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Covid-19: what treatments are being investigated?

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1252 (Published 26 March 2020) Cite this as: BMJ 2020;368:m1252

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Rapid Response:

Digitalis for coronavirus infection!

Dear Editor

Coronavirus infection and its disease COVID-19 has become a global plague and no effective
treatments are available, just supportive care. Some patients have mild flu symptoms of infection
whereas others develop respiratory distress syndrome with high mortality.

Several of the RNA viruses, such as influenza and coronavirus, hit the lungs and use the same
molecular mechanisms to cause morbidity and mortality. In younger persons with strong immune
systems the avian flu influenza virus H5N1 can induce respiratory distress syndrome by triggering a
«cytokine storm» of pro-inflammatory cytokines as a reaction to the virus, which might be fatal.

Multi organ failure with increased TNF-a may follow and then patient is in a very critical condition. (1)

The cardiac glycoside digitoxin potently inhibits the transcription factor NF-kB and by that abolish
the production of the pro-inflammatory cytokines and these cytokines are a prerequisite for the
viruses to infect the lung epithelial cells. Thus, it has been shown that viruses that target lung
epithelial cells are severely impaired by cardiac glycosides. (1,2,3,5)

William Withering, more than 200 years ago, showed that patients with cardiac congestion benefited
from treatment with Foxglove extracts containing Digitalis, i.e. cardiac glycosides. More than 60
years ago Skou described the Na,K-ATPase and one learnt that Digitalis and other cardiac glycosides
have a positive inotropic effect on the heart by inhibiting this ion pump. For a long time the
physiological effects of cardiac glycosides were explained by just the inhibition of this ion pump and
the subsequent ion changes. For us it became evident that other mechanisms as well must be
involved when we showed that digitoxin could induce apoptosis in an array of cancer cells in
concentrations that did not affect normal cells. (4)

Lately we have learnt that Na,K-ATPase is a key protein, works as a receptor, that is able to interact
with an array of signalling proteins that can trigger complex signalling cascades that are pivotal for
the life and death of the cell and relevant both for cancer and inflammation.

In fact, laboratory data show potent anti-viral effects of cardiac glycosides in clinically relevant
concentrations by hindering entry of the virus into the lung epithelial cells as well as direct inhibitory
effects on the virus replication. (3,5)

Digitalis, in the form of digitoxin and digoxin, are among the oldest drugs used still today. The safety
profiles are well known. Cardiac glycosides, such as digitoxin, urgently should be tested
against coronavirus infection.

References:

1. Haux J. Digitalis for Bird flu? Can Med Assoc J 2006 DOI:
https://doi.org/10.1503/cmaj.051372

2. Yang Q, Huang W, Jozwik C et al. Cardiac glycosides inhibit TNF-alpha/NF-kappaB signaling
by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc
Natl Acad Sci U S A 2005; 102:9631-6.

3. Nimmerjahn F, Dudziak D, Dirmeier U et al. Active NF- kappaB signalling is a prerequisite
for influenza virus infection. J Gen Virol 2004; 85:2347-56.

4. Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med
Hypotheses 1999; 53:543-8.

5. Amarelle L, Lecuona E. The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview. Int J
Mol Sci 2018; 24:19.

Competing interests: No competing interests

30 March 2020
Johan Haux
Consultant oncologist
Skaraborgs sjukhus and Skövde University. Sweden
Skaraborgs sjukhus and Skövde University. Sweden