Ivermectin, Aspirin, Dexamethasone and Enoxaparin as Treatment of Covid 19

Between 30 and 50% of patients who contract COVID 19 will be asymptomatic or
oligosymptomatic. This fact will not give rise to the consult, and will directly affect a
notorious sub-registration of the cases.

The second, even more disturbing, premise is that these patients are as contagious as the
moderate and severe cases.

The virus incubation period has been calculated at 5.1 days (95% CI, 4.5 to 5.8 days), and
97.5% of patients are said to have symptoms at 11 days (95% CI 8.2 to 15.6 days).

A mortality of 5.7% has been calculated. The average COVID patient presents with fever (78%),
cough (60-79%) and myalgias or fatigue (35.8 to 44%).

55% develop dyspnea, which appears on average 8 days after the onset of symptoms.

To the manifestations expressed above, the presence of bilateral conjunctival injection
should be added, without associated secretions, hypogeusia, skin rash and hyposmia.

Diagnostic confirmation is made through laboratory studies, which can be performed on a wide
variety of biological samples.

Bronchoalveolar lavage samples showed the highest sensitivity (93%), followed by sputum
samples (72%), nasal swabs (63%), fiberoptic brush biopsy (46%), pharyngeal swabs (32%),
feces ( 29%) and, finally, blood (1%). A sensitivity of 91% is reported in saliva samples.

Evidence suggests that a subgroup of patients with severe forms of COVID 19 may have cytokine
storm syndrome.

Therefore, we recommend the identification and treatment of hyperinflammation using existing
approved therapies with proven safety profiles to address the immediate need to reduce
increasing mortality (see Therapeutic Proposal).

Secondary hemophagocytic lymphohistiocytosis (SHLH) is a poorly recognized hyperinflammatory
syndrome characterized by fatal and fulminant hypercytokinemia with multiple organ failure.

In adults, SHLH is most often triggered by viral infections, and occurs in 3.7-4.3% of sepsis
cases.

The cardinal features of sHLH include constant fever, cytopenias, and hyperferritinemia;
Pulmonary involvement (including ARDS) occurs in approximately 50% of patients.

A cytokine profile that resembles sHLH is associated with the severity of COVID-19 disease,
characterized by an increase in interleukin (IL) -2, IL-7, granulocyte colony stimulating
factor, protein 10 inducible by interferon-γ, monocyte chemoattractant protein, macrophage
inflammatory protein 1-α and tumor necrosis factor-α.

Mortality predictors from a recent multicenter retrospective study of 150 confirmed cases of
COVID-19 in Wuhan, China included elevated ferritin (mean 1297.6 ng / ml in non-survivors
versus 614.0 ng / ml in survivors; p <0.001) and IL-6 (p <0.0001), suggesting that mortality
could be due to viral hyperinflammation.

However, cases have been reported where tissue and organ involvement has been found whose
concentration of ACE receptors is very dissimilar (myocardium, brain). In all of them, the
common denominator was small vessel thrombosis, as seen in entities such as Catastrophic
Antiphospholidic Syndrome.

Currently the Virchow triad factors have been narrowed down in more detail:

Circulatory stasis: abnormalities of hemorrheology and turbulence in vascular bifurcations
and stenotic regions.

Injury to the vascular wall: abnormalities in the endothelium, such as atherosclerosis and
associated vascular inflammation.

Hypercoagulable state: abnormalities in the coagulation and fibrinolytic pathways and in
platelet function associated with an increased risk of VTE and other cardiovascular diseases
(such as coronary artery disease [CPA], heart failure and stroke in patients with AF). All
lead to a state of hypercoagulability, which could explain the formation of microthrombosis
in different locations, as has been repeatedly reported in patients with COVID 19.

BASES OF THE PROPOSED THERAPEUTICS They rest on four pillars: Ivermectin, Aspirin,
Dexamentasone and Enoxaparin. IVERMECTIN Ivermectin is a broad-spectrum antiparasitic, with
vermicidal and ectoparasiticidal properties. It was discovered and marketed for animal use in
the early 1980s.

Approved in 1997 by the FDA for single-dose strongyllidiasis of 200 mcg / kg and crusted
scabies (Scabies Norway) in patients with AIDS at a dose of 200 mcg / kg, every week for 2
weeks.

In Argentina, it has been available for human use for almost 20 years. But, much more
recently, its viricidal effects have been compiled on different varieties of flavivirus,
dengue, Zica, Chikunguña, etc.

Ivermectin has been reported to be a SARS-CoV-2 inhibitor. This activity is believed to be
due to the dependence of many different RNA viruses on IMPα / β1 during infection. These
reports suggested that the inhibitory activity of ivermectin nuclear transport may be
effective against SARS-CoV-2, since they demonstrate that ivermectin has antiviral action
against the clinical isolate of SARS-CoV-2 in vitro, with a single dose capable to control
viral replication in 24-48 hours. in vitro.

Although in vitro studies have used doses that -extrapolated to those recommended in the
treatment of ectoparasitosis in humans- might seem high, the truth is that studies carried
out in healthy volunteers, more than two decades ago, proved that the usual doses they can be
increased tenfold, without significant side and / or adverse effects.

ASPIRIN Aspirin is the common name for acetylsalicylic acid. The chemical production is based
on the salicylic acid obtained by synthesis. Its most common uses and for what it was first
used was as an analgesic (for pain), antipyretic (to lower fever) and anti-inflammatory. It
is classified as a non-steroidal anti-inflammatory drug (NSAID). In 1989 the first large
study was published that proved that Aspirin reduces cardiovascular risk, acting as an
antiplatelet agent.

These were low-dose Aspirin, and the risk of myocardial infarction was found to decrease by
44% when the previously named dose of Aspirin was administered.

HEPARIN AND ENOXAPARIN Heparins are injectable anticoagulant substances. A distinction should
be made between standard heparin or unfractionated heparin (HNF) and low molecular weight
heparins (LMWH).

HNF is made up of a heterogeneous mixture of polysaccharide chains of variable length.

LMWHs are the result of fragmentation of HNF by different methods to achieve products with
lower and more homogeneous molecular weights. They are also made up of a mixture of
polysaccharide chains and their average molecular weight is much lower. The antithrombotic
and anticoagulant activity of HNF is related to the ability to inhibit factor Xa and factor
IIa respectively. LMWHs have less inhibitory activity to thrombin or factor IIa but maintain
the same potency with respect to factor Xa, so it is expected that they present a lower risk
of bleeding but the same antithrombotic activity.

CORTICOSTEROIDS Systemic corticosteroids are powerful anti-inflammatory and immunosuppressive
agents. They can be administered intravenously, intramuscularly, orally, intralesionally, and
topically. Its side effects increase with high, long and frequent doses. Corticosteroids are
drugs frequently used in various clinical situations, because they are powerful
anti-inflammatories and immunomodulators. Glucocorticoids passively diffuse through the cell
membrane, then join soluble receptor proteins in the cytoplasm. They are used, among others,
for the treatment of some rheumatic diseases. A separate case, well known but not studied in
the current contingency, is acute adrenal insufficiency.

CURRENT IDEA TRIAL Based on the precedent data, we started a Clinical Trial based on the
above-mentioned four drugs, on a gradual scale, and according the severity of each case. In
order to determine the dose and combination, we developed our own Severity Score.

INTERPRETATION:

Mild cases Only minor criteria findings Moderate cases 3 major crit. findings, or 2 major + 2
minor Severe cases 4 major crit. Findings or 3 major + 2/3 minor

Based on the previous criteria, we used the following combinations and doses:

DISEASE SEVERITY Firm Suspicious Case or Confirmed case 24 mg orally at a dose of 200 ug / kg
in a single dose, to be repeated a week later Aspirin 250 mg orally Moderate clinical stage
36 mg orally at a dose of 400 ug / kg in a single dose, to be repeated a week later
Dexamethasone 4 mg/day (parenteral) Aspirin 250 mg orally Low Flow Washed Oxygen or Oxygen
Concentrator Severe case with bilateral pneumonia 48 mg via gastric cannulae, to be repeated
a week later Dexamethasone 4 mg/day (parenteral) Enoxaparin100 UI/kg (1 mg/kg) Mechanical
Ventilation