COVID Prevention Protocol

1 Scoop

once per day

Ongoing

Additional notes

"This is the very best multi-vitamin available in the world. It is expensive, but worth it. Alternates include: 1. Men's Nutrients, also listed in your shopping cart 2. Womeen's Nutrients, also listed in your shopping cart You only need to choose one of the three."

1-2 Capsules

evening

Ongoing

Additional notes

"In addition to promoting restful sleep, melatonin has been shown to reduce inflammation and may help protect the lungs. “Preventive use of Melatonin in the pandemic management. Juan Carlos Flores, Buenos Aires, Argentina ( mailto:jcflores.caidba@gmail.com ) Management of lung injury, the main cause of death in the current COVID 19 pandemics is, legitimately, one of the topics that is raising great concern worldwide. In this respect, I consider we have several objectives to pursue, namely: 1) The implementation of an effective quarantine is essential, and then “early or immediate” detection by a specific test of each suspicious subject in order to proceed to effective isolation and elaboration of national and provincial case registries 2) effective protection of health care professionals with appropriate equipment and training on the appropriate use of such equipment; studying the pathology to try and understand how the disease works and identify possible “preventive and therapeutic” targets, and 3) an algorithm-based treatment plan reached by consensus to avoid inconsistencies or acting with panic as a result of not knowing what to do or for lack of training on the plan or protocol, and finally to wait for the development of a vaccine. Here we will only deal with the “trial or prevention trial” of a drug or group of drugs in the earliest possible phase, which might change as we receive opinions, looking for consensus of suspicious subjects when early symptoms appear such as anosmia, dysgeusia, or symptoms in the risk population (cough, fever, pain, shortness of breath).We would also seek consensus of the health care staff working in these scenarios that currently have an unacceptable contagion and death rate and could be the target groups for the use of this preventive treatment. If the indication is released to the population at large there will not be sufficient stock of the drug to treat the group that develops the disease. The proposed treatment is administration of melatonin or one of its numerous agonists available in the market at a dose agreed by consensus and applying the protocol to be established by this working group is there is agreement on the potential benefit. Viral infections are often associated with immune-inflammatory injury, in which the level of oxidative stress increases significantly and has negative effects on the function of multiple organs. The application of melatonin may prolong patients’ survival time, which may provide a chance for patients’ immune systems to recover and eventually eradicate the virus. Rationale: Previous data on the use of Melatonin in the management of serious radiation-related lung injuries and infectious diseases prior to the current pandemic have shown that melatonin has proven effects as evidenced in the bibliography cited below. Melatonin has significantly reduced mortality and has helped to recover the function of the alveolar epithelium in mice treated with bleomycin. It has also been used in the prevention of breast cancer and to reduce radiotherapy- induced toxicity. An excellent work was conducted in Italy in 2013 demonstrating its role in infectious viral diseases. Apart from the pineal gland, the retina and the intestines, melatonin is produced in leucocytes, both in peripheral blood and in the bone marrow. Human lymphoid cells are an important physiological source of melatonin since resting and phytohemagglutinin stimulated human lymphocytes synthesize and release large amounts of melatonin, with the melatonin concentration in the medium increasing up to five times the nocturnal physiological levels in human serum. Carrillo-Vico A, Calvo JR, Abreu P, Lardone PJ, Garcia-Morino S, Reiter RJ, Guerrero JM. Evidence of melatonin synthesis in human lymphocytes and its physiological significance: possible role as intracrine, autocrine and/or paracrine substance. FASEB J 2004, 18:537– 539. It has also shown significant effects in the management of sepsis related to bacterial and viral conditions. Venkataramanujam Srinivasan, Mahaneem Mohamed and Hisanori Kato. Use of melatonin has been beneficial in treating premature infants suffering from severe respiratory distress syndrome and septic shock in 2012. Melatonin in Bacterial and Viral Infections with Focus on Sepsis: A Review Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2012, 6, 30-39 Melatonin significantly decreased mortality and restored the function of the alveolar epithelium in bleomycin-treated mice. However, pulmonary function mainly depends on type II alveolar epithelial cells (AECIIs) and is linked to mitochondrial integrity. We also found that melatonin reduced the production of reactive oxygen species (ROS) and prevented apoptosis and senescence in AECIIs. Lu Zhang1,2, Fang Li3 , Xiaomin Su1,2,4, Yue Li1,2, Yining Wang1,2, Ruonan Fang1,2, Yingying Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction Experimental & Molecular Medicine (2019) 51:73 LET US STOP HERE, With my highest respect, let me state that this is a summary of the proposal I am trying to make. In these times of stress and high levels of anxiety worldwide and with excess of communication, it is necessary to set the grounds for a proposal and provide concrete, actual data. I am attaching a list of publications that explain the numerous mechanisms of action of melatonin. The virus binds with high affinity (ten times higher than SARS- CoV) to the ACE2 receptor (angiotensin converter enzyme 2) to activate inflammasome NLRP3, causing a violent immune response with a potentially lethal cytokine storm. This has been taken from the brilliant summary elaborated by María Jesús Rodriguez. SARS-CoV-2 produces a huge inflammation, mostly as a result of releasing large amounts of interleukin 1β (IL-1β). In summary, melatonin has several mechanisms of action: a) Reduces the oxidative stress caused by radiation. Prevents and reduces lung lesions. This effect, not so well tolerated in the elderly, may be one of the major mechanisms. The publications on radiation-induced lung lesions provide conclusive evidence on this site and mechanism of action. Huang SH, Cao XJ, Liu W, Shi XY, Wei W: Inhibitory effect of melatonin on lung oxidative stress induced by respiratory syncytial virus infection in mice. J Pineal Res 2010, 48:109– 116. See bibliography below, all articles available in full text. b)Has very well-studied effects on ACEII. Regulates the expression of this receptor that according to Peng Zhou is greatly involved in the relation of the virus with alveolar damage. Probably, the virus acts at this level as studies point out, but there are several other mechanisms involved, such as oxidative stress, inflammation and alteration of the immune system at large. Some of them could act connected between them. The role of ACE2 is conversion of angiotensin I to angiotensin 1- 9 and angiotensin II to angiotensin 1-7. These final products have vasodilator, antifibrotic, anti-inflammatory effects and promote natriuresis. All such effects reduce blood pressure, counteracting the action of angiotensin II. It has been observed that the severe cases of COVID-19 present very high levels of antiotensin II and, in turn, the angiotensin II level has been correlated with the viral load of SARS-CoV-2 and with lungdamage. This disbalance of the renin-angiotensin-aldosteron level might be related to ACE2 inhibition by the virus. This effect was observed in the SARS outbreak in 2003 (71,72). Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. November 27, 2003;426(6965):450-4. 72. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. NatMed. August, 2005;11(8):875-9. Yadi Zhou1 , Yuan Hou1 , Jiayu Shen1 , Yin Huang1 , William Martin 1 and Feixiong Cheng1,2,3 Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS- CoV-2 Cell Discovery (2020) 6:14 Network-based identification of potential drug combinations for 2019-nCoV/SARS-CoV-2 Mercaptopurine plus Melatonin Peng Zhou1,5, Xing-Lou Yang1,5, Xian-Guang Wang2,5, Ben Hu1 , Lei Zhang1 , Wei Zhang1 , Hao-A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature | http://www.nature.com <http://www.nature.com/> 29 January 2020. c) It has proven to have a very important mechanism of action on cytokines as shown by several studies. Immuno-modulating and inhibiting actions against the production and activation of pro-inflammatory mediators. See bibliography.Rüdiger Hardeland. Aging, Melatonin, and the Pro- and Anti- Inflammatory Networks Int J Mol Sci. 2019 Mar; 20(5): 1223 J Pineal Res. 2016 Mar;60(2):193-205Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation,a target of melatonin. 1,2 1,2 1,2 1,2Volt H , García JA , Doerrier C , Díaz-Casado ME , Guerra-Librero 1,2 . A , López LC The multiple action sites and pathways of melatonin described in these publications, which are only just some examples, provide the rationale to understand why this drug has been tested in ventilator- associated respiratory distress, pneumonia and bacterial and/or viral sepsis, Ebola and others. We do not know which is the main site of action of the virus and where melatonin would have its greater benefit. Discussing it would make no sense, investigating probably would. This is what many investigators are doing and in time will communicate their conclusion. But there seems to be no doubt that Melatonin has proven effects, both in radiation-related lung lesions and in infectious diseases in children and adults as well as a preventive effect in the latency period of the disease. FINALLY, in my opinion, under the present circumstances, it is worth investigating the short-term effect of this drug that has so few side effects, of course with the informed consent of each subject in the groups proposed and having reached consensus, defining what loading and maintenance dose we would use. I suggest we discuss evaluating if we would use agonists or melatonin or one or the other interchangeably. We could contact laboratories, if necessary, to assess the availability of these substances around the world. Please find bibliography on the mechanisms of pneumonia associated with coronavirus, radiation-related pneumonitis, infectious diseases, respiratory distress and molecular mechanisms and effects of melatonin and other mediators. Please send your opinions, agreements or disagreements or whatever scheme you suggest if there is consensus. Then, I would submit a concrete proposal to analyze and define the treatment promptly. There is no editorial or commercial interest. I think it will be possible to make contributions based on the bibliography listed below. ABC PROTOCOL: Preventive use of Melatonin at risk population in the pandemic of COVID-19. Informed consent. Protocol bioethics committee. To confirm the low-risk profile of the drug and the support found in the literature to the use of the drug in prevention of severe lung lesions and other requirements. Definition of at-risk population. The drug should be taken only by the at-risk population, the rest to follow a tryptophane and melatonin rich diet (tomato, chicken, walnuts, rice and other products). Dosing. 3 mg at night: young individuals with higher levels of melatonin production. 6 mg at night: individuals over 40 with lower levels of melatonin production. 6 mg at night and 3 mg in the morning: older and high-risk individuals. Asses whether the patient tolerances the doses. Assess the equivalence of different melatonin agonists vs. melatonin and at the same time other possibilities to investigate and describe the mechanism of action. Results. Biometric data of the patient, dosing, type of melatonin to be administered, severity of initial symptoms, precocity of the initiation of treatment to identify the best timing, measuring related mediators and clinical parameters and incidence of evolution to respiratory distress with cytokine storm, or if the condition is attenuated and time is allowed for the patient immune system to respond as in younger individuals in order to confirm the scientific grounds of possible effects. Adverse effects, toxicity. Recording every drug-related event. Combining with Q 200 mg daily may be an alternative regime in older individuals with little chances of accessing mechanical ventilation, history of severe respiratory pathology and other parameters to be defined by the investigators that join this initial proposal. Keeping a comparative registry: as it is not possible to randomize or apply a double-blind or prospective approach under the present conditions, comparison could be made with colleagues that do not follow the protocol or patients that refuse the treatment, or with early access to the drug, or comparing with previous site statistics. Mandatory bibliography: 1) Silvestri, M. & Rossi, G. A. Melatonin: its possible role in the management of viral infections-a brief review. Ital. J. Pediatr. 39, 61 (2013). 1121311 2) Wu X ,Ji H ,Wang Y ,Gu C ,Gu W ,Hu L ,Zhu L . Melatonin Alleviates Radiation-Induced Lung Injury via Regulation of miR-30e/NLRP3 Axis.Oxid Med Cell Longev.2019Jan 10;2019:4087298. 3) Alicia González-González, María Dolores Mediavilla and Emilio J. ánchez-Barceló * Melatonin: A Molecule for Reducing Breast Cancer Risk Molecules 2018, 23, 36 Michela Silvestri and Giovanni A Rossi* 4) Sanchez-Barcelo EJ1,Mediavilla MD,Alonso-Gonzalez C,Reiter RJ. Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs.2012Jun;21(6):819-31. 5) Wei Hu1,2,*, Chao Deng3,4,*, Zhiqiang Ma5,*, Dongjin Wang1 , Chongxi Fan5 , Tian Li2 , Shouyin Utilizing melatonin to combat bacterial infections and septic injury British Journal of Pharmacology (2017) 174 754–768 754 6) VIVEK MEHTA, M.D. RADIATION PNEUMONITIS AND PULMONARY FIBROSIS IN NON–SMALL-CELL LUNG CANCER:PULMONARY FUNCTION, PREDICTION, AND PREVENTION Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 1, pp. 5–24, 2005 7) RUSSEL J. REITER, DARIO ACUÑA-CASTROVIEJO, DUN-XIAN TAN, AND SUSANNE BURKHARDTFree Radical–Mediated Molecular Damage. Mechanisms for the Protective Actions of Melatonin in the Central Nervous System Ann N Y Acad Sci.2001Jun;939:200-15. 8) Bagher Farhood1 , Akbar Aliasgharzadeh 1 , Peyman Amini 2 , Abolhasan Rezaeyan 3 , Alireza Mitigation of Radiation-Induced Lung Pneumonitis and Fibrosis Using Metformin and Melatonin: A Histopathological Study Medicine 2019, 55, 417 9) Lisa E. Gralinski, a Armand Bankhead III,b Sophia Jeng, b Vineet D. Menachery, a Sean Proll, c Sarah Mechanisms of Severe Acute Respiratory Syndrome CoronavirusInduced Acute Lung Injury Medicine July/August 2013 Volume 4 10) Anna Lierova1 , Marcela Jelicova1 , Marketa Nemcova1 , Magdalena Proksova2 , Jaroslav Pejchal3 , Cytokines and radiation-induced pulmonary injuries Journal of Radiation Research, Vol. 59, No. 6, 2018, pp. 709–753 11) Matthew Frieman,a Boyd Yount,b Sudhakar Agnihothram,b Carly Page,a Eric Donaldson. Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease Journal of Virology p. 884 – 897 January 2012 Volume 86 Number 2 12) Robert L. Kruse Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China F1000Research 2020, 9:72 Last updated: 18 FEB 2020 13) Geng-Chin Wu1,2, Chung-Kan Peng3 , Wen-I Liao4 , Hisn-Ping Pao1 , Kun-Lun Huang3,5* Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production Respiratory Research (2020) 21:65 14) koruyucu etkisi: Deneysel çalışma Erhan Durceylan1, Ebubekir Aksu1, Hacer Boztepe1, Protective effects of melatonin on lung damage associated with one-lung ventilation: An experimental study Melatoninin tek akciğer ventilasyonuna bağlı akciğer hasarı üzerine Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 1, pp. 5–24, 2005 15) VIVEK MEHTA, M.D Radiation Neumonitis and pulmonary fibrosis in non.small cell lung Cancer: Pulmonary function, prediction and prevention. Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 1, pp. 5–24, 2005 16) VIJAYALAXMI, PH.D.,* RUSSEL J. REITER, PH.D.,† DUN-XIAN TAN, M.D., PH.D.,† TERENCE S. MELATONIN AS A RADIOPROTECTIVE AGENT: A REVIEW Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 3, pp. 639–653, 2004 17) Gaia Favero,1 Lorenzo Franceschetti,1 Francesca Bonomini,1,2 Luigi FabrizioRodella. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation International Journal of Endocrinology 18) Srinivasan, V., Mohamed, M. & Kato, H. Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat. Endocr. Metab. ImmuneDrug Discov. 6, 30–39 (2012). 19) Tan, D. X., Korkmaz, A., Reiter, R. J. & Manchester, L. C. Ebola virus disease: potential use of melatonin as a treatment. J Pineal Res.2014Nov;57(4):381-4 20) Tan, D. X., Manchester, L. C., Terron, M. P., Flores, L. J. & One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 42, 28–42 (2007) 21) Robbins ME, Diz DI. Pathogenic role of the renin-angiotensin system in modulating radiation-induced late effects. Int J Radiat Oncol Biol Phys. (2006) 64:6–12. Prof Dr Juan Carlos Flores Doctor en Medicina FIPP CIPS Comisión Nacional de Medicina del Dolor FAAAAR Fundación Dolor AAARBA CAIDBA S.R.L. EPP Award Fundación CAIDBA Centro Médico Postgrado de Entrenamiento Universitario en Técnicas Intervencionistas CAIDBA y UNLP http://www.caidba.com.ar <http://www.caidba.com.ar/>"

2 Gels

once per day

Ongoing

Additional notes

"Curcumin has been shown to reduce inflammation and decerase viral activity for COVID-19. It also works very well to reduce bone and joint pain. You may take up to 10 per day during pain flares or for post-procedure discomfort."

3 Capsules

once per day

Additional notes

"N-acetylcysteine promotes the production of glutathione, a potent antioxidant that supports immune function. It also reduces the severity of the flu."

1 Capsule

once per day

Ongoing

Additional notes

"TAKE WITH FOOD! Otherwise may cause stomach upset. A large body of research shows that zinc has strong anti-viral properites against many viruses."

1 Capsule

twice per day

1 Capsule

once per day

Additional notes

"EGCg (epigallocatechin gallate) is a key active component of green tea (Camellia sinensis) leaves. It is valued for its antioxidant properties and has been studied extensively for weight loss through promotion of fat metabolism and for its role in supporting overall health and wellness. This formula contains green tea standardized to 45% EGCg. Made with non-GMO ingredients."

3 Capsules

twice per day

Ongoing

Additional notes

"in divided doses, with meals Take this OR Spectra Infinite Nutrition if you are a man."

3 Capsules

twice per day

Ongoing

Additional notes

"Take with meals. Take this OR Spectra Infinite Nutrition if you are a woman."

1 Capsule

once per day

Ongoing

Additional notes

"in divided doses with a meal. Can Vitamin D Help? Vitamin D levels are related to better immunity and may explain why respiratory viruses don’t impact as many people during the summer (6-10). A new study this week looked at Vitamin D levels and inflammatory markers in hospitalized COVID-19 patients in Germany, South Korea (S. Korea), China (Hubei), Switzerland, Iran, UK, US, France, Spain, Italy (11). Patients with the lowest Vitamin D levels were about 15% more likely to get severe COVID-19 and the nasty cytokine storm that everyone has been discussing. So get outside to make more Vitamin D or take 5,000 U of D3 each day, either way, this study, if it makes it through peer review, could be another arrow in the quill for why being outdoors is so critical to our health. (6) Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194–200. doi:10.1016/j.jcv.2010.12.006 (7) Leary PF, Zamfirova I, Au J, McCracken WH. Effect of Latitude on Vitamin D Levels. J Am Osteopath Assoc. 2017 Jul 1;117(7):433-439. doi: 10.7556/jaoa.2017.089. (8) Zittermann A, Pilz S, Hoffmann H, März W. Vitamin D and airway infections: a European perspective. Eur J Med Res. 2016;21:14. Published 2016 Mar 24. doi:10.1186/s40001-016-0208-y (9) Hughes DA, Norton R. Vitamin D and respiratory health. Clin Exp Immunol. 2009;158(1):20–25. doi:10.1111/j.1365-2249.2009.04001.x (10) Medscape. What is the prevalence of vitamin D deficiency in the US? https://www.medscape.com/answers/128762-54281/what-is-the-prevalence-of-vitamin-d-deficiency-in-the-us Accessed 3/21/20. (11) Daneshkhah A, et al. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv 2020.04.08.20058578; doi: https://doi.org/10.1101/2020.04.08.20058578"

2 Capsules

once per day

Take with water

Ongoing

1 Capsule

twice per day

Take with water

Ongoing