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.