Abstract: Editorial Ivermectin may be a clinically useful anti-­inflammatory agent for late-­stage COVID-19 James J DiNicolantonio ‍ ‍,1 Jorge Barroso-­Arranda,2 Mark McCarty3 To cite: DiNicolantonio JJ, Barroso-­Arranda J, McCarty M. Ivermectin may be a clinically useful anti-­inflammatory agent for late-­stage COVID-19. Open Heart 2020;7:e001350. doi:10.1136/ openhrt-2020-001350 Accepted 25 August 2020 © Author(s) (or their employer(s)) 2020. Re-­use permitted under CC BY-­NC. No commercial re-­use. See rights and permissions. Published by BMJ. 1 Department of Preventive Cardiology, Mid America Heart Insitute, Kansas, Missouri, USA 2 Clinica Libre de Adicciones, Tijuana, Baja California, Mexico 3 Catalytic Longevity Foundation, San Diego, California, USA Correspondence to Dr James J DiNicolantonio; ​ jjdinicol@​gmail.​com Ivermectin, on the WHO’s List of Essential Medications, has been in clinical use since 1981 as an orally and topically active agent for treating a range of parasitic infections in humans, including river blindness and lymphatic filariasis. It is also widely used in veterinary practice. Anecdotally, the use of the standard clinical dose of ivermectin, 9 mg once, has been associated with some cases of rapid clinical resolution in severe hospitalised COVID-19; clinical studies evaluating its utility in this regard are underway. Ivermectin is reported to inhibit the proliferation of SARS-­CoV-2 in vitro, but the IC50 for this effect, 2 µM, has been noted to be 35-­fold higher than the maximal concentration achieved after the administration of the approved clinical dose (9 mg) to humans, casting doubt on the utility of this agent as an antiviral drug in COVID-19 unless very markedly higher doses are used.1 2 However, drugs blocking viral replication would be expected to be of lesser utility in the context of the late, cytokine storm-­associated phase of COVID-19 and anecdotes of ivermectin’s success in this disorder pertain to that phase. Hence, consideration should be given to the possibility that ivermectin is acting as an anti-­inflammatory in these cases. This prompted us to search the research literature on ivermectin for anti-­ inflammatory actions. In 2008, Zhang et al studied the impact of ivermectin in mice challenged with intraperitoneal lipopolysaccharide (LPS). They chose a dose of LPS that induced 100% mortality within 5 days. They then demonstrated that oral ivermectin, administering 2 hours prior to LPS, dose dependently reduced mortality in the LPS-­ treated mice, with a significant 50% reduction in mortality being achieved at a 4 mg/kg dose.3 In vitro studies likewise confirmed the ability of this agent to block cytokine production by LPS-­ challenged macrophages.3 4 When we extrapolate this dose from 20 g mice to 70 kg humans, using the two-­thirds power of relative body mass (ratio of body surface areas) as a correction factor, 4 mg/ kg in mice corresponds to about 18 mg in humans—double the standard clinical dose. Allometric scaling by the three-­fourths power (Kleiber’s law) yields a dose of 36 mg.5 A study of related interest, published a year later, examined the impact of ivermectin—a group of 16-­ membered macrocyclic lactone derivatives of which ivermectin is a member—on LPS signalling in the RAW 264.7 murine macrophage-­derived cell line. In concentrations ranging from 0.625 to 5 mg/L, ivermectin suppressed activation both of NF-­kappaB and the stress-­activated MAP kinases JNK and p38.6 Moreover,..