Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 ( Isotretinoin in Treatment of COVID-19) (Randomized)

The study is a randomized interventional comparative Phase III trial. 10000 adult male
and female patients with positive COVID-19 diagnosis and fulfilling the below outlined
inclusion criteria will be enrolled into the study.

Isotretinoin(13cis RA) may be able to inhibit COVID 2019 entry via down regulation of
ACE2 , AT1 protein and Ang II-mediated intracellular calcium release rather than
inhibition of interleukin-6 (IL-6) and this is discussed as follow :

The COVID-19 pandemic caused by SARS-COV-2 has infected over 2,000,000 people causing
over 150,000 deaths. A key host cellular protein required for the virus entry is
angiotensin-converting enzyme 2 (ACE2) whose expression has been demonstrated in many
tissues including alveolar epithelial type II cells in lungs, oral mucosa ,intestine,
heart, kidney, endothelium and skin. ACE2-expressing cells can act as home cells and are
prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and
replication. A study demonestrated that patients with hypertension and diabetes mellitus
may be at higher risk of SARS-CoV-2 infection, as these patients are often treated with
ACE inhibitors (ACEIs) or angiotensin II type-I receptor blockers (ARBs), which have been
previously suggested to increase ACE2 expression. In another study by Sinha et al who
analyzed a publicly available Connectivity Map (CMAP) dataset of pre/post transcriptomic
profiles for drug treatment in cell lines for over 20,000 small molecules, isotretinoin
was the strongest down-regulator of ACE 2 receptors. On the other hand, they found 6
drugs in CMAP that are currently being investigated in clinical trials for treating
COVID-19 (chloroquine, thalidomide, methylprednisolone, losartan, lopinavir and
ritonavir, from clinicaltrials.gov), none of which was found to significantly alter ACE2
expression (P>0.1) Moreover, another study demonstrated that isotretinoin is a potential
papain like protease (PLpro) inhibitor which is a protein encoded by SARS-CoV-2 genes and
considered one of the proteins that should be targeted in COVID-19 treatment by
performing target-based virtual ligand screening.

Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV)
and SARS-CoV FP FP have shown that calcium (Ca2+) plays an important role for fusogenic
activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D)
residuesdemonstrated that intracellular Ca2+ enhances MERS-CoV WT PPs infection by
approximately two-fold and that E891 is a crucial residue for Ca2+interaction. Electron
spin resonance revealed that this enhancement could be attributed to Ca2+ increasing
MERS-CoV FP fusion-relevant membrane ordering. Intriguingly, isothermal calorimetry
titration showed that MERS-CoV FP binds one Ca2+, as opposed to SARS-CoV FP which binds
to two Ca2+ ion.

Angiotensin II increases the intracellular calcium activity in podocytes of the intact
glomerulus. The L-type Ca2+ channel blocker nicardipine did not influence the Ang
II-mediated [Ca2+] increase and it has been postulated that SARS-CoV-2 binding to ACE2
may attenuate residual ACE2 activity, skewing the ACE/ACE2 balance to a state of
heightened angiotensin II activity leading to pulmonary vasoconstriction and inflammatory
and oxidative organ damage, which increases the risk for acute lung injury (ALI). AngII
via AT1 receptors upregulates many proinflammatory genes, such as vascular cell adhesion
molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6).30
but 13cis RA specifically down-regulated the AT1 protein in a dose- and time-dependent
manner. Down-regulation of the AT1 expression leads to reduced AngII-mediated
intracellular calcium release Similarly with receptor down-regulation, Treatment with
13cRA resulted in a significant reduction in AT1 mRNA .13cRA has a glucose- and RAR/RXR
independent mechanism for transcriptional inhibition of AT1,

Isotretinoin(13cis RA) and ATRA may be able to inhibit COVID 2019 infection via inducing
the antiviral immunity and this is discussed as follow :

Since effective immune response against viral infections depends on the activation of
cytotoxic T cells that can clear infection by killing virus-infected cells , boosting the
numbers and function of T cells in COVID-19 patients is critical for successful recovery.
A recent study reported that the 82.1% of COVID-19 cases displayed low circulating
lymphocyte counts. A CoV infects macrophages, and then macrophages present CoV antigens
to T cells. This process leads to T cell activation and differentiation, including the
production of cytokines associated with the different T cell subsets (Th17), followed by
a massive release of cytokines for immune response amplification. The continued
production of these mediators due to viral persistence has a negative effect on NK, and
CD8 T cell activation. However, CD8 T cells produce very effective mediators to clear CoV
However, the factors which might cause the reduction in count, and the activation status
of T cells in COVID-19 patients, remain uninvestigated.

Recent study of 522 COVID patients and 40 healthy controls from two hospitals in Wuhan,
China demonstrated that T cell numbers are negatively correlated to serum IL-6, IL-10 and
TNF-α concentration, with patients in decline period showing reduced IL-6, IL-10 and
TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients have
significantly higher levels of the exhausted marker programmed cell death protein(PD-1)
as compared to health controls. Moreover, increasing PD-1 and Tim-3 expression on T cells
could be seen as patients progressed from prodromal to overtly symptomatic stages,
further indicative of T cell exhaustion. T cell exhaustion is a progressive loss of
effector function due to prolonged antigen stimulation, characteristic of chronic
infections. Dendritic cell inhibition is connected to exhaustion of CD8+ T cell
polyfunctionality during chronic hepatitis C virus infection. CD8 T cells produce very
effective mediators to clear nCoV2019.

Dendritic cells (DCs) play a key role in innate immune and adaptive immune responses. As
the strongest antigen presenting cells in the organism, they effectively stimulate the
activation of T lymphocytes and B lymphocytes, thus combining innate and adaptive
immunity. Immature DCs have strong migration ability, and mature DCs can effectively
activate T cells in the central link of startup, regulation, and maintenance of immune
responses. Thus, once the maturation process of DCs is blocked, it directly affects the
initiation of subsequent adaptive immune response. MERS-CoV-2 is able to affect human
dendritic cells and macrophages in-vitro .Productive replication of Middle East
respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate
immune response.

Another study proposed that C -C chemokine receptor type 4 (CCR4) contributes to T cell
lung homing imprinting. It was found that lung DCs induce the expression of CCR4 on T
cells. Lung DCs-activated T cells traffic more efficiently into the lung and protect
against influenza more effectively compared with T cells activated by DCs from other
tissues. Lim and colleagues suggested that CXCR4 plays a role in CD8+ T cell migration to
airway tissues

Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality
during chronic hepatitis C virus infection. CD8 T cells produce very effective mediators
to clear nCoV2019

Presence of RA in different tissues is very imprtant for immune induction and fighting
viral infection, for example, RA is present at high concentrations in the small intestine
due to metabolizing dietary vitamin A by gut epithelial cells. In this local environment,
RA activates and primes dendritic cells (DCs) to become CD103+ DCs that produce RA.3,
4CD103+ DCs are migratory cells that activate naive T cells in mesenteric lymph nodes to
become effector T cells that contribute to both intestinal homeostasis and immunity.and
also RA is an important signal that induces IgA-producing B cells. The gut homing T cells
and B cells play essential roles in protecting the digestive tract from pathogens.

Retinoic acid (atRA) can inhibit the spontaneous apoptosis of activated human T
lymphocytes in vitro. 13-cis RA activates Th2 cytokine production Enhanced circulating
dendritic cell numbers.

So, according to this previous studies the principal investigator suggests that T cells
lymphopenia and exhaustion may be resulted by Dendritic cells (DCs) infection and
inhibition by MERS-CoV-2.

Retinoic acid has profound effects on cellular proliferation and differentiation.
Moreover, it has been reported that ATRA exhibits both anti-inflammatory and
immunoregulatory effects. Recent studies have shown that FOXP3 expression and the immune
function of Regulatory T cells (Tregs ) can be enhanced by ATRA in in both patients and
mouse models. .13Retinoic acid (RA) is produced by a number of cell types, including
macrophages and dendritic cells, which express retinal dehydrogenases that convert
vitamin A to its main biologically active metabolite, all-trans RA. All-trans RA binds to
its nuclear retinoic acid receptors that are expressed in lymphoid cells and act as
transcription factors to regulate cell homing and differentiation. RA production by
CD103+ dendritic cells and alveolar macrophages functions with TGF-b to promote
conversion of naive T cells into Foxp3+ regulatory T cells and, Thereby, maintain mucosal
tolerance

So, principal investigator expects high inducing of Dendritic cells (DCs) by retinoic
acid treatment which will lead to T cells activation and migration with less exhaustion
phenomenon.

According to this protocol treatment with retinoic acid will induce FOXP3 and
CD8+,CD4+,CD25+,FOXP3+ Tregs which their absence during acute infection alters the
ability of the host to limit tissue damage and inducesT cells which were dramatically
reduced in COVID-19 patients to exert its antiviral and anti-inflammatory effect
protecting lung cells and neural cells from the inflammatory and the destructive effect
of IL-6, IL-1, and TNF-α which are induced and highly expressed in COVID 2019 patients.

Researchers from Wenzhou, China looked at clinical laboratory features including lipid
levels of patients with COVID 19. They found dramatic reductions in the cholesterol
levels of patients infected with COVID 19, compared with healthy controls .The study
provides data to suggest that cholesterol levels decline quite rapidly during the early
stages of infection and increase as the patient starts to recover. Therefore, indicating
that cholesterol may have an important role to play in defending the body against such
infections According to our protocol depending on previous studies the principal
investigator demonstrated that there is a strong relation between immune system and
cholesterol levels .When the cholesterol level is low specifically in the case of viral
infection like COVID 2019 infection the immune system is impaired and the antiviral
immune cells will be declined and inhibited :-

Cellular cholesterol is a component of the plasma membrane and is also essential in cell
proliferation. Regulation of intracellular cholesterol levels has been proposed as a
mechanism to regulate T cell and macrophages proliferation. Intracellular cholesterol
level is regulated by two competing pathways, cholesterol uptake and efflux, and ABCA1
plays a major role in the cholesterol efflux pathway. The ATRA induces ABCA1 expression
and ABCA1-dependent cholesterol efflux in activated primary human CD4+ T cells implying
that RA could affect T cell functions by regulating the cellular cholesterol levels.

ATRA upregulates ABCA1 expression only in activated CD4+ T cells, indicating that
induction of ABCA1 by ATRA and 13 cis Retinoic Acid may play an important role in immune
response.

Retinoic acid and liver X receptor agonist synergistically inhibit HIV infection in CD4+
T cells by up-regulating ABCA1-mediated cholesterol efflux.

So, the principal investigator expects that retinoic acid treatment will highly induce T
cells and anti-inflammatory regulatory T cells, T helper via cholesterol efflux and
inducing ATP-binding cassette transporter (ABCA1) and protect lung and neural cells and
inhibit COVID 2019 infection.

The genome of Middle East Respiratory Syndrome Coronavirus is recognized by melanoma
differentiation-associated protein-5 (MDA5), retinoic acid inducible gene-1 (RIG-1) and
endosomal toll-like receptor 3 (TLR3) as pathogen-associated molecular patterns. This
recognition resulted in the formation of type-1 interferon (IFN1). As an evasion
mechanism, virus synthesize proteins that hinder the production IFN1 in the pathway.

RA also acts directly on macrophages at both mucosal sites and other immunological sites.
AtRA modulates peritoneal macrophage activation by endotoxin and IFN-γ by suppressing TNF
production and nitric oxide (NO) synthesis .In addition, at RA inhibits the expression of
PGE2 and COX-2 and the release of TNF, which are induced by bacterial lipopolysaccharide
(LPS) in murine peritoneal macrophages .

A study reported recently that substance (ATRA) have preventive effects on pulmonary
fibrosis by inhibiting IL-6-dependent proliferation and TGF-β1-dependent trans
differentiation of lung fibroblasts. Also, another studies demonstrated that
13-cis-retinoic acid and other retinoid analogs inhibit IL-1-induced IL-6 production and
that this effect is analog-specific and, at least partially, transcriptionally mediated.
This effect was dose-dependent with an IC50 of 10(-7) M RA and significant inhibition
being noted with doses of RA as low as 10(-8) M. IL-10 production was inhibited by ATRA
administration.

A study demonstrated that TLR3(-/-), TLR4(-/-), and TRAM(-/-) mice are more susceptible
to SARS-CoV than wild-type mice but experience only transient weight loss with no
mortality in response to infection. In contrast, mice deficient in the TLR3/TLR4 adaptor
TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss,
mortality, reduced lung function, increased lung pathology, and higher viral titers . New
studies showed that the high level of IFN-α/β produced from the TLR3-IRF3/IRF7 pathway
and IFN-β is the reason for inhibiting DENV replication. 13Cis retinoic Acid induced
significant upregulation of toll-like receptor 3 (TLR3) resulting in an immune response
to dsRNA intermediate which can be partially generated during CoV-2 replicationTLR3
sensitized by dsRNA and cascades of signaling pathways (IRFs and NFκB activation,
respectively) are activated to produce type I IFNs. The production of type I IFNs is
important to enhance the release of antiviral proteins for the protection of uninfected
cells. Sometimes, accessory proteins of CoV can interfere with TLR3 signaling and bind
the dsRNA of CoV during replication to prevent TLR3 activation and evade the immune
response. 13Cis retinoic Acid induced significant upregulation of toll-like receptor 3
(TLR3) , mitochondrial antiviral-signaling protein (MAVS) and retinoid-induced gene I
(RIG-I) and IFN regulatory factor 1 expression in a time-dependent.

In further research, Tsai .and Chen showed the high level of IFN-α/β produced from the
TLR3-IRF3/IRF7 pathway and IFN-β is the reason for inhibiting DENV replication. In HUH-7
cells, huTLR3 can recognize DENV-1 and induce the expression of IFN-β, which can enhance
the expression of huTLR3 on the contrary . TLR3 also induces type I IFN during WNV.

Doctors treating the sickest Covid-19 patients have zeroed in on a new phenomenon: Some
people have developed widespread blood clots, their lungs peppered with tiny blockages
that prevent oxygen from pumping into the bloodstream and body.As with so much else about
the Covid-19 response, health experts are learning about the symptom on the fly. Blood
clots are common in patients who are immobilized, but they seem to be smaller and cause
far more severe damage in some Covid-19 patients. Doctors have said they see patients
with blood clots forming not only in their lungs, but also in blood vessels. Autopsies
have also revealed blood clots in kidneys and other organs, which some experts say
suggests an overwhelming immune system response to the virus that inflicts harm on the
body

Retinoic acid, is known to possess in vivo anti-inflammatory, anti-platelet and
fibrinolytic activities. A study investigated the in vitro thrombin and platelet
aggregation inhibitory activities of retinoic acid and retinaldehyde.Retinoic acid,
retinaldehyde and retinol exhibited potent inhibition of thrombin, with IC50 values of
67μg/ml, 74μg/ml and 152μg/ml, respectively for the inhibition of thrombin (Sigma); and
49μg/ml, 74μg/ml and 178μg/ml, respectively for the inhibition of thrombin (plasma).
Amongst vitamin A and its derivatives, retinoic acid showed the highest inhibition of
both the forms of thrombin.

Isotretinoin(13cis RA) may be able to inhibit COVID 2019 infection via reversIing the
androgenic induction and activation effect of (DHT) on TMPRSS2 expression and helps to
prevent cleaving and activating both the spike protein (S) of COVID 2019 and the viral
receptor, and this is discussed as follow :

TMPRSS2 is both the most frequently altered gene in primary prostate cancer and a
critical factor enabling cellular infection by coronaviruses, including SARS-CoV-2. The
modulation of its expression by steroids could contribute to the male predominance of
severe infections and given that TMPRSS2 has no known indispensable functions, and
inhibitors are available, it is an appealing target for prevention or treatment of
respiratory viral infections

TMPRSS2, a key regulator in prostate cancerTMPRSS2 was first identified in prostate
cancer shortly after the gene had been originally cloned. Prostate cancer cell lines
strongly upregulated TMPRSS2 expression in response to androgens . TMPRSS2 is expressed
on the luminal side of the prostate epithelium, and its expression is increased in
prostate cancer tissue compared to non-cancerous prostate tissue. Notably, the TMPRSS2
gene is a partner in one of the most common gene fusion eventsin solid tumors: somatic
gene rearrangements involving TMPRSS2 witha member of the ETS family of oncogenic
transcription factors, most commonly ERG. This fusion occurs in approximately 50% of
primary prostate cancers among men of European ancestry.While ERG is not normally
regulated by androgen, the gene fusion juxtaposes the androgen receptor regulatory
elements of TMPRSS2 with the ERG gene. The ERG gene is consequently controlled by
androgen receptor signaling and expressed highly in prostate cancers harboring the
TMPRSS2: ERG fusion. Intriguingly, the prevalence of the TMPRSS2: ERG fusion is lower in
prostate tumors of both black and Asian men. The relevance of this to the current
COVID-19 pandemic is unclear.TMPRSS2: ERG fusion- cancers also have a distinct set of
risk factors related to hormonal signaling. For example, men with higher genetically
determined transcriptional activity of the androgen receptor have a higher risk of
TMPRSS2: ERG fusion-positive prostate cancer but not of fusion-negative prostate cancer

TMPRSS2 is an androgen receptor signaling target gene and an androgen-regulated
cell-surface serine protease expressed predominantly in prostate and lung epithelial cell
TMPRSS2 is normally expressed several fold higher in the prostate relative to any other
human tissue, though the normal physiological function(s) remains unknown. Importantly,
unlike other TTSPs, TMPRSS2 transcription is regulated by androgenic ligands and the
androgen receptor (AR). There is a positive correlation between AR and TMPRSS2 in
microdissected primary tumor epithelium (r2 = 0.39 ; p <0.001).

Dihydrotestosterone (DHT) significantly and dramatically induced the expression of
TMPRSS2 protein with two molecular masses of 60 (full-length) and 38 kDa (N-terminus) in
a dose responsive manner

Data from Chinese outbreak show death rates for men almost 50 per cent higher than for
women show that Early research from China suggests women and children are less likely to
die than men if they catch the coronavirus. Death rates for Covid-19, the disease those
infected with the coronavirus develop, are low for everyone: only 2.4 per cent of the
44,672 people in the Chinese study died. But although roughly even numbers of men and
women catch the disease, men are more likely to develop such a serious case of Covid-19
they die.

More than 70 percent of Italy's coronavirus deaths have been among men but scientists
there admit they are mystified by the gender gap. At least 3,400 people in Italy have
died of the devastating disease - it yesterday announced it had a higher death Toll than
China - but less than 1,000 of them have been women. Men are also more likely to pick up
the infection in the first place and account for 60 percent of confirmed cases, according
to Italy's public health research agency. An earlier analysis found that 80 per cent of
the deaths were in men and just 20 per cent were in women - but the gap has narrowed over
time

According to this data the principal investigator thinks that there is a strong relation
between high mortality in males and androgenic effect specifically the effect of DHT on
TMPRSS2 protein which is used by covid 2019 in cell invasion and entry and depending on
this data related to six hormones specifically (DHT) , The investigator was able to
discover whey women and children less likely to die from illness than men. So, the
investigator divided infected patients according to their six hormone because TMPRSS2 is
an androgen-regulated cell-surface serine protease expressed predominantly in prostate
and lung epithelial cell TMPRSS2.

Androgen(DHT) potential effect on TMPRSS2 expression in children is less than its effect
in females and males followed by viral severity and vigrousity in men compared with
children and women. .

Androgen (DHT) potential effect on TMPRSS2 expression in females is less than in males
followed by viral severity and vigrousity in men compared with females .

So, the principal investigator thinks that when some researchers investigated the role of
sex steroids in SARS-CoV pathogenesis by comparing gonadectomized and control
counterparts after infection. Gonadectomy or treatment with flutamide, a non-steroidal
anti-androgen did not affect morbidity and mortality in male mice following lethal MA15
infection, They may be were wrong in their conclusions in suggesting that androgens do
not play a role in SARS-CoV pathogenesis because Gonadectomy or treatment with flutamide
will not completely affect or inhibit DHT and its derivatives(5α-Androstan-3α,17β-Diol)
concentration in tissues and blood because after inhibiting testosterone with flutamide .
the pathway of DHT formation will be activated to compensate the inhibited testosterone
levels so the TMPRSS2 expression will be significantly induced by DHT and the treated
animals will not be affected in case of flutamide treatment but in case of Gonadectomy
the expression of TMPRSS2 will be decreased by DHT inhibition only if along time has
passed on Gonadectomy in order to make sure that DHT and its derivatives completely
declined in levels that will not allow it to affect on expression of TMPRSS2 and in
female mice after blocking estrogen receptors it died because increasing formation of
androgenic hormones.

A study demonstrated that 13- cis -Retinoic acid competitively and reversibly inhibits
Dihydrotestosterone So, the principal investigator expects a significant modulation of
TMPRSS2 expression after treating with 13- cis -Retinoic acid via temporary preventing
the effect of dihydrotestosterone(DHT) on TMPRSS2 promoting and expression. And the type
II transmembrane serine proteases TMPRSS2 which can cleave and activate the spike protein
(S) of the severe acute respiratory syndrome coronavirus (SARS-CoV) for membrane fusion.
In addition, these proteases cleave the viral receptor, the carboxypeptidase
angiotensin-converting enzyme 2 (ACE2), and it was proposed that ACE2 cleavage augments
viral infectivity.

A study demonstrated that COVID-19 reduces testosterone levels in men by altering the
functioning of the gonads. So could the increased severity of the disease in men be due
to lowered testosterone. But according to the principal investigator explanation COVID-19
reduces testosterone levels because there is a dramatic reductions in the cholesterol
levels of patients infected with COVID 19, compared with healthy controls . Cholesterol
levels decline quite rapidly during the early stages of infection and increase as the
patient starts to recover.Therefore, indicating that cholesterol may have an important
role to play in defending the body against such infections and depending on the principal
investigator explanation, Testosterone is synthesized starting from cholesterol through a
well-characterized steroid biosynthetic pathway involving the sequential action of
multiple enzymes So, when cholesterol levels are decreased, this decrease will followed
by decreasing in testosterone level and according to this explanation testosterone
therapy in COVID 2019 is not recommended but temporary inhibitor of DHT is recommended
such as Isotretinoin because this treatment by testosterone will inhibit cholesterol
synthesis by feedback inhibition and decrease cholesterol uptake by Leydig cells in
testis and this also will lead to over increase in DHT lvels and its derivatives in
different tissues, which will induce TMPRSS2. because DHT is a potent activator of
TMPRSS2 and this will be followed by processing and activation of COVID2019 spike protein
to bined its ACE2 receptors in lung and kidney leading to their damage specifically in
testis because it contains high levels of proteases and ACE2. Serine proteases are
emerging as important contributors to the production, maturation, and functional
competence of spermatozoa.

Depending on this data and according to this protocol, The principal investigator expects
and suggests that retinoic acid is specific modulator of androgens specifically DHT not
testosterone and could reverse the androgenic induction and activation effect of (DHT) on
TMPRSS2 expression and prevent cleaving and activating both the spike protein (S) of
COVID 2019 and the viral receptor, the carboxypeptidase angiotensin-converting enzyme 2
(ACE2). (All ideas and michanisms specifically role of Androgen in TMPRSS2 activation in
COVID-19: Serendipity or opportunity for intervention and the inhibition of ACE2 ,AT1
protein and Ang II-mediated intracellular calcium release pathway which is responsible
for SARS-CoV-2 cell fusion and entry included in the research protocol were submitted to
Academy of scientific research and technology - Egypt- on 1 April , 2020. in Call no.
2/2019/ASRT- Ideation Fund)

Promising features of COVID 2019 treatment according Principal Investigator Protocol:

1. This medication have the feature of Aerosolized Drug Delivery to increase its
efficacy beside Oral administration, Which makes it distinct from other medication
in which should dose be only given orally. A study demonstrated that treating with
13 cis retinoic acid aerosolized via inhalation rout did not cause any damage in
lung cells. Repeated high doses of 13 cis retinoic by inhalation resulted in
moderate loss of body weight, but microscopic investigation of ten tissues including
lung and oesophagus did not detect any significant aerosol-induced damage. The
results suggest that administration of isotretinoin via powder aerosol inhalation is
probably superior to its application via the oral route in terms of achieving
efficacious drug concentrations in the lung.

2. Inhaled isotretinoin might provide sufficient drug to the target cells for efficacy
while avoiding systemic toxicity.

3. A study demonstrated that 13 cis retinoic is used in treating Emphysema (emphysema
is a lung condition that causes shortness of breath)

4. ATRA has been reported to induce formation of new alveoli and returns elastic recoil
in the lung to approximately normal values in animal models of emphysema.

5. Strong expectation of complete COVID 2019 blockade from cell entry and infection
depending on strong ethics, researches and references.

6. Availability of our compounds.

7. Ease of application.

8. Expectation of COVID 2019 treating of by more than one distinct mechanism.

9. Expectation of High induction of anti- inflammatory T cells and significant
inhibition of IL-6 at low concentrations.

10. Controlling Accompanying cytokine storm.

11. No interactions with Egyptian protocol drugs were found.