Silymarin in COVID-19 Pneumonia

To date, there are no drugs or other therapeutics approved by the U.S. Food and Drug
Administration (FDA) to prevent or treat COVID-19 that has spread globally resulting in the
ongoing pandemic as declared by the World Health Organization (WHO) on 11 March 2020. While
the majority of patients have mild symptoms, some progress to viral pneumonia and multi-organ
failure (MOF).

Older age, cardiovascular disease, diabetes mellitus, chronic respiratory illness, systemic
hypertension, and malignancy are all associated with an increased risk of death in COVID-19.

In fatal cases of human severe acute respiratory syndrome-associated coronavirus (SARS-CoV),
Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 infections, patients
suffer from severe respiratory distress necessitating mechanical ventilation. Previous
studies showed that genetic susceptibility and inflammatory cytokines (Interleukins: IL-6, 8,
10, Tumor Necrosis Factor [TNF] and Vascular endothelial growth factor [VEGF]) are closely
related to the occurrence of acute respiratory distress syndrome (ARDS).

Cytokine storm is another life-threatening condition, and likely a leading cause of fatality.

Rapid viral replication and apoptosis together with virus-induced angiotensin-converting
enzyme 2 (ACE-2) down-regulation and shedding and antibody-dependent enhancement (ADE) are
responsible for aggressive inflammation caused by SARS-CoV-2, which is closely related to
SARS-CoV; where both viruses hijack the same entry receptor ACE-2 suggesting the likelihood
of the same population of cells being targeted and infected.

A Previous study demonstrated that p38 mitogen-activated protein kinase (p38 MAPK) and its
downstream targets are activated in SARS-CoV infected Vero E6 cells and that activation of
p38 MAPK enhances the cytopathic effects of SARS-CoV infection.

Interestingly, the p38 MAPK pathway is a key regulator of proinflammatory cytokine synthesis,
which may contribute to the chronic low-grade inflammation observed with ageing. Another
study hypothesized that ageing up-regulates the activation of p38 MAPK as well as the
pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in mouse lung and is accompanied by
disturbances in oxidant-antioxidant status.

Furthermore, it was shown that p38 MAPK pathway is involved in the inflammatory response
induced by cigarette smoke exposure, endotoxin and oxidative stress, through activation and
release of pro-inflammatory cytokines, and it was postulated that inhibition of p38 MAPK
prevented allergen-induced pulmonary eosinophilia, mucus hypersecretion and airway
hyper-responsiveness.

p38 MAPK was identified as a possible target in vascular cells, which can be activated by
high glucose levels and diabetes, where at moderate and commonly encountered levels of
hyperglycemia, p38 MAPK appears to be activated by PKC-δ isoform-dependent processes.

Numerous preclinical studies have addressed the role of p38 MAPK in ischemic heart disease,
myocardial infarction, and atherosclerosis.

Hence, The investigators of this clinical trial have concluded that p38 MAPK pathway
activation could explain the increased risk of death from COVID-19 in older age, diabetes
mellitus, cardiovascular disease, systemic hypertension and chronic respiratory diseases.
Therefore, p38 MAPK inhibitors may play a promising role in the treatment of SARS-CoV-2 and
COVID-19 improving the clinical outcomes.

Silymarin, an extract from the seed of the milk thistle plant (Silybum marianum [S.
marianum]) is widely known for its hepatoprotective functions, mainly due to its
anti-oxidative, anti-inflammatory, and immunomodulatory effects.

Recent studies documented the antiviral activities of Silymarin against several viruses;
including flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunia virus
and Mayaro virus), influenza virus, hepatitis B virus and Human Immunodeficiency Virus (HIV);
in addition to its anti-oxidative and anti-inflammatory role.

Furthermore, a recent study demonstrated the role of Silymarin in attenuating cigarette smoke
extract-induced inflammation via simultaneous inhibition of autophagy and extracellular
signal-regulated kinase/p38 mitogen-activated protein kinase (ERK/ p38 MAPK) pathway in human
bronchial epithelial cells, as well as attenuating up-regulation of pro-inflammatory
cytokines TNF-α, IL-6 and IL-8 and concluded that Silymarin might be an ideal agent treating
inflammatory pulmonary diseases.

This clinical trial aim at evaluating the role of Silymarin in the treatment of adults with
COVID-19 Pneumonia