharm, RPh, PCCA Clinical Compounding Pharmacist; Sebastian Denison, RPh, FAARM (candidate), PCCA Clinical Compounding Pharmacist; Yi Liu, PharmD, PhD, PCCA Research Pharmacist; and Matthew Glisch, PharmD (candidate), PCCA Clinical Services Intern

This article was updated September 28, 2020

COVID-19 has changed many aspects of our lives as individuals and as practitioners. The novel coronavirus, SARS-CoV-2, has presented many challenges to entire health care systems. Since patients with the virus had not been treated before, treatment protocols had to be developed from prior experience with viruses that have similar genomics to SARS-CoV-2. As the outbreak has swept across various countries in turn, we learn more and more. Professional organizations, such as the American Society of Health System Pharmacists (ASHP), have collected data on various agents that are being studied for the treatment of SARS-CoV-2. Treatment and scientific data are evolving quickly as we navigate this pandemic, making recommendations challenging. PCCA Clinical Services has received questions regarding treatment options for COVID-19 daily since the beginning of March 2020. As always, we’re providing information based on the best scientific evidence available. In this article, we will first review some of the research into the morbidity, mortality and pathogenicity of SARS-CoV-2. Then, we will explore some potential non-prescription and prescription options based on research.

Please note that we collected the information presented in this article in March, April and May 2020, and since we are gaining new knowledge on this subject all the time, new studies, reviews and analyses likely have been published since we wrote this. Therefore, we present this information as a starting point and encourage you to stay abreast of the evolving research landscape that is developing around SARS-CoV-2.

Illustration of SARS-CoV-2 from the Centers for Disease Control and Prevention (CDC).

Morbidity, Mortality & Pathogenicity of SARS-CoV-2

As this pandemic has played out, certain morbidity and mortality trends have emerged. The original group of individuals thought to be more at risk included individuals who are 65 years of age or older and those with chronic conditions, such as cardiovascular disease, diabetes mellitus, asthma and a compromised immune system. Interestingly, this original grouping was not entirely correct. As age demographics were collected, it became clear that all age groups were susceptible to the possibility of severe effects from COVID-19. There were several reports of elderly individuals who had mild cases of COVID-19 and younger individuals in their 20s and 30s with more severe cases that placed them in the ICU.

What factors make some younger people susceptible to severe cases? According to a research team from Italy, nutritional status appears as a relevant factor influencing the outcomes of patients with COVID-19. ¹ Uncontrolled hyperglycemia, with or without the diagnosis of diabetes, also is a factor significantly affecting mortality rates in COVID-19 patients.² Higher body mass index is also associated with poor prognosis, especially in patients with comorbidities.¹ From this data, we can conclude that overall well-being, food quality and lifestyle can affect outcomes.

When SARS-CoV-2 infects an individual, it binds to the epithelial cells in the nasal cavity and starts replication. There is a local propagation of the virus and suppression of the initial innate immune response. ³ Usually, this occurs within the first one to two days. Over the next few days, the virus continues to spread along the respiratory tract, causing a “robust” immune response. Laviano et al. state that COVID-19 patients show an increased inflammatory response upon hospital admission.¹ COVID-19 patients possess different levels of cytokines and chemokines at different points in the progression of this disease. There are increases in numerous inflammatory markers, including interleukin (IL)-1β, IL-7, IL-8, IL-10, interferon (INF)-γ, macrophage inflammatory protein (MIP), and tumor necrosis factor (TNF)-α. COVID-19 patients also have high plasma IL-6. This dysregulation of the immune system accompanied by an abnormal chemokine and cytokine response can result in a “cytokine storm,” which in turn causes significant tissue damage.⁴ This is seen in more severe cases of COVID-19.

Recently, some researchers have proposed another mechanism by which the virus works. This involves an observed interaction of the virus with red blood cells. It was observed that the viral protein ORF8 and other surface proteins bind to porphyrin. At the same time, other viral proteins attack the heme found on the 1-beta chain of hemoglobin to remove the iron from it.⁵ This causes decreasing quantities of hemoglobin that are able to carry oxygen and carbon dioxide. This also increases the amount of oxidized iron in the bloodstream that adds to the oxidative-stress load already present in the body. The body tries to compensate for this overload by releasing zinc to balance it.⁶ Over time, the body can become zinc deficient. This has been indirectly validated by numerous reports from COVID-19 patients of a loss or alteration in taste and smell, which has been shown in the past to be a symptom of zinc deficiency.⁷ Some clinicians state that the symptoms they are seeing in many patients in a way mimic high altitude sickness or even malaria.

More COVID-19 information on The PCCA Blog: “ What is ‘maskne,’ and what can we do about it? ”

Potential Non-Prescription Options

Given this information, it would theoretically be a good clinical approach to consider supplements that would support the immune system, reduce the inflammatory response and complement the action of any pharmaceutical interventions. Here are some potential options for clinical consideration.

Zinc

Zinc has been used to decrease the length and severity of the common cold. ⁸ It has also proven effective as adjunctive treatment in severe pneumonia in pediatric patients.⁹ Zinc is crucial for the growth, development and maintenance of immune function. It contributes to a number of innate and adaptive immune signaling pathways.¹⁰ Zinc also has antioxidant and anti-inflammatory properties.⁷ A 2020 article in The BMJ stated that “since zinc boosts the overall immune response, all patients with COVID-19 would derive some benefit from zinc supplementation, especially those with latent zinc deficiency.”¹¹ Zinc has shown activity in other coronaviruses in vitro, such as those that cause SARS, MERS and EAV. Specifically, the addition of a zinc ionophore blocks the replication of some of these viruses in cell culture.¹¹

This evidence would theoretically make zinc a supplement that could be of benefit to patients with COVID-19. To date, one article by Carlucci et al., a non-peer-reviewed retrospective study looking at hospitalized SARS-CoV-2 patients in several countries, shows promising results. Through univariant analyses, it showed that zinc sulfate as an add-on therapy to hydroxychloroquine and azithromycin did increase the frequency of patients being discharged home. It also decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. It did not affect length of hospital stay, ventilation (when used) or length of stay in ICU.¹² The clinician should consider this in making therapeutic choices.

Some researchers have proposed a dosage of 30–50 mg elemental zinc. ¹³ One should consider the oral bioavailability of the form of zinc used in an individual formulation. Also, appropriate conversion calculations should be performed in order to achieve the correct elemental zinc dosage. It is also important to remember that copper should be given in the appropriate ratio to maintain balance with zinc.

Vitamin D

Vitamin D has been proven to reduce the risk of upper respiratory tract infections, modulate innate and adaptive immunity, and enhance the expression of antioxidation-related genes (glutathione reductase and glutamate cysteine ligase modifier subunit). Vitamin D induces cathelicidins, LL-37 and defensins that can decrease viral replication rates, decreasing levels of pro-inflammatory cytokines (TNF-α and INF-γ) that can produce the inflammation associated with lung-lining injury that can progress to pneumonia. Vitamin D also increases the levels of anti-inflammatory cytokines.¹⁴

These mechanisms would theoretically make vitamin D a good candidate for supplementation. In a review by Grant et al., clinical and epidemiological findings showed serum levels of 25-hydroxyvitamin D (25(OH)D) inversely correlated with severe cases associated with pneumonia, increased production of pro-inflammatory cytokines, increased C-reactive protein (CRP), increased risk of sepsis and acute respiratory distress syndrome (ARDS). The authors of this study suggested a dosage of vitamin D3 10,000 IU daily for a month to rapidly increase circulating levels of 25(OH)D into the preferred range of 40–60 ng/mL, then take 5,000 IU daily as a maintenance dose.¹⁴

Another study by Alipio suggested a strong association between serum 25(OH)D levels and clinical outcome in patients with confirmed SARS-CoV-2 infection. This study is a retrospective, multicenter study that looked at 212 patients from three different hospitals in Southeast Asia.¹⁵ A different study also showed that CRP is a surrogate marker for severe COVID-19 and is associated with vitamin D deficiency. The authors’ findings suggest that vitamin D may reduce COVID-19 severity by suppressing the cytokine storm in COVID-19 patients.¹⁶ While the data shows a strong association in both studies, a randomized clinical trial that measures actual vitamin D levels should be done to validate this association. Vitamin D has also shown action against respiratory syncytial virus, influenza and dengue.^14,17 However, no in vitro or clinical trials have been done to determine the effectiveness of vitamin D in suppressing SARS-CoV-2 to as of May 2020.

“This dysregulation of the immune system accompanied by an abnormal chemokine and cytokine response can result in a ‘cytokine storm,’ which in turn causes significant tissue damage.”

Melatonin

Melatonin has an antioxidant effect and consistently shows anti-inflammatory activity in vitro and in human studies. In vitro, melatonin shows anti-inflammatory effects by inhibiting SIRT1, which regulates macrophages. It also inhibits NF-kB activation in T cells and lung tissue, which is involved in ARDS. Other pro-inflammatory cytokines that can be suppressed by melatonin in vitro are TNF-α, IL-1β, IL-6 and IL-8.¹⁸

Melatonin is highly effective in protecting cells from damage related to severe inflammatory conditions.¹⁹ In animal models with sepsis or ischemia-reperfusion induced acute lung injury, melatonin pretreatment showed protective effects to the lungs via reduced oxidation and inflammation.^20,21 In a lipopolysaccharide-induced acute lung injury mice model, melatonin was able to reduce the pulmonary injury and decrease the infiltration of macrophages and neutrophils into lungs by inhibiting the NLRP3 inflammasome.¹⁸ NLRP3 is known to be involved in sepsis and other hyper-inflammatory processes. However, its role in SARS-CoV-2 infection is unclear.

The previous evidence would suggest that melatonin would also be a good candidate for supplementation. A meta-analysis from 2019 showed a decrease in inflammatory markers TNF-α and IL-6 within the dosage range of 3–25 mg per day for 4–60 days.²² One note of caution, though: Melatonin can also be pro-inflammatory in patients with rheumatoid arthritis, so health care practitioners should take care when administering in these patient groups.

Vitamin C

Clinical trials have shown that vitamin C decreases the frequency, length and severity of the common cold as well as the incidence of pneumonia. ²³ One of the actions of ascorbic acid is inhibition of NLRP3 inflammasome activation.²⁴ There have been many vitamin C trials with varied results. A meta-analysis in 2019 by Hemila looked at 18 controlled trials with 2,004 patients and evaluated whether vitamin C altered the length of stay in ICU and duration of mechanical ventilation. The patients were all critically ill with mixed conditions. Most were cardiac patients; however, there were also septic, burn and pulmonary patients. In 12 trials with 1,766 patients, IV vitamin C reduced the length of ICU stay on average by 7.8%. In six trials, orally administered vitamin C reduced the length of ICU stay by 8.6%. In three trials in which patients needed mechanical ventilation for over 24 hours, vitamin C shortened the duration of mechanical ventilation by 18.2%. All differences were significant.²³

There is no direct evidence on the effects of vitamin C against SARS-CoV-2, but at least one clinical trial using a 24 Gm daily dose in COVID-19 patients is ongoing. Typical daily dosing of vitamin C ranges from 500–3,000 mg, with even higher doses used during times of acute infection. ²⁵

Transmission electron microscope image of SARS-CoV-2 (colorized blue) from the CDC .

Potential Prescription Options

As health care professionals, we must emphasize any health strategies for our patients — nutrition and supplementation, as noted above, as well as activity and sleep — and focus on treating preexisting conditions. As compounders who innovate, we have medications that we are already formulating that may have the potential to immunomodulate and prevent the cytokine storm.

Two specific drugs with which we are currently compounding have literature discussing how they each have immunomodulatory effects: naltrexone and oxytocin. Below are a few selected discussions pertaining to how they may offset the cytokine storm cascade and potentially prevent patients from significant consequences of a COVID-19 infection.

Naltrexone

In a hypothesis article, Brown and Panksepp noted that patients with preexisting conditions that are inflammatory in nature would potentially benefit from the use of naltrexone.²⁶ This hypothesis on health benefits has been borne out by multiple literature references, all pointing to immunomodulatory effects of naltrexone by regulation through the toll-like receptor (TLR) system, interacting with both TLR 4 and TLR 9. ^27,28,29 In a small study on women with fibromyalgia, low-dose naltrexone “was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF).” Although the study was limited in size, the changes were considered significant.³⁰ These findings suggest that naltrexone has the potential to modulate the secretion of inflammatory cytokines in response to intracellular TLR activity. The authors of another article noted that by anatomization of the TLRs, naltrexone causes immune cell down-regulation and, in some cases, halts production of IL-1, IL-6, TNF-α and TGF-α, as well as down-regulating and controlling IL-10 and IL-1a, thus potentially preventing the inflammatory cascade and a cytokine storm.³¹

Therefore, it may be beneficial to initiate low-dose naltrexone for any patient who has an underlying health condition, or any patient who is over the age of 45 with risk factors for future health concerns (obesity, hypertension, pre-diabetic). Practitioners might start the patient at 1.5 mg and titrate up to 4.5 mg as a target, which would be similar to a clinical trial initiated in May 2020.³²

“As compounders who innovate, we have medications that we are already formulating that may have the potential to immunomodulate and prevent the cytokine storm.”

Oxytocin

Oxytocin has long been known as the snuggle hormone, but recently, literature has shown this to be a dynamic chemical with multiple effects, including anti-anxiety properties and neuro-immunomodulatory effects.^33,34,35 In a review article, the author indicates that proper regulation of the immune system relies on appropriate oxytocin, and is involved in both humoral and adaptive immune responses.³⁶ Furthermore, another review article shows a direct effect of oxytocin levels and concomitant inflammatory cascades both centrally and in the periphery in the cardiovascular system.³⁷

This indicates that oxytocin may be useful as an adjunct treatment of COVID-19. A potential suggestion might be 24 IU of oxytocin nightly to promote sleep and decrease stress. It may even be beneficial to combine oxytocin with naltrexone in one formulation, such as PCCA Formula #13535 ( naltrexone, oxytocin and melatonin sublingual suspension ).

None of these recommendations are indicated to treat an active COVID-19 patient, but we present them to health care practitioners for clinical consideration to potentially prevent the cytokine storm that may ultimately be the decider of the outcome.

More information about the new coronavirus on The PCCA Blog: “ Hand-Washing, Nasal Sprays and Masks — What Research Is Saying ”

We are still in the midst of this pandemic, and in years to come, we will still be arguing what “should” have been done, and more importantly, how we treat those infected to minimize harm and prevent death. Currently, many strategies for treatment are controversial and will require time to properly vet and develop.³⁸ To see ASHP’s data collection on various agents that are being studied for the treatment of SARS-CoV-2, which we mentioned above, go to their COVID-19 evidence table.

Non-pharmaceutical interventions have a significant role in transmission and will continue to have a positive role in our containment of this outbreak (i.e., social distancing, wearing masks and good hand hygiene).³⁹ Pharmaceutical treatment will require better science to determine the best treatment protocols and a safe, effective vaccine, although even with over 200 individual sites researching and testing, that may still be months if not years away.^38,40 Finally, the overall well-being of the individual can play a significant role in impact and outcome, with age, weight, sex, nutritional status, preexisting conditions, and even mental health all being examined as factors.^41,45 Hopefully through continued research and ongoing global efforts, we will come to proven solutions for patients soon.
 

Deborah Clark, BSPharm, RPh, is a Clinical Compounding Pharmacist at PCCA. She previously worked in two independent hybrid pharmacies in Charlotte, North Carolina, managing compounding operations. While there, she worked with a local veterinary specialty and emergency hospital providing compounded medications for challenging veterinary patients. She also worked with the Carolina Raptor Center and several smaller veterinary clinics in the Charlotte Metro area. Deborah’s compounding experience also includes hospice, hormone replacement therapy (HRT), pain management, wound care, sterile products and pediatrics. She is certified in medication therapy management, and she is an associate member of the Society of Veterinary Hospital Pharmacists.

Sebastian Denison, RPh, FAARM (candidate), PCCA Clinical Compounding Pharmacist, received his BSc in Pharmacy at the University of British Columbia. He worked at Northmount Pharmacy in North Vancouver for 11 years, specializing in HRT, veterinary, pain and sports compounding. He also was the Manager of Pharmacy Operations with the 2010 Vancouver Winter Olympic/Paralympic Games, and then the Manager of the Whistler Olympic Village Polyclinic Pharmacy. Sebastian speaks at physician, pharmacist and other health care professional education symposiums and events. He has recently lectured for the American Academy of Anti-Aging Medicine on nutrition and pain, pharmacy compounding and collaborative practice, and alternative uses for naltrexone. Sebastian is currently completing the Metabolic Medical Institute's Fellowship in Metabolic & Nutritional Medicine.

Yi Liu, PharmD, PhD, is a research pharmacist in the Research and Development department at PCCA. She joined PCCA as a clinical pharmacy researcher in the Clinical Services department in 2018 and started her current role in 2019. Yi graduated from Ohio University with a PhD in molecular and cellular biology in 2012. She also worked as a postdoctoral research fellow in the Houston Methodist Research Institute for three years prior to starting pharmacy school. Yi received her PharmD from the University of Houston College of Pharmacy in 2019.

Matthew Glisch, PharmD (candidate), PCCA Clinical Services Intern, is pursuing his Doctor of Pharmacy at the Creighton University School of Pharmacy and Health Professions.

A version of this article was originally published in the Apothagram, PCCA’s members-only magazine.

References

1. Laviano, A. Koverech, A., & Zanetti, M. (2020). Nutrition support in the time of SARS-CoV-2 (COVID-19). Nutrition, 74. https://dx.doi.org/10.1016%2Fj.nut.2020.110834

2. Antrim, A. (2020, April 17). Study: Patients with COVID-19, diabetes, uncontrolled hyperglycemia have significantly higher mortality. Pharmacy Times. www.pharmacytimes.com/news/study-patients-with-covid-19-diabetes-uncontrolled-hyperglycemia-have-significantly-higher-mortality

3. Mason, R. J. (2020). Pathogenesis of COVID-19 from a cell biology perspective. European Respiratory Journal, 55. https://doi.org/10.1183/13993003.00607-2020

4. Tufan, A., Avanoğlu Güler, A., & Matucci-Cerinic, M. (2020). COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turkish Journal of Medical Sciences, 50(Suppl. 1), 620–632. https://doi.org/10.3906/sag-2004-168

5. Wenzhong, L., & Li, H. (2020). COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv. https://doi.org/10.26434/chemrxiv.11938173.v7

6. Read, S. A., Obeid, S., Ahlenstiel, C. & Ahlenstiel, G. (2019). The role of zinc in antiviral immunity. Advances in Nutrition, 10(4), 696–710. https://doi.org/10.1093/advances/nmz013

7. Pisano, M., & Hilas, O. Zinc and taste disturbances in older adults: A review of literature. The Consultant Pharmacist, 31(5), 267–270. https://doi.org/10.4140/TCP.n.2016.267

8. Prasad, A. S. (2008). Zinc in human health: Effect of zinc on immune cells. Molecular Medicine, 14(5–6), 353–357. https://doi.org/10.2119/2008-00033.prasad

9. Rao, G., & Rowland, K. (2011). PURLs: Zinc for the common cold — Not if, but when. The Journal of Family Practice, 60(11), 669–671.

10. Qasemzadeh, M. J., Fathi, M., Tashvighi, M., Gharehbeglou, M., Yadollah-Damavandi, S., Parsa, Y., & Rahimi, E. (2014). The effect of adjuvant zinc therapy on recovery from pneumonia in hospitalized children: A double-blind randomized controlled trial. Scientifica, 2014. https://doi.org/10.1155/2014/694193

11. Dave, V. K., & Hylton, C. A. (2020). Rapid response: Zinc supplementation and containment of COVID-19 virus pandemic. The BMJ, 368(8236). https://doi.org/10.1136/bmj.m864

12. Carlucci, P., Ahuja, T., Petrilli, C. M., Rajagopalan, H., Jones, S., & Rahimian, J. (2020). Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: Outcomes in hospitalized COVID-19 patients. MedRxiv. https://doi.org/10.1101/2020.05.02.20080036

13. McCarty, M. F., & DiNicolantonio, J. J. (2020). Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus. Progress in Cardiovascular Diseases. Advance online publication. https://doi.org/10.1016/jpead.2020.02.007

14. Grant, W. B., Lahore, H., McDonnell, S. L., Baggerly, C. A., French, C. B., Aliano, J. L., & Bhattoa, H. P. (2020). Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients, 12(4), 988. https://doi.org/10.3390/nu12040988

15. Alipio, M. (2020). Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019 (COVID-2019). SSRN. http://dx.doi.org/10.2139/ssrn.3571484

16. Daneshkhah, A., Agrawal, V., Eshein, A., Subramanian, H., Roy, H. K., & Backman, V. (2020). The possible role of vitamin D in suppressing cytokine storm and associated mortality in COVID-19 patients. MedRxiv. https://www.medrxiv.org/content/10.1101/2020.04.08.20058578v4

17. Martínez-Moreno, J., Hernandez, J. C., & Urcuqui-Inchima, S. (2020). Effect of high doses of vitamin D supplementation on dengue virus replication, toll-like receptor expression, and cytokine profiles on dendritic cells. Molecular and Cellular Biochemistry, 464 (1–2), 169–180. https://doi.org/10.1007/s11010-019-03658-w

18. Zhang, R., Wang, X., Ni, L., Di, X., Ma, B., Niu, S., Liu, C., & Reiter, R. J. (2020). COVID-19: Melatonin as a potential adjuvant treatment. Life Sciences, 250. https://doi.org/10.1016/j.lfs.2020.117583

19. Favero, G., Franceschetti, L., Bonomini, F., Rodella, L. F., & Rezzani, R. (2017). Melatonin as an anti-inflammatory agent modulating inflammasome activation. International Journal of Endocrinology, 2017. https://doi.org/10.1155/2017/1835195

20. Chen, H.-H., Chang, C.-L., Lin, K.-C., Sung, P.-H., Chai, H.-T., Zhen, Y.-Y., Chen, Y.-C., Wu, Y.-C., Leu, S., Tsai, T.-H., Chen, C.-H., Chang, H.-W., & Yip, H.-K. (2014). Melatonin augments apoptotic adipose-derived mesenchymal stem cell treatment against sepsis-induced acute lung injury. American Journal of Translational Research, 6(5), 439–458.

21. Wang, M.-L., Wei, C.-H., Wang, W.-D., Wang, J.-S., Zhang, J., & Wang, J.-J. (2018). Melatonin attenuates lung ischaemia-reperfusion injury via inhibition of oxidative stress and inflammation. Interactive Cardiovascular and Thoracic Surgery, 26(5), 761–767. https://doi.org/10.1093/icvts/ivx440

22. Zarezadeh, M., Khorshidi, M., Emami, M., Janmohammadi, P., Kord-Varkaneh, H., Mousavi, S. M., Mohammed, S. H., Saedisomeolia, A., & Alizadeh, S. (2019). Melatonin supplementation and pro-inflammatory mediators: A systematic review and meta-analysis of clinical trials. European Journal of Nutrition. Advance online publication. https://doi.org/10.1007/s00394-019-02123-0

23. Hemilä, H. (2004). Vitamin C supplementation and respiratory infections: A systematic review. Military Medicine, 169(11), 920–925. https://doi.org/10.7205/milmed.169.11.920

24. Choe, J.-Y., & Kim, S.-K. (2017). Quercetin and ascorbic acid suppress fructose-induced NLRP3 inflammasome activation by blocking intracellular shuttling of TXNIP in human macrophage cell lines. Inflammation, 40(3), 980–994. https://doi.org/10.1007/s10753-017-0542-4

25. Alschuler, L., Weil, A., Horwitz, R., Stamets, P., Chiasson, A. M., Crocker, R., & Maizes, V. (2020). Integrative considerations during the COVID-19 pandemic. Explore. Advance online publication. https://doi.org/10.1016/j.explore.2020.03.007

26. Brown, N., & Panksepp, J. (2009). Low-dose naltrexone for disease prevention and quality of life. Medical Hypotheses, 72 (3), 333–337. https://doi.org/10.1016/j.mehy.2008.06.048

27. Selfridge, B. R., Wang, X., Zhang, Y., Yin, H., Grace, P. M., Watkins, L. R., Jacobson, A. E., & Rice, K. C. (2015). Structure-activity relationships of (+)-naltrexone-inspired toll-like receptor 4 (TLR4) antagonists. Journal of Medicinal Chemistry, 58(12), 5038–5052. https://doi.org/10.1021/acs.jmedchem.5b00426

28. Cant, R., Dalgleish, A. G., & Allen, R. L. (2017). Naltrexone inhibits IL-6 and TNFα production in human immune cell subsets following stimulation with ligands for intracellular toll-like receptors. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2017.00809

29. Voogdt, C. G. P., & van Putten, J. P. M. (2016). The evolution of the toll-like receptor system. In D. Malagoli (Ed.), The Evolution of the Immune System: Conservation and Diversification (pp. 311–330). Academic Press. https://doi.org/10.1016/B978-0-12-801975-7.00013-X

30. Parkitny, L., & Younger, J. (2017). Reduced pro-inflammatory cytokines after eight weeks of low-dose naltrexone for fibromyalgia. Biomedicines, 5(2). https://doi.org/10.3390/biomedicines5020016

31. Imai, Y., Kuba, K., Neely, G. G., Yaghubian-Malhami, R., Perkmann, T., van Loo, G., Ermolaeva, M., Veldhuizen, R., Leung, Y. H. C., Wang, H., Liu, H., Sun, Y., Pasparakis, M., Kopf, M., Mech, C., Bavari, S., Peiris, J. S. M., Slutsky, A. S., Akira, S., … Penninger, J. M. (2008). Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell, 133(2), 235–249. https://doi.org/10.1016/j.cell.2008.02.043

32. Sims, M. (2020). Study of immunomodulation using naltrexone and ketamine for COVID-19 (SINK COVID-19) [NCT04365985]. https://clinicaltrials.gov/ct2/show/NCT04365985

33. Jurek, B., & Neumann, I. D. (2018). The oxytocin receptor: From intracellular signaling to behavior. Physiological Reviews. https://doi.org/10.1152/physrev.00031.2017

34. Koch, S. B. J., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2016). Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacology, 41(8), 2041–2051. https://doi.org/10.1038/npp.2016.1

35. Yuan, L., Liu, S., Bai, X., Gao, Y., Liu, G., Wang, X., Liu, D., Li, T., Hao, A., & Wang, Z. (2016). Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. Journal of Neuroinflammation, 13. https://doi.org/10.1186/s12974-016-0541-7

36. Wang, Y.-F. (2016). Center role of the oxytocin-secreting system in neuroendocrine-immune network revisited. Journal of Clinical & Experimental Neuroimmunology, 1 (1).

37. Wang, P., Wang, S. C., Yang, H., Lv, C., Jia, S., Liu, X., Wang, X., Meng, D., Qin, D., Zhu, H., & Wang, Y.-F. (2019). Therapeutic potential of oxytocin in atherosclerotic cardiovascular disease: Mechanisms and signaling pathways. Frontiers in Neuroscience. https://doi.org/10.3389/fnins.2019.00454

38. Kakodkar, P., Kaka, N., & Baig, M. N. (2020). A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus cisease 2019 (COVID-19). Cureus, 12 (4). https://doi.org/10.7759/cureus.7560

39. Lai, S., Ruktanonchai, N. W., Zhou, L., Prosper, O., Luo, W., Floyd, J. R., Wesolowski, A., Santillana, M., Zhang, C., Du, X., Yu, H., & Tatem, A. J. (2020). Effect of non-pharmaceutical interventions to contain COVID-19 in China. Nature. https://doi.org/10.1038/s41586-020-2293-x

40. U.S. Food & Drug Administartion. (2020, May 12). Coronavirus Treatment Acceleration Program (CTAP). https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap

41. Centers for Disease Control and Prevention. (n.d.) Groups at higher risk for severe illness. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.