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\begin{document}

\title{Methylene blue in SARS COV -2: Blue romance may be a solution of black
tragedy}



\author[1]{Seyyed Mohammad Ghahestani}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 30, 2024}


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\selectlanguage{english}
\begin{abstract}
In previous publications the role of kininogen system has been
postulated. On those publications the possible role of Icatibant,
Ecallantide and Aprotinin in treatment of SARS Cov-2 has been raised. In
this paper we raise the hypothetical potential of Methylene Blue in
treatment of SARS COV 2. This medication may abort effects of Bradykinin
by inhibition of NO Synthase inhibitor and promote oxygen saturation
while it is inexpensive and ubiquitously accessible. Clinical studies
can not be over emphasized.%
\end{abstract}%



\sloppy


\par\null

Ghahestani Seyyed Mohammad*1,Sara Karimi 2,Mohammad Hamidi Madani3

\textbf{*1:} \textsuperscript{1}Children Medical Center Hospital, Tehran
University of Medical Sciences (TUMS), Tehran, Iran. Email:
mgrosva@gmail.com.No:+989128491811

Address: Pediatric Urology Ward,Children Medical Centre Hospital ,Gharib
St, Keshavarz Blvd,Tehran,Iran

2:Sara Karimi, Alborz University of Medical sciences. E
mail:Sarakarimi1984@yahoo.com

No:+989133004032

3: Mohammad Hamidi Madani.Labbafinejad Hospital, Shahid Beheshti
University of Medical Sciences(SBMU). Email:m.hamidimadani70@gmail.com
Phone No:+989393898696

Abstract:

In previous publications the role of kininogen system has been
postulated. On those publications the possible role of Icatibant,
Ecallantide and Aprotinin in treatment of SARS Cov-2 has been raised. In
this paper we raise the hypothetical potential of Methylene Blue in
treatment of SARS COV 2. This medication may abort effects of Bradykinin
by inhibition of NO Synthase inhibitor and promote oxygen saturation
while it is inexpensive and ubiquitously accessible. Clinical studies
can not be over emphasized.

\emph{Methylene Blue in SARS COV -2: Blue romance may be a solution of
black tragedy}\textbf{.}

Ghahestani Seyyed Mohammad*, Sara Karimi, Mohammad Hamidi Madani

\emph{*Tehran University of Medical Sciences(TUMS)}

\emph{mgrosva@gmail.com}

Since emergence and wide spread dissemination of SARS- COV-2 all efforts
in the scientific community have been focused on understanding the
pathophysiology of the disease, alongside all aspects of a global health
problem and its complexities. More over the scientific community is
trying to accelerate the velocity of knowledge dissemination beyond that
of the virus transcontinental sweep over by various strategies of fast
track, green open access and preprints. At the same time, we must try to
avoid any enticement for exoneration in accuracy and methodological
soundness of the studies.

In this paper we try to raise either a new or under noticed medication
for this disease based on an in-press accepted manuscript of senior
author of this manuscript and some other independent researchers.(1-3)

\textbf{Discussion:}

Hitherto three main territories of physio-pathogenesis of the virus have
been targeted.

A)The virus and its mechanism of replication and envelope integrity
which have been aimed as potential targets of antiviral drugs e.g.
Remdesivir, Favipiravir and Kaletra.(4-7)

B) The receptor of the virus in the body, the most notorious of them
known as ACE 2 which has been addressed by actually distracting the
virus by a recombinant soluble ACE 2 product(8). The intriguing part of
the story is that indigenous ACE2 is a functional receptor/enzyme in the
body so as it can not be innocuously irreversibly antagonised with any
means, without serious adverse consequences. (9, 10).

C)The immunologic cascade known to ensue in a phenomenon known as
``cytokine storm'' which has previously been observed in other viral
diseases e.g. Influenza(11, 12)

The terminology ``cytokine storm'' may be misleading (and may be not) in
conveying this implicit presumption as a ``proved fact'' that no
cytokine or autacoid can be impeached as the starter or the main player
of the game. This presumption has not been approved yet, although it may
subsequently unveil as true.

Some authors including main author of this article preceded to raise
theoretical pivotal role of kininogen system in SARS Cov-2 scenario.(2,
3) {[} Reference(1) was in non-peer reviewed status{]} . In our article,
we tried to imply that Kininogen system, may be not ``a bean in the bean
pot ``of all the events of the disease. Our paper has been accepted in
Iranian Journal of Allergy Asthma and Immunology (IJAAI as In-press
publication.(13)

Whatsoever in our In-press paper we tried to substantiate the special
clinical features of this disease with clinical tentative
characteristics of the disease, Dry cough, Lung vascular leakage
syndrome, ameliorating effect of zinc, deleterious role of ACEI and
early drop in saturation. More un published and / or non-peer reviewed
data are being propagated (14) ) to hypothesize mechanism of haemoglobin
distraction from oxygen exchange.

In above mentioned papers about kininogen implication in SARS- COV-2
scenario, medications have been proposed: Icatibant as a B2 Bradykinin
receptor antagonist, Ecallantide and Aprotinin.

All these medications have favourable and unfavourable profiles.
Icatibant and Ecallantide which have formally been approved for
treatment of hereditary angioedema, are classified as orphan drugs and
are quite expensive and unavailable in many settings. Aprotinin on the
other hand has received a black box warning due to hypersensitivity and
its effects on coagulation system are somewhat concerning for
clinicians(15).

It is noteworthy that none of these medications have been reported to be
used in SARS COV-2 and yet there are no studies performed to prove pre
requisites of these theories comprising assessment of Bradykinin levels
in sampled lung tissue. As far we know that Bradykinin plasma level may
not be trustworthy due to autacoid and transience nature of the
molecule.

A re contemplation on mechanism of Bradykinin action in the body and
literature search, led us to the notion that several Bradykinin
functions were exerted Via NO, a factor previously named as Endothelial
Derived Relaxation Factor(16). Having read the un-published theories
about haemoglobin drop out of oxygen exchange process(14), the
consideration of NO as an allosteric ligand of haemoglobin(17, 18) seems
sound.

NO synthase inhibitors and remarkably Methylene Blue have been shown to
neutralize effects of Bradykinin(19). There upon a ubiquitously
available NO Synthase inhibitor, Methylene Blue may seem(19, 20) to be
effective in impediment of disease process and promote haemoglobin
recruitment and oxygen saturation.

In comparison with Icatibant, regardless of price or availability, it is
post receptor, does not induce complex cascade coagulopathies and while
we know Bradykinin is unstable and may harbour in the lung as a trench,
Methylene Blue may prevail all through the body and seize the affected
haemoglobin. As a bona fide proximal kinin cascade adjoining hemostasis
axis is least affected. All these speculations must be clinically
assessed.

Interestingly there are reports of Methylene Blue role in COVID 19
story(21, 22). However these studies are considering Methylene Blue in
context of Photo dynamic therapy which has been the nearest pre-existing
scenario on the counter of clinicians yet (22)for treatment of other
diseases and remarkably not Methylene Blue per se.

More over Methylene Blue has been deemed effective in sepsis in numerous
reports(23, 24) and some vascular leakage syndromes(25) which supports
our notion that Methylene Blue must not go un noticed as a potential
treatment in advanced stages of SARS COV-2.

We can add that some direct antiviral effects have been reported for
Methylene Blue (26) some focusing on photodynamic treatment. We have not
meticulously explored these properties in our consideration yet to see
whether it has any direct effect on this kind of RNA virus.

\textbf{Conclusion:}

We think that Methylene Blue as an inexpensive ubiquitously available
medication, has a considerable potential to be considered in treatment
of SARS COV2.

We did not have a rapid access to set-up of a clinical study and it was
prudent to share the idea with scientific community as soon as possible
in this special situation.

Paradoxical and unexpected effects have been observed in Methylene Blue
administration in other diseases if not meticulously done. Adverse
reaction may happen in patients with a history of serotonergic
medications as anti- depressants which may specially be prevalent these
days(27). So any clinical step must be taken cautiously. In the other
hand we must know that we are in a scrambling global health emergency
and too much obsessive methodology may leave us with many dead patients
to treat at the end of the day.

1. van de Veerdonk F, Netea MG, van Deuren M, van der Meer JW, de Mast
Q, Bruggemann RJ, et al. Kinins and Cytokines in COVID-19: A
Comprehensive Pathophysiological Approach. 2020.

2. Tolouian R, Vahed SZ, Ghiyasvand S, Tolouian A, Ardalan M. COVID-19
interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin
system; looking at a potential treatment. Journal of Renal Injury
Prevention. 2020;9(2).

3. Seyed-Mohammad Ghahestani M, Javad Mahmoudi P, Sakineh Hajebrahimi M,
4 , Amir-Babak Sioofy-Khojine D, PhD5,3,6*, Hanieh Salehi-Pourmehr P,
Fatemeh Sadeghi-Ghyassi P, et al. Bradykinin as a Probable Aspect in
SARS-Cov-2 Scenarios: Is Bradykinin Sneaking out of Our Sight?

. Iranian journal of allergy asthma and immunology( In- Press
publication). 2020.

4. Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible
therapeutic option for the COVID-19. Travel medicine and infectious
disease. 2020.

5. Ko W-C, Rolain J-M, Lee N-Y, Chen P-L, Huang C-T, Lee P-I, et al.
Arguments in favour of remdesivir for treating SARS-CoV-2 infections.
International Journal of Antimicrobial Agents. 2020.

6. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental
treatment with favipiravir for COVID-19: an open-label control study.
Engineering. 2020.

7. Lim J, Jeon S, Shin H-Y, Kim MJ, Seong YM, Lee WJ, et al. Case of the
index patient who caused tertiary transmission of COVID-19 infection in
Korea: the application of lopinavir/ritonavir for the treatment of
COVID-19 infected pneumonia monitored by quantitative RT-PCR. Journal of
Korean medical science. 2020;35(6).

8. Alhenc-Gelas F, Drueke TB. Blockade of SARS-CoV-2 infection by
recombinant soluble ACE2. Kidney International. 2020.

9. 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. 2003;426(6965):450-4.

10. Santos R, Ferreira AJ, Verano-Braga T, Bader M.
Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players
of the renin-angiotensin system. J endocrinol. 2013;216(2):R1-R17.

11. Liu Q, Zhou Y-h, Yang Z-q. The cytokine storm of severe influenza
and development of immunomodulatory therapy. Cellular \& molecular
immunology. 2016;13(1):3-10.

12. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG.
Into the eye of the cytokine storm. Microbiol Mol Biol Rev.
2012;76(1):16-32.

13. Seyed-Mohammad Ghahestani M, Javad Mahmoudi P, Sakineh Hajebrahimi
M, 4 , Amir Babak Sioofy Khojine D, PhD5,3,6*, Hanieh Salehi-Pourmehr P,
Fatemeh Sadeghi-Ghyassi P, et al. Bradykinin as a Probable Aspect in
SARS-Cov-2 Scenarios: Is Bradykinin Sneaking out of Our Sight?. Iranian
journal of allergy asthma and immunology( In- Press publication). 2020.

14. Read R. Flawed methods in ``COVID-19: Attacks the 1-Beta Chain of
Hemoglobin and Captures the Porphyrin to Inhibit Human Heme
Metabolism''. 2020.

15. Siehr S, Stuth E, Tweddell J, Hoffman G, Troshynski T, Jones D, et
al. Hypersensitivity reactions to aprotinin re-exposure in paediatric
surgery. European journal of cardio-thoracic surgery. 2010;37(2):307-11.

16. Linz W, Wohlfart P, Sch\selectlanguage{ngerman}ölkens BA, Malinski T, Wiemer G. Interactions
among ACE, kinins and NO. Cardiovascular research. 1999;43(3):549-61.

17. Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, et
al. Enzymatic function of hemoglobin as a nitrite reductase that
produces NO under allosteric control. The Journal of clinical
investigation. 2005;115(8):2099-107.

18. Kim-Shapiro DB, Schechter AN, Gladwin MT. Unraveling the reactions
of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics.
Arteriosclerosis, thrombosis, and vascular biology. 2006;26(4):697-705.

19. Rhaleb N-E, Dion S, Barabé J, Rouissi N, Jukic D, Drapeau G, et al.
Receptors for kinins in isolated arterial vessels of dogs. European
journal of pharmacology. 1989;162(3):419-27.

20. Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis
by methylene blue. Biochemical pharmacology. 1993;45(2):367-74.

21. Yu B, Jin C, Zhang J, Wu H, Zhou X, Yao H, et al. Methylene blue
photochemical treatment as a reliable SARS-CoV-2 plasma virus
inactivation method for blood safety and convalescent plasma therapy for
the COVID-19 outbreak. 2020.

22. Henry M, Summa M, Patrick L, Schwartz L. A cohort of cancer patients
with no reported cases of SARS-CoV-2 infection: the possible preventive
role of Methylene Blue. Substantia. 2020:888-.

23. Galili Y, Kluger Y, Mianski Z, Iaina A, Wollman Y, Marmur S, et al.
Methylene blue--a promising treatment modality in sepsis induced by
bowel perforation. European surgical research. 1997;29(5):390-5.

24. Kwok ES, Howes D. Use of methylene blue in sepsis: a systematic
review. Journal of intensive care medicine. 2006;21(6):359-63.

25. Umbrello M, Gardinali M, Ottolina D, Zanforlin G, Iapichino G.
Systemic capillary leak syndrome: is methylene blue the silver bullet?
Case reports in critical care. 2014;2014.

26. Floyd RA, Schinazi RF. Antiviral therapy using thiazine dyes. Google
Patents; 2002.

27. Hencken L, To L, Ly N, Morgan JA. Serotonin syndrome following
methylene blue administration for vasoplegic syndrome. Journal of
cardiac surgery. 2016;31(4):208-10.

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