Two highly promising agents in combating COVID-19 – the result of
manual scanning
SARS-CoV-2 COVID-19
The possible successful candidates have to pass two thresholds. The
first threshold is related to urgency:
Essential criteria that should characterize possible successful candidate
agent:
Safety
The agent should be of proven safety as safety studies take years.
Easily implemented widely
A well- known agent that almost available in every country.
Easily manufactured
Can be manufactured for billions of suspected patients around the
world in a relatively short period of time i.e. weeks not months.
Could be used for prophylaxis
Prophylaxis is always a better choice and definitely can prevent
the deterioration of the current situation.
Treat or assist in treatment
In the current situation, any hand that can improve the numbers are
more than welcomed as the current protocols are almost passive. The candidate
agent does not need to be the be all end all solution.
Provide protection for other organs not only lungs either before or
after full recovery
Continuous reports are revealing the damaging effects of this virus
on increasing number of organs and that is only in the short term.
Can be tested clinically fast to reveal its success rate or even
excluded
A regimen that can be implemented almost in every place not in
hospitals or ICU only will be of a great advance.
Do not counter-indicate with other current treatment protocols
Has possible antiviral effect
An agent that provide symptomatic treatment in addition to some or
possible antiviral effect will be favoured on other agents.
Works through multiple important pathways
Due to the current situation, an agent that can modify many
measures should be given the priority in trials.
After passing the first threshold it would be expected that the two
agents’ names will not end with -mab or -mib or even -vir.
The second threshold is related to the virus behavior:
|
COVID-19
feature to act upon
|
Effect
of Agent A
|
Effect
of Agent B
|
|
IL-6
(cytokine storm)
|
OK
|
OK
|
|
CD4+
|
OK
|
OK
|
|
CD8
|
OK
|
|
|
CRP
|
OK
|
OK
|
|
Lymphopenia
|
OK
|
|
|
Telomere
length
|
OK
|
Likely
|
|
NF-kB
|
OK
|
OK
|
|
Nk-cells
|
OK
|
|
|
TNF- alpha
|
OK
|
OK
|
|
Possible
antiviral effect
|
OK
|
OK
|
|
Other
|
*CK-MB levels
* maintenance
of airway surface liquid
|
*Restore
ciliary activity and mucus clearance.
*Antithrombotic
effect.
*Autophagy
* Porphyrin
|
I HAVE USED QUOTES EXTENSIVELY FOLLOWED BY THE REFERENCE LINK SO
THAT THE READER CAN SEE WITH MY EYES AND TO AVOID ANY UNINTENTIONAL MISWORDINGS
WHILE PARAPHRASING. I BELIEVE THIS UNCOVENTIONAL METHOD IS BETTER FOR FAST AND
EFFECTIVE DELIVERY OF THE IDEA
COVID-10 characteristics as the published studies tell us so far:
“Significant decreases in the counts of T cells, especially CD8 + T
cells, were observed as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels
in the peripheral blood in the severe cases compared to those in the mild
cases. T cell counts and cytokine levels in severe COVID-19 patients who
survived the disease gradually recovered at later time points to levels that
were comparable to those of the mild cases.”
“The levels of IFN-γ and TNF-α in CD4+ T cells were lower in the
severe group than in the mild group, whereas the levels of granzyme B and perforin
in CD8+ T cells were higher in the severe group than in the mild group. The
activation molecules showed no differences in CD4+ T cells, whereas the levels
of HLA-DR and TIGIT in CD8+ T cells were higher in the severe group than in the
mild group. These data indicate that COVID-19, similar to some chronic
infections, damages the function of CD4+ T cells and promotes excessive
activation and possibly subsequent exhaustion of CD8+ T cells. Compared with
the healthy control and mild group, the frequency of multi-functional CD4+ T
cells (positive for at least two cytokines) decreased significantly in the
severe group.”
“Most of the infected patients were men (30 [73%] of41); less than
half had underlying diseases (13 [32%]), including diabetes (eight [20%]),
hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age
was 49.0 years (IQR 41.0-58.0).”
“Absolute number of T lymphocytes, CD4+T and CD8+T cells decreased
in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5
and 89.0 × 106/L) than moderate cases (640.5, 381.5 and 254.0 × 106/L). The
expressions of IFN-γ by CD4+T cells tended to be lower in severe cases (14.1%)
than moderate cases (22.8%).”
“The total number of B cells, T cells and NK cells were significantly
decreased in patients with COVID-19, and particularly in severe cases.”
“Elevated C-reactive protein (CRP) is an important feature of
COVID-19”
“While the disease seems to have a milder course in children than
adults, a manuscript by Qifang Bi on MedRxiv(https://www.medrxiv.org/content/10.1101/2020.03.03.20028423v1)
suggests that children are at a similar risk of infection as the general
population. This conclusion was driven from 391 cases and 1286 close contacts
identified by the Shenzhen CDC.”
“AT2 cells promote surfactant biosynthesis, self-renewal and
immunoregulation. Thus, SARS-CoV-2 appears to not only damage the AT2 cells
leading to the direct injury to alveoli, but also raise alveolar surface tension
to induce dyspnoea.”
“Chen (manuscript available on Preprints:
https://www.preprints.org/manuscript/202002.0258/v2) found that ACE2 expression
in the lung increases with age. A high viral load in elderly patients could
therefore be associated not only with low immunity but also with high expression
of the ACE2 receptor. This could explain the high degree of severe disease in
older patients with SARS-CoV-2(Chen, Li Lancet Inf Dis 2020, see below).”
“25 patients confirmed COVID-19 pneumonia”
“Lymphopenia (lymphocyte count, median 0•81×10 9 /L, IQR,
0•55-1•05×10 9 /L) mostly occurred in 19 patients (76%).”
“APE in the 10 patients was found dominantly located in small
branches of the pulmonary artery.”
acute pulmonary embolism (APE)
“An incidental finding of a low lymphocyte count was associated
with a 1.6-fold increase in the risk of death from any cause and a 1.5- to
2.8-fold increased risk of death from cancer, cardiovascular disease,
respiratory disease, infections and other causes. During the study period, a
total of 10,372 people died. Older age was associated with decreasing
lymphocyte counts. The link between lymphopenia and death may be because of
reduced immune capacity to survive potentially lethal diseases. Lymphopenia
could also indicate frailty which could lead to illness and death.”
“We further show that children are at similar risk of infection as
the general population, though less likely to have severe symptoms; hence
should be considered in analyses of transmission and control.”
“The degree of lymphopenia and a proinflammatory cytokine storm is
higher in severe COVID-19 patients than in mild cases, and is associated with
the disease severity.”
“The lymphocyte count decreased in 38% patients after admission.
The number (percent) of cases classified as non-severe and severe was
240(80.6%) and 58(19.4%) respectively. Thirty-two patients (10.7%) needed ICU
care. Compared to the non-severe cases, severe cases were associated with older
age, underlying diseases, as well as higher levels of CRP, IL-6 and ESR.”
“These data indicated that activation of the NF-κB signaling
pathway represents a major contribution to the inflammation induced after
SARS-CoV infection and that NF-κB inhibitors are promising antivirals in
infections caused by SARS-CoV and potentially other pathogenic human
coronaviruses.”
“It is possible to prevent aggravation of COVID-19 pneumonia
modulating NF-κB activation.”
“Increased CK-MB levels tended to occur in male patients and patients
with current smoking. High CK-MB on admission was associated with higher
mortality. High CK-MB was associated with increased inflammatory levels and
decreased lymphocytes.” COVID-19
“Autophagy is triggered by SARS-CoV2 virus for its
replication and autophagy inhibitory treatments might be considered promising
therapeutics.”
“Telomere dysfunction is one biologic mechanism of aging,
which primarily manifests as pulmonary fibrosis but can also restrict leukocyte
proliferation. It is conceivable that poor outcomes from COVID-19 could be
linked to short telomeres, as has been reported with pulmonary fibrosis, ARDS,
and sepsis.”
Coronavirus, Telomere Shortening, and Your Immune System with Dr.
Sewell
“Dr. Patrick Sewell discusses the relationship between the aging
immune system and susceptibility to the coronavirus (COVID-19).”
About half of all Covid-19 deaths appear to be happening in care homes in some
European countries.
First Agent:
Vitamin C
“VC effectively represses the accelerated cellular senescence,
improves the stem cell self-renewal, decreases SASP in WS MSCs, and alleviates
telomere attrition.”
“higher lutein, zeaxanthin, and vitamin C concentrations were strongly
associated with longer telomere length.”
“In the context of the current study findings, previous in vitro,
in vivo, and clinical studies suggested that non-provitamin A carotenoids have
greater protective effects against DNA damage than provitamin A carotenoids.37
This is consistent with the finding of the current study that lutein and
zeaxanthin, which are non-provitamin A carotenoids, were directly related to
LTL, whereas no such association was seen for the provitamin A carotenoids
retinol, β-carotene,
α-carotene,
and β-cryptoxanthin.”
“If these associations are causal, one might assume that Lu∼Zx– and vitamin C–related LTL protection has the potential to
prevent or modify the course of numerous widespread diseases that are among
the major contributors to mortality and morbidity in aging societies.”
“When cells were treated with 100 μM of vitamin
C for 48 h, anti-aging effects, specifically on the expression of telomere-related genes and their functionality in aging
cells, were observed.”
“rapid and complete resolution of these complications with
parenteral ascorbic acid infusion.”
Cytokine storm
male mice
“researchers have highlighted the mechanisms of vitamin C as being
non-invasive and have suggested it as a promising tool to treat lung fibrosis”
“IL-6 concentration was also suppressed by AA (rat lung)”
“Vitamin C mitigated oxidative stress and proinflammatory mediator
suggesting a possible mechanism for vitamin C in severe CAP.”
community-acquired pneumonia (CAP)
“Vitamin C significantly decreased ROS, DNA damage, TNF-α, and
IL-6. Vitamin C inhibited LPS-induced ROS, DNA damage, TNF-α, IL-6, and p38 in
macrophages cells. Vitamin C inhibited autophagy in LPS-induced macrophages cells.
These findings indicated that severe CAP exhibited significantly increased
oxidative stress, DNA damage, and proinflammatory mediator.”
“IL-1, IL-6, and IFN-alpha lung levels
were lower in the treated animals compared to the controls.”
“Pharmacologic ascorbate is a pro-oxidant that eliminates
influenza virus in the lung, and therefore
reduces lung inflammation and lowers death rate in
this mouse model.”
“The high dose intravenous ascorbic
acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients.”
“However, Mohseninet al have described a protective
effect of oral ascorbic acid (500 mg 4 times daily) on NO2
induced bronchial hyperresponsiveness in humans,35 suggesting
that oral supplemental doses of ascorbic acid are able to reach the
respiratory tract.”
“Plasma vitamin C concentrations in patients from two different
mid-European populations”
“In patients with vitamin C concentrations < 40 mumol/L, all
indexes of inflammation were relatively high, whereas those with concentrations
> 80 mumol/L (upper quartile of control subjects) showed clearly lower
values.”
“Our studies indicate that smokers have a compromised antioxidant
status and elevated concentrations of tumour necrosis factor and interleukin-6
as a consequence of smoking.”
“a 21% lower plasma vitamin C (P = 0.04) concentration was observed
in smokers, than in non-smokers despite a similar intake of this vitamin by the
two groups.”
“We conclude that in the mouse, large doses of vitamin C alter
pulmonary defense mechanisms against S. pneumoniae; however, these changes do
not appear to convey a substantial advantage to the host.”
“Leucocyte interferon assayed in lung
fibroblasts titrated 0.2-0.3 log10 units higher in the presence of 5 mug ascorbic acid than in the absence of the latter.”
“AS treatment significantly down-regulated the levels of
pro-inflammatory mediators. Then, the natural product AS reduced the
detrimental result promoted by methacrylates in clinical dentistry, in fact
restore cell proliferation, reduce the pro-inflammatory cytokine, downregulate
ROS production and of NFkB/pERK/ERK signaling path. In synthesis, AS, could
improve the quality of dental care and play a strategic role as innovative
endodontic compound easy to use and with reasonable cost.”
“Vitamin C (500 mg twice daily) has potential
effects in alleviating inflammatory status by reducing hs-CRP, IL-6, and FBG in
hypertensive and/or diabetic obese patients.”
“The present meta-analysis shows that vitamin C supplementation
reduces serum CRP level, particularly in younger subjects, with higher CRP
baseline level, at a lower dosage and intravenous administration.”
“Regarding serum concentration of these cytokines, particularly
IL-6, there was a decrease between TP(2) and TP(3) following AA application in
the treated donors.”
“Furthermore, a significant reduction was found in serum AST and
ALT levels in the recipients of treated group on the 3(rd) day.”
100 mg/kg AA infusion
“all these phenomena were significantly attenuated: FMD decreased
less, while sICAM-1, 8-iso-PGF2a, nitrotyrosine and IL-6 were less increased”
“Vitamin C was even more effective than GLP-1 in decreasing all
these phenomena”
“It is worthy of interest that vitamin C was more efficacious than
GLP-1 in counterbalancing the effects of hyperglycemia post hypoglycemia”
“Infusing high dose intravenous vitamin C
into this patient with virus-induced ARDS was
associated with rapid resolution of lung injury with no evidence of
post-ARDS fibroproliferative sequelae.”
virus-induced acute respiratory distress syndrome
“AA usage appears to be associated with improved highly active
antiretroviral therapy (HAART) adherence and HAART effectiveness as adjudicated
by HIV viral loads and CD4+ T-cell counts”
mice, H1N1 infection
“Administration of red ginseng and vitamin
C enhanced the activation of immune cells like T and NK cells, and
repressed the progress of viral lytic cycle. It also reduced lung
inflammation caused by viral infection, which consequently increased the
survival rate.”
“In conclusion, the protective effects of vitamin
C on influenza virus-caused pneumonia might
be related to its inhibition of CORT synthesis, which reduces the susceptibility
to influenza viral infection in restraint-stressed mice. These findings provide
a new mechanism for the effects of vitamin C on
influenza virus-induced pneumonia in
restraint-stressed mice.”
“As shown in Figure 4, the gene expressions of IL-1β
and IL-6 and the protein level of TNF-α in the model group were
significantly increased as compared to the virus group (P
< 0.01, P
< 0.05). Administration of vitamin C could significantly decrease these gene
and protein expressions (P < 0.05, P
< 0.01). The above results indicated that vitamin C was more potent than
edaravone for protection of the animal from influenza-caused pneumonia and
inflammation caused under restraint stress.”
“Addition of ascorbic acid (AA) resulted in more proliferation of
NK cells without influencing NK-cell functionality.”
“Conclusions The clinical study of ascorbic
acid and EBV infection showed the reduction in EBV EA IgG and EBV VCA
IgM antibody levels over time during IVC therapy that is consistent with
observations from the literature that millimolar levels of ascorbate hinder
viral infection and replication in vitro.”
“vitamin C shows in vivo anti-viral immune
responses at the early time of infection, especially against influenza virus, through increased production of IFN-α/β.”
“The data presented here provide evidence that concomitant use of
intravenously administered ascorbic acid may have
beneficial effects on herpes zoster-associated pain, dermatologic findings and
accompanying common complaints.”
“We had a case in which a patient with herpes zoster did not
respond to conventional therapy so we attempted to administer intravenous
infusion of vitamin C which resulted in an
immediate reduction in the pain.”
“The use of the vitamin C appears to
be an interesting component of alternative therapeutic strategies in the
treatment of HZ. Especially for therapy-resistant cases of PHN, vitamin C administration should be examined as an
additional option. To test and confirm the clinical findings, randomized
clinical studies concerning the use of vitamin C
in the concomitant treatment of zoster-associated neuralgia should be
performed.”
“Therefore, a working strategy must be developed to combat
influenza pandemics. In this review we have addressed this problem and reviewed
the published studies on ascorbic acid in the
common cold and influenza and laboratory studies on the effect of ascorbic acid on influenza virus.
We have also correlated the clinical and laboratory studies and developed a
hypothesis to prevent influenza pandemics.”
cultured cell lines
“NM demonstrated high antiviral activity evident even at prolonged
periods after infection. NM antiviral properties were comparable to those of
conventional drugs (amantadine and oseltamivir); however, NM had the advantage
of affecting viral replication at the late stages of the infection process.”
“(NM), containing lysine, proline, ascorbic
acid, green tea extract, N-acetyl cysteine, selenium among
other micro nutrients”
“Proper use of ascorbic acid as
described here could provide effective containment for the flu pandemic.”
“Vit C, in a pharmacological dose, decreased cell proliferation
through an inhibitory effect on cyclin-dependent kinase 2 (CDK2) (4.4-fold;
p < 0.01), mainly due to the stimulatory effect on the expression
of cyclin-dependent kinase (CDK) inhibitors, such as p21 and p53 (3.2- and 2.8-fold, respectively;
p < 0.001), but not caspase pathway.”
“In splenic tissues, nicotine significantly decreases the protein
levels and the mRNA expression of P53 and
increases the protein levels of Bcl2 and its expression. Administration of Vit.
C. to nicotine-treated rats completely reversed the decrease in P53 levels and its mRNA expression and the increase in
Bcl2 levels and its mRNA expression to the control values”
“Our results clearly demonstrated that CDDP and VC treatment
exhibited ameliorative effect on induction of cell death by p53 overexpression and generation of hydrogen peroxide
in SiHa cells, thereby reducing the dosage of CDDP required to induce cell
death in cancer cells.”
My comment: The ascorbic acid effect on p53 is
needed to reduce the effect of N-acetylcysteine on p53 as shown in the next
section.
“four studies showed that CK-MB levels were lower in children
receiving intravenous vitamin C combined with
conventional therapy than in those receiving conventional therapy alone”
“Extra Dose of Vitamin C Based on a Daily Supplementation Shortens the Common Cold: A Meta-Analysis of 9 Randomized Controlled Trials.”
2018
“Extra doses of vitamin C could benefit some patients who
contract the common cold despite taking daily
vitamin C supplements.”
“400 healthy volunteers were recruited from staff and
students of the Australian National University, Canberra, ACT, between May 1998
and November 1999. The trial continued for 18 months.”
“Doses of vitamin C in excess of 1 g daily taken shortly after
onset of a cold did not reduce the duration or
severity of cold symptoms in healthy adult
volunteers when compared with a vitamin C dose less than the minimum
recommended daily intake.”
My comment: choosing only healthy volunteers
constitutes a big flaw in study design. Another question arises: what were the
pathogens behind the cold symptoms? Not to mention that many layout people
consider any runny nose a cold; that’s to say, does the study mistakenly
included allergic rhinitis or seasonal rhinitis?
mice
“These data suggest that vitamin C is
required for an adequate immune response in limiting lung pathology after
influenza virus infection.”
“In patients with proximal femoral fractures, preoperative AA concentrations
were significantly lower compared to elderly patients without an acute
fracture. A significant decrease of 33.8% in AA plasma level was measured on
the day after surgery with a significant recovery up to the time of discharge.
The preoperative AA status did not have any significant effect on clinical
outcome. However, inadequate AA levels (<50 and="" complications.="" discharge="" incidence="" increased="" mol="" of="" postoperative="" severity="" significantly="" span="" the="" upon="">
“Low ascorbate levels in diabetes appears to be a
consequence of the disease itself and not due to inadequate dietary intake
of vitamin C.”
“In five trials with 598 participants exposed to short periods of
extreme physical stress (including marathon runners and skiers) vitamin C
halved the common cold risk.”
“This study provides evidence that vitamin C supplementation may
enhance resistance to the postrace URT infections that occur commonly in
competitive ultramarathon runners and may reduce the severity of such
infections in those who are sedentary.”
“The clinical effects of vitamin C supplementation in elderly
hospitalised patients with acute respiratory infections.”
“Vitamin C for preventing and treating pneumonia”
2007
“Each of these trials found a statistically significant (80% or
greater) reduction in pneumonia incidence in the vitamin C group. We identified
two therapeutic trials involving 197 pneumonia patients. Only one was satisfactorily
randomised, double‐blind and placebo‐controlled. That trial studied elderly
patients in the UK and found lower mortality and reduced respiratory symptom
scores in the vitamin C group; however, the benefit was restricted to the most
ill patients.”
“Since
the 1930s, a few German and US physicians have proposed that vitamin C might be
beneficial in the treatment of pneumonia (Bohnholtzer
1937; Hemilä
1999; Hochwald
1937). Gander and Niederberger concluded from a series of 15 cases
that "the general condition is always favourably influenced [by vitamin C]
to a noticeable extent, as is the convalescence, which proceeds better and more
quickly than in cases of pneumonia which are not treated with vitamin C" (Gander
1936). Benefit from intravenous vitamin C was reported in a series
of over 40 cases (Klenner
1948; Klenner
1951) and in three cases of viral pneumonia (Dalton
1962). A large dose of oral vitamin C was also claimed to be
beneficial in patients with viral pneumonia (Cathcart
1981; Luberoff
1978). “
“The
effect of vitamin C on the common cold has been studied extensively. A major
finding from the trials is the heterogeneity in its effects. Although the
largest trials found no effect on common cold incidence, the incidence was
reduced in trials with participants under heavy acute physical stress and in
British males, which was explained as the result of a diet low in vitamin C (Hemilä
1996; Hemilä
1997b; Hemilä
2006a; Hemilä
2010). Consequently, it is possible that the effects of vitamin C on
other respiratory infections are also modified by various factors, such as
physical stress and dietary vitamin C intake. Also, two large trials found
considerable divergence in the effects of vitamin C depending on the type of
cold. Vitamin C decreased the incidence of 'chest colds' (‐18%; cough or other
chest symptoms) but not of 'simple colds' (+1%; runny nose or sneezing) (Elwood
1976; Hemilä
1997b). Similarly, vitamin C decreased the incidence of 'throat colds'
(‐21%) but not 'nose colds' (‐2%) (Anderson
1973; Hemilä
1997b). These two trials thus suggest that vitamin C might have a
greater effect on infections affecting the lower respiratory tract. “
“The effect of vitamin C on the severity of URIs was also different
between male and female swimmers, so that vitamin C was beneficial for males,
but not for females. Our study indicates that vitamin C does not affect the
rate of respiratory infections in competitive swimmers. Nevertheless, we found
that vitamin C decreased the duration and severity of respiratory infections
in male swimmers, but not in females. This finding warrants further research.”
“Compared with the placebo group, the active-treatment group had significantly
fewer colds (37 vs 50, P<.05), fewer days challenged virally (85 vs
178), and a significantly shorter duration of severe symptoms (1.8 vs
3.1 days, P<.03).”
Bad design
“Volunteers were eligible for the study if they were aged over 18
years, not pregnant or planning to become pregnant, in good general health,
and did not take vitamin supplements regularly or take vitamin C, echinacea,
zinc or Chinese herbal preparations regularly at the onset of a cold.”
“They were to take the medication at onset of cold symptoms and on
the following two days.”
“However, widespread (wrong) conviction that the vitamin has no
proven effects on the common cold still remains.”
“In this article, these three reviews are shown to contain serious
inaccuracies and shortcomings, making them unreliable sources on the topic.”
“Thirty‐one
comparisons examined the effect of regular vitamin C on common cold
duration (9745 episodes). In adults the duration of colds was reduced by 8% (3%
to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C
shortened colds by 18%. The severity of colds was also reduced by regular
vitamin C administration.”
“Seven
comparisons examined the effect of therapeutic vitamin C (3249
episodes). No consistent effect of vitamin C was seen on the duration or
severity of colds in the therapeutic trials. “
“These findings suggest that ascorbic acid
can be used as an inactivating agent for fixed rabies virus grown in cell culture particularly for the
preparation of diagnostic reagents.”
“Vitamin C and SARS coronavirus
Published:
01 December
2003
Sir,
Recently,
a new coronavirus was identified as the cause of the severe acute respiratory
syndrome (SARS).1 In the absence of a specific treatment for SARS, the
possibility that vitamin C may show non-specific effects on severe viral
respiratory tract infections should be considered. There are numerous reports
indicating that vitamin C may affect the immune system,2,3 for
example the function of phagocytes, transformation of T lymphocytes and
production of interferon. In particular, vitamin C increased the resistance of
chick embryo tracheal organ cultures to infection caused by an avian
coronavirus.4 Studies in animals found that vitamin C modifies susceptibility
to various bacterial and viral infections,3 for example protecting broiler
chicks against an avian coronavirus.5 Placebo-controlled trials have shown
quite consistently that the duration and severity of common cold episodes are reduced
in the vitamin C groups,3 indicating that viral respiratory infections in humans
are affected by vitamin C levels. There is also evidence indicating that
vitamin C may affect pneumonia.3 In particular, three controlled trials with
human subjects reported a significantly lower incidence of pneumonia in vitamin
C-supplemented groups,6 suggesting that vitamin C may affect susceptibility to
lower respiratory tract infections under certain conditions. The possibility
that vitamin C affects severe viral respiratory tract infections would seem to
warrant further study, especially in light of the recent SARS epidemic.”
My comment: a lot of pieces of evidence have
been published since then. More interestingly, vitamin C is likely to be more
relevant to SARS-COV-2 than it did with SARS-COV.
“Vitamin C in megadoses administered before or
after the appearance of cold and flu symptoms relieved and prevented the
symptoms in the test population compared with the control group.”
“an essential cofactor for many enzymes including a group of
enzymes that modulate epigenetic regulation of gene expression.”
“To
examine the cross sectional relationship between respiratory
function and plasma vitamin C.”
“The association in women was weaker and not statistically
significant.”
“These
findings are consistent with other studies of vitamin C and respiratory function and suggest that vitamin C may
be protective for lung function through the whole normal range of dietary
intake and lung function.”
“We found an inverse association of URTI incidence among women for
vitamin C”
“No association was found for vitamin C among men.”
upper respiratory tract infection
(URTI)
“The present study is the first observational study to suggest that
intake of vitamin C from food is sufficient to lower the risk of URTI among women.”
“We conclude that enhancement of hypoxic reactivity by ascorbic
acid in elderly women, as demonstrated in this study, might have therapeutic
potential. Our general findings suggest that further investigations are warranted
to establish the role of ascorbic acid in respiration control.”
“In addition, in vivo deficiencies in ascorbate
result in serious physiological problems owing to the requirement for ascorbate
as a cofactor for the prolyl hydroxylase enzymes involved in collagen
biosynthesis and the integrity of blood vessels. It is therefore difficult to
separate primary effects on the immune system from more systemic problems
resulting from ascorbate deficiency that may influence the functioning of the
immune system indirectly.”
“Our results indicate that ascorbate plays a key role in modulating
expression of genes encoding accessory molecules that are involved in signal
transduction through TCRαβ, resulting in positive selection
of functional, adult-type T-cells. We also demonstrate a role for ascorbate in
modulating T-cell maturation in vivo. Our studies indicate an
important role for ascorbic acid in regulating both development and function of
T-cells.”
“We show that induction and maintenance of Cd8
expression are dependent on ascorbic acid.”
“Circulating leukocytes contain 80-fold more ascorbate than does
the plasma.”
“In 12 trials with 1766 patients, vitamin C reduced the length
of ICU stay on average by 7.8% (95% CI: 4.2% to 11.2%; p
= 0.00003). In six trials, orally administered vitamin C in doses of 1–3 g/day
(weighted mean 2.0 g/day) reduced the length of ICU stay by 8.6% (p
= 0.003). In three trials in which patients needed mechanical ventilation for
over 24 hours, vitamin C shortened the duration of mechanical ventilation
by 18.2% (95% CI 7.7% to 27%; p = 0.001).”
“A topical C-paste has been found very effective in the treatment
of herpes simplex and, to a lesser extent, in the treatment of some Kaposi's
lesions.”
“Glucocorticoids should be avoided in view of the evidence that
they can be harmful in cases of viral pneumonia and ARDS from influenza.10Rescue
therapy with high-dose vitamin C can also be considered.”
“In summary, the present analysis demonstrated the regulatory
effect of continuous IVC on lymphopenia, ANC and NLR.”
“The effect of a single oral dose of vitamin C on the intracellular
ascorbate concentration of immunocompetent cells, like monocytes and
neutrophils, is characterized by a sigmoidal response curve (Fig. 2). In
adults, a vitamin C intake of approximately 100 mg/d results in complete
intracellular saturation [50].”
“Conclusion Our data indicate that iv high-dose vitamin C treatment
increases TLC, which strongly implies improvement of immune function,
especially in patients with severe lymphopenia.”
total lymphocyte count (TLC)
“These findings suggest that high dietary VC intake reduces
glucocorticoid-induced T-cell dysfunction by maintaining intracellular
antioxidant activity.”
“The evidence suggests that lung ascorbic acid levels are decreased
following the development of pulmonary edema, irrespective of how it was
caused.”
“Recent research has assessed a peculiar epigenetic role for AA.
Namely, the oxidation of 5-mc (5-methylcytosine) to 5-hmc
(5-hydroxymethylcytosine), as part of dynamic DNA demethylation, is catalyzed
by TET (ten-eleven translocation) dioxygenase enzymes, for which AA is a
critical co-factor [23,145].
Interestingly, no other
antioxidant displayed such an epigenetic mechanism.”
“Our study shows a positive association between maternal vitamin C intake and fetal telomere
length. These findings may provide a method of understanding and preventing
adult-onset disease and mortality through intrauterine reprograming.”
My comment: if vitamin C proven effective in
management of COVID-19 in future clinical trials, then it we could claim a
protective effect for the baby.
“Suppression of CFTR-mediated Cl secretion of airway epithelium in vitamin C-deficient mice.”
“Taken together, the CFTR-mediated Cl(-) secretion of airway epithelium is susceptible to oxidative stress,
which suggests that supplementation of the antioxidant might be beneficial
for the maintenance of airway surface liquid.”
“This study highlighted the advantages of combination of
anti-tuberculosis drugs and vitamin C to eradicate the microbial infections.”
“We further showed that the antioxidant ascorbic acid (vitamin C)
could inhibit the ethanol-induced reactive oxygen species (ROS) production and
NF-κB activation and protect the ethanol-treated embryos against microencephaly
and growth retardation.”
“Vitamin C Forestalls Cigarette Smoke Induced NF-κB Activation in Alveolar Epithelial Cells”
“All these results demonstrate that vitamin C prevents
CS(E)-induced NF-κB activation and thus it could be used for the prevention of
CS-induced inflammatory diseases.”
“Infusing high dose intravenous vitamin C into this patient with
virus-induced ARDS was associated with rapid resolution of lung injury with no
evidence of post-ARDS fibroproliferative sequelae. Intravenous vitamin C as a
treatment for ARDS may open a new era of therapy for ARDS from many causes.”
“Estimated prevalence and predictors of vitamin C deficiency within UK's low-income population”
In total, 46% of men and 35% of women in the low-income/materially
deprived population were estimated to have either deficient or depleted
vitamin C status.”
“Results suggest that 1 of 7 young adults has serum ascorbic
acid deficiency, in part, because of unmet recommended dietary intakes.
Furthermore, serum ascorbic acid deficiency is associated with elevated markers
of chronic disease in this population of young adults, which may have long-term
adverse health consequences.”
“Our study emphasizes the prevalence of vitamin C deficiency in
elderly patients, particularly those who live in nursing homes.”
Second Agent:
N-acetylcysteine (NAC)
“
””
mostly men above 70
“High-dose NAC (600 mg bid) for 1 year reduces exacerbations and
prolongs time to first exacerbation in high-risk but not in low-risk Chinese
patients with COPD.”
“Both NAC 600 and 1200 mg/day were associated with a significantly
higher proportion of patients achieving normalised CRP levels compared with
placebo (52% and 90% vs 19% of patients; p </= 0.01); however, NAC 1200
mg/day was superior to NAC 600 mg/day (p = 0.002). Furthermore, treatment with
NAC 1200 mg/day was more efficacious than NAC 600 mg/day in reducing IL-8
levels and difficulty of expectoration”
????
“However, we found no significant changes in IL6,
CRP and BDNF levels following NAC treatment.”
“Short-term oral NAC treatment resulted in reduction of circulating
IL-6, suggesting that such treatment could be a useful strategy in blunting the
inflammatory response in PD patients.”
“In patients with abnormal CRP at baseline, normalisation of CRP
was achieved in 27 (90%) patients in the NAC1200 group, 13 (52%) in the NAC600
group and five (19%) in the placebo group, with statistically significant
differences between groups”
“Moreover, the reduction of CRP at T10 was significantly greater in
the NAC1200 group than in the NAC600 group (p < 0.002).”
“NAC group exhibited significantly greater reduction on hs-CRP
levels than placebo group from baseline to week 12.”
“Preoperative administration of N-acetylcysteine
did not attenuate postoperative systemic or pulmonary inflammation or oxidative
damage after lung resection.”
mice
“Administration of NAC could attenuate the alveolar wall structure
damage induced by O3 exposure and reduce the amount of infiltrated
inflammatory cells, total and differential leukocyte counts (P < 0.05), as
well as the IL-6, IL-8 (P < 0.01) and MDA release (P < 0.05).”
“MeHg-induced expression of MCP-1 and IL-6 mRNA was reduced by
10-20% in the presence of 5mM NAC (co-treatment experiment) compared to cells
treated with MeHg only. Pre-treatment of cells with 0.5 or 5mM NAC at 0.5 or 1h
and its subsequent washout before MeHg addition suppressed MCP-1 and IL-6
cytokine expressions. Post-treatment of cells with NAC after MeHg addition also
suppressed the cytokine induction, but the magnitude of suppression was
evidently lower than in co-treated cells even though the H2O2 generation was
almost completely suppressed by NAC.”
“Evaluation of the laboratory data revealed that serum levels of
hs-CRP, IL-6, PTH, ferritin and ESR were significantly
lower following NAC treatment”
“In conclusion, we observed that NAC treatment in ESRD patients
could have an anti-inflammatory effect as was evaluated by measuring the serum
levels of hs-CRP and IL-6. Additionally, a significant decrease in serum Ca and
PTH levels was noticed. We suggest that the ESRD patients may benefit from the
anti-inflammatory and anti-oxidative stress effects of NAC.”
“oral supplementation of 600 mg NAC every 8 h for 72 h can reduce
HsCRP, MPO, and Gal-3 levels in AMI patients receiving fibrinolytic therapy. Results
of our study will provide more options for supplementation therapy to improve
management of IMA patients.”
“Porphyrin accumulation was decreased in the
presence of 0.1-7.5 mM LC (24.8%-31.4% suppression in HMEC-1 cell; 35.8%-48.9%
suppression in A431 cells), and in the presence of 0.1-10.0 mM NAC (30.9%-58.0%
suppression in HMEC-1 cells; 8.5%-45.3% in A431 cells). The suppression
occurred in a LC or NAC dose-dependent fashion.”
“The antioxidant NAC has proved useful in the management of COPD
reducing symptoms, exacerbations and accelerated lung function decline. It has
been shown to inhibit influenza virus replication and to diminish the
release of inflammatory and apoptotic mediators during virus infection.”
“in vitro infection model of alveolar type II A549 cells infected
with influenza (strains A and B) and RSV:
Our results indicate a significant induction of MUC5AC, IL8, IL6 and TNF-alpha that is strongly inhibited by NAC at
the expression and at the release level.”
Recombinant
human TGF-β1
“The changes in oxidant/antioxidant enzymes and IL-6 release were
reversed by the antioxidants N-acetyl-cysteine
(NAC) and ebselen.”
“The effectiveness of NAC has been shown in patients with some lung
diseases such as acute respiratory distress syndrome (ARDS),20,21
idiopathic pulmonary fibrosis (IPF),22,23
chronic obstructive pulmonary disease (COPD),14,24
influenza17,25
specially influenza A (H5N1),26
cystic fibrosis27
and smoking-related damage.28
However, studies on the efficacy of NAC on pneumonia, especially the VAP remain
limited.”
“These data suggest that NAC is safe and effective to prevent and
delay VAP and improve its complete recovery rate in a selected, high-risk ICU
population.”
“Persistent respiratory syncytial virus (RSV) infections have been
associated with the exacerbation of chronic inflammatory diseases, including
chronic obstructive pulmonary disease (COPD). This virus infects the respiratory
epithelium, leading to chronic inflammation, and induces the release
of mucins and the loss of cilia activity, two factors that determine mucus
clearance and the increase in sputum volume.”
“The results indicated that NAC significantly inhibited viral
infection in a dose-dependent fashion (Fig. 1B). The dose of 1 mM reduced infection by 51%
compared to control cells, while the maximum dose used in this investigation
(10 mM) almost abolished virus infection of the cultures.”
“In summary, we conclude that NAC inhibited RSV infection in
differentiated NHBEC cultures, restoring normal ciliary activity and inhibiting
mucin release. These results support the beneficial effects of NAC treatment
for the management of respiratory diseases, including COPD, in which 64% of
exacerbations are associated with respiratory virus infection.”
“In addition to effects on NF-B, NAC could influence virus
replication by its interference with p38.”
“NAC-induced suppression of chemokine/cytokine production in
H5N1-infected cells appears to also involve inhibition of activation of p38 and
NF-B.”
“NAC has a good safety profile and has been administered in oral doses
of 6,000–8,000 mg daily for several months to HIV-infected patients without
evident ill effects.”
“Patients with a propensity to develop edema from heart failure or
liver disease were excluded because each tablet of the study drug contained 200
mg of sodium for a daily total of 800 mg. Patients taking long-acting nitrates
were excluded because NAC may potentiate drugs of this class.”
My comment on this study: This study shows no clinical
benefit for patients with COPD with chronic bronchitis. However, the study does
not found any oxidative effects or related byproducts for the NAC arm which is
hard to accept; this raise high probability that the NAC drug samples used have
a very low bioavailability. This is explanation is supported by the almost
similar adverse effects to the placebo arm.
The authors clearly stated that there are features that are not
understandable:
“By administering a large dose of NAC, we anticipated that
measurements of plasma thiol couples might reflect a reduction in systemic
oxidative stress. However, within the limitations of our sample size, we were
unable to show that NAC had any such effect for reasons that are not
understood.”
Long term
“We show here that NAC treatment decreased oxidative stress
and cell senescence in the lungs. As expected, these effects were
associated with decreased lung emphysema. However, the risk of
developing lung adenocarcinoma was increased, possibly by weakening of the
tumorigenesis-barrier effect of cell senescence. This work constitutes the
first proof-of-concept evidence to our knowledge that NAC, while reducing the
lung alterations associated with aging and lung oxidative stress, can also
promote lung cancer initiation.”
“Regarding T-helper cell function, namely T-helper cell type 1
(Th1) and T-helper cell type 2 (Th2) balance, it was reported that treatment
with NAC in vivo and in vitro promoted a Th1 response through increased
intracellular glutathione level in antigen-presenting cells”
“lower concentrations of NAC (≥1 μM) were sufficient to reduce
the release of IL-6 elicited by LPS. “
“NAC caused this relative increase of CD4+ T cell numbers in spite
of decreasing glutathione levels and not by increasing the glutathione level.”
In men – 8 days oral
“NAC administration significantly influenced the resting and
post-exercise level of glutathione (+31%) as well as the resting activity of glutathione
enzymes (glutathione reductase, -22%; glutathione peroxidase, -18%). The
oxidative damage markers, i.e., protein carbonylation and lipid peroxidation
products (thiobarbituric acid reactive substance) were reduced by NAC by more
than 30%. NAC noticeably affected the plasma level of EPO (+26%), haemoglobin
(+9%), haematocrit (+9%) and erythrocytes (-6%) at rest and after exercise.”
“N-acetylcysteine improved oxygenation,
reduced lung edema, decreased
polymorphonuclears in BAL fluid, and diminished peroxidation and
meconium-induced airway hyperreactivity compared with untreated animals.”
“NAC exhibits potent anti-mycobacterial effects and may
limit M. tuberculosis infection and disease both through suppression of the
host oxidative response and through direct antimicrobial activity.”
“Several studies across multiple cell types have demonstrated that
NAC induces the activity of telomerase, an enzyme that rebuilds telomere caps,
by constraining telomerase to the nucleus [35–37].
An increase in γH2AX is associated with shorter telomeres [38].
Therefore, while the effect of NAC on telomerase in T cells has not been
investigated, it is reasonable to postulate that NAC has a telomere-protective
effect, since NAC reduces γH2AX levels.”
“Notably, treatment with the antioxidant N-acetyl cysteine (NAC)
significantly reduced upregulation of the DNA damage marker γH2AX,
subsequent ATM activation, and cell death.”
“T cells with short telomeres, indicative of a longer replicative history,
have higher baseline levels of γH2AX, a delayed DNA repair response, and are
also more susceptible to cell death (49, 50).
Erosion of telomeres correlates with poor persistence and patient responses in
clinical trials (51).”
“N-acetylcysteine Enhances T Cell Functions and T Cell Growth in Culture “
“In cultures of peripheral blood T cells, NAC (10 mM) stimulated
growth by at least 4- to 6-fold after two passages. These results show that
NAC, nontoxic even at 20 mM, is an effective enhancer of T cell function and a
remarkable enhancer of growth. Results from other laboratories show that NAC,
which increases glutathione levels, suppresses HIV replication presumably
via suppression of the activation of transcriptional factor NF-kappa B.”
“Thus, the anti-influenza activity of NAC appears to be
strain-dependent as already supposable from previous studies”
“This is the most likely mechanism by which
NAC reduces the activation of NF-κB pathway.”
“NAC was shown to limit lung inflammation, damage associated
with the virus, and limit viral growth, at least in vitro. However, the
antiviral activity was highly variable depending on the influenza A strain. The
reasons for these inter-strain variations are still unknown but might be
related to the level of NF-κB activation required for the virus to achieve its
infectious cycle.”
“NAC significantly reduced postischemic CK-MB release”
“NAC confers cardioprotection against diabetic heart I/RI primarily
through inhibiting excessive autophagy which might be a major mechanism
why diabetic hearts are less tolerant to I/RI.”
Possible synergism between Vitamin C and N-acetylcysteine or at
least additive effect:
“in agreement with the higher supplementation of NAC (a cysteine
precursor) in these units. This is relevant in the light of the emerging
concept of a significant correlation between cysteine efflux and erythrocyte
ageing in vivo.
This effect might represent a
clear advantage over supplementation with vitamin C alone, which does
directly help to cope with oxidative stress via ascorbate oxidation, but does
not promote replenishment of the GSH reservoirs via up-regulation of cysteine
levels.”
“As mitochondria are protected in hADMSCs after treating with
NAC/AAP, down-regulation of AIF, H2AX, and PARP1 occur, and may subsequently
activate genes that are involved in the synthesis and repair of DNA. However,
enhanced proliferation through inhibition of necroptotic can also be another
possible mechanism to explain the synergistic effects of NAC/AAP.”
“The analysis reflected that NAC/AAP yielded a better protection
than either drug alone.”
“Lung Tumor sizes were slightly but significantly decreased in mice
treated with AsA and more so in those treated with NAC and NAC plus AsA,
their combination being significantly more effective than each
individually.”
Suggested treatment dose:
(This dose is to guide medical professionals and researchers not
for the patients’ use without medical supervision. Do not attempt to change the
dose regimen or modulate it except ONLY after trying the stated dose regimen
and not giving a satisfactory results).
1 gm oral vitamin C twice per day and 600 mg Acetylcysteine oral
twice per day on the first suspicion of COVID-19 infection without waiting for
the test results to start treatment.
Vitamin C 1 gm oral twice daily + Acetylcysteine 600 mg oral twice
daily for 5-10 days until two days after disappearing of the symptoms.
In case that oral administration is no longer possible:
One to 3 gm Vitamin C IV route is administered every 6 hrs, total
daily dose above 14 gm does not seem to give any additional benefit.
In addition to: 600 mg IV Acetylcysteine twice daily. Lower dose is
not recommended and higher dose does not seem to add any benefit.
What does this regimen add?
First, it highlights the importance of using this combination while
other investigational studies are trying either of them only. Second, it
pinpoints that the regimen should be adopted from the very beginning not to
expose the medication to the latest disease stages where the failure is almost
inevitable which will lead to statistical insignificance and subsequence
abandoning of the medication.
Considering both the high theoretical evidence provided and the
high safety margin of both medications, the adoption of using and trying the
regimen in the most hit countries: Italy, NY USA and France should be started
immediately as medical observations without tedious procedures in organized
clinical trials. This implementation includes both hospitalized or home
patients. After one week of accelerated use the results will be clear whether
to proceed in more rigorous clinical trials with four arms: placebo,
combination, agent A, agent B with intent to treat and without abandoning the
current protocols in each country i.e. this regimen will be add-on therapy.
Knowing that both agents are considered as a food supplement in many countries,
it is like telling people to eat broccoli so no excuse in hesitation to give it
a try. It is definitely unethical to leave patients without treatment when these
such strong evidence supports the possible effective regimen which more
importantly considered to be two of the most safest constituents on earth.
While the author contend that the evidence provided is strong
enough to believe that the expected results will exceed 80% cure rate and even
more than 80% reduction in mortality rate, it should be noted that my unbiased
predictions are as follows:
Not less than 50% efficacy when using both agents as instructed. In
the worst-case scenarios, the efficacy of this regimen will be statistically
significant. I predict that it will be effective in the most vulnerable groups
as elders above 60 years, young black Americans and obese people. I will not be
surprised if the regimen would not be effective (or barely effective) in the young
invulnerable group. Also, I have a quite strong believe that using only one
agent (I don’t know precisely which) will be effective only in men or women
i.e. gender specific, and that is one of many reasons why I recommend using
both agents empirically right from the beginning. I state these predictions to
enlighten any future clinical studies so as not to prejudice any agent of them
due to bad design.
While synergism is predictable, I aim only for the additive effect.
It is highly probable that the regimen will have a protective
effect on many other organs other than lungs.
The article will be updated -within a week- with a third agent (not
an antioxidant) for countries that do not have N-acetylcysteine.
Conflict of Interests:
The author declares no conflict of interests.
About the author:
Almost retired pharmaceutical expert in regulatory affairs,
scientific and pharmaceutical business with more than 10 years of experience in
different multinational and local pharmaceutical companies in different
positions. The author has no ties to pharmaceutical business for more than two
years.
Mohamed Mostafa A. Ezzat (Blogatee)
