IL-6 Inhibitors for treatment of severe Covid19
Hyper-inflammation and blood clotting are classic complications as Covid19 progresses in hospitalized patients. Strategies to reduce this include blood thinners, steroids, JAK-STAT inhibitor Baricitnib and IL-6 inhibitor Tocilizumab among others.
A recently published clinical trial from UK demonstrated reduced mortality in severe Covid19 in patients given Interleukin-6 inhibiting monoclonal antibody Tocilizumab.
353 patients were assigned to Tocilizumab group and 402 to control / placebo in this prospective Randomized Controlled Trial. Mortality in Tocilizumab group was 28 % ( 98 / 353 ) while mortality in placebo group was 35.2% ( 142 / 402 ). This was a statistically significant finding which brings 'Toci' back in the limelight in hospital management of severe Covid19.
https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1
Covid-19 Treatment by JAK-STAT Inhibition
Olumiant / Baricitinib is a Janus Kinase (JAK 1&2 ) inhibiting monoclonal antibody
JAK-STAT ( Janus Kinase - Signal Transducer and Activator of Transcription) is a signalling pathway through which cytokines such as IL-6 , IL-2, IL-8, TNF etc are mediated. Inhibiting this this can result in a dampening of inflammation more pronounced than inhibitors of individual cytokines such as IL6 inhibition with Tocilizumab.
Last month Baricitinib received an Emergency Use Authorization for use in severe Covid19
https://www.fda.gov/media/143822/download
Baricitinib is FDA approved drug for third line treatment of Rheumatoid Arthritis.
The EUA was based upon results of ACTT-2 trial in which patients received Remdesivir alone or Remdesivir with Baricitnim. For that reason the EUA has been limited for this to be used alongside Remdesivir in USA.
https://clinicaltrials.gov/ct2/show/NCT04401579?term=actt&draw=2&rank=3
Currently
ACTT-3 trial is testing Interferon Beta and ACTT-4 trial is a larger
trial testing Baricitnib with Remdesivir and Dexamethasone.
Dosage is 4 mg tablet once a day for two weeks or until hospital discharge
Risks include blood clotting and infections. It is anticipated that patients started on this drug will already be on steroids, antivirals, antibiotics and anticoagulants
Transient liver enzyme rise can be seen and ESRD / dialysis is a contra-indication.
Another Janus Kinase 1 & 2 inhibitor is being investigated for Covid19 in Germany
https://clinicaltrials.gov/ct2/show/NCT04338958
JAK-STAT signalling pathways is also a target for anti cancer therapies to reduce chronic inflammation within the body.
Diet and lifestyle can also be pro-inflammatory or anti-inflammatory. Presence of chronic inflammation within the body has been identified as a significant risk factor for adverse Covid19 outcomes, metabolic diseases, adverse cardiovascular outcomes and cancer. Actions which one can take to reduce chronic inflammation within body include
-Maintain an ideal weight
-Be active and exercise
-Sleep well, treat any undelying Obstructive Sleep Apnoea
-Reduce stress
-Minimize
pro-inflammatory foods such as processed long storage items, processed
sugars, particularly those containing high fructose corn syrup,
saturated trans-fats such as deep fried foods and foods containing trans
fats. Choose fibre rich carbohydrates such as natural fruit and brown
bread over processed and refined carbohydrates.
-Maximize fresh fruits, fresh vegetables, Omega-3 containing oily fish ( not fried ), use of high Monounsaturated fat containing cooking oil such as Olive, Safflower and Avocado oil, use of Avocado based oils / spreads, nuts such as walnuts and specific anti-inflammatory foods, herbs and spices discussed below.
Dietary supplements and food substances with reduce inflammation via JAK-STAT Pathway
The following scientific paper discusses naturally occurring dietary Phytocompounds which reduce Cancer and tumor growth by inhibition of JAK/STAT signalling pathway.
https://www.mdpi.com/2073-4409/9/6/1451/htm
Curcumin blocks STAT3 phosphorylation, thereby blocking STAT3 dimer translocation from cytoplasm into the nucleus of human multiple myeloma cells
Resveratrol (present in peanuts, berries, and grapes) obstructed JAK phosphorylation and, as a result, blocked STAT1 phosphorylation in human epidermoid carcinoma
In human multiple myeloma (U266) cells, bergamottin (found in grape juice, lime, lemon, and bergamot oils) has been found to suppress a constitutive activation of STAT3
Chalcone, a α,β-unsaturated flavonoid ( found in oranges, strawberries, tomatoes, bean sprouts and spices such as licorice) restrained the phosphorylation of STAT3 in LPS- and IL-6-regulated endothelial cells
The anticancer impact of formononetin ( found in beans, carrot, cauliflower, iceberg lettuce, green peas, and red potatoes ) was found to be mediated by the
impairment of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)
and STAT3 signaling pathways
In vitro studies demonstrate that cardamonin ( Ilaichi ) has the ability to be a new anticancer agent for glioblastoma by virtue of its ability to act as a STAT3 inhibitor
Caffeic acid ( found in wine, tea and coffee ) blocked STAT3 phosphorylation by suppressing Src tyrosine kinase, which inhibited the proliferation and caused the downregulation of VEGF in the human renal carcinoma cells
By suppressing Src and JAK2 phosphorylation, ursolic acid ( found in apples, prunes, bilberries, cranberries, basil, lavender, rosemary, peppermint, thyme, elder flower, oregano, and hawthorn) prevented the activation of STAT3 in prostate carcinoma cells.
Thymoquinone is the active component of black cumin (Nigella sativa L./ Kalongi ) seed oil, and preclinical studies have established its cancer prevention effects. Thymoquinone caused downregulation of STAT3 activation in addition to a decrease in activity of JAK2 and c-Src in human gastric cancer cells.
A study demonstrated that the anticancer effect of β-caryophyllene oxide, present in numerous essential oils including clover, guava, oregano and rosemary oil was mediated through interfering with the activation of STAT3 in
carcinoma cells, such as multiple myeloma cells (U266) and human
prostate cancer cells (DU145)
Capsaicin ( chilli peppers ) hindered IL6-induced STAT3 activation and impaired the advancement of multiple myeloma xenograft tumors in male thymic mice by suppressing STAT3 activation by inactivating JAK1 and c-Srcin in various preclinical cancer models
Diosgenin is a steroidal sapogenin that occurs in nature. It is a bioactive component present in fenugreek (Trigonella foenum-graecum L. / Methi ) seeds. Diosgenin suppressed the phosphorylation of c-Src, JAK1, and JAK2 in HCC cell lines. This phytochemical increased the expression of SH-PTP2, and consequently inhibited STAT3 activation triggered by IL-6.
Lignans are present in an assortment of natural products, including pumpkin seeds, flax seeds, sesame seeds, broccoli, soybean, and various berries. These suppress the development of malignant tumors, specifically hormone-sensitive ones, such as neoplasms of the prostate, breast, and endometrium
Quercetin ( onions, apples, strawberries, Kalongi ) and EGCG ( Green tea ) are dietary phytochemicals with antiinflammatory and antitumor effects. In Cholangiocarcinoma cells JAK/STAT pathway activation by proinflammatory cytokine interleukin-6 and interferon-γ in CCA cells was suppressed by pretreatment with quercetin and EGCG.
https://pubmed.ncbi.nlm.nih.gov/24038588/
In
summary, chronic inflammation within our body has several negative
impacts including increased risk of severe Covid19 in the short term and
increase cancer risk in the long term. In addition to a healthy active
lifestyle, reducing stress, sleeping well, maintaining ideal weight and
exercising, we can also make positive dietary choices which reduce
chronic inflammation within our body.
Naturally occuring dietary anti-inflammatories which inhibit IL6 and JAK-STAT :
Curcumin / Turmeric inhibits IL6
https://pubmed.ncbi.nlm.nih.gov/14500688/
Quercetin found naturally in apples, onions and berries inhibits IL6
https://pubmed.ncbi.nlm.nih.gov/16426496/
Thymoquinone from Kalongi seed oil / Nigella Sativa inhibits STAT3 phosphorylation
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1476-5381.2010.00874.x
Allium Sativum present in Garlic has anti inflammatory and anti oxidant properties
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417560/#B16
Ginger extracts reduce inflammation including inhibition of IL6
https://pubmed.ncbi.nlm.nih.gov/28369951/
Cardomonim / Elaichi inhibits STAT-3 pathway
https://link.springer.com/article/10.1007%2Fs13277-015-3673-y
Diasgonin found in Fenugreek / Methi inhibits JAK1, JAK2 and STAT3
https://www.sciencedirect.com/science/article/abs/pii/S030438350900696X
Beta Caryophyllene present in Clover / Laung and Oregano Oil / Ajvain reduces inflammation through pathways including STAT3
https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.816
Brassinnin present in cruciferous vegetables such as Cauliflower, Broccoli and Cabbage inhibits STAT3.
Beta Escin found in horse chestnut / chota akhrot inhibits IL6 and STAT3
https://jpet.aspetjournals.org/content/334/1/285.short
EGCG ( Green Tea ) inhibits IL6
https://www.pnas.org/content/105/38/14692
Asafoetida / Heeng inhibits JAK / STAT pathway
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/asafoetida
Cumin Seeds / Jeera have anti-oxidant effects
https://pubmed.ncbi.nlm.nih.gov/23034115/
Youtube Videos on this topic:
Food Allergies & Inflammation-3 mins
Anti-Inflammatory Diet-Livestream with dietician
Anti-Inflammatory Diet-Livestream with dietician 2
I obtained my primary medical education from India and post graduate MD in Family Medicine from the United Kingdom. After working in National Health Service, England for 15 years, I moved to Canada five years ago. As a Family Physician, I consider my speciality as engaging patients, interpreting medical information for them, guiding them through their health journey, promoting wise health choices and encouraging early detection and management of disease.
The information on this blog is accurate as per time of publishing. Scientific information and evidence changes dynamically and my opinions would change accordingly.
Patient confidentiality must be upheld at all times and any patients wishing to discuss specific medical scenarios on social media are requested to do so anonymously in 'third party' sense.
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