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
Baudou, Lespine, Durrieu, Serious Ivermectin Toxicity and Human ABCB1 Nonsense Mutations, N Engl J Med,
doi:10.1056/NEJMc1917344
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
Dinicolantonio, Mccarty, Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase, Open Heart,
doi:10.1136/openhrt-2020-001337
Froh, Thurman, Wheeler, Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes, Am J Physiol Gastrointest Liver Physiol,
doi:10.1152/ajpgi.00503.2001
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
Lynagh, Webb, Dixon, Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel, J Biol Chem,
doi:10.1074/jbc.M111.262634
Mccarty, Iloki-Assanga, Lujan, Activated glycine receptors may decrease endosomal NADPH oxidase activity by opposing ClC-3-mediated efflux of chloride from endosomes, Med Hypotheses,
doi:10.1016/j.mehy.2019.01.012
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, 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
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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