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\begin{document}

\title{A European pharmacotherapeutic agent Roflumilast exploring integrated
preclinical and clinical evidences for SARS CoV-2 mediated inflammation
to organ damage}



\author[1]{yogendra  Singh}%
\author[2]{ Neeraj   Fuloria}%
\author[2]{Shivkanya Fuloria}%
\author[3]{Vetriselvan  Subramaniyan}%
\author[4]{Waleed  Almalki}%
\author[5]{ Fahad  Al-abbasi}%
\author[5]{Imran  Kazmi}%
\author[6]{Sobhit  Rajput}%
\author[7]{Gaurav Gupta}%
\affil[1]{Maharishi Arvind College of Pharmacy}%
\affil[2]{AIMST University}%
\affil[3]{MAHSA University}%
\affil[4]{Umm Al-Qura University}%
\affil[5]{King Abdulaziz University}%
\affil[6]{Aligarh College of Pharmacy}%
\affil[7]{Suresh Gyan Vihar University}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
COVID-19 has spread globally, affecting almost 160 million individuals.
Elderly and pre-existing patients (such as diabetes, heart disease and
asthma), seems more susceptible to serious illness with COVID-19.
Roflumilast was licensed for usage in the European Union in July 2010 as
a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been shown to
decrease bleomycin-induced lung fibrosis, lung hydroxyproline, right
heart thickning in animal prophylactic. The current study reviewed
existing data that the PDE-4 inhibitor protects not just renal tissues
but also other major organ systems after COVID-19 infection by
decreasing immune cell infiltration. These immune-balancing effects of
roflumilast were related with a decrease in oxidative and inflammatory
burden, caspase-3 suppression, and increased PKA/cAMP levels in renal
and other organ tissue.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

COVID-19 has spread globally, affecting more than 216,867,420 documented
occurrences and 4,507,837 fatalities in individuals. Elderly and
pre-existing patients (such as diabetes, heart disease and asthma),
seems more susceptible to serious illness with COVID-19. Due to changes
in blood glucose and other diabetes-related complications, diabetic
individuals who become infected can be hard to treat. A significant
comorbidity towards the occurrence of SARS CoV-2-related COVID-19
includes inflammatory cytokine storm, acute kidney injury, myocarditis,
thrombosis, ARDS, TIA mediated cerebral complication that ultimately
leads to multi-organ failure. A recent case report illustrates an
atypical initial presentation and subsequent complications throughout
the middle-aged man. The person complained of abdominal discomfort and
vomiting then was diagnosed with a severe acute renal damage. During the
hospitalization, the study participant sustained a myocardial infarction
and respiratory failure. This indicates that this patient most likely
developed cardiorenal syndrome as a result of COVID-19-associated acute
renal injury.\textsuperscript{1} Notably, the main contributor to the
above-mentioned consequences of organ damage and death is inflammation.

In an early stage of SARS CoV-2 attack, pro-inflammatory cytokines
circulating including IFN-\selectlanguage{greek}γ, \selectlanguage{english}IL-1/2/6/8, and TNF-\selectlanguage{greek}α, \selectlanguage{english}directly exacerbate
the damage by attracting various leukocyte populations to the site of
injury, resulting in a devastating inflammatory pathway. As a result of
that~excitation of immune cells including~the natural and acquired host
defence systems become overloaded, resulting in the release of more
proinflammatory cytokines which are accumulated or cleared from~the
glomerulus, causing damage to the nephron tubular segments and
epithelial cell death mediated metabolic
dysregulation.\textsuperscript{2, 3} Furthermore, in laboratory
experiments, leukocyte--platelet (PLT) function has been proven to be
integral to leukocyte recruitment.\textsuperscript{4}~and the
progression of the vascular inflammation and
thrombosis.\textsuperscript{5} In COVID-19 infection, systemic
inflammation is linked with a 'procoagulant' condition defined by
excessively elevated tissue factor and factor VIIa levels. These
findings imply that the prothrombotic activity of circulating leukocytes
may contribute to the elevated cardiac, cerebral and renal vascular risk
observed in individuals infected with COVID-19.\textsuperscript{6} In
the early stage of the SARS CoV-2 assault, hyperinflammatory and
activation of the immune system, together with oxidation load lead to
various pathological changes in renal tissue, including cell
proliferation, podocyte (proteinuria), deposition of ECM (extracellular
matrix), pro apoptotic factor activation. While the immunosuppression
found in the late phase of COVID-19 disease/drug (steroids) associated
impairs the body's defenses, aggravating organ
damage.\textsuperscript{7} In addition, the peripheral blood count in
SARS CoV-2 patients for monocytes and neutrophils in this comparable
time frame suggests immune system dysregulation at the late COVID 19
stage. In addition, the peripheral blood count in SARS CoV-2 patients
for monocytes and neutrophils in this comparable time frame suggests
immune system dysregulation at the late COVID 19
stage.\textsuperscript{8} Additionally, we observed an elevated
concentration of plasma leucocytes (CD10 and CD16, for instance) and
abnormal blood neutrophil motility, both of which indicate an increased
risk of mortality.\textsuperscript{8, 9}

Roflumilast was licensed for usage in the European Union in July 2010 as
a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been approved as
a 'constraint' treatment to bronchodilators by the EMA summary and,
under the GOLD guidelines, an effect also exists in patients not
'controlled on the combination of Fixed Dose LABAs like formoterol and
ICS such as beclomethasone dipropionate. Moreover, roflumilast
coadministration with budesonide in Asian and Caucasians did not affect
the state of steady disposition of either drugs and had no consequences
for its safety or tolerability which also denote that it may be consumed
without or with meal.\textsuperscript{10} However, roflumilast cessation
might be because of the medicine that is relatively costly and,
subsequent to complex prescription procedures or unpleasant effects,
poor understanding of roflumilast~indications between the
clinicians.\textsuperscript{11} Recently a study results show that
roflumilast protects from cerebral ischemia functional sequelae, which
may be connected to its anti-inflammatory
characteristics.\textsuperscript{12} Another research also shows in
particular that roflumilast inhibitor of PDE-4 prevents LPS from
releasing NO, IL-1\selectlanguage{greek}β, \selectlanguage{english}TNF-\selectlanguage{greek}α \selectlanguage{english}from the production of the macrophage through
suppression of activation of SAPK/JNK, p38 MAPK, NF-kB
mechanisms.\textsuperscript{13} Roflumilast has been shown to decrease
bleomycin-induced lung fibrosis, lung hydroxyproline,~right
heart~thickning~in animal prophylactic and curative trials; it has also
been shown to prevent intracinary pulmonary artery muscularization. The
inhibitor PDE4 was utilised in the bronchoalveolar lavage fluid to
diminish bleomycin-induced transcripts for Tumor necrosis factor -
alpha, transforming growth factor-beta, connective tissue growth factor
synthesis, endothelin-1,~aI(I)collagen, and mucin Muc5ac in the lung, as
well as to decrease the levels of IL-13, Tumor necrosis factor - alpha,
and Transforming growth factor-beta. Moreover, lung fibrosis,
al(I)collagen, right heart thickness generated by bleomycin have been
reduced with roflumilast, but not dexamethasone
group.\textsuperscript{14} Additionally, another study found that
roflumilast and roflumilast N-oxide suppressed macrophages' release
like~cell attracting molecules and TNF-alpha release in
lungs.\textsuperscript{15}

Inflammation and immunological response~are strongly related to
increased PDE-4 synthesis. There are five major PDE-4 isoforms. They are
PDED-4A, PDED-4B, PDED-4C, PDED-4D, and PDED-4E. PDE-4B is highly
upregulated on neutrophils and monocytes, resulting in the discharge of
many inflammation-inducing agents.\textsuperscript{16} In contrast to
earlier experimental findings, where LPS injection was shown to
stimulate TNF production from circulating leukocytes in PDE-4B knockout
mice, it appears that this transcript~detrimental effect in inflammatory
conditions has been completely
inhibited.\textsuperscript{17}Additionally, suppression of PDE-4B
repressed apoptotic cell death and inflammation molecule biosynthesis in
renal tubular epithelial cell when treated with cisplatin. Previously,
when ovalbumin was given to rats' bronchiolar lavage fluid, PDE-4B/D
expression was found to be greater than in that of controls. The higher
expression of these isoforms was noted in only the lavage fluid of rats
with ovalbumin exposure, however, the overexpression of PDE-4B only
helped rescue allergic symptoms in this study.\textsuperscript{18} The
high-dose Roflumilast significantly reduced PDE-4B/D transcripts,
suggesting key involvement of these two isoforms in ARDS linked with
COVID-19. These data further indicate that inhibitions of both
transcripts are adequate to raise cAMP levels in renal tissue that have
a protective impact on the kidney. Pre-treatment dosage of Roflumilast
addictively decreased renal oxidative stress, inflammatory cytokines,
and renal tissue MPO expression. The MPO neutrophil enzyme is strongly
pro-oxidizing and pro-inflammatory.\textsuperscript{19} Thus, the
inhibitory effects of roflumilast on inflammatory and oxidative injury
in COVID-19 infection-induced acute renal injury may be due to the fact
that neutrophil recruitment and migratory restriction.~ Additionally, a
research indicates that roflumilast may be helpful in atherothrombotic
disorders as well as inflammatory vasculitis that is not primarily
associated with lung damage.\textsuperscript{20} Notably, Roflumilast
was found to improve glucose uptake and~insulin sensitivity. This was
linked with stimulation of PKA/cAMP/CREB axis, that leads to
PCG-1-dependent activation of mitochondrial energy
production.\textbf{Fig. 1} Depicts the Possible Role of Roflumilast in
SARS CoV-2 Mediated Inflammation to Organ Damage

The current study reviewed existing data that the PDE-4 inhibitor
protects not just renal tissues but also other major organ systems after
COVID-19 infection by decreasing immune cell infiltration. These
immune-balancing effects of roflumilast were related with a decrease in
oxidative and inflammatory burden, caspase-3 suppression, and increased
PKA/cAMP levels in renal and other organ tissue. The findings
observations provide fresh light on the late phase events associated
with COVID-19-related inflammation and the mechanisms behind
roflumilast's organ protective effects.

\textbf{Acknowledgment:} Not Applicable.

\textbf{Funding:} There was no specific funding for this study.

\textbf{Competing Interests:} The authors declare no competing interest.

\textbf{Availability of data and material} : No datasets were generated
or analyzed during the current study.

\textbf{Author Contributions}

Y.S., N.K.F. and S.F. proposed a study; V.S. and W.H.A. participated in
all important intellectual content section of the study; F.A.A. and I.K.
prepared figures; S.S.R. and G.G. proofread the whole manuscript. All
authors approved the content of the manuscript.

\textbf{Ethics Declarations}

\textbf{Ethical Approval:} Not Applicable

\textbf{Consent to Participate:} Not Applicable

\textbf{Consent to Publish:} Not Applicable

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