Tuesday, January 28, 2020

Treating Wuhan Coronavirus with re-purposed medicines

Image/Dr. Fred Murphy & Sylvia Whitfield/CDC

If Wuhan Coronavirus escapes control and becomes endemic, hospitals throughout the world will have their work cut out to cope with treating large numbers of patients. We do not know yet whether antiviral medications will be effective, and specific treatments are probably going to be very expensive. Vaccination will be enormously helpful, but it will take months before it is widely available.

Given that we are probably facing a global medical emergency, doctors  need to try all approaches that offer benefit. We should not be bound by convention. One promising pathway of treatment is to use re-purposed established medicines to treat the "cytokine storm" that causes some patients to become very ill.

Cytokine storm (better termed Cytokine Release Syndrome) is an exaggerated reaction on the part of the cellular immune system. A positive feedback loop forms between cytokines released at the site of infection, which attract more defence cells, which produce more cytokines.

It is this vicious circle that causes Wuhan Coronavirus infection to have such high mortality - currently about 2.5% of cases [source].

Several medicines which are currently licensed for other purposes may be able to moderate and reduce the cytokine release syndrome.

1. Simvastatin and Gemfibrozil, both lipid-lowering drugs in common use, have been shown to have an effect in reducing the cytokine response. In the case of Simvastatin, an effect has been shown in humans, albeit not in acute infection. Simvastatin also has an effect on the replication of some viruses. It decreases OX40 which is a protein secreted by T-cells that keeps them from dying, and therefore perpetuates the feedback loop [i]. Terblanche has reviewed the properties of simvastatin [ii]. Fedson provides a 2013 review of statins and other agents in influenza which is also encouraging.

2. ACE Inhibitors and Angiotensin II receptor blockers are medications in common use against hypertension. The Renin-angiotensin system is involved in the cytokine storm[iii]. ACE is involved in pulmonary inflammation[iv],[v]. They have been shown to reduce the cytokine feedback loop[vi]. A possible connection between the virus and the ACE2 protein has been identified [source].
Mortensen (2012) found improved outcomes in patients age 65 years or over with influenza associated pneumonia who used statins, and lesser imporvements with ACE blockers.

3. TNF Blockers are medications routinely used in arthritis and other inflammatory conditions, and work by inhibiting Tumour Necrosis Factor (TNF) which is implicated in cytokine storm. They may possibly have a role to play in cytokine release syndrome, but they are relatively costly compared to 1 and 2 above.

4. Naltrexone, an established opioid receptor antagonist, may inhibit cytokine storm. There is evidence from animal studies[vii],[viii],[ix],[x] that shows it may be clinically effective. It is inexpensive.

5. Antioxidants such as Ascorbic acid may have a role to play in reducing the adverse effects of cytokine storm.

Note that the above five groups of medicines are already in use, and therefore have been tested for human acceptability. They are relatively inexpensive. Their side effects are known. It is true that we do not know what happens when they are used in patients infected with the the Wuhan Coronavirus, but the only way to find out in good time is to test them.

They may have adverse effects in the given situation, they may have no benefit, but equally, one or more of them, alone or in combination, may prove helpful, and the experiment will be worthwhile – even, possibly, game-changing.

In conclusion, there are several modalities of treatment for Wuhan Coronavirus that must be tried in the present outbreak. Their deployment will be “off-licence” and their effectiveness must be monitored, but to test their effectiveness in the situation that we are currently in would be ethical and rational.

[i] Liu B, Yu G, Yang Z, Sun L, Song R, Liu F, et al. Simvastatin Reduces OX40 and OX40 Ligand Expression in Human Peripheral Blood Mononuclear Cells and in Patients with Atherosclerotic Cerebral Infarction. The Journal of International Medical Research. 2009;37:601-10.
[ii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751082/
[iii] Genctoy, G; B Altun et al. (February 2005). "TNF alpha-308 genotype and renin-angiotensin system in hemodialysis patients: an effect on inflammatory cytokine levels?". Artif Organs 29 (2): 174–178.
[iv] Marshall, RP; P Gohlke et al. (January 2004). "Angiotensin II and the fibroproliferative response to acute lung injury". Am J Physiol Lung Cell Mol Physiol (Royal Free and University College London Medical School) 286 (1): 156–164. PMID 12754187.
[v] Moldobaeva, A; EM Wagner (December 2003). "Angiotensin-converting enzyme activity in ovine bronchial vasculature". J Appl Physiol (Department of Medicine, Johns Hopkins University) 95 (6): 2278–2284.
[vi] Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int. 2002;62(S82):S12-S22.
[vii] Peng X, Mosser DM, Adler M, et al. Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages, Journal of Leukocyte Biology. 2000;68:723-728.
[viii] Hola N V, Zaji Cova A, Krulova M, Blahoutova V, Wilczek H. Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clinical & Experimental Immunology 2003;132:40-45.
[ix] Lin S L, Lee Y M, Chang H Y, Cheng Y W and Yen M H. Effects of naltrexone on lipopolysaccharide-induced sepsis in rats. J Biomed Sci. 2005;12:431-40. 
[x] Greeneltch KM, Haudenschild CC, Keegan AD, Shi Y. The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production. Brain Behav Immun. 2004;18:476-84.

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