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Analgesics Use and the Coronavirus: Finding Answers Through Biological Knowledge Graph

Posted on March 31st, 2020 by in COVID-19

a. 121 ARDS-induced proteins whose activity and/or abundance are upregulated by ARDS

A Chinese physician who was battling the outbreak of coronavirus recently approached one of our colleagues1. This physician had a very simple question: What would be the best standard pain relief (i.e. an analgesic) to use on sick patients with severe acute respiratory distress syndrome (ARDS)? To address this question, we aimed to identify the effects of various non-steroidal anti-inflammatory (NSAID) drugs on proteins that are upregulated by ARDS.

This kind of information can be systematically and automatically extracted and analyzed using the Elsevier text mining tool Medscan, then added to a continuously expanding knowledge graph of biologically relevant scientific information, currently accessible by using our Pathway Studio tool.

Our first objective was to identify proteins whose activity and/or abundance are upregulated by ARDS. We initially identified a total of 121 ARDS-induced proteins (a), which were narrowed down to the top 22 important candidates (b) based on the underlying number of references as supporting evidence. Each of these references could be examined down to the individual sentence level (c).

[Click images below to open in new window and look more closely]

b.

c.

Next, we aimed to determine the relationship of our target drugs (i.e. activator or inhibitor) on our top ARDS-related protein candidates. The drugs we chose to look at included aspirin, ibuprofen (Advil, Motrin), acetaminophen (paracetamol, Tylenol) and naproxen (Aleve, Naproxen).

Aspirin was found to regulate 17/22 of the top candidate proteins, and, not surprisingly, it was identified as a net inhibitor of these proteins [(d), activated proteins highlighted in green to the left, inhibited proteins highlighted in yellow in the center, and proteins with no relevant information are to the right)].

d.

Interestingly, while fewer candidates (9/21) were related to Ibuprofen (e), the pattern of net inhibition was maintained for drug interaction with ARDS-related proteins (7/9 inhibited proteins).

e.

Similar to Ibuprofen, Naproxen was identified to react with only 9/21 candidate proteins; however, it showed an even mix with no net overall effect (4/9 inhibited proteins) on top ARDS-related proteins.

Of main importance, acetaminophen analysis showed that this class of analgesics, which interacts with 13/21 of our top ARDS-related protein candidates, was identified as a net activator (11/13) of these proteins. Alarmingly, this suggests that paracetamol and Tylenol may not be helpful for treating advanced cases of severe ARDS triggered by pathogens such as the coronavirus. This could be related to the fact that acetaminophen in large doses can cause acute liver injury2. In fact, major proinflammatory proteins associated with hepatotoxicity (CCL2, TNF, IL1B, MPO, IL6) are also elevated in ARDS. This suggests that caution should be taken when administering large doses of acetaminophen (e.g. Tylenol) to patients already at risk of respiratory failure, which could increase the possibility of a synergistic negative reaction.

Finally, while applying this kind of analysis to real-world cases should be considered with caution, we should not ignore such alarming results. Therefore, awareness should be raised on this issue, which can, along with proper physicians’ recommendations, prevent lethal effects on patients with severe ARDS triggered by pathogens. As they say, an ounce of prevention is worth a pound of cure! Just another example of how Elsevier is working to bring the highest quality data in the most effective manner to where it belongs — to patients, doctors, researchers and to you.

Next time we‘ll do a similar type of analysis looking at the effects of an exciting new potential therapeutic treatment for coronavirus, the anti-malarial drug hydroxychloroquine3.

References:

  1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513.
  2. Yan M, Huo Y, Yin S, Hu H. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol. 2018 Jul;17:274-283.
  3. Guo, D. Old Weapon for New Enemy: Drug Repurposing for Treatment of Newly Emerging Viral Diseases. Virol. Sin. (2020). https://doi.org/10.1007/s12250-020-00204-7

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