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)

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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.