Corresponding author: Both authors
Date: Monday, April 6, 2020
Confirmed novel coronavirus disease (nCoV or COVID-19),
1st reported to the world health organization (WHO)
end of last year, evolved since January 30th 2020 into
an unprecedented worldwide pandemic . As we write, confirmed cases
reached more than 1.7 million people with more than 103 thousand deaths
globally . We and other believe the observed death percentage of about
21% for cases with final outcome far exceed the reported natural
COVID-19 mortality. One major element in this lethal scenario is the
fact that COVID-19 is a new emergent strain which is highly infectious
and lethal through its modified spike protein. On the other hand, severe
pneumonia, acute respiratory distress syndrome, sepsis, septic shock,
and multi-organ failure and death occur in about 20 to 30% of cases.
Among these approximately about 5% would be in critical condition at
any given point in time . These figures already strained even the best
healthcare systems known in modern times including those of Europe and
North America. Most plausible explanation of this toxic COVID-19
pandemic progression is the duality of a highly transmittable disease
coupled with a massive cytokine storm and exaggerated immune response
that a proportion of patients go through .
COVID-19 Vaccine Development Taskforce is working to finance, develop
and deploy vaccines with fair global distribution. Additionally, several
groups continue to explore several potential host and viral targets to
make drug therapy breakthroughs. Pending the design of very specific
effective antiviral therapy, clinicians and researchers alike focus
their efforts on best re-employment of re-purposed molecules (e.g.
melatonin). Remedisivir is probably the most promising antiviral ahead
so far. Evidence for hydroxychloroquine ± azithromycin is insufficient .
Based on this last study, It seems that Azithromycin is crucial for
those patients presenting with a lower respiratory tract or lung
infection. However, azithromycin has no known antiviral activity and the
mechanism by which it produced this positive outcome is probably through
its immune modulating and anti-inflammatory effect. Nevertheless,
progression persisted (6 cases out of 26) which may be explained by the
lower concentration of azithromycin in serum and the central nervous
system where significant viral tropism exists. Hence, we should
investigate more options in this current surge.
Melatonin is a relatively safe and accessible molecule, now sold over
the counter in Jordan and around the world. This is a natural pineal
gland hormone which is broadly used in many indications including
cardiovascular, neurological and endocrinology. Many studies showed that
it assists in eradicating viral infections with multiple positive
anti-inflammatory, immune-modulatory, as well as neuro- and other vital
organ protective effects. Melatonin interferes with multiple COVID-19
targets, including the angiotensin converting enzyme 2 (ACE 2), it also
has anti-oxidative stress, anti-inflammatory and cytokine modulatory
effects in sepsis, septic shock, acute respiratory syndrome, and
multi-organ failure. It has human cell membrane stabilizing effect which
may interfere with viral budding. Melatonin, at a dose of 10 mg or
higher (orally or intravenously), reduced a number of markers/cytokines
including C-reactive protein and tumor necrosis factor (TNF α) and
prevented progression to chronic lung disease especially in the setting
of sepsis in adult and pediatric populations. For example, it reduced
ischemic re-perfusion injury and multi-organ failure in septic patients.
Moreover, melatonin can target the potential central nervous system
tropism of similar viruses in animal models. We have proposed to our
Jordan COVID-19 crisis committee in a letter to Editor of reputable
journals a combination of melatonin and ascorbic acid (authors’
correspondence). Furthermore, an analysis of the first 12 cases of
COVID-19 in the United States revealed that there was one case of a
middle-age (i.e. 50 to 59-year-old) man who had bilateral consolidation
pneumonia and received as needed melatonin doses. This patient had early
signs of multi-organ injury based on high liver enzymes; ALT and AST of
389 and 190 U/L, respectively. Procalcitonin was consistent with a local
inflammation at a level of 0.13 ng/ml. All these values persisted at
this average for 13 days. In this case, the outcome was eventually
clearance of the positive COVID-19 sample in 8 days and hospitalization
continued for 7 days only. Further support to this potential adjuvant
role of melatonin in COVID-19 infections comes from China itself, as
summarized by Zhang and his colleagues.
Glycyrrhizin is a steroid-related chemical structure obtained from
licorice root with inhibitory action on oxygen and nitrogen
species-mediated lung damage. Nature again presents us with this
molecule which has broad spectrum antiviral activity. Glycyrrhizin was
more active back in 2003 against the older closest human relative of
COVID-19, namely, the severe acute respiratory syndrome coronavirus
(SARS CoV) than a variety of medications including ribavirin. It also
has protective effects against sepsis, septic shock, acute respiratory
distress syndrome and multi-organ injury. Glycyrrhizin follows a
dose-independent pharmacokinetics with observed distribution largely
confined to the vascular compartment at a dose range of 40 to 120 mg
oral daily. In Jordan, there is a local product that contains this
ingredient under the brand name Dilamuc Syrup® from Jerash
Pharmaceuticals. Usual adult dose is 15 ml divided three times daily
(daily dose of 24.6 mg of glycyrrhizin). Friends in the domestic poultry
business uses nebulized forms of this molecule to treat various
dangerous viral respiratory illnesses including avian flu. Therefore, in
this emergent pandemic, we strongly recommend conducting randomized
controlled or at least open label trials of adding melatonin and
glycyrrhizin protocols to the management of COVID-19 patients with
different severity levels. A recommended protocol that can be trialed
for COVID-19 crisis is as follows:
- Melatonin: start dose at 10 mg oral stat post first blood level and
escalate to a target dose of 5 to 80 mg daily, given 60% in the
evening and 40% in the morning based on age and severity.
- Glycyrrhizin: start with 5 ml (8.2 mg) three times daily, escalate to
a target dose of 5 to 10 ml (8.2 to 16.4 mg) three times daily.