Antimalarials for COVID-19 Treatment: Rapid Reversal of Oxygen Status Decline with the Nobel Prize-Honored Macrocyclic Lactone Ivermectin (US, 2020-06-15)

[-] TrumpLyftAlles | 1 points | Jun 23 2020 18:43:47

The analysis of pharmacology and toxicology of ivermectin might be interesting. Otherwise, not much here.

# Abstract The worldwide spread of the COVID-19 pandemic has prompted intense interest among researchers, physicians and patients in viable treatment options. Among the first antimalarial drugs repurposed for treatment of this pandemic was hydroxychloroquine (HCQ), as pioneered at Marseille’s main COVID-19 treatment hospital. HCQ’s unusual pharmacology has limited its effectiveness in advanced stages of the disease, but 3,300 mixed stage COVID-19 patients treated in Marseille with HCQ and azithromycin (AZ) had a mortality rate 16% of the world average. Optimal tissue levels of HCQ require several days to accrue, and some advanced stage COVID-19 patients may have cardiac complications that require screening for HCQ use. The Marseille research team found more generally that other antimalarial drugs were active in vitro against the SARS-CoV-2 virus.

HCA + AZT reduces fatalities A LOT?!

One such antimalarial drug of Nobel Prize-winning distinction is ivermectin (IVM). As determined by a US research team from a database spanning 169 hospitals in three continents, 704 COVID-19 patients treated with a single, low dose of IVM (150 µg/kg) had a mortality rate that was one-sixth (1.4% vs. 8.5%) of that of untreated, case-matched controls.

This is the no-longer-accessible Usefulness of Ivermectin Surgisphere study which I still believe to be credible, but is largely rejected.

Treatments of 71 COVID-19 patients with IVM at 200 µg/kg plus HCQ, AZ and Zinc by a clinical team in Florida yielded a statistically significant reduction in mortality, with reversals in 1-2 days of rapidly deteriorating oxygen status.

This the the Broward County ICON study.

The pharmacology and toxicology of IVM is briefly reviewed, indicating the potential for an even sharper response at increased, safe doses. The central role of the CD147 transmembrane receptor in the binding of SARS-CoV-2 is considered. A catch and clump scenario for impedance of capillary flow through viral bindings to blood cells via CD147 is proposed as a possible explanation for the observed rapid clinical response to IVM and for other puzzling aspects of COVID-19.

[-] elkrange | 1 points | Jun 23 2020 18:50:32

The CD147 receptor: the nexus of penetration and morbidity for malaria and COVID-19

... A pattern of circulatory system damage is also seen in COVID-19 patients with such features as intravascular clots and peripheral ischemia. 116,121,122 One clinical reviewer summarized that COVID-19 “is a systemic disease that primarily injures the vascular endothelium.”123 One possible cause of both such hypoxemia and vascular injury could be the invasive binding of hemoglobin in the red blood cell (RBC) by the SARS-CoV-2 virus, as proposed in an intriguing hypothesis derived through molecular modeling.124 Another possible explanation proposed below posits only the binding, not penetration, of virus to RBCs and the endothelial lining of blood vessels, causing a catch and clump impedance of blood flow.

These blood-related COVID-19 morbidities mesh with an intriguing commonality between COVID-19 and malaria centering around the RBC and the CD147 transmembrane receptor. The spur to exploring this connection was the observation by an investigator from the Marseille research team that most of the antimalarial drugs tested in vitro were found active against the SARS-CoV-2 virus.125 Key to the infectious process of malaria is the penetration of the host’s RBCs by plasmodium falciparum in its merozoite form, facilitated by surface proteins on this tiny one-celled organism.126,127 For all strains of P. falciparum tested, a particular ligand-receptor pair, the parasite ligand pfRh5 and the transmembrane receptor CD147 on the RBC, was found essential to the parasite’s binding to host RBCs that preceded its subsequent penetration. 128,129 In vitro, CD147 antagonists blocked parasite invasion of RBCs,128 and in vivo, a recombinant anti-CD147 antibody cleared established malarial infections with no overt toxicities.129,130

This same transmembrane receptor, CD147, has recently been identified, along with ACE2,131 as a key binding site for SARS-CoV-2 spike protein. 132 This binding was demonstrated by surface plasmon resonance and ELISA assays and by the competitive inhibition of SARS-CoV-2 in vitro by an anti-CD147 antibody.132 Cyclophilin A and B, molecules that bind with and activate CD147, can also serve as binding partners for CD147 in its attachment to SARS-CoV-2 spike protein.133 Although the binding affinity of molecules of SARS-CoV-2 spike protein to CD147 is weaker than to ACE2, the surface densities of these molecules on virus and of CD147 on cells (e.g., \~1,700 on each RBC134) would allow multiple bonds with significant combined affinity.135

To test the role of CD147 in the clinical course of COVID-19, a humanized monoclonal antibody against CD147, meplazumab was used to treat 17 hospitalized COVID-19 patients. 136 These patients, 6 with severe disease and 7 in critical status, had an average time to viral clearance of 3 days vs. 13 days for controls. Similar statistically significant improvements versus controlsin case severity and time to hospital discharge were achieved in the treated group. Although the small number of cases and lack of randomized controls precludes firm conclusions on clinical efficacy, these clinical findings align with multifaceted in vitro indications of CD147 as a clinically relevant binding site for the SARS-CoV-2 virus.

[-] elkrange | 1 points | Jun 23 2020 18:50:40

Catch and clump impedance of blood flow: a hypothesis

As noted above, the respiratory system is the point of penetration and central base of infection for COVID19, yet the vasculature is emerging as central to the morbidity of this disease. Circulating through lung alveolar tissue about once per minute,137 blood cells can efficiently spread the virus.133 But beyond these known fundamentals, three central questions emerge. What is the biological mechanism behind blood and vasculature-based morbidities of COVID-19? Why do patients who progress to a serious condition often do so suddenly, with a rapid decline of oxygen status about a week after disease onset?138 And what caused the stabilization and improvement over the course of 12-48 hours for the Florida patients who had rapidly deteriorating oxygen status, as also occurred in the case report?

A starting point to approach these questions is the distribution of ACE2 and CD147 in key tissues of interest. Both of these receptors are expressed in alveolar and other lung tissue and in the endothelial lining of the vasculature. 131,133,136,139,140 But only CD147, not ACE2, is present in RBCs and white blood cells.133,141 The distribution of CD147 receptors is especially well established for RBCs,142,143 with an average of about 1,700 per RBC found in one study.134 The possibility of an inflammatory cascade spurred by SARS-CoV-2 binding of white blood cells is suggested by multiple indications of a central role of CD147 and its partner cyclophilins in inflammatory processes behind several conditions, including ventilator-induced lung injury and atherosclerosis.136,139,140,144-146 In a mouse model of acute lung inflammation, anti-CD147 antibodies significantly reduced neutrophil infiltration of lung tissue and associated tissue pathology.139,144

But CD147, which is abundantly distributed on RBCS and can act as an adhesion molecule there, 139,147-149 could also enable binding of viral particles to RBCs, platelets and endothelial cells lining the capillaries. Although contact between virus particles and blood cells may only be surface bindings that dynamically detach and reattach,133 the catches and clumps as depicted in Figure 1 could still impede blood flow

Viral particles attached to CD147 receptors on RBCs in this figure, as well as those attached to CD147 or ACE2 receptors on the endothelial lining of capillaries are represented as “catches.” For visibility, SARSCoV-2 viral particles (actual size about 0.10-0.12 µm150) are shown at about six times actual scale relative to the diameter of the capillary cross section (which is typically 3-10 µm). The RBC, having a disk diameter of about 8 µm and thickness of about 2 µm, 151 fits tightly within the capillary wall, often distorting its shape to fit, 152 sometimes flowing through capillaries as small as 2-3 µm in diameter.151 Thus, these attached viral particles, per their actual size, would not cause a gross obstruction to RBC passage but would rather act like tiny Velcro hooks in roughening the RBC and endothelial surfaces, causing a drag on flow.

Since both RBCs and platelets, which also have CD147 receptors,145,153 are densely distributed in blood flowing through capillaries,154,155 virally-linked clusters of both types of cells as depicted can also form. These clumps as well as catches would cause the most drag on blood flow in smaller capillaries including those in the lung, the average diameter of which is 6 µm. 156 Although single file flow of such cells in capillaries would limit cluster formation mainly to abutting pairs or strings of cells, larger clusters of red and white blood cells, all of which have CD147 receptors,133,134,141-143 could form in larger blood vessels. These would then create bottlenecks as they progressed from arteries and arterioles into capillaries.

RBCs can in fact form aggregates even under normal conditions, without virus, joined by macromolecules in plasma, under conditions of low blood flow shear rates,157 such as in veins. 158 But such aggregation is reversible, the RBCs separating at higher shear rates.157 This process can proceed in a positive feedback loop, with RBC aggregation slowing blood flow, and new RBC clumps then more likely to form under such conditions.157 In the presence of SARS-CoV-2 virus, blood flowing in capillaries even at moderate velocity might form catches and clumps having enough binding affinity to cause some drag on flow. Slower flow in turn would promote furthersuch aggregation, causing a cascade of viral-mediated catching and clumping.

Although viral-cell bindings would be dynamically detaching and reattaching, a flow rate below a certain threshold would allow this cascading drag on blood flow by viral-mediated catches and clumps to proceed. Such a cascade of blood flow impedance, which would limit oxygen transfer by RBCs both from lungs and into tissue, could explain the sudden decline of oxygen status often experienced by those COVID-19 patients who deteriorate to serious status. It could explain blood clots and “COVID toes”159 sometimes experience by patients. The dissolution of such bonds, on the other hand, by an agent that competitively bound to either viral spike protein or the CD147 receptor, would diminish the binding affinity of viral spike protein to the CD147 receptor and loosen these catches and clumps.

This catch and clump hypothesis for diminished oxygen status in COVID-19 patients could explain one more puzzling aspects of this disease: the resilience of younger people and increasing age-related vulnerability of others. Several studies of blood flow in different tissues found much greater flow velocities in younger vs. older subjects. For capillary flow under toe and finger nails, flow rates in subjects of average age 26 were almost double those of average age 63.160 In other studies of capillary flow in various tissues, older subjects had 23%161 and 40%162 diminished flow velocity vs. younger subjects and a 47% decrease in flux amplitude.162 Difference in flow rates in arteries for older vs. younger subjects were significant but less pronounced: 26% lower,163 27% lower,164 and 27% lower. 165 The much greater blood flow rates in younger age groups could be sufficient to overcome viral spike protein-CD147 binding forces and prevent a cascade of impeded capillary flow from developing.

While no positive determination has yet been made, there are suggestive indications that the antimalarial drugs of prime interest for COVID-19 treatment may be CD147 inhibitors. Doxycycline reduced CD147 levels in a carcinoma cell line166 and in human gingival crevicular fluid.167 AZ and other macrolide agents inhibit the binding and penetration of RBCs by the malarial parasite,168 and AZ also decreases the expression of metalloproteinase molecules closely related to CD147.168-170 IVM is a macrocyclic lactone with a 16-carbon core, similar in molecular structure to the 15-carbon macrolide antibiotic AZ171-174 CD147 appears to promote joint irritation and damage175-177 and atherosclerotic plaque growth178 in rheumatoid arthritis (RA), the latter a major factor in significant excess mortality for RA patients due to cardiovascular disease.178 HCQ is an effective and widely used drug for RA, and its use yielded a three-fold reduction in cardiovascular events in 241 RA patients compared with untreated controls.68

Also, a molecular modeling study found that ivermectin had the greatest multi-domain shielding potency for SARS-CoV-2 spike protein of more than 100 agents tested, with heparin second in shielding potency. 111 Clinical benefit was indicated using heparin for COVID-19 patients in assorted studies,121,179,180 with most pronounced response obtained in conjunction with azithromycin.121 A conversion of milligrams per week to moles per week of higher-end clinical doses of heparin (40,000 units per day) and ivermectin (400 µg/kg once per week) yields a factor of 12 greater for the weekly dose of ivermectin vs. heparin.181,182

[-] movethroughit | 1 points | Jun 23 2020 23:52:15

"Treatments of 71 COVID-19 patients with IVM at 200 µg/kg plus HCQ, AZ and Zinc by a clinical team in Florida yielded a statistically significant reduction in mortality, with reversals in 1-2 days of rapidly deteriorating oxygen status."

"This the the Broward County ICON study."

Baghdad study? I don't think ICON included HCQ, just Ivermectin or SOC Control.

[-] TrumpLyftAlles | 1 points | Jul 02 2020 20:29:12

From this 2020-04-13 news story:

Two weeks ago, Dr. Rajter started adding Ivermectin to the cocktail of drugs currently used to treat COVID-19: hydroxychloraquine, azithromycin, and zinc sulfate.

The abstract of the ICON study doesn't mention hydroxychloraquine or the other components of the cocktail.

The PDF mentions everything except zinc (weirdly):

Baseline data was collected at the time of ivermectin administration for the ivermectin group; for the usual care group baseline was either at the time of administration of hydroxychloroquine or, if not used, at the time of admission. Information collected included COVID-19 testing results, patient demographics, pre-existing comorbid conditions, initial vital signs, chest imaging studies, laboratory results, and the use of hydroxychloroquine with and without azithromycin in order to describe the cohort and to identify potential cofounders between groups.