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Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors

DiNicolantonio et al., Open Heart, doi:10.1136/openhrt-2021-001655
Apr 2021  
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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 suggesting that the effectiveness of ivermectin in the cytokine storm phase of COVID-19 may be, at least in part, an anti-inflammatory effect mediated by increased activation of glycine receptors on leukocytes and possibly vascular endothelium.
Reviews covering ivermectin for COVID-19 include1-41.
DiNicolantonio et al., 19 Apr 2021, peer-reviewed, 3 authors.
This PaperIvermectinAll
Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors
Dr James J Dinicolantonio, Jorge Barroso-Aranda, Mark F Mccarty
Open Heart, doi:10.1136/openhrt-2021-001655
somewhat analogous anti-inflammatory protection in COVID-19, as has previously been suggested. 26 27 However, in light of accumulating evidence that ivermectin may have important utility for the primary prevention of COVID-19, it is likely that it also exerts an antiviral effect with respect to SARS-CoV-2, as suggested by in vitro studies. 3 28 It is not clear whether glycine receptor agonism might have anything to do with this effect.
References
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Didier, Loor, Decreased biotolerability for ivermectin and cyclosporin A in mice exposed to potent P-glycoprotein inhibitors, Int J Cancer, doi:10.1002/ijc.2910630220
Ding, Svingen, Pedersen, Plasma glycine and risk of acute myocardial infarction in patients with suspected stable angina pectoris, J Am Heart Assoc, doi:10.1161/JAHA.115.002621
Dinicolantonio, Barroso, Mccarty, Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19, Open Heart, doi:10.1136/openhrt-2020-001350
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Li, Bradford, Wheeler, Dietary glycine prevents peptidoglycan polysaccharide-induced reactive arthritis in the rat: role for glycine-gated chloride channel, Infect Immun, doi:10.1128/IAI.69.9.5883-5891.2001
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Mealey, Bentjen, Gay, Ivermectin sensitivity in collies is associated with a deletion mutation of the MDR1 gene, Pharmacogenetics, doi:10.1097/00008571-200111000-00012
Rodrigues, De Sá, Ishimoto, Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients, J Exp Med, doi:10.1084/jem.20201707
Schmith, Zhou, Lohmer, The Approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19, Clin Pharmacol Ther, doi:10.1002/cpt.1889
Shan, Haddrill, Lynch, Ivermectin, Ivermectin, an unconventional agonist of the glycine receptor chloride channel, J Biol Chem, doi:10.1074/jbc.M011264200
Viktorov, Ivermectin inhibits activation of Kupffer cells induced by lipopolysaccharide toxin
Wang, Lynch, A comparison of glycine-and ivermectinmediated conformational changes in the glycine receptor ligandbinding domain, Int J Biochem Cell Biol, doi:10.1016/j.biocel.2011.11.005
Wheeler, Ikejema, Enomoto, Glycine: a new antiinflammatory immunonutrient, Cell Mol Life Sci, doi:10.1007/s000180050030
Wheeler, Rose, Yamashima, Dietary glycine blunts lung inflammatory cell influx following acute endotoxin, Am J Physiol Lung Cell Mol Physiol, doi:10.1152/ajplung.2000.279.2.L390
Wheeler, Stachlewitz, Yamashina, Glycine-gated chloride channels in neutrophils attenuate calcium influx and superoxide production, Faseb J, doi:10.1096/fasebj.14.3.476
Wheeler, Thurman, Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine, Am J Physiol, doi:10.1152/ajplung.1999.277.5.L952
Yamashina, Konno, Wheeler, Endothelial cells contain a glycine-gated chloride channel, Nutr Cancer, doi:10.1207/S15327914NC402_17
Zhang, Ma, Jiang, Glycine attenuates lipopolysaccharideinduced acute lung injury by regulating NLRP3 inflammasome and NRF2 signaling, Nutrients, doi:10.3390/nu12030611
Zhang, Song, Ci, Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflamm Res, doi:10.1007/s00011-008-8007-8
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