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Abstract

The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. So, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children do not suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats also do not suffer from the virus they transmit, and bats too have a much higher level of melatonin. Viruses generate an explosion of reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. Melatonin inhibits the programmed cell death which coronaviruses induce, causing significant lung damage. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks the inflammasome. The immune response is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the negative effects of coronavirus infection on patients’ health after the active phase of the infection is over.
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International Reviews of Immunology
ISSN: 0883-0185 (Print) 1563-5244 (Online) Journal homepage: https://www.tandfonline.com/loi/iiri20
Can melatonin reduce the severity of COVID-19
pandemic?
Alex Shneider, Aleksandr Kudriavtsev & Anna Vakhrusheva
To cite this article: Alex Shneider, Aleksandr Kudriavtsev & Anna Vakhrusheva (2020): Can
melatonin reduce the severity of COVID-19 pandemic?, International Reviews of Immunology, DOI:
10.1080/08830185.2020.1756284
To link to this article: https://doi.org/10.1080/08830185.2020.1756284
Published online: 29 Apr 2020.
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COMMENTARY
Can melatonin reduce the severity of COVID-19 pandemic?
Alex Shneider
a,b
, Aleksandr Kudriavtsev
c,d
, and Anna Vakhrusheva
c
a
CureLab Oncology, Inc, Dedham, Massachusetts, USA;
b
Department of Molecular Biology, Ariel University, Ariel, Israel;
c
Biological
Faculty, Lomonosov Moscow State University, Moscow, Russia;
d
Emanuel Institute of Biochemical Phisics, RAS, Moscow, Russia
ABSTRACT
The current COVID-19 pandemic is one of the most devastating events in recent history.
The virus causes relatively minor damage to young, healthy populations, imposing life-
threatening danger to the elderly and people with diseases of chronic inflammation.
Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-
19 pandemic more similar to other typical outbreaks. Children dont suffer from COVID-19
as much as their grandparents and have a much higher melatonin level. Bats are nocturnal
animals possessing high levels of melatonin, which may contribute to their high anti-viral
resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen spe-
cies, and melatonin is the best natural antioxidant that is lost with age. The programmed
cell death coronaviruses cause, which can result in significant lung damage, is also inhibited
by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome
activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety
and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates
immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is
known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks
due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-
the-counter drug melatonin, we may be immediately able to prevent the development of
severe disease symptoms in coronavirus patients, reduce the severity of their symptoms,
and/or reduce the immuno-pathology of coronavirus infection on patientshealth after the
active phase of the infection is over.
ARTICLE HISTORY
Received 2 April 2020
Accepted 6 April 2020
KEYWORDS
SARS-CoV-2; Melatonin;
Coronavirus; Apoptosis; Bat;
COVID-19
Elderly have reduced level of melatonin
The effect of SARS-CoV-2 on humans is clearly age-
related. So far, very few deaths from COVID-19 have
been recorded in people under the age of 20, while
the elderly have an excessively high mortality rate. We
hypothesize that, at least partially, the increased sensi-
tivity to coronavirus in the elderly is due to their
reduced level of melatonin.
The study [1] measured the concentration of mela-
tonin in 81 healthy people (44 men and 37 women)
aged 1 to 92 years. The authors observed a significant
negative correlation between the daily concentration
of melatonin in the blood and age. At the same time,
there was no difference between men and women.
Daily variations in melatonin in young people (age 26
þ/-2 years) were in the region of 7 pg/ml, and in peo-
ple aged 84 þ/-2 years, the level of melatonin dropped
to 2 pg/ml. A significant difference was also observed
in the production of melatonin at night. A night peak
of melatonin for young people was observed at the
level of 83 þ/-20 pg/ml, while for the elderly - only
11.2 þ/-1.6 pg/ml.
The concentration of melatonin in the blood was
assessed for 367 people (210 men and 157 women)
during both morning (from 7:30 to 10 am) and even-
ing (from 11 pm to 1 am) hours. The age range was
from 3 to 90 years old [2]. The highest concentration
of melatonin (329.5 þ/-42 pg/ml) was in 1-3 year old
children. After this age, there was a sharp decline in
the average melatonin level by almost 80%. Then a
negative correlation between age and melatonin con-
centration remained over the period of 20-90 years.
Here are the average melatonin values for the age
groups: 1-3 years old 260 pg/ml, 5-7 y.o. 160 pg/
ml, 7-11 y.o. 100-110 pg/ml, 11-15 y.o. 80-85 pg/
ml, 15-50 y.o. 50-55 pg/ml, 50-70 y.o. 27.8 pg/ml,
70-90 y.o. 15.3 pg/ml. The age-related changes in
melatonin levels were observed during the nightly
production of melatonin only. For daytime melatonin,
no difference was found. Such an age-dependent
CONTACT Alex Shneider ashneider@curelab.com CureLab Oncology, Inc., Dedham, MA 02021, USA.
ß2020 Taylor & Francis Group, LLC
INTERNATIONAL REVIEWS OF IMMUNOLOGY
https://doi.org/10.1080/08830185.2020.1756284
biphasic drop in melatonin (a sharp decline followed
by a more moderate drop) is characteristic not only of
humans but was detected in rats and some other
mammals as well [2]. An age-dependent decline in
nighttime melatonin levels was also reported for both
genders in a review which summarizes data of 18
studies analyzing melatonin levels in blood as a func-
tion of age [3]. Thus, the application of melatonin
may partially alleviate age-related comorbidities exac-
erbating SARS-CoV-2 infection and increasing its
risk [4,5].
Bats have higher levels of melatonin
than humans
The dominant hypothesis today is that SARS-CoV-2
virus is a zoonosis that took place many times in
human history [6]. Natural carriers of these viruses
are bats of the genus Rhinolophus. Bats transmit coro-
naviruses [7,8], while suffering minimal to no symp-
toms [9]. The origins of batscoronaviruses and
factors of viral pathogenesis [911] are only partially
understood. Mechanisms of anti-viral resistance in
bats are understood even less, remaining mostly on
the level of hypothesis [8,12,13]. SARS-CoV-2 is 96%
identical to another bats coronavirus Bat-SARSr-CoV
RaTG13 [14]. If one excludes the option of a labora-
tory spill, considering only the option of natural
transmission from bats to humans, it would be logical
to assume that the virus is relatively harmless for its
natural host during longtime coexisting [1517].
We are not aware of any comprehensive study ana-
lyzing the role of melatonin in bats anti-viral immun-
ity; however, we believe it plays a significant
contributing role. Melatonin production is controlled
by photosensitive retinal-containing receptors via nor-
epinephrine and adrenergic receptors [18]. Melatonin
is produced in response to darkness and its synthesis
is inhibited by light [19]. Rhinolophus bats are noctur-
nal hunters. During the day, they hide in dark places,
such as caves or bat mines, staying awake at night.
Thus, they are less exposed to daylight which would
reduce their melatonin level. Indeed, a number of
studies indicate that the concentration of melatonin in
bats at night varies from 60 to 500 pg/ml and that the
daytime concentration also remains at a high level of
20-90 pg/ml depending on the species [20,21]. As
described above, melatonin levels are lower in
humans, especially in elderly populations. Thus,
among other factors, could bats be protected from the
severe effects of coronavirus by possessing a high level
of melatonin?
Melatonin reduces infection-associated
oxidative stress
Viral respiratory infections are associated with oxida-
tive stress characterized by elevated levels of reactive
oxygen (ROS) and/or nitrogen species (RNS) [22].
Oxidative stress sensitive genes were upregulated in
the peripheral blood mononuclear cells of SARS-CoV-
1 human patients [23]. Viral infections causing severe
lung injury and oxidative stress in the lung may form
a positive feedback loop. For example, SARS-CoV
induces oxidative stress; oxidative stress induces the
expression of PLA2G2D phospholipase; higher expres-
sion of PLA2G2D reduces anti-viral immunity, mak-
ing the virus more lethal. Notably, the expression of
PLA2G2D is naturally increased with age [24].
Depriving bats of their antioxidant protection
increases the lethality of coronavirus. At the same
time, experimental animals with deleted components
of ROS-generating machinery may be more resistant
to respiratory viruses [25].
Melatonin possesses high antioxidant properties. It
binds up to 10 free radicals per molecule, while such
classic antioxidants as vitamins C and E bind just one
[26]. Also, melatonin has a high bioavailability, pene-
trating blood-brain barrier and placenta [27].
Indirectly, the antioxidant properties of melatonin are
linked to an increased activity of superoxide dismu-
tase, glutathione peroxidase, reductase and cata-
lase [2831].
Coronavirus activates inflammasome and
causes inflammation, which melatonin reduces
Researchers believe that SARS-CoV-2 causes severe
lung pathology by inducing pyroptosis [32], a highly
inflammatory form of programmed cell death [33].
Pyroptosis in macrophages and other immune cells of
the immune system can lead to symptoms such as
lymphopenia [34] that blocks an effective immune
response to the virus. As the molecular biology of
SARS-CoV-2 is yet to be studied, we have to use data
on the inflammatory mechanisms of SARS-CoV-1. A
viral protein encoded by ORF8b directly interacts with
inflammasome NLRP3 (nucleotide-binding domain
leucine-rich repeat (NLR) and pyrin domain contain-
ing receptor 3) [35], which activates the adaptor pro-
tein ASC and caspases 4,5 and 11. This leads to a
disruption of the cell membrane and the inflammatory
release of cell content to the extracellular space [36].
Simultaneously, it induces pro-inflammatory cytokines
(e.g. IL-1bbIL-18) [37]. Thus, it is necessary to
inhibit pyroptosis by acting on NLRP3, preferably
2 A. SHNEIDER ET AL.
immediately in the lungs. The mechanisms of NLRP3
inhibition have been studied [38], and melatonin
reported as NLRP3 inflammasome inhibitor [39]. On
the model of bacterial pneumonia, LPS-induced ALI
mouse model, it was shown that melatonin success-
fully inhibits pneumonia through interfering with
NLRP3 inflammasome, protecting macrophages from
pyroptosis [40]. Other publications also demonstrate
that melatonin may be an effective inhibitor of pyrop-
tosis and pathologies associated with it [4146].
Melatonin can reduce immunosuppression
induced by chronic stress and sleep
deprivation
The COVID-19 societal crisis has led to massive and
prolonged stress, anxiety and sleep deprivation, which
shall become a subject of systemic scientific analysis.
These obvious factors may have a severe negative
effect on the immune system and peoplesability to
resist COVID-19 as well as other infections.
Stress and sleep deprivation may have a dual effect
on the immune system. Short-term stress has an
immunomodulating effect. In contrast, prolonged
stress suppresses immunity. Chronic stress reduces the
number and activity of protective immune cells while
stimulating immunosuppressive mechanisms (for
example, increasing the number and/or activity of
regulatory T-cells) and producing a pro-inflammatory
response [47]. Similar effects on immunity are
observed with short-term and chronic sleep depriv-
ation. It is the latter that has a more negative effect
on immunity, while short sleep insufficiency can even
have a hormesis effect [48].
The immune system, like the neuroendocrine one,
has its own rhythms. For example, the overnight
release of melatonin is synchronized with the peak of
the proliferation of progenitor cells for their subse-
quent differentiation into granulocytes and macro-
phages [4951]. The phagocyte activity increases
concomitantly with the nocturnal peak of melatonin
based on circadian rhythms [52]. There is also a
decrease in the number and activity of natural killer
cells at night, along with anti-inflammatory cytokines
(e.g. IL-10), with a simultaneous increase in the num-
ber of naive T-cells and pro-inflammatory cytokines
such as IL-2, IL-6, IL-12, TNF-alpha [53]. The
increase in the pro-inflammatory effect is limited in
duration (only during the night) and is compensated
by the strong anti-inflammatory response that prevails
during the day. In the case of sleep deprivation, an
even greater increase in the pro-inflammatory level
was shown: doubled mRNA level of cytokine IL-1b
[54], increased levels of IL-6 and TNF-alpha receptors
[55], and reduced levels of anti-inflammatory IL-10
[48,53]. Not surprisingly, sleep deprivation leads to
multiple diseases associated with chronic inflamma-
tion such as cognitive, cardiovascular, metabolic and
other disorders [56,57].
Other effects of sleep deprivation included
decreased lymphocyte proliferation after 48 hours
without sleep [58]; reduced phagocyte activity after
72 hours of sleep deprivation [59]. Healthy volunteers
sleeping less than 6 hours for a week had reduced lev-
els of neutrophil phagocytosis, lower levels of NADPH
oxidase, and fewer CD4þT cells, which are necessary
for anti-infective defense and proper vaccination
response. The level of NADPH oxidase remained
reduced even after a week of the restored amount of
sleep, which indicated long-lasting effects of sleep
deprivation [60]. Moreover, sleep deprived people
immunized against the influenza A virus revealed a
much lower level of antibodies than those immunized
without sleep deprivation [61]. Also, immunization
against the hepatitis A virus showed lower antibody
titers in people with a lack of sleep after one night
[62]. Suppression of the immune system resulting in
pathogenic microorganisms in blood and sepsis was
recorded in sleep-deprived rats [63]. Long-term sleep
deprivation leads to oxidative stress, reducing the
activity of antioxidant enzymes [64,65]. Consequently,
long-term sleep deprivation and/or chronic stress
leads to the deterioration of immune functions
through the disturbance of barrier mechanisms by
suppressing the phagocytosis, reducing proliferation
and activity of some leukocytes, in particular CD4
þ
T
cells, while increasing T-suppressors as well as elevat-
ing oxidative stress and pro-inflammatory back-
ground. Thus, people with chronic sleep deprivation
and/or stress are particularly susceptible to infec-
tious diseases.
The production of melatonin is significantly
impaired in people with chronic insomnia. The longer
a person has experienced symptoms of insomnia, the
greater the effect on melatonin concentration: if more
than five years, then peak value 72.1 ± 25.0 pg/ml (age
41.8 ± 11.7 years; duration 15.3 ± 5.9 years;), if less,
then the peak value is 98.2 ± 23.9 pg/ml (age
40.6 ± 6.5 years; duration 3.8 ± 1.5 years) [66].
However, in the case of chronic stress, initially, the
concentration of melatonin rises significantly as a pro-
tective mechanism exerting anti-inflammatory and
antioxidant effects, dropping sharply after [67].
INTERNATIONAL REVIEWS OF IMMUNOLOGY 3
Thus, restoring (even partially) normal sleep habits
and reducing anxiety through melatonin may have a
significant public health effect during current COVID-
19 crisis.
Melatonin can be utilized in combinations
with drugs and treatments
Currently, the following drugs are most often used to
treat coronavirus infection: the combination of the
antiviral drugs lopinavir/ritonavir [68], nucleotide
analogs that inhibit RNA-dependent-RNA polymerize
of the virus ribavirin [69] and remdesivir [70], anti-
malarial drug hydroxychloroquine (less toxic analog of
chloroquine) [71], sometimes in combination with the
antibiotic azithromycin [72], and the glucocorticoid
methylprednisolone [73]. According to a recent study
on lopinavir/ritonavir, the combination of drugs used
to treat AIDS did not show any benefits compared to
standard hospitalization [74]. One of the reasons may
be the dose-limiting toxicity of these drugs.
Nevertheless, it is shown in animal studies that mela-
tonin and alpha lipoic acid can reduce damage to the
kidneys from oxidative stress caused by the lopinavir/
ritonavir combination [75]. Therefore, if melatonin is
used as an adjuvant to this combination, the side
effects of the drug combination can be reduced, and
the dose increased.
Ribavirin, remdesivir and other nucleotide analogs
targeting RNA-dependent RNA polymerase are a
popular strategy. Indeed, neither humans nor animals
have this enzyme, thus, in principle, substances of this
group can be highly selective. Combining nucleotide
analogs with melatonin may provide additional bene-
fits. For example, melatonin increased ribavirin
potency as an anti-influenza agent, probably due to
the immunomodulatory functions of melatonin [76].
In vitro studies have shown that ribavirin in combin-
ation with melatonin shows improved properties for
inhibiting replication and respiratory syncytial
virus [77].
Chloroquine and hydroxychloroquine are viewed
today as the most promising anti-COVID-19 drugs
[71,72,78,79]. One could apprehend that melatonin
would interfere with them because it was reported
that the anti-malaria effectiveness of chloroquine was
greatly increased by a melatonin antagonist,
Luzindole, and/or bright light at night, which reduced
melatonin production. However, these worries are
unwarranted because the anti-malaria effect of mela-
tonin suppression is based on the direct benefits mal-
arial plasmodium gains from direct interaction of
melatonin with its melatonin receptors. This inter-
action leads to the activation of malaria Ca
2þ
signal-
ing pathway and eventually to increased parasitemia.
None of these molecular events, and pathologies asso-
ciated with them, can take place during coronaviral
infection due to the completely different nature of the
infective agent. At the same time, even the research
on the anti-malaria effect of melatonin antagonists
noticed that high doses of melatonin are beneficial for
malaria treatment because they inhibit programmed
cell death and oxidative stress [80]. Thus, applying
melatonin as an adjuvant to chloroquine and hydroxy-
chloroquine treatments of COVID-19 may reduce the
necessary doses, and thus toxicity, of these
agents [81].
Methylprednisolone is used to relieve edema, which
is justified in the case of SARS, where, as previously
indicated, edema contributes significantly to lung dys-
function, leading to their failure. The activity of mela-
tonin as a protective drug compared to
methylprednisolone was studied in mice with spinal
cord injuries [82]. It was shown that the protective
properties in comparison with methylprednisolone in
melatonin were higher. The combination of these
drugs has led to even greater efficacy for relieving
edema [83], so melatonin can be used in combination
with prednisone to relieve edema with greater efficacy
in patients suffering from pneumonia with SARS-
CoV-2.
From all of the above, the need for clinical trials to
verify the effectiveness of melatonin as an adjuvant
used in combination with other drugs is evident.
Melatonin as a vaccine adjuvant and antiviral
immune stimulant
Vaccines made our entire modern civilization possible
together with soup and antibiotics eradicating horrify-
ing infections. Currently, multiple efforts to generate
safe and effective vaccines against coronaviruses, spe-
cifically anti-COVID-19, are underway. For example,
the experimental vaccine mRNA-1273 (Moderna,
Inc.), which is in the first stage of clinical studies [84].
This virus may be a good target for vaccine develop-
ment because, unlike the influenza virus, it has a low
mutation rate, which would make it unlikely for it to
escape the immune response.
However, even when/if such a vaccine would be
developed, it may not be as effective for the elderly
and other sensitive population groups as it would be
for young healthy adults. Limited immune response to
vaccines was reported for these groups before due to
4 A. SHNEIDER ET AL.
immunosenescence [85,86]. Thus, adjuvants enhancing
vaccine efficacy in the elderly are urgently needed
amidst the COVID-19 crisis and melatonin may be
one of them [87]. Natural killer and CD4
þ
cells, as
well as cytokine production necessary for effective
vaccine response, are enhanced by melatonin partially
reverting age-related immune decline. For younger
populations, supplementing preventive vaccination
with preventive and/or therapeutic melatonin use may
constitute a feasible strategy as well due to its immu-
nomodulating properties [88].
Use of melatonin as an antiviral immunostimulant
may be further supported by the following animal
data. It prevented the development of paralysis and
death in mice infected with sublethal doses of the
encephalomyocarditis virus [89] as well as reducing
the mortality in mice infected with encephalitis viruses
[90]. Also, it improved some immune parameters after
trauma-hemorrhage [91]. It is worth noting that lack
of sleep reduces the bodys ability to respond to viral
infections. The shorter the sleep, the higher the fre-
quency of colds [92], and one of the most important
factors in this may be melatonin [93]. Thus, mela-
tonin intake can increase the protective functions of
the body against infections.
Can melatonin prevent the main danger, post-
COVID-19 lung fibrosis?
One of the most important complications of COVID-
19 can be pulmonary fibrosis, which may manifest
itself as a progressive disease with a terminal stage
characterized by severe pulmonary hypertension and
pulmonary heart disease. Although it is not yet pos-
sible to predict what the actual mortality due to
respiratory failure and the 5-years survival will be for
COVID-19, this was a common danger for most
patients during the previous SARS-CoV-1 epidemic
[94]. Pulmonary fibrosis can be a side effect of mech-
anical ventilation [95] due to the mechanical stress
leading to an epithelial-mesenchymal transition [96].
Oxidative stress is an additional risk factor for the
development of fibrosis [97]. Animal studies have
shown that the inhibition of oxidative stress can pro-
tect against the development of fibrosis [98]. The role
of melatonin antioxidant properties in the prevention
of COVID-19 post-infection complications should be
addressed with no delay. Melatonins ability to protect
patients from pulmonary fibrosis through the Hippo/
YAP pathway has already been shown [99].
Considering that millions of people can be infected
with COVID-19, while only several tens of thousands
were with SARS-CoV-1, applying melatonin to pre-
vent pulmonary fibrosis may be even more important
than mitigating the acute SARS-CoV-2 infection
per se.
Can melatonin reduce the risk of mechanical
ventilation?
Although elderly people possess a higher mortality
rate, a high number of young COVID-19 patients
receive mechanical ventilation due to low blood oxy-
gen saturation and difficulty breathing [100].
Mortality was increased in patients even with moder-
ate hyperoxemia (with Pa (O2)>100 mm Hg), staying
for 1 to 7 days on artificial respiration apparatuses, as
shown by the multicenter cohort observational study
[101]. Ventilation was reported to enhance pulmonary
inflammation in acute lung damage [102] and
increased oxidative stress in the alveoli [103]. As pre-
sented above, melatonin may be quite effective against
oxidative stress. Thus, melatonin may resolve a
contradiction between the urgent clinical necessity to
give a patient mechanical ventilation and the threat
this ventilation may possess.
Economic feasibility
Modern medicine often operates in a price-ignorant
manner, placing the burden on the economies of
developed countries and widening the gap between
rich and poor nations. Melatonin is an inexpensive
product with scalable production. It has a long shelf
life, the simplest mode of transportation, and can be
self-administered orally in remote areas. No severe
side effects are expected in the case of occasional
overdoses. Thus, using melatonin to mitigate a world-
wide pandemic outbreak may be a feasible and
socially responsible public health measure. Also, some
hospital systems and glass manufacturers may con-
sider implementing simple and inexpensive light fil-
ters, reducing the amount of melatonin-reducing blue
light in favor of red light less effecting mela-
tonin [104].
Can melatonin harm?
Anything can harm if used inappropriately, and/or if
the population is large enough there will always be
people oversensitive to any factor. However, the acute
toxicity of melatonin was reported to be very low
[105107]. Even high doses, such as 16.6 g/day
administered for 3045 days, demonstrated no
INTERNATIONAL REVIEWS OF IMMUNOLOGY 5
recorded toxicity. Also, we are not aware of any con-
vincing human data demonstrating chronic melatonin
toxicity. In fact, no toxicity was reported in phase II
clinical trials of 1400 women receiving 75 mg of mela-
tonin nightly for 4 years [108]. Nevertheless, available
data does not warrant the conclusion that melatonin
would be as harmless if taken during the daytime.
Also, we should be very cautious about melatonin
being given to healthy children, adolescent popula-
tions going through puberty or even young adults nat-
urally producing high levels of endogenous melatonin.
It could be the case that externally administered mela-
tonin could interfere with their internal melatonin
production. Thus, the typical prophylactic intake of 1-
3 mg doses during the peak of the pandemic should
not cause any harm to healthy adult populations.
Neither should we expect any additional harm if
higher doses of melatonin are administered during the
span of confirmed infection and, even more so, venti-
lation. We also believe that the relatively prolonged
intake of melatonin by those who are at risk of post-
infection fibrosis would be a warranted risk-reducing
measure [109].
What the next steps must be?
The history of biomedical science, public health, and
medical practice knows many examples of mental
inertia and the price it cost in lives [110]. Under nor-
mal circumstances, the conclusion of this review
would be to initiate prospective clinical studies divid-
ing patients into case-control groups with one group
receiving standards of care alone, and another the
standards of care supplemented with melatonin.
However, under the current COVID-19 crisis, we see
a severe ethical problem with this otherwise correct
approach. Lets assume that we conduct exactly this
type of study and then conclude that melatonin
reduces rates of hospitalization, demand in inhalation
equipment and trained personal, Morality and inci-
dence in irreversible post-infection complications.
Considering the fact that melatonin is known as a
safe, inexpensive, readily-available OTC product, how
would we justify to millions of people, who did not
benefit from it at the time of a deadly crisis, that they
and their relatives (who may not be alive anymore)
were not timely informed of the potential benefits of
melatonin? Thus, we believe that one should immedi-
ately conduct comprehensive retrospective studies
comparing disease progression among patients who
were or were not self-administering melatonin during
the course of their disease. Although such data is not
readily available yet, it is still possible to collect. The
retrospective studies should be supplemented with a
prospective one following the incidences and severity
of post-infection complications in patients receiving
and not-receiving melatonin. However, in addition to
these above-mentioned conventional research strat-
egies, we propose to immediately inform doctors,
nurses, healthcare providers, and the general public of
the potential benefits of melatonin. Extraordinary sit-
uations require out-of-the-box modus operandi. The
lack of timely action is, in and of itself, an action.
Acknowledgments
The authors would like to thank Dr. Yuri Gankin and Dr.
Andrey Komissarov for their intellectually stimulating dis-
cussions and Aaron Shneider for his comprehensive editor-
ial work and medical communications effort.
Disclosure statement
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the art-
icle. The authors declare that the research was conducted in
the absence of any commercial or financial relationships
that could be construed as a potential conflict of interest.
The authors declare that there is no conflict of interest that
could be perceived as prejudicing the impartiality of the
research reported. The authors declare that they did not
receive financial support from any private or public institu-
tion for performing this work, writing and publishing
this paper.
ORCID
Alex Shneider http://orcid.org/0000-0002-2150-6727
Aleksandr Kudriavtsev http://orcid.org/0000-0002-
3918-5618
Anna Vakhrusheva http://orcid.org/0000-0001-7948-1254
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Background: Coronavirus pandemic is currently a global public health emergency. At present, no pharmacological treatment is known to treat this condition, and there is a need to review the available treatments. Objective: While there have been studies to describe the role of chloroquine and hydroxychloroquine in various viral conditions, there is limited information about the use of them in COVID-19. This systematic review aims to summarize the available evidence regarding the role of chloroquine in treating coronavirus infection. Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used for this review. A literature search was performed using PUBMED & Google Scholar to find articles about the role of CQ in COVID-19 patients. Results: We included 19 publications (Five published articles, three letters/correspondence, one commentary, five pre-proofs of accepted articles, one abstract of yet to be published article, and four were pre-prints (not yet peer-reviewed) articles) in this systematic review. All the articles mentioned about the role of chloroquine and /or hydroxychloroquine in limiting the infection with SARS-CoV-2 (the virus causing COVID-19). Conclusions: There is theoretical, experimental, preclinical and clinical evidence of the effectiveness of chloroquine in patients affected with COVID-19. There is adequate evidence of drug safety from the long-time clinical use of chloroquine and hydroxychloroquine in other indications. More data from ongoing and future trials will add more insight into the role of chloroquine and hydroxychloroquine in COVID-19 infection.
Article
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Background: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile. Results: Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
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Background: At the end of 2019, a novel coronavirus outbreak causative organism has been subsequently designated the 2019 novel coronavirus (2019-nCoV). The effectiveness of adjunctive glucocorticoid therapy in the management of 2019-nCoV-infected patients with severe lower respiratory tract infections is not clear, and warrants further investigation. Methods: The present study will be conducted as an open-labeled, randomized, controlled trial. We will enrol 48 subjects from Chongqing Public Health Medical Center. Each eligible subject will be assigned to an intervention group (methylprednisolone via intravenous injection at a dose of 1-2 mg/kg/day for 3 days) or a control group (no glucocorticoid use) randomly, at a 1:1 ratio. Subjects in both groups will be invited for 28 days of follow-up which will be scheduled at four consecutive visit points. We will use the clinical improvement rate as our primary endpoint. Secondary endpoints include the timing of clinical improvement after intervention, duration of mechanical ventilation, duration of hospitalization, overall incidence of adverse events, as well as rate of adverse events at each visit, and mortality at 2 and 4 weeks. Discussion: The present coronavirus outbreak is the third serious global coronavirus outbreak in the past two decades. Oral and parenteral glucocorticoids have been used in the management of severe respiratory symptoms in coronavirus-infected patients in the past. However, there remains no definitive evidence in the literature for or against the utilization of systemic glucocorticoids in seriously ill patients with coronavirus-related severe respiratory disease, or indeed in other types of severe respiratory disease. In this study, we hope to discover evidence either supporting or opposing the systemic therapeutic administration of glucocorticoids in patients with severe coronavirus disease 2019. Trial registration: ClinicalTrials.gov, ChiCTR2000029386, http://www.chictr.org.cn/showproj.aspx?proj=48777.
Article
Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
Article
Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
Article
Aims A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp). Materials and methods In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin. Key findings The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease. Significance The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.