Selenium Needed for Ebola Treatment: Open Letters from University Scientists

By Richard A. Passwater, Ph.D.

October 22, 2014

 

Preliminary results from African clinics indicate that the essential mineral selenium improves Ebola outcomes and the physicians are preparing their data for submission to medical journals. (The scientific basis for using the essential nutrient selenium in the treatment of Ebola). The process of data compilation, journal review and publication is lengthy. In the meantime, several university scientist have published open letters to researchers that justify using selenium in the treatment and prevention of Ebola Hemorrhagic Fever. The World Health Organization declared in August that it is indeed ethical to use promising “unproven” treatments in Ebola patients. (http://www.nbcnews.com/storyline/ebola-virus-outbreak/who-ethics-panel-unproven-drugs-can-be-used-ebola-patients-n178391)

The open letters have been signed by university scientists from several continents including the following: Graham H Lyons B Agric Sci, Master of Public Health, PhD, University of Adelaide, South Australia; Ethan Will Taylor, PhD, Senior Research Professor, Dept. of Chemistry and Biochemistry, and Dept. of Nanoscience, University of North Carolina, Greensboro, USA; Gerhard N. Schrauzer, PhD, MS, FACN, CNC, Professor Emeritus, Department of Chemistry and Biochemistry, University of California, San Diego, CA, USA, Director, Biological Trace Element Research Institute, San Diego, CA, USA;  Margaret Rayman, BSc DPhil (Oxon) RPHNutr, Professor of Nutritional Medicine, Department of Nutrition and Metabolism, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK;  Alawode Oladele, MD, MPH, Chief Executive Officer, Global Initiative for the Advancement of Nutritional Therapy, (GIANT), Inc., Atlanta, GA, USA; Prof. Roland Gärtner, MD, Department of Internal Medicine IV, Ludwig Maximilian University, Munich, Germany; and, Lijun Zhao, MD, PhD, Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, China.

The consensus at this time (October 2014) seems to recommend using fact-acting inorganic sodium selenite (preferably via IV) during acute Ebola viral infections and for health-care workers and the general population to maintain optimal selenium levels by using organic selenium-containing compounds such as selenium-rich yeast or selenomethionine. The amounts of IV selenium suggested are described in the following open letters. The amount of selenium supplementation suggested for health-care workers is 400 micrograms daily during exposure. The amount of selenium supplementation for the general population in the selenium deficient regions is 200 micrograms daily. Excessive selenium, as with most minerals, can be toxic and long-term levels above 1,000 micrograms (1 milligram) are not recommended.

 

The Open Letters:

 

1)    Selenium needed for Ebola treatment

 by Graham H Lyons B Agric Sci, Master of Public Health, PhD

University of Adelaide, South Australia

October 2014

 

I am a micronutrient researcher who has specialised in selenium (Se) since 2001. I believe Se should be a key component of treatment for Ebola patients.  The correct use of Se in treatment for Ebola as recommended below is likely to reduce significantly the mortality rate and should be implemented as a matter of urgency.

 As an RNA virus, Ebola will be more active, and indeed will mutate to more virulent forms, in a Se-deficient host, e.g. a person with a plasma Se concentration less than around 75 micrograms/litre, a level common in Sub-Saharan Africa. As the disease progresses, in the absence of supplemented Se, the patient will become progressively more Se deficient, increasing oxidative stress/lipid peroxidation and compromising immunity (Beck et al, 1995; Beck et al, 2001; Taylor et al, 1994: Taylor et al, 1997).  In addition, Se plays a role in the regulation of blood clotting via its effects on the thromboxane/prostacyclin ratio, and effects on the complement system. Selenium has an anti-clotting effect, whereas Se deficiency has a pro-clotting or thrombotic effect. Proliferation of Ebola virus is likely to impose an unprecedented Se demand on the host, potentially leading to severe lipid peroxidation and cell membrane destruction, and contributing to haemorrhagic symptoms (Ramanathan & Taylor, 1997). People who are infected with the virus are more likely to recover if they can maintain an adequate Se status.

A role for Se in Ebola treatment is also supported by the results of Chinese researchers, who treated patients in an outbreak of viral haemorrhagic fever with oral sodium selenite, obtaining dramatic reductions in mortality: after 9 days of Se dosage, the death rate fell from 100% (untreated) to 37% (treated) in the very severe cases, and from 22% to zero in the less severe cases (Hou, 1997)

Suggested Se forms: sodium selenite or sodium selenate.

Suggested dose (based on Hou et al 1997): 2 milligrams (i.e. 2000 micrograms) of selenate/selenite per day (which equates to 800 micrograms of actual Se). Preferably, administer the Se as a split dose, eg 400 micrograms in the morning and 400 mcg in the evening, otherwise one dose of 800 mcg/day. Take orally with a cup of water (it has no taste or smell). Intravenous administration is likely to be even more effective (use same dose). Starting with selenite/selenate powder and using successive dilutions it is easy to provide the required dose in 10-50 ml of water.

Suggested duration: 10 days (followed by a maintenance dose of 0.25-0.5 of the above dose for a further 20 days).

Safety: No adverse effects would be expected at this dose over this period, or indeed up to 30 days. Doctors in Melbourne dosed prostate cancer patients with over 15 milligrams selenate per day for 2 months with minimal side-effects Corcoran et al, 2010)

Cost: using a cost of A$200 for one kilogram of selenate or selenite (and I believe it can be bought cheaper than this if 50kg+ amounts are purchased, eg from the Lewer Corporation, Sydney), an amount which would provide enough Se for 500,000 daily doses at the above recommended rate, the cost of treating one person for 10 days is around half a cent, i.e. negligible.

The main other treatment component which is likely to be effective against Ebola (especially when used in combination with Se) (Hou, 1997) is glycyrrhizin, a triterpenoid from licorice with liver protective and antiviral, anti-inflammatory and antidiabetic effects (Pu et al, 2013). Glycyrrhizin had a stronger benefit than the antiviral drug ribavirin in an animal study and was 30 times less toxic and 30 times less expensive (Utsunomiya et al, 1997). Its anti-inflammatory effect is related to its ability to inhibit the enzyme 11 beta-hydroxysteroid dehydrogenase (Asl & Hosseinzadeh, 2008). The recommended antiviral dose: 600 mg/day, preferably IV as its bioavailability will be lower via oral. There appears to be synergism between glycyrrhizin and selenium: In a mouse model, combined selenite and glycyrrhizin inhibited immune complex-mediated tissue injury more effectively than either treatment alone (Hou, 1997).

Selenium treatment (ideally together with glycyrrhizin) is urgently needed in the current Ebola epidemic. At the recommended dose it is safe, effective, inexpensive and likely to reduce mortality by at least 50%.

 

References

Beck MA, Shi Q, Morris VC & Levander OA 1995. Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nat Med 1: 433-436.

Beck MA, Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, Barclay D & Levander OA 2001. Selenium deficiency increases the pathology of an influenza virus infection. FASEB J 15: 1481-1483.

Corcoran NM, Hovens CM, Michael M, Rosenthal MA & Costello AJ 2010. Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer. Br J Cancer 103: 462-468.

Hou J-C 1997. Inhibitory effect of selenite and other antioxidants on complement-mediated tissue injury in patients with epidemic hemorrhagic fever. Biol Trace Elem Res 56: 125-130.

Pu JY, He L, Wu SY, Zhang P & Huang X 2013. Anti-virus research of triterpenoids in licorice. Bing Du Xue Bao 29: 673-679.

Ramanathan CS & Taylor EW 1997. Computational genomic analysis of hemorrhagic fever viruses. Biol Trace Elem Res 56: 93-106.

Taylor EW, Ramanathan CS, Jalluri RK & Nadimpalli RG 1994. A basis for new approaches to the chemotherapy of AIDS: novel genes in HIV-1 potentially encode selenoproteins expressed by ribosomal frameshifting and termination suppression. J Med Chem 37: 2637-2654.

Taylor EW, Nadimpalli RG & Ramanathan CS 1997. Genomic structures of viral agents in relation to the biosynthesis of selenoproteins. Biol Trace Elem res 56: 63-91.

Utsunomiya T, Kobayashi M, Pollard RB & Suzuki F 1997. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother 41: 551-556.

 

2)     To all medical personnel treating Ebola infected patients:

 

For your URGENT consideration, we are sending you this information about an established drug from Germany, approved for oral and IV use in Intensive Care and with a strong record of success for treating SEPSIS, which has similarities to Ebola virus (EBOV) pathology. The drug is called SELENASE, and is simply a sterile formulation of sodium selenite, which is also used for dietary selenium supplementation in many countries. It is supplied exclusively in Europe by Biosyn GmbH (Stuttgart). There are compelling reasons to believe that this drug could have benefits in the treatment of EBOV patients, because:

1. Leading Ebola pathogenesis experts from NIH [1] and USAMRIID [2] have concluded that there are strong similarities between the pathologies of EBOV hemorrhagic fever (HF) and sepsis, as per this quote (from Ref. [2] p. 257).:

"The clinical manifestations of EBOV HF in nonhuman primates are in many ways consistent with clinical findings in severe sepsis. Similarities exist between the paradigm of inflammation in the pathogenesis of both sepsis and EBOV HF (49). The shared features include involvement of various cytokines and mediators such as interleukin (IL)6 and tumor necrosis factor (TNF)α. Activation of the coagulation cascade is also prominent in both severe sepsis and EBOV infection of nonhuman primates...” [2]

2. Selenase has been used extensively in Germany and elsewhere for treatment of sepsis with good success [3,4]. See data on this web page: http://selenase.com/selenaser/selenaser_reduces_mortality/

3. The ability of selenite to block TNFalpha mediated inflammation is well established, via its inhibition of NFkappa B, and thereby downstream proinflammatory cytokines, apoptosis, etc. Many international scientists, including Alain Favier in France, as well as US scientists at NIH, have shown the ability of selenite to specifically block TNF/NFkB signaling (e.g., [5]). This activity could help block the “cytokine storms” contributing to both sepsis and HF pathology.

4. The benefits of selenite in inhibiting intravascular coagulation in both sepsis and potentially in HF can also be understood as a consequence of the role of Se in inhibiting blood clotting via the role of selenoproteins on the thromboxane/prostacyclin ratio (see attached PDF with several relevant abstracts [6]).

5. Most significantly, selenite therapy has already been PROVEN to have lifesaving benefits in HF involving a different HF virus. In an outbreak of viral HF in China several decades ago, a regimen of 2 mg of sodium selenite per day orally for 9 days gave an overall 80% reduction in mortality, as reported by Dr. JianCun Hou at a 1996 conference in Germany on selenium and antioxidants in viral diseases. See attached PDF [7]; the key text section and figure where he discussed the results from the clinical trial are highlighted.

During past Ebola outbreaks, Biosyn has offered to provide selenase at no cost to Ebola patients, but it was never acted on because the outbreaks were small and quickly contained. They have informed us that again they would be willing to provide the drug to MSF or other agencies; the person to contact at the company is Dr. Thomas Stiefel, one of the company founders (Thomas_Stiefel@biosyn.de).

This is NOT an experimental drug. It is a nutritional supplement formulated for oral or injection use, and is approved in Europe, and (as sodium selenite) commonly included in multivitamins and widely sold over the counter in the USA as a dietary supplement. Selenite (e.g. as selenious acid, USP) has also been used in hospital settings to provide selenium in total parenteral nutrition formulations.

In conclusion, we believe that there is a strong rationale for this to be tried as a potential addition to the formulary for the treatment of EBOV HF patients, using Biosyn’s dosage guidelines for the use of selenase in sepsis.

References

1.      Bray M, Mahanty S. Ebola hemorrhagic fever and septic shock. J Infect Dis 2003; 188: 613–7.

2.      Hensley LE, Geisbert TW. The contribution of the endothelium to the development of coagulation disorders that characterize Ebola hemorrhagic fever in primates. Thromb Haemost. 2005; 94:25461.

3.      Huang TS, Shyu YC, Chen HY, Lin LM, Lo CY, Yuan SS, Chen PJ. Effect of parenteral selenium supplementation in critically ill patients: a systematic review and metaanalysis. PLoS One. 2013; 8(1):e54431.

4.      Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strauss R, MeierHellmann A, Insel R, Radke J,Schüttler J, Gärtner R. Selenium in Intensive Care (SIC): results of a prospective randomized, placebocontrolled, multiplecenter study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med. 2007; 35:11826.

5.      Kim IY, Stadtman TC. Inhibition of NFkappa B DNA binding and nitric oxide induction in human T cells and lung adenocarcinoma cells by selenite treatment. Proc Natl Acad Sci USA. 1997; 94:129047.

6.      Several abstracts on the anticoagulation mechanism of dietary selenium (attached PDF).

7.      Hou JC. Inhibitory effect of selenite and other antioxidants on complementmediated tissue injury in patients with epidemic hemorrhagic fever. Biol Trace Elem Res. 1997; 56:12530.

 

Your most serious consideration of this information would be greatly appreciated.

 August 19, 2014

Signed:

 

Ethan Will Taylor, PhD
Senior Research Professor,
Dept. of Chemistry and Biochemistry, and Dept. of Nanoscience,
University of North Carolina, Greensboro, USA

Gerhard N. Schrauzer, PhD, MS, FACN, CNC
Professor Emeritus, Department of Chemistry and Biochemistry,
University of California, San Diego, CA, USA
Director, Biological Trace Element Research Institute, San Diego, CA, USA

Margaret Rayman, BSc DPhil (Oxon) RPHNutr
Professor of Nutritional Medicine
Department of Nutrition and Metabolism
Faculty of Health and Medical Sciences
University of Surrey, Guildford, UK

Alawode Oladele, MD, MPH
Chief Executive Officer,
Global Initiative for the Advancement of Nutritional Therapy, (GIANT), Inc., Atlanta, GA, USA

Prof. Roland Gärtner, MD
Department of Internal Medicine IV,
Ludwig Maximilian University,
Munich, Germany

Lijun Zhao, MD, PhD
Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry,
College of Life Sciences,
Shaanxi Normal University,
Xi'an, China