Repurposing of Sodium Thiosulfate (STS) in the treatment of COVID 19 or SARS Cov-2 Viral pandemic of 2019-2020
Repurposing or repositioning of medications to treat emerging diseases is not a new concept; however, I wish to share the story of utilizing sodium thiosulfate (STS) as a repurposed drug in the treatment of calciphylaxis and how even now this drug could possibly assist in the treatment of COVID 19 viral pandemic of 2019-2020 [1].
Repurposing of STS started out with a paper on vascular ossification calcification that included calciphylaxis in 2005 [2] and subsequent multiple papers regarding the use of STS in the treatment of calciphylaxis [3-7]. Importantly, there have been many other papers dealing with the use of STS in the treatment of calciphylaxis over the years (202 papers in pub med with search terms for sodium thiosulfate and calciphylaxis) and STS is often a part of the multimodal treatment strategy. Recently, 2 days ago, a repurposing of an older malaria drug, hydroxychloroquine, to treat patients with COVID-19 gave me the idea or concept to share this question with an international group of researchers on Research Gate.
Here is a list of other approved medications that are also being considered for repurposing as follows: Tocilizumab - sold under the name Actemra, Kaletra/Aluvia HIV drugs, Hydroxychloroquine as previously mentioned and Remdesivir is a broad spectrum anti-viral medication. There are undoubtedly many more under consideration and are also important in this pandemic crisis.
Sodium Thiosulfate (STS) is a potent antioxidant.
Instead of one unpaired electron as in most antioxidants, STS has (2) unpaired electrons that can be readily donated to sequester reactive oxygen/nitrogen species (RONS). During this chemical reaction process of sequestering RONS, STS also is capable of generating glutathione (GSH) a naturally occurring intracellular antioxidant and thus increases the cellular antioxidant strength in a region actively being damaged (Fig. 1 and 2).
Figure 1. This figure demonstrates the chemical structure of sodium thiosulfate, which is an anti-browning, reducing, and antioxidant agent: Capable of donating electrons to re-pair unpaired damaging electrons to be an effective antioxidant as well as a chelator of cations such as the calcium excess in calcific uremic arteriolopathy – CPLX [2].
Figure 2. Possible chemical reaction of STS to generate glutathione (GSH) [2]
Known side effects of sodium thiosulfate (STS) used to treat calciphylaxis
Here is what we know since sodium thiosulfate has become the standard of care in patients with calciphylaxis globally. Obviously, any known allergy to this or a similar sulfur-containing product would preclude its use see references [2-7]. STS may induce an acidosis early-on and with prolonged use could induce osteoporosis see references [2-7].
Sodium Thiosulfate Protective à To Detrimental Cytokine and Reactive Oxygen/Nitrogen Species Storm and Vascular Collapse
Upon initial infection with COVID 19 there is a cauldron of redox chemistry with excessive RONS (the first line of defense against the COVID 19 virus produced by the body’s protective inflammatory response to infection. The cells of immune response include the 1st responder’s neutrophils, mast cells and chronic persistent macrophages - with monocyte migration and monocyte to macrophage transformation at the infectious site of the nasopharyngeal bronchial lining epithelial cells, pneumocytes and capillary endothelial cells.
As these inflammatory cells attempt to clear the virus from these passageway epithelial cell’s they generate RONS with a staggering amount of unpaired reactive oxygen and nitrogen unpaired electrons and toxic cytokines, which over time creates a cytokine storm and RONS beget RONS and cytokines evoke more inflammatory invasion and thus create the cytokine storm. The healthy surrounding cells of the upper and lower pulmonary epithelial, pneumocytes and capillary (blood-oxygen barrier) endothelial cells become a source of collateral damage that originally was intended to result in deleting the invasion of viral envelope DAMPs and PAMPs recognized by these cells in a response to injury and wound healing mechanism to the invading COVID 19 viruses in the pulmonary tissues.
In turn, this RONS storm and cytokine storm leak into the systemic circulation and the protective lining of the endothelial cells (endothelial glycocalyx (ecGCx)) may become damaged and are attenuated and/or lost, which results in a marked increased vascular permeability and loss of intravascular contents into the surrounding extravascular interstitial capillary space. Unfortunately, this loss of intravascular volume due to a ‘capillary leak syndrome’ [8-10] may result in vascular collapse with decreased cardiac output and decreased perfusion of the brain with relative ischemia over time and result in the death of the host or COVID 19 infected patients that have progressed to being on ventilator life support.
Indeed, the COVID 19 virus infection-induced this pulmonary infection with bilateral pneumonia’s requiring ventilator treatment an acute respiratory distress syndrome (ARDS) syndrome (ARDS is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue) but these patients actually may be dying of vascular collapse due to a loss of their local and systemic endothelial glycocalyx due to a cytokine and RONS STORM!
In conclusion sodium thiosulfate (STS) would have to be given intravenously; however, these critically ill patients with all have an intravenous established intravenous port to administer medication so it should not be viewed as invasive since these lines are already available. This antioxidant effect might possibly restore some effective endothelial cell function and even re-establish the endothelial glycocalyx or assist in its restoration. The increase in venous or arterial Syndecans may be a key laboratory readout of endothelial glycocalyx loss and systemic vascular collapse [10]. Additionally, patients on ventilators with COVID 19 certainly apply to these thoughts and concepts. The concept of increased pulmonary and possible systemic microvascular permeability is currently a possibility that is not being discussed a great deal at the moment but should be. Further, novel ideas for the prevention of this are of great importance during the COVID 19 pandemic. Drugs that may help to eliminate the excessive RONS with excessive over-reactive cytokines and cytokine storm (such as sodium thiosulfate STS) need to be considered as it relates to capillary leak syndrome with vascular collapse due to viral sepsis of the COVID 19 virus.
References
1. Xue H, Li J, Xie H, Wang Y. Review of Drug Repositioning Approaches and Resources. Int J Biol Sci. 2018 Jul 13;14(10):1232-1244. doi: 10.7150/ijbs.24612
2. Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol. 2005 Mar 18;4:4. Review
3. Hayden MR, Kolb LG, Khanna R. Calciphylaxis and the cardiometabolic syndrome. J Cardiometab Syndr. 2006 Winter;1(1):76-9.
4. Hayden MR. Calciphylaxis and the cardiometabolic syndrome: the emerging role of sodium thiosulfate as a novel treatment option. J Cardiometab Syndr. 2008 Winter;3(1):55-9
5. Hayden MR, Goldsmith D, Sowers JR, Khanna R. Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate. Int Urol Nephrol. 2008;40(2):443-51. doi: 10.1007/s11255-008-9373-4. Review.
6. Hayden MR, Goldsmith DJ. Sodium thiosulfate: new hope for the treatment of calciphylaxis. Semin Dial. 2010 May-Jun;23(3):258-62. doi: 10.1111/j.1525-139X.2010.00738.x
7. Sowers KM, Hayden MR. Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. Oxid Med Cell Longev. 2010 Mar-Apr;3(2):109-21. doi: 10.4161/oxim.3.2.11354. Review.
8. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017 Jul;92(1):37-46. doi: 10.1016/j.kint.2016.11.029
9. Colombo R, Wu MA, Castelli A, Fossali T, Rech R, Ottolina D, Cogliati C, Catena E. The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood. J Crit Care. 2020 Mar 4;57:177-184. doi: 10.1016/j.jcrc.2020.02.016.
10. Bøe OW, Sveen K, Børset M, Druey KM. Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson's Disease). Am J Case Rep. 2018 Feb 16;19:176-182. doi:10.12659/ajcr.906514
11. Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533.
THIS CONCEPT OF REPURPOSING – REPOSITIONING OF MEDICATIONS THAT ARE ALREADY AVAILABLE IS OPEN TO DISCUSSION AND COMMENTS
Sincerely with gratitude,
Melvin R Hayden, MD
Yes, indeed and I would like to share a paper with everyone that may open more
eyes wide open... by Vincent and Slutsky regarding the imagined scope of what may come to be in hospitals around the globe currently and into the summer of 2020. OVERWHELMED
While I have faith in our systems the IMAGINE paper is eye-opening to the possibilities of the COVID 19 pandemic!
Vincent JL, Slutsky AS Coronavirus: just imagine…. Crit Care. 2020 Mar 16;24(1):90. doi: 10.1186/s13054-020-2824-8
22 March 2020
VERY IMPORTANT FOR REPURPOSING EXISTING MEDICATIONS
SODIUM THIOSULFATE (STS).
I found this mouse model to assist in our understanding of why sodium thiosulfate may help with human COVID-19. This model goes into great depth to improve our understanding and a MUST READ for those interested! STS decreased toxic cytokines and MMP-9. While this is due to pathogenic etiology, it
is still a pathogen INJURY and the body responds very similar to any infectious
injury in a similar manner due to the response to injury mechanism.
Sakaguchi M, Marutani E, Shin HS, Chen W, Hanaoka K, Xian M, Ichinose F. Sodium thiosulfate attenuates acute lung injury in mice. Anesthesiology 121: 1248 –1257, 2014. doi:10.1097/ALN.0000000000000456.
I am in hopes of obtaining human pathologic tissues infected with COVID-19
placed in standard TEM fixatives plus Standard TEM fixatives with 2% lanthanum nitrate to define the glycocalyx of epithelial cells and the endothelium glycocalyx in the near future to establish some novel changes in the remodeling of the alveolar and Blood-gaseous Oxygen Barrier (BGOB) and the pulmonary microvessel capillaries
Melvin R Hayden, MD
Columbia, MO USA
As there is no known drug for COVID19 and finding a new candidate and then going through safety evaluations, trials and marketing can take a long long time. Considering the pandemic repurposing drugs can reduce time as these drugs have been extensively tested for human safety already and dose and quantity known. Side effects are known and ways to address those side effects also known. As they are marketed compounds several early attempts may exist where scientists have tried to test their anti-viral effect. Moreover in many cases tentative or actual mechanism of action is known, making it easier to predict its efficacy in case of COVID19. Analysis of Old data should be thoroughly performed before going to a quick clinical trial and then for broader use. This should have started weeks or months back.
Thank you Manash K paul for fine assesment of this current pandemic.
Hayden
What are some of your thoughts regarding the repurposing of hydroxychloroquine and azithromycin for COVID-19?
This is open for discussion and your input
Melvin Hayden
There was a study investigating use of azithromycin in combination with hydroxychloroquine, it appeared that combination of these medication would have additional benefit, but there were methodologic concerns about the control groups for the study, and the biologic basis for using azithromycin in this setting is unclear.
Article Hydroxychloroquine and azithromycin as a treatment of COVID-...
Farzaneh Sadeghi
This is excellent! and please continue following this question.
Feel free to contribute.
Hayden
Currently, as I see the picture of what is going on in the COVID-18 pandemic there may be 3 major issues with COVID-19
Virion Storm or virus LOAD
REDOX Storm
Cytokine Storm
Certainly, from paper uploaded by Farzaneh Sadeghi it appears that the combination of hydroxychloriquine azithramycin appears to reduce the viral load
see graph in this paper by Gautret P, Lagier JC, Parola P et al.. and in turn could affect the other two storms by decreasing viral load. Since this combo was approved in US yesterday to treat COVID-19 emergency use we hope to learn even more as new hot spots or infective continue to evole as well as in other parts of the world. So much remains to be learned and it is so wonderful to see the world come together regarding this pandemic.
Hayden
There are at least three "Storms" that are ongoing in COVID-19 infections:
1. Viral load STORM
2. Redox STORM ( reactive oxidative nitrosative stress)
3. Cytokine STORM (that is most often discussed as of late)
All three of these horrific storms must be addressed in addition to currently provided assisted ventilation to keep patients surviving!
Each of these storms is important individually; however, they are functioning synergistically so probably if one storm can be somewhat counteracted it may be that the others will also improve.
Since much of my past work with transmission electron microscope has dealt with the capillary endothelium, I also believe that endothelial activation and dysfunction as a result of all of these storms is a major contributor to the impairment of the blood-gas barrier and alveolar gas exchange especially in T2DM since the lung is also an end-organ of T2DM and diabetes has appeared recently in New York City and in New Orleans as a major contributory factor as a co-morbid disease that seems to be associated with increased morbidity and mortality. So now it is more important than ever to consider the lung as an end-organ of T2DM just as I have found this to be true in the brain at the neurovascular unit.
Melvin R Hayden
I would like to be more specific and add a paper from Metabolism that highlights the importance of good glucose control for diabetics in ICUs since that is so very important and points to a team approach and coming together. Another thing is very important now is that patients with T2DM and their families may not be coming into clinics due to fear of becoming infected with COVID-19 and also since these patients are prone to depression with higher risk their glucose control may suffer as they lose interest especially if they have impaired cognition due to a diabetic cognopathy. This is a very important read while it may divert away somewhat we should not overlook this problem and the increased morbidity and mortality associated with T2DM in ICUs since this appears as a merging problem especially in New York City and New Orleans La.
Hill MA1, Mantzoros C2, Sowers JR3. Commentary: COVID-19 in Patients with Diabetes. Metabolism. 2020 Mar 24:154217. doi: 10.1016/j.metabol.2020.154217
Article Acquired Long QT Syndrome: A Review of the Literature
This review discusses in more detail the points I outline below.
Several medications that have been recommended for the treatment of Covid-19 are associated with prolongation of the QTc interval and therefore torsade de pointes and sudden cardiac death.
The evidence of the potential benefit of chloroquine and hydroxychloroquine in the treatment of Covid-19 is increasing.
Other medications which may be used in this cohort include the macrolide antibiotics (e.g. azithromycin). These can also prolong the QTc interval. Administering several medications that may prolong the QT interval is associated with a high risk of complications.
In medicine risks and benefits must be balanced. Safety netting is important whenever there is a great potential benefit but also a very significant risk. In that context QTc intervals, renal and liver function must be monitored closely in patients treated with chloroquine and or macrolides. They should probably not be started if the baseline QTc is more than 450 ms. It should probably be stopped if the QTc increases 25% above baseline. It should definitely be stopped if QTc is above 500 ms. This is an evolving situation and recommendations may change as the potential risks and benefits become clearer.
Beta-blockade is used in the treatment of congenital and acquired long QT syndrome, so may be beneficial in this setting.
A very well written and overview regarding of HCQ and Azithromycin has been posted today on Research gate which discusses in detail the reason for repurposing
HCQ and Z pac and also dicusses in detail the role ACE2 receptor and ACEi and ARBs in COVID-19 and I will attach the link for others to read. This paper is free to download and read on Research Gate. Currently, there is a great deal of controversary regarding the use of ACEi and ARBS that has not been totally resoved by the American Heart Association and others to date.
NOVEL UNORTHODOX STRATEGIES TO REDUCE THE CASE FATALITY RATE OF COVID-19 IN HIGH RISK GROUPS INCLUDING PATIENTS USING ACE INHIBITORS. Prof. Tibor Hlavaty, MD, PhD1,2, Anna Krajcovicova, MD, PhD2
COVID-19: AHA Guidance on Hypertension, Latest on Angiotensin Link
https://www.medscape.com/viewarticle/927952?nlid=134824_3041&src=WNL_mdplsnews_200403_mscpedit_diab&uac=369550CG&spon=22&impID=2334074&faf=1#vp_2
This topic is open to discussion and individual thoughts and views
Hayden 4/4/2020
Dear researchers I searching for data, support, and explanations for the dramatic worst mortality data of Lombardia (N. Italy) in the first pandemic phase. Thanks for possible aid.
https://www.researchgate.net/post/The_novel_Coronavirus_in_N_Italy_Lombardia_COVID19_2019nCoV_SARSCoV2_shows_a_fatality_rate_compatible_with_SARS-MERS_Why
Linked pre-print papers: https://www.researchgate.net/publication/341325862
Stay safe --sv--
- Badges
- Science topic
- Similar topics
- Correction