<div>Marciano Lee<sup>1</sup>, Elise Anderson<sup>1</sup>, Ali
Farooq<sup>1</sup>, Mohammed Yasin<sup>1</sup>, Yazan
Alkawaleet<sup>1</sup>, Frank Annie<sup>2</sup></div><div>Charleston Area Medical Center, Department of Cardiology, 3200
MacCorkle Ave. SE,</div><div><div>Charleston, WV 25304</div></div><div>CAMC Health Education and Research Institute, 3200 MacCorkle Ave. SE,</div><div><div>Charleston, WV 25304</div></div><div>Corresponding:</div><div>Frank Annie MA; MPA; PhD</div><div>Research Scientist (Department of Cardiology)</div><div>CAMC Health Education and Research Institute</div><div>3200 MacCorkle Ave. SE,</div><div>Charleston, WV 25304</div><div>Cell 304 -395 – 3830</div><div>Phone 304-388-9921</div><div>Fax: 304-388-9921</div><div>Email:
Frank.H.Annie@camc.org</div><div>Keywords:</div><div>COVID-19, GEMFIBROZIL, IMMUNE MODULATING TREATMENT</div><div>Abstract:</div><div>The current Covid-19 viral infection has been declared a pandemic
causing significant global morbidity and mortality predominantly from
the manifestation of severe acute respiratory syndrome (SARS). It has
been designated as SARS-CoV 2. Epidemiological studies show predilection
in patients with associated chronic medical conditions including those
with cardiovascular disease. Exaggerated host immune response known as
cytokine storm syndrome (CSS) leading to acute lung injury (ALI) and
acute respiratory distress syndrome (ARDS) is the proposed mechanism for
the development of SARS in Covid-19 infection. Gemfibrozil has proven
benefits in patients with cardiovascular disease. More importantly, it
has established anti-inflammatory, anti-oxidative, and anti-migratory
properties. Gemfibrozil has shown survival benefits as immune modulation
of ALI/ARDS from viral pathogens. This article reviews the potential of
gemfibrozil as adjuntive immue modulating therapy for SARS associated
with Covid-19 infected patients who have associated cardiovascular
disease.</div><div>Introduction:</div><div>The severe acute respiratory syndrome (SARS) seen in Covid-19 infection
share similarities with previous coronavirus epidemics, particularly
SARS-CoV 1 and the Middle East Respiratory Syndrome (MERS-CoV). (1) It
has been designated SARS-CoV 2. Acute lung injury (ALI) with subsequent
development of acute respiratory distress syndrome (ARDS) from robust
host hyper-immune response is the proposed pathophysiological mechanism.
This so called ”cytokine storm” may be independent of viral load and
replication. (2) Thus, the rationale for adding immune modulating
strategies on top of antiviral/antimicrobial therapies is warranted to
prevent this complication and hopefully improve survival. The
development of ALI/ARDS amplifies mortality in Covid-19 infection, more
so in patients with associated chronic medical conditions including
cardiovascular disease. (3)</div><div>Gemfibrozil, a drug discovered over 40 years ago, have beneficial
effects and safety profile in both primary and secondary prevention of
cardiovascular disease. (4) In addition to its lipid lowering ability,
it has important immune modulating properties that inhibit
pro-inflammatory factors involved in cytokine storms.(5) It is a
peroxisome proliferators-activated receptor (PPAR) agonist known to
reduce the release of inflammatory cytokines including interleukin-6
(IL-6), tumor necrosing factors (TNF) and interferon-gamma (IFN-g).</div><div>IL-6 elevation have been reported as an important marker of severity
with Covid-19 infection. (3) Together with other markers for
inflammation such as CRP, the degree of IL-6 elevation correlates with
increased morbidity and mortality.</div><div>Gemfibrozil has shown survival benefits by attenuating ALI/ARDS
development from viral etiologies. (6) Since gemfibrozil is currently
indicated for patients with cardiovascular disease, its adjunctive use
does not have to be repurposed for SARS associated with Covid-19
infection. Therefore, Gemfibrozil’s potential as an immune modulating
strategy to prevent ALI/ARDS cannot be ignored.</div><div>Immune Modulating Targets for Gemfibrozil in Covid-19 SARS pathogenesis:</div><div>Gemfibrozil has been shown to attenuate pro-inflammatory effects of
disease states through its immune-modulating, anti-inflammatory and
anti-migratory properties. (5). It belongs to the fibrate family of
drugs used to lower plasma lipds and cholesterol. They are one of
several known synthetic lignads acting as agonists to the PPARs. (7)
Their action in turn decrease serum levels of TNF, IFN-g and IL-6. (8,9)</div><div>As an an anti-inflammatory, gemfibrozil reduces superoxide production
and expression of nuclear factor kB (NF-kB). (10) Moreover, it inhibits
astrocyte production of TNF, IL-1b, IL-6 and nitric oxide (NO)
production. (11) Gemfibrozil also promotes the production of
anti-inflammatory cytokine IL-4. (12) It reduces the production of
C-reactive protein (CRP), TNF-a and IL-6 in peripheral blood mononuclear
cells. It inhibits the production of cyclooxygenase-2 (COX-2) and
prostaglandins. (13)</div><div>As an immune-modulating agent, gemfibrozil attenuates pro-inflammatory
transcription factor activation. This includes IFN-g regulatory factor 1
(IRF-1)bidning to gamma activation site (GAS), nuclear factor-kB
(NF-kB), activator protein 1 (AP-1), and CCAT/enhancer binding protein
beta (C/EBPb). (5) It also promotes switching of T helper (Th) cells
from the pro-inflammatory Th1 to anti-inflammatory Th2. Production of
Th2-specific cytokines is amplified including IL-4, IL-5 and IL-10. (14)</div><div>As an anti-oxidant, gemfibrozil not only prevents low density
lipoprotein (LDL) peroxidation but also acts on other signals of
inflammation. Reactive oxygen species (ROS) have emerged as important
signaling molecules during inflammatory conditions. Excessive ROS
generation results in damage to most cellular components of the living
organism. Gemfibrozil is known to inhibit ROS-mediated inflammation.
(15) It has free radical scavenging ability as well. Its para-hydroxyl
metabolite has been shown to reduce the burden of ROS. (16)</div><div>As an anti-migratory agent, gemfibrozil affects the expression of
cell-surface adhesion molecules icluding intracellular adhesion molecule
1 (ICAM-1), VCAM-1 and selectins inhibiting trans endothelial migration
of mononuclear cells and macrophages. (17) It also down-regulates the
expression of chemokines including monocyte chemotactic protein 1
(MCP-1), macrophage inflammatory protein 1 (MIP-1), monokines induced by
IFN-g (MIG) and IL-8. The expression of IL-8 induces inflammation,
monocyte/macrophage recruitment, angiogenesis and vascular smooth muscle
migration. Thus, gemfibrozil can function as an anti-migratory factor by
down-regulating the expression of different soluble chemokines and
inhibit the expression of different cell surface proteins and selectins.</div><div>Discussion:</div><div>Over the years, viral pathogens including Influenzas and Coronaviruses
cause ALI/ARDS from excessive release of pro-inflammatory cytokines and
chemokines described in cytokine storm syndromes. They induce much
higher transcription and up regulation of TNF genes including TNF
related aptoptosis-inducing lignad and TNF-mRNA in human
monocyte-derived macrophages. (18) This macrophage activation syndrome
(MAS) seen with the current SARS-CoV 2 may be a dysregulated host
response to Covid-19 viral induced immunosuppression and lymphopenia
leading to unintended ALI/ARDS consequences at the site of infection.
(19) The development of ALI/ARDS and the need for ventilator support
portends to increased mortality rates. Markers of inflammation including
CRP and IL-6 have been used as surrogates for MAS, and their degree of
elevation have correlated well with disease severity. (3)</div><div>Experiments with SARS-CoV indicate that MAS induced cytokine storms
result more from amplification of gene related inflammatory signals
regardless of viral load. In one model, immune modulation of receptor
sites or alteration of recruitment signals resulted in dramatic
improvement in host survival with viral load remaining constant. (20)
This suggests that immune modulating therapy may have as important a
role in addition to antiviral therapy in altering the course of Covid-19
infection. Reports of clinical improvement have been reported with the
adjuvant use of IL-6 antagonists including tocilizumab. However, cost
and repurposing use of these medications may be limiting factors.</div><div>Gemfibrozil has been in clinical use for patients with cardiovascular
disease and has achieved generic status. In addition, it has vital
immune modulating properties against cytokine storms that mitigate the
development of ALI/ARDS from both viral and nonviral pathogens. (21). It
not only reduces the levels of IL-6, TNF and IFN-g. But it has also been
shown to attneuate gene recruiting signals of inflammation utlizing
human equivalent dosing. In one animal study, the adjuvant use of
gemfibrozil resulted in enhanced host survival that developed ALI/ARDS
from viral pathogens. (6) Enhanced survival is seen even after exposure
to the virus. This implies that gemfibrozil has the potential to be a
treatment rather than a preventive therapy in human disease.</div><div>Therefore, the potential of gemfibrozil as adjunct immune modulating
therapy in conjunction with antiviral treatment for SARS associated with
Covid-19 infection in patients with associated cardiovascular disease is
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