Clinical Review
Therapeutic Strategies
with Synbiotics, Thalidomide, and Celecoxib forSevere COVID-19 Pneumonia
Short title: Treatment for severe COVID-19 pneumonia
Masato Hada, MD, Pharmacist
Hada Clinic,
clinichada@cy.tnc.ne.jp
Corresponding author
Masato Hada, MD, Pharmacist (Medical Practitioner)
Hada Clinic, 1728-2 Oooka, Numazu City, Shizuoka Prefecture, Japan
Phone: +081559525779; FAX: +81559525779
E-mail address:
clinichada@cy.tnc.ne.jp
Key words: proinflammatory cytokines, macrophages, SARS-CoV,
thalidomide, celecoxib
Abbreviations used in this paper:
PAMP: pathogen-associated molecular pattern
PRRs: pattern-recognition receptors
TLR: Toll-like receptor
SARS: severe acute respiratory syndrome
MERS: Middle East respiratory syndrome
NF-κB: nuclear factor kappa B
IL: interleukin
TNF-α: tumor necrosis factor-α
TGF-β: Transforming growth factor-β
SARS-CoV: severe acute respiratory syndrome coronavirus
MERS-CoV: Middle East respiratory syndrome coronavirus
COVID-19: 2019 novel coronavirus
ACE2: angiotensin-converting enzyme 2
MyD88: myeloid differentiation factor 88
COX-2: cyclooxygenase-2
AMPK: AMP-activated protein kinase
VEGF: VEGF
bFGF: basic fibroblast growth factor
MCP-1: monocyte chemoattractant protein-1
iNOS: inducible nitric oxide synthase
Summary
Dysregulation of proinflammatory cytokines promotes immune-mediated
injuries. Epithelial-cell proliferation and an increase in lung
macrophages have both been associated with
the 2003 SARS-CoV infection.
Proinflammatory cytokines as well as lipopolysaccharide and
pathogen-associated molecular
patterns (PAMPs) promote macrophage transition which promotes ongoing
inflammation. PAMPs are primarily sensed by Toll-like receptors and/or
by angiotensin-converting enzyme 2; this interaction serves to activate
NF-κB to promotes synthesis and
secretion of proinflammatory cytokines. Activated immune cells secrete
large amounts of specific proinflammatory cytokines including IL-1,
IL-6, IL-8, TNF-α, and TGF-β1 which can promote severe lung injury. As
such, immunomodulatory drugs alone may have an impact on the cytokine
storm even without the addition of antiviral agents. The central
transcription factor, NF-κB,
induces angiogenesis during cancer progression; combinations of
pharmacological agents, including thalidomide and celecoxib, show
promising results in cancer treatment studies. This may be due to a
low-level, chronic cytokine storm similar to that described for acute
and chronic hepatitis as well as for cirrhosis and hepatoma. As
previously described, I have used thalidomide, celecoxib, and low dose
cytotoxic agents since 2000 for the successful treatment of a variety of
cancers. This regimen is cited or introduced in leading medical
journals. Thalidomide is an immunomodulatory agent that modulates the
activities of NF-κB in combination
with the cyclooxygenase-2 inhibitor, celecoxib. The combination of
thalidomide and celecoxib might limit the inflammatory symptoms when
used to treat severe COVID-19 pneumonia due to infection with
SARS-CoV-2.