Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19
DiNicolantonio et al.,
Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19,
Open Heart, doi:10.1136/openhrt-2020-001350 (Review)
Review suggesting that ivermectin may be useful for late stage COVID-19. Authors note that ivermectin, in doses at or modestly above the standard clinical dose, may have important clinical potential for managing disorders associated with life-threatening respiratory distress and cytokine storm, such as advanced COVID-19.
DiNicolantonio et al., 6 Sep 2020, peer-reviewed, 3 authors.
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,..
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