Artemisinin, arteannuin-B, sgp130Fc and COVID-19
I'm more of a blogger, or early Christmas present giver, than may be ideal for a book author. I've been working on a section of my new book that might be beneficial for SARS-CoV-2 prevention and COVID-19 treatment. It may also help explain what makes some people more susceptible for developing severe COVID-19 illness rather than remaining asymptomatic as others who test positive for the SARS-CoV-2 virus.
The book is in very early stages but is on a platform where you can get an e-copy early (minimum price Free, Leanpub/Tipping The Clock Toward Health) and then be informed of updates with an email subscription. I'm copying the artemisinin section here in case it may be helpful. The theme of the book is not CoV specific so the excerpt is also including it within a larger topic.
The too long;didn't read - a different extract of wormwood, arteannuin-B, may be a more effective anti-viral and anti-inflammatory, than the artemisinin; while the artemisinin may help with a chronic anemia of inflammation type iron overload problem, which may occur with COVID-19 recovery or when the illness is severe. Artemisinin has also been found useful for autoimmune disease and possibly as a cancer treatment. The bigger CoV specific information is a theory about interleuken-6 (IL-6) and a genetic difference that may explain why some people can be asymptomatic carriers of the virus - their immune system doesn't overreact to IL-6 - and for those more at risk for over-reacting a protein our body normally makes (sgp130Fc) may be an effective treatment because it would just be needed in the overactive amount (five times the normal level).
Merry Christmas - I never could save a present I bought early.
Autoimmune Disease and other Chronic conditions
What if you are feeling so sick that nothing seems cheerful? There are no guarantees that eating healthier will be a cure-all, however you don’t know without trying and some symptom relief might be possible at least. Giving time a chance to help may also help. It can take seven days for the intestinal lining to start to heal and longer for most other areas of the body. Take care of your brain because most types of brain cells do not get replaced regularly the way that cells throughout the rest of the body are retired and replaced with new cells. The advantage in the foods and phytonutrients that tip the body away from inflammatory pathways and towards the production of antioxidants and increased immune function is modulation - moderation.
Immunomodulators and other types of modulating chemicals can shift the activity slightly towards more active or less active. An overactive immune system can also be dangerous. Modulation can be moderate - just the right amount of activity. The healing foods and phytonutrients may help moderately increase immune activity without over activating it into an autoimmune level of action. And they may moderately inhibit the inflammatory pathways without suppressing them totally as may occur with immunosuppressive drugs. During an infection we need the inflammatory pathways but we do not need an overactive response.
Too many inflammatory chemicals can lead to their attacking our healthy body cells in an immune response called a Cytokine Storm or Sepsis Shock. An autoimmune over-reaction may involve molecular mimicry where a food protein or other substance that is similar to our own body’s chemicals sets off an allergic type of immune response against the body chemical, not just the dietary protein.
Wormwood, Artemisia annua, an anti-malarial herb used in Traditional Chinese Medicine, and source of Artemisinin and arteannuin-B .
Wormwood is a medicinal herb used in Traditional Chinese Medicine (TCM). An extract of it is used to treat malaria. Artemisinin, the extract, has also been found to help modulate the immune system, which may be helpful for the treatment of autoimmune disease. Derivatives of artemisinin have also been studied for use as antiviral and anticancer treatments. (52⁸⁷) White blood cells can help identify, kill, and remove infected, damaged, or cancerous cells in a process called autophagy however the response can also become overactive in the case of autoimmune disease or a cytokine storm.
Immunomodulating herbs and drugs can help stimulate an immune response while also inhibiting too large of a response. Artemisinin was found to be helpful for rheumatoid arthritis, which has been shown to be due to a pathogen with an intracellular form, (53⁸⁸), and not helpful for osteoarthritis which is due to overuse or other physical trauma. (54⁸⁹) Artemisinin is a phytonutrient extract of the herb wormwood. It is used as a malaria treatment and in Africa ten grams of the dried herb may be used daily as a prevention against malaria, a mosquito borne parasitic disease affecting blood cells. (55⁹⁰)
The whole herb, wormwood (Artemisia annua), may contain other phytonutrients with stronger anti-viral effects than artemisinin, as whole herb extracts were found more effective against the SARS-CoV-2 virus than artemisinin alone (cell-based study). The World Health Organization (W.H.O.) expressed concern that use of a whole herb extract for non malarial illness in the population might result in an increase in artemisinin-resistant malaria strains. (56⁹¹) That concern may be overlooking the synergistic - additive - effect phytonutrients within a plant may have.
Many plants have phytonutrients that work together beneficially, helping health in different ways that have an additive effect: one may help offset a negative effect of another, or one may help one symptom and another might help a different symptom. Ginger root, for example, has over 400 bioactive phytonutrients.
Artemisinin chemically is a sesquiterpene lactone - an aromatic terpene. Two strains of Artemisia annua were chemically analyzed and found to have slightly different ratios and types of sesquiterpenes and terpenes, (57⁹²) so other aromatic chemicals in the whole herb may also be helping health in various ways. One in particular, arteannuin-B, has been found to work with artemisinin against the malaria parasite in a combination that was more effective than if the artemisinin was used alone. (58⁹³) Switching to a whole herb extract or using the combination of arteannuin-B and artemisinin might reduce the risk of the malaria parasite becoming artemisinin resistant instead of increasing the risk about which the W.H.O. expressed concern. (56⁹⁴)
Bioactive - chemicals with some biological effect within our bodies, it might be beneficial or harmful for a particular person depending on the person’s underlying level of health or genetic differences, or gender, age or other factors.
Artemisinin chemically is attracted to cells with excess iron which infectious microbes need for growth and so do cancer cells. The phytonutrient can stop protein replication within the iron rich cell which stops the replication of the infectious microbe. It also seems to bind with the excess iron which in itself can cause oxidative damage - rust might be a more familiar term for oxidative damage affecting iron. If Rheumatoid arthritis is due to an intracellular pathogen then artemisinin may be helping by stopping the underlying infection. It can help in cancer because cancer cells also tend to have extra iron and it may be helpful for the anemia of chronic inflammation which also involves excess iron in cell storage instead of being used to carry oxygen within red blood cells and may be involved in symptoms of extreme tiredness during later stages or recovery from an infection.
The amazing thing about artemisinin in comparison to other antimalarial medications is a low toxicity risk comparatively. Healthy cells are not targeted. Normal function does not seem to be disrupted although it may have pro-inflammatory effects. Arteannuin-B, on the other hand, has been found to have significant anti-inflammatory effects:
“Arteannuin-B inhibits the LPS-activated production of PGE2 four times more than artemisinin or dihydroartemisin, and it has a strong inhibitory effect on the proinflammatory interleukines IL-1β, IL-6, TNF-α.”. (Lutgen 2013, 58⁹⁵)
Reducing interleukin-6 levels would likely be helpful for treating COVID-19 illness. It is increased by the SARS-CoV-2 virus and by the infection process naturally. It can help fight infection and has pro and anti-inflammatory types. A protein (sgp130Fc) helps control the pro-inflammatory type but it is normally present in amounts lower than would be needed during later stages of COVID-19 illness (the name of the disease caused by an infection with the SARS-CoV-2 coronavirus, a new virus in the group of cold and influenza viruses). Providing sgp130Fc as a treatment may help treat the people with the more severe inflammatory reaction. There seems to be a genetic susceptibility regarding the over sensitivity to IL-6 levels which may help explain why some people don’t get very sick and others get severely ill with a SARS-CoV-2 infection. (59⁹⁶)
“Recent studies about polymorphism within the IL-6R genes, showed how some IL-6 Receptor variants could be a much better substrate for the shedding protease ADAM17, resulting in a reduced response to inflammation and infectious states, in terms of sIL-6R increase . Those individuals are also protected from many chronic inflammatory diseases .” (59⁹⁷)
This theory, if true, could help point out who is more at risk for a severe immune reaction to a SARS-CoV-2 infection - people with chronic inflammatory diseases - it suggests they have the more active immune response by their IL-6 Receptor. Knowing who is more at risk can help identify who needs to be more self-protective and who may benefit from preventive treatment or early treatment for suspected symptoms. And they may be the people who might be helped by providing the protein sgp130Fc that inhibits the pro- inflammatory IL-6 Receptor. There is enough of the inhibiting protein to block the receptor activity during normal health but the level of IL-6 can increase five-fold during an infection - while no extra sgp130Fc is made. The excess IL-6 starts inflammatory activity in surrounding cells creating an increasing inflammatory response. (59⁹⁸)
Panic? Or use the information about our genetic immune responses and infection risks to be more proactive about our own health? or our communities' health?
We can defend from within by providing our bodies with the extra nutrients that our unique genetic metabolism or infection or disease may require for our cells to cope. Vitamin C and other antioxidants and phytonutrients can also help reduce IL-6 and other inflammatory chemicals.
~~~~ end of book excerpt as it was written
addition: The protein sgp130Fc has also been found helpful to treat an animal model of Rheumatoid arthritis. The treatment used was 2.5 mg/kg which was given intravenously to the animals daily three weeks after the induction of the disease condition. Thy hypothesis that the treatment would also improve vascular health in the animals was not disproved. (60) Vascular health is commonly negatively effected in Rheumatoid arthritis along with the symptoms of swollen and painful joints, typically starting in the fingers and toes and progressing to the feet and ankles.
The protein sgp130Fc may also be helpful for treating ulcerative colitis and Irritable Bowel Syndrome. It is tested in human clinical trials for the two bowel conditions by Ferring Pharmaceuticals and I-MAB Biopharma. The version of the protein being produced and tested by the pharmaceutical companies is being called Olamkicept. (61)
The protein may also affect the risk of Alzheimer's dementia or other inflammatory brain conditions. The protein does not cross the blood brain barrier but affects throughout the rest of the body may still affect the brain by causing an increase of soluble interleuken-6 Receptors which then can increase brain inflammation. The spg130Fc would need to be delivered into the brain somehow to inhibit the soluble IL-6 R and reduce inflammation. (61)
Maybe it would help reduce the amount of the soluble IL-6 Receptors that would be available to enter the brain if given intravenously within general circulation, I don't know enough about this topic. It is nice to have some hope though. Previous treatment approaches for Alzheimer's dementia have focused on reducing amyloid protein and it has not been found very helpful for improving the condition.
Pomegranate polyphenols (ellagic acid) can cross the blood brain barrier after metabolism by intestinal bacteria transforms them into urolithins. (62) Pomegranate peel extract also has been used to help form nanoparticles. Urolithin a is being given orally as a nanoparticle to help reduce oxidative stress during treatment with the cancer drug cisplatin. Mortality rate improved in an animal-based study with the addition of the urolithin a. (63) Maybe a combination of spg130Fc and urolithin could cross the blood brain barrier.
Cautions for use of spg130Fc may be needed if liver disease is present, and use for cancer treatment would be dependent on the specific cancer type. It might help treat some types and worsen other types. (61)
Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.
52. Hou L, Huang H. Immune suppressive properties of artemisinin family drugs. *Pharmacol Ther*. 2016;166:123-127. doi:10.1016/j.pharmthera.2016.07.002 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035609/]
53. Mattman, Lida H., *Cell Wall Deficient Forms: Stealth Pathogens, 3rd Ed.,* CRC Press, October 26, 2000 [https://www.crcpress.com/Cell-Wall-Deficient-Forms-Stealth-Pathogens/Mattman/p/book/9780849387678]
54. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. *Nat Rev Rheumatol* 16, 155–166 (2020). https://doi.org/10.1038/s41584-020-0372-x [https://www.nature.com/articles/s41584-020-0372-x]
55. *Chinese absinthe,* wikiphyto.org [http://www.wikiphyto.org/wiki/Absinthe_chinoise]
56. Mark Peplow, *Artemisinin Raises Hopes and Fears Amid COVID-19.* Chemical & Engineering News, May 27, 2020, cen.acs.org [https://cen.acs.org/biological-chemistry/infectious-disease/Artemisinin-raises-hopes-fears-amid-COVID-19/98/i21]
57. Czechowski T, Larson TR., Catania TM., et al., Detailed Phytochemical Analysis of High- and Low Artemisinin-Producing Chemotypes of Artemisia annua. *Front Plant Sci* 2018;9, DOI=10.3389/fpls.2018.00641 [https://www.frontiersin.org/articles/10.3389/fpls.2018.00641/full]
58. Pierre Lutgen, *Was artemisinin the wrong choice; is arteannuin-B the better one?* Dec. 6, 2013, malariaworld.org [https://malariaworld.org/blog/was-artemisinin-wrong-choice-arteannuin-b-better-one]
59. Magro G, SARS-CoV-2 and COVID-19: Is interleukin-6 (IL-6) the ‘culprit lesion’ of ARDS onset? What is there besides Tocilizumab? SGP130Fc. *Cytokine: X* 2(2), June 2020, 100029 https://www.sciencedirect.com/science/article/pii/S2590153220300094
60. Ruth Davies, Jessica O Williams, Katie Sime, et al., Therapeutic Blockade of Interleukin-6 Trans-Signalling Restores Vascular Function in Murine Collagen Induced Arthritis. Meeting Abstract 1447: *2016 ACR/ARHP Annual Meeting.* Sept 28, 2016, https://acrabstracts.org/abstract/therapeutic-blockade-of-interleukin-6-trans-signalling-restores-vascular-function-in-murine-collagen-induced-arthritis/
61. Alzheimer's Drug Discovery Foundation, *Olamkicept*, Last updated on Jan 2, 2020 , CognitiveVitality.org, alzdiscovery.org https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Olamkicept-Cognitive-Vitality-For-Researchers.pdf
62. Kujawska M, Jourdes M , Kurpik M, et al., Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite—Urolithin A—In the Brain. Int. J. Mol. Sci. 2020, 21(1), 202; https://doi.org/10.3390/ijms21010202
63. Dianxiong Zou, Raghu Ganugula, Meenakshi Arora, et al., Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI. *Amer J Phys-Renal Phys* 2019 317:5, F1255-F1264 https://journals.physiology.org/doi/abs/10.1152/ajprenal.00346.2019