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Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion

Scheim, D., SSRN, doi:10.2139/ssrn.3636557
Dec 2020  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
 
*, now with p < 0.00000000001 from 104 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19ivm.org
Review of ivermectin for COVID-19 treatment and a hypothesized mechanism of action. Author proposes that ivermectin's antiviral activity against SARS-CoV-2 may be mediated by competitive binding to the CD147 receptor, which is densely distributed on red blood cells. This could reduce viral spike protein binding to CD147, hypothesized to cause "catch" and "clump" vascular occlusion that impedes blood flow and underlies key morbidities of COVID-19. Higher doses of ivermectin, up to 10 times the 200 μg/kg used in a clinical study, have been well tolerated and could yield greater clinical benefits. The hypothesized mechanism has a parallel in malaria, where infected red blood cells cause clumps and vascular adhesion that underlie disease severity. The greater incidence of severe malaria and COVID-19 for blood groups A or B vs. O is noted as supporting evidence. Nailfold capillaroscopy is proposed to test the hypothesis by monitoring blood flow in COVID-19 patients before and after ivermectin intake.
Reviews covering ivermectin for COVID-19 include1-41.
Scheim et al., 31 Dec 2020, peer-reviewed, 1 author. Contact: dscheim@alum.mit.edu.
This PaperIvermectinAll
Review and perspective Ivermectin for COVID-19 treatment: clinical response at quasi-threshold doses via hypothesized alleviation of CD147-mediated vascular occlusion
David E Scheim
The worldwide spread of the COVID-19 pandemic has prompted clinical testing of existing drugs with indicated activity against the SARS-CoV-2 virus. Among antimalarial drugs of such potential is ivermectin (IVM), a macrocyclic lactone of Nobel Prize-winning distinction. A retrospective study of 173 COVID-19 patients treated with IVM in four Florida hospitals at a dose of 200 μg/kg yielded a 40% reduction in mortality compared with 107 controls (15.0% vs. 25.2%, p=0.03). Mortality was cut by 52% with IVM for patients having severe pulmonary disease (38.8% vs. 80.7%, p=0.001). Stabilization and then improvement over 1-2 days frequently occurred for patients who had rapidly deteriorating oxygen status. It is proposed that higher doses of IVM could yield sharply greater clinical benefits. In several clinical studies, IVM at doses of up to 2,000 μg/kg, ten times that used in the Florida study, were well tolerated. The potential for major dose-response gains is evaluated based upon studies indicating that IVM shields SARS-CoV-2 spike protein and that this spike protein binds to the CD147 transmembrane receptor as well as to ACE2. The abundant distribution of CD147 on red blood cells (RBCs) suggests a hypothesized "catch" and "clump" framework whereby virally-mediated bindings of RBCs to other RBCs, platelets, white blood cells and capillary walls impede blood flow, which in turn may underlie key morbidities of COVID-19. The proposed catch and clump scenario for COVID-19 has a parallel in malaria, for which CD147 is central to the infectious process. The core morbidity of severe malaria is caused by similar clumps and adhesions to endothelium centering around infected RBCs. These underlie the much greater incidence of severe malaria for blood groups A or B vs. O, caused by adhesive RBC membrane trisaccharides associated with blood groups A and B. COVID-19 is likewise much more prevalent for blood groups A or B vs. O. More generally, hemagglutination, the formation of such RBC-pathogen clusters, is common for enveloped viruses. Under this hypothesized framework, a significantly higher rate of capillary flow in younger people could explain a corresponding decreased severity of COIVD-19. This proposed hypothesis and the associated potential for major IVM dose-response gains could be tested, for example, by monitoring blood flow in COVID-19 patients before and after IVM intake using nailfold capillaroscopy.
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