Zinc Iodide in combination with Dimethyl Sulfoxide for treatment of SARS-CoV-2 and other viral infections
Ba X Hoang MD, PhD, Bo Han MD, Willian Fang M.S., B.S, Huy Q Hoang MD
Zinc Iodide and Dimethyl Sulfoxide composition is proposed as therapeutic agents to treat and prevent chronic and acute viral infection including SARS-CoV-2 infected patients. The therapeutic combinations have a wide range of virucidal effect on DNA and RNA containing viruses. Besides the virucidal effects, the therapeutic compound also exhibits an anti-inflammatory, immunomodulating, antifibrotic, antibacterial, antifungal and antioxidant effects. The therapeutic compound can be used as an effective and safe antiseptic and disinfectant for human and animals.
COVID-19 pandemic caused by SARS-CoV-2 virus a type of Coronavirus is posing a worldwide threat with its high infectivity and virulence. 1Globally, the virus has already caused a costly number of hospitalizations and deaths resulting in many countries taking quarantine actions, to limit the spread of infection. The WHO declared the disease the sixth public health emergency, and then recently declared the coronavirus outbreak a pandemic.2
There is currently no cure for this disease, meaning there are no approved antiviral drugs or vaccine options available for treatment besides symptomatic therapy. Companies and researchers across the world are dedicating their time and effort into finding an effective therapy for COVID-19, but this may take far too long. Patients with severe cases are getting supportive care, managing life threatening symptoms of viral pneumonia and acute respiratory distress syndrome (ARDS). Even with medical professionals working day and night, the death toll has been steadily increasing, with more and more countries being infected. There is an urgent need for effective, safe, inexpensive and readily available therapeutic approach for SARS-CoV-2 and viral infection.
Zinc as antiviral agent
Positive-stranded RNA (+RNA) viruses are the single largest group of RNA viruses including many infectious pathogens. They have evolved a variety of replication strategies but share the same mechanism that an RNA-dependent RNA polymerase (RdRp), functions as the core enzyme of their RNA-synthesizing machinery. Given their crucial function in the viral replicative cycle, RdRps are key targets for antiviral research.
Zinc ions and zinc-ionophores, have previously been described as potent inhibitors of various RNA viruses. These compounds have shown efficacy in disrupting the replication pathway, showing antiviral effect. Increasing intracellular Zinc ion and administration of zinc ionophores have been shown to impair replication of a wide range of viruses including rhinoviruses3, influenza4, coxsackievirus5, mengovirus6, picornavirus6, herpes7, and even corona viruses8.Krenn et al. demonstrated that two metal ion binding compounds (zinc ionophores), pyrithione and hinokitiol causes a rapid import of extracellular zinc into the virus. Increased intracellular Zn2+ concentrations have been shown to efficiently impair replication of RNA viruses by interfering with correct proteolytic processing of viral polyproteins. A study by TeVelthuis et al.8 has shown that coronavirus replication can be inhibited by increased Zn2+ levels by inhibiting SARS-CoVRdRp activity during the elongation phase of RNA synthesis, without demonstrating detectable cytotoxicity. The mechanism of action is hypothesized that the zinc ions directly affect template binding. However, in other studies, zinc ions seemed to locate into the mitochondria, and the mechanism of inhibition is unclear.6 Other studies had noted an inhibitory effect of Zn2+ on the activity of purified RdRps from rhinoviruses and hepatitis C virus, but not investigated in any detail.9, 10
Zinc as immune supporter
Zinc is an essential trace element for humans and serves as a cofactor in many transcription factors and enzymes that play a critical role in growth and development, metabolism, immune function, and wound healing.11 This mineral is found throughout the body, in the cells, and is needed as the central ion for over >300 enzymes to work.12 Additionally, it plays a huge part in normal immune function. This micronutrient is crucial for maintaining homeostasis of both innate and adaptive immune systems and its deficiency is correlated with compromised immune cell development and functions.13 One of the major clinical symptoms in zinc deficient patients is depressed immunity, which leads to adverse clinical outcomes including increased infections and frequency of disease.13
Studies have shown that zinc is necessary for the activity of immune mediators including cytokine activity, contribute to membrane stabilization, and a major intracellular regulatory of lymphocyte apoptosis.13 Clinically, the use of zinc has been proven effective against infectious diseases in the human population. After supplementing zinc in the elderly population, there was a significant decrease of infections in 12 months compared to the placebo group.14 Randomized double blinded placebo-controlled trials have shown that daily zinc supplementation can reduce the incidence and duration of chronic diarrhea by 25-30%15, reduce rates of acute respiratory infection up to 45%16, and can even decrease the duration of the common cold.17
Zinc as anti-inflammatory and antioxidant
Clinical trials for Zinc supplementation have also demonstrated decreased oxidative stress biomarkers and decreased inflammatory cytokines in the elderly with zinc supplementation.14 In the experimental model of zinc deficiency in humans, the investigators showed that zinc deficiency per se increased the generation of IL-1β and its mRNA in human mononuclear cells following LPS stimulation. Zinc supplementation also upregulates A20, a zinc transcription factor, which inhibits the activation of NF-κB.18 NF-κB pathway is the prototypical proinflammatory signaling pathway in cellular responses.19 Downregulating this pathway leads to a decreased generation of inflammatory cytokines. Controlling oxidative stress and chronic inflammation is important because they are contributing factors for several chronic diseases attributed to aging, such as atherosclerosis and related cardiac disorders, cancer, neurodegeneration, immunologic disorders and the aging process itself.20
Iodine is an extremely effective broad-spectrum antiseptic with low toxicity.21 Iodine has very high germicidal activity targeting bacterial exotoxins and enzymes,22 making developing resistance difficult.23Fischer et al.24 demonstrated that after a single dose of oral potassium iodide to a human subject increased serum I- concentrations and resulted in the increase of I- in the upper airway secretion. The increased concentration of iodide in the demonstrates robust activity against two major respiratory viral pathogens, adenovirus, and RSV. This study suggests by using an iodide compound to activate the lactoperoxidase/I2/ H2O2 system can contribute to airway antiviral defense, and the delivery of I- to airway mucosa may augment innate antiviral immunity.
There have been many historical reports of immune deficiencies among populations of iodine-deficient people.25 A lack of iodine is widespread in modern dietary and lifestyle, with high dietary perchlorate, glucosinolate, thiocyanate, calcium nitrate, cobalt and rubidium interfere with iodine metabolism and may increase iodine requirements.26 Household hygiene products such as chlorine containing beach and fluoride in water and toothpaste further depletes iodine in our body.27 Leukocyte myeloperoxidase enzyme uses iodine in cell-mediated immunity and is an important component of many immune cells.28 Additionally, iodides also has many other biologic effects including regulating inflammation, improving phagocytosis of bacteria by immune cells, and boosting the innate immune system.26 Iodine molecules are difficult to transport, with high instability, since they tend to tend to sublimate.
Dimethyl sulfoxide (DMSO) is an all-natural substance derived from wood pulp. It was discovered in 1963, that the compound could penetrate the skin and other membranes without damaging them and could carry components into the biological system. DMSO is commonly used as a solvent to dissolve water-insoluble drugs or test samples in both in vivo and in vitro experiments. DMSO can readily induce oxidative stress, raise oxygen levels, and act as an antiviral agent.29, 30 This compound has shown to revise septic conditions associated with viral infection-induced dysregulated immuno‐inflammatory responses.31, 32 Mechanistically, DMSO is a potent antioxidant that can regulate transcription factor activation in septic animals, and act as a carrier for other drugs. Several studies have been done on the effect of DMSO infusion for patients with cancer, showing efficacy with limited side effects.33 Intra-venous infusion of DMSO with sodium bicarbonate brought on symptomatic relief in patients with metastatic prostate cancer,34 and demonstrated better pain control for refractory cancer pain.35
Zinc Iodine-DMSO therapeutic compound
In the current treatment plan, we are using a combination of Zinc Iodide ( ZnI2 )with Dimethyl Sulfoxide for the prevention and treatment of viral infection and sepsis. The therapeutic compound combines the 2 ingredients ZnI2 and DMSO, and has demonstrated strong synergetic efficacy in controlling symptoms, preventing, and treating all types of viral infection and sepsis.
The dose of ingredients in the current therapeutic compound is:
The therapeutic compound in the current invention can be manufactured into an oral liquid, soft gel, suspension, aerosol, nasal and oral sprayers, gel or cream for oral and oral topical use, transdermal application, eye or ear drops, rectal suppositum, intramuscular injection, intravenous administrations, and nebulization.
Example 1: The compound for oral administration can be formulated as the following:
5 grams (5000 mg) of Zinc Iodide with purity of 99.4% to 99.9 % mixing with 1000 ml of 50% Dimethyl sulfoxide solution. (Compound ZnDM-O).
Example 2: The compound for intravenous application can be formulated as the following
5 grams (5000 mg) of Zinc Iodide with purity of 99.8%-99.9% mixing in 1000 ml of Dimethyl Sulfoxide 99.9 % pharmaceutical grade solution. (Compound ZnDM-IV).
Example 3: The compound for nasal, oral sprayers can be formulated as the following
Zinc Iodide: 2000 mg, DMSO pharmaceutical grade (99.8%-99.9%): 100ml, water 900 ml. (Compound ZnDM-SP)
Example 4: The compound for aerosol use or via nebulization can be formulate as the following
Zinc Iodide 1000 mg, DMSO pharmaceutical grade (98.8%-98.9%) 200 ml and water for injection 800 ml ( CompoundZnDM-AN)
Clinical cases examples:
Even though we have not tried Zinc Iodide-DMSO treatment for SARS-CoV-2 infected patients, we report herein briefly 6 patients with similar pathologies and clinical features of COVID-19. The anecdotal evidence showed a viable clinical efficacy and good safety profile of Zinc Iodide-DMSO treatment for respiratory viral infections and complications of the diseases.
A 65-year-old male patient with a history of lung cancer was admitted with complaints of non-productive cough, sneezing, headache, chest pain, muscle pain breathing difficulty. He had tachycardia with heart rate of 115 per minute, respiratory rate 36 breaths per minute, oxygen saturation 86% with oxygen therapy and, fever of 38-39°C for the last 3 days. The patient had been taking antibiotic (penem and vancomycin), cough medicines, and antipyretics for the last 3 days, but his conditions and symptoms were not improved.
A chest X-ray examination showed right side pneumonia and pleural effusion of the left and right side of the lung. The patient had been treated on admission with penem and vancomycin despite his normal leucocyte count with adding of Dexamethasone 20 mg daily and oral Tamiflu. After 24 hours, the patient’s general condition and symptoms were not improved. His liver enzymes and blood lactate levels were elevated, and serum creatine increased. The patient had also developed thrombocytopenia and leukopenia. The patient was diagnosed with viral pneumonia and possible pre-septic condition. His fever was 39.5°C in 3 hours after 1000 mg of paracetamol intravenous infusion.
The patient started treatment with an infusion of 20 ml of the Compound ZnDM-IV mixing with 500 ml of Sodium Chloride 0.9% with a speed of 50 drops per 1 minute. In 5 hours after infusion, the patient’s fever had dropped to 37.6 °C without antipyretic drugs. The patient was then recommended to stop antibiotic treatment, dexamethasone, and Tamiflu, and continued with ZnDM-IV solution of 15 ml mixing with 500 of Sodium Chloride every 12 hours for the next 4 days. His symptoms remarkably improved after 48 hours after treatment with more than 50% reduction in coughing, chest pain, respiratory distress, and fatigue. His fever was completely controlled in 72 hours.
The patient continued treatment with ZnDM -IV 20 ml mixing with 500 ml of sodium chloride 0.9% every 24 hours for 10 more days. During this period of treatment with ZnDM-IV, his symptoms continued to improve, as well as his general health status.
Chest X-ray examination 15 days after treatment with ZnDM-IV showed more than 80% reduction in left-side pneumonia and 60% reduction in both side pleural effusion. The leucocyte count and blood lactate level were in normal ranges. The patient’s thrombocytopenia, liver enzymes, and creatine had all decreased compared to before ZnDM-IV treatment data.
A 69-year old man presented with high fever, sore throat and unproductive cough lasting for 5 days. The patient was diagnosed as influenza A infection. The patient had a long history of smoking and COPD. He took no specific treatment but food supplements and herbal medicines for his COPD symptoms control. The patient had received antibiotics, solumedrol infusion, paracetamol orally, bronchodilator nebulization and Tamiflu. Despite the treatment, his fever and cough remained in 3 days after starting the treatment. On the 4th days, the patient developed acute respiratory failure with SpO2 87% on 6 L/minute Oxygen mask. Chest X-gray examination revealed sign of pneumonia and pathogens were detected in the sputum. The patient started treatment with nebulization of 5 ml of ZnDM-AN with oxygen every 4 hours. After 2 treatments with ZnDM-AN, his fever, cough was remarkably improved and SpO2 was raised to 94% with 3 L/Minute Oxygen mask. After 4 treatments with ZnDM-AN, the patient had no fever and needed no more antipyretic drugs. The dose of solumedrol was reduced to 50% and the drug was totally eliminated after 8 days of treatment.
The patient continued treatments with ZnDM-AN nebulization 4 times daily and he was free from oxygen therapy and corticosteroids in 5 days after starting the treatment. The chest X-ray examination in 7 days of treatment showed the remarkable improvement in pneumonia (inflammatory reaction) and breathing capacity of the lung. The patient was discharged from hospital with no symptoms of pneumonia and had satisfactory lung function in 21 days from the start of treatment with ZnDM-AN.
A 43-year-old male presented with a fever of 38.5°C, dyspnea, myalgia, dry cough, and severe sneezing. His symptoms began 12 hours before and were significantly getting worse. The patient had a past medical history of gastritis, stomach ulcers, and chronic active hepatitis B. Patient had been taking antiviral for the last 2 years. Because of his liver disease, the patient was unable to take any antipyretic drugs for his current symptoms. The patient was diagnosed with respiratory viral infection and started treatment with ZnDM-O 5 ml mixing with 150 ml of water every 8 hours. After 6 hours of treatment with ZnDM-O, all symptoms related to the current disease improved significantly, and his fever was reduced to 37.6°C without antipyretic therapy. The patient continued to take ZnDM-O 5 ml, 3 times a day for 6 days. His symptoms related to respiratory viral infection were completely controlled in 72 hours. The patient’s health status normalized in 5 days after beginning treatment with ZnDM-O.
An 82-year-old female with a history of breast cancer with no history of specific treatment presented with congestive heart failure, stage II kidney failure, hypotension, and type 2 insulin dependent diabetes. On admission, the patient had a fever of 39 °C, severe dry cough, sore throat, myalgias, chest and nasal congestion, tachycardia with heart rate of 114 beats per minute, and respiratory rate of 32 breaths per minute. Despite prior treatment with Paracetamol total dose of 3000 mg, the patient’s symptoms had not improved. The patient’s blood count was normal, and biochemistry panel showed remarkable elevation of C-reactive protein to 146 mg/L, SGPT to 121 IU/L, SGOT to 114 IU/L. The patient’s chest X-ray examination revealed no sign of pneumonia and reduction of lung volumes.
The patient started treatment with 4 ml of ZnDM-O every 6 hours with 100 ml of water. After 6 hours of treatment, the patient’s fever decreased to 37.8 °C without antipyretic drugs. Her presenting symptoms were reduced, and after 24 hours of the therapy with ZnDM-O, the patient’s fever was down to 37.4°C, heart rate of 98 beats per minute, and respiratory rate of 28 breaths per minute.
The patient continued treatment with ZnDM-O 4 ml mixing with 100 ml of water, 3 times daily for the next 9 days. Her fever resolved completely in 72 hours of treatment, and her symptoms related to current viral infection was remarkably reduced by the 5th days of treatment. The patient has no significant symptoms related to respiratory viral infection after 10 days of treatment with ZnDM-O.
A 51-year-old female presented with acute burning pain due to vulval blisters. The patient has been diagnosed with genital herpes and took Acyclovir 400 mg 3 times a day for the last 3 days with no significant improvement of her symptoms, but a minimal reduction in the sizes of vulval blisters.
The patient started treatment with 5 ml of ZnDM-O mixing with 150 ml of water, 3 times daily.
After 6 hours of initial treatment of ZnDM-O, the patient’s pain level was reduced by more than 50%. The patients stopped taking Acyclovir and continued to take ZnDM-O 5 ml, 3 times daily mixing with 150 ml of water for the next 9 days. Her pain completely resolved in 3 days, and vulval blisters healed within 6 days of treatment of ZnDM-O.
A 76-year-old female presented with painful blisters on both sides of her face and in the mouth with a fever of 38 °C. The blisters increased in number with discharge in her face and mouth despite treatment of Acyclovir 400 mg, three times daily for 3 days. The patient started treatment with ZnDM-O 5 ml mixing with 150 ml of water 3 times daily. Her pain level reduced significantly 6 hours after beginning treatment and was completely controlled in 72 hours. The blisters and watery discharge remarkably reduced in 24 hours after treatment with ZnDM-O. The blisters were healed in 12 days of treatment.
Viral infections such as SAR-CoV-2 (COVID-19), influenza, RSV, and many others are usually associated with increased oxidative stress leading to oxidative cellular and tissue damages resulting in multi-organ failure. The proposed therapeutic combination of Zinc Iodide-DMSO can be used effectively for the treatment of SARS-CoV-2 infected patients by suppressing viral replication and virulence, decreasing inflammation and reducing organ damages. Zinc Iodide-DMSO might also be used as a preventive agent for respiratory viral infections including SARS-CoV-2 by boosting the innate immune defense and reducing pathogen infectiveness.
Further clinical trials are needed to validate the effectiveness and develop an optimal therapeutic protocol for possible application of Zinc Iodide-DMSO in patients with viral infections.
1. Jernigan DB. Update: Public Health Response to the Coronavirus Disease 2019 Outbreak—United States, February 24, 2020. MMWR. Morbidity and Mortality Weekly Report. 2020;69.
2. Luttikhuizen DT, Harmsen MC, Van Luyn MJ. Cellular and molecular dynamics in the foreign body reaction. Tissue Eng. 2006;12:1955-1970.
3. Korant B, Kauer J, Butterworth B. Zinc ions inhibit replication of rhinoviruses. Nature. 1974;248:588-590.
4. Oxford J, Perrin D. Inhibition of the particle-associated RNA-dependent RNA polymerase activity of influenza viruses by chelating agents. Journal of General Virology. 1974;23:59-71.
5. Lanke K, Krenn B, Melchers W, Seipelt J, Van Kuppeveld F. PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells. Journal of general virology. 2007;88:1206-1217.
6. Krenn B, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld F, Seipelt J. Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. Journal of virology. 2009;83:58-64.
7. Kaushik N, Anang S, Ganti KP, Surjit M. Zinc: a potential antiviral against hepatitis E virus infection? DNA and cell biology. 2018;37:593-599.
8. Te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS pathogens. 2010;6.
9. Ferrari E, Wright-Minogue J, Fang JW, Baroudy BM, Lau JY, Hong Z. Characterization of soluble hepatitis C virus RNA-dependent RNA polymerase expressed in Escherichia coli. Journal of virology. 1999;73:1649-1654.
10. Hung M, Gibbs CS, Tsiang M. Biochemical characterization of rhinovirus RNA-dependent RNA polymerase. Antiviral research. 2002;56:99-114.
11. Dardenne M. Zinc and immune function. European journal of clinical nutrition. 2002;56:S20-S23.
12. McCall KA, Huang C-c, Fierke CA. Function and mechanism of zinc metalloenzymes. The Journal of nutrition. 2000;130:1437S-1446S.
13. Maares M, Haase H. Zinc and immunity: An essential interrelation. Archives of biochemistry and biophysics. 2016;611:58-65.
14. Prasad AS, Beck FW, Bao B, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. The American journal of clinical nutrition. 2007;85:837-844.
15. Yazar AS, Güven Ş, Dinleyici EÇ. Effects of zinc or synbiotic on the duration of diarrhea in children with acute infectious diarrhea. Turk J Gastroenterol. 2016;27:537-540.
16. Rerksuppaphol S, Rerksuppaphol L. A randomized controlled trial of zinc supplementation in the treatment of acute respiratory tract infection in Thai children. Pediatric Reports. 2019;11.
17. Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews. 2013.
18. Prasad AS. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Experimental gerontology. 2008;43:370-377.
19. Lawrence T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harbor perspectives in biology. 2009;1:a001651.
20. Prasad AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Current Opinion in Clinical Nutrition & Metabolic Care. 2009;12:646-652.
21. Kelly FC. Iodine in medicine and pharmacy since its discovery—1811–1961: SAGE Publications; 1961.
22. Klossner BL, Widmer H-R, Frey F. Nondevelopment of resistance by bacteria during hospital use of povidone-lodine. Dermatology. 1997;195:10-13.
23. König B, Reimer K, Fleischer W, König W. Effects of Betaisodona® on parameters of host defense. Dermatology. 1997;195:42-48.
24. Fischer AJ, Lennemann NJ, Krishnamurthy S, et al. Enhancement of respiratory mucosal antiviral defenses by the oxidation of iodide. American journal of respiratory cell and molecular biology. 2011;45:874-881.
25. Black R. Micronutrient deficiency: an underlying cause of morbidity and mortality: SciELO Public Health; 2003.
26. Bilal MY, Dambaeva S, Kwak-Kim J, Gilman-Sachs A, Beaman KD. A role for iodide and thyroglobulin in modulating the function of human immune cells. Frontiers in immunology. 2017;8:1573.
27. Rogan W, Paulson J, Baum C, et al. Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem. Pediatrics. 2014;133:1163-1166.
28. Klebanoff SJ, Kettle AJ, Rosen H, Winterbourn CC, Nauseef WM. Myeloperoxidase: a front‐line defender against phagocytosed microorganisms. Journal of leukocyte biology. 2013;93:185-198.
29. Huang S-H, Wu C-H, Chen S-J, Sytwu H-K, Lin G-J. Immunomodulatory effects and potential clinical applications of dimethyl sulfoxide. Immunobiology. 2020:151906.
30. Chang CK, Albarillo MV, Schumer W. Therapeutic effect of dimethyl sulfoxide on ICAM-1 gene expression and activation of NF-κB and AP-1 in septic rats. Journal of Surgical Research. 2001;95:181-187.
31. Chang CK, Llanes S, Schumer W. Inhibitory effect of dimethyl sulfoxide on nuclear factor-κB activation and intercellular adhesion molecule 1 gene expression in septic rats. Journal of Surgical Research. 1999;82:294-299.
32. Guo Q, Wu Q, Bai D, et al. Potential use of dimethyl sulfoxide in treatment of infections caused by Pseudomonas aeruginosa. Antimicrobial agents and chemotherapy. 2016;60:7159-7169.
33. X Hoang B, A Levine S, G Shaw D, et al. Dimethyl sulfoxide as an excitatory modulator and its possible role in cancer pain management. Inflammation & Allergy-Drug Targets (Formerly Current Drug Targets-Inflammation & Allergy). 2010;9:306-312.
34. Hoang BX, Le BT, Tran HD, et al. Dimethyl sulfoxide–sodium bicarbonate infusion for palliative care and pain relief in patients with metastatic prostate cancer. Journal of pain & palliative care pharmacotherapy. 2011;25:350-355.
35. Hoang BX, Tran DM, Tran HQ, et al. Dimethyl sulfoxide and sodium bicarbonate in the treatment of refractory cancer pain. Journal of pain & palliative care pharmacotherapy. 2011;25:19-24.