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