Ivermectin Maybe?
Ivermectin was discovered in 1967 at the Japanese Kitasato Institute. First approved for river blindness, a neglected tropical disease caused by Onchocerca volvulus, a parasitic worm. Ivermectin would prove effective against many parasites by manipulating the chloride ion channels that are imperative to their motor function, paralysis of the parasite ensues which ultimately leads to starvation and death. Fortunately for us mammals our blood brain barrier protects us from this toxicity. It was an effective drug for parasitic infections and would prove safe and effective over several decades against a variety of conditions including malaria, trichomoniasis, scabies, and leishmaniasis.
Evidence continues to mount for the use of Ivermectin as a potential treatment for Covid-19. We have long known the drug has broad antiviral properties, with even some evidence for use against cancer. One recent article in the Journal of Molecular Structure would summarize its history well with a single sentence.
“Ivermectin has gained much popularity due to a strong background of magical applications against a broad spectrum of pathogens.”
These in vitro experiments are intriguing but converting agar plate results into real life treatments is rarely a straight line. The concentration levels required to achieve those results for example are basically unreachable in the tissue or plasma. Despite that fact it appears to somehow be working to reduce mortality and multiple theoretical mechanisms have been proposed.
Spike protein shielding – Ivermectin binds to the ACE2 enzyme and the spike protein giving it the ability to shield the viral spike and inhibit viral entry by two pathways both on the cell and on the virus.
P2X4 Receptor Allosteric Modulation- It appears two distinctive sites on the P2X4 receptor bind to Ivermectin causing enhanced ATP-mediated secretion of CXCL5 a pro inflammatory chemokine which attracts neutrophils perhaps helping kickstart our immune response.
Nuclear transport inhibition - Importin α/β1 is vital to viral entry into the cell Ivermectin antiviral effects upon HIV, West Nile Virus, Dengue Virus and other RNA viruses appear to be mediated via this pathway. Recently, Ivermectin was shown to inhibit replication of covid-19 as well but the mechanism it accomplished this by is unclear.
Viral protein inhibition – Nucleotide and nucleoside inhibitors like Remdesivir and Favipiravir are FDA approved for HIV and were used early on, showing some effectiveness with 68% clinical improvement reported in a compassionate clinical use. Viral RNA polymerase is a potential therapeutic drug target and Ivermectin has a high affinity for it thereby obstructing its function.
Ionophor theory – Coming from the deepest part of left field; an ionophor is a compound with the ability to bind cations and transport them across a membrane in a small hydrophilic pocket surrounded by a hydrophobic shell. This class of compounds has shown antibiotic activity and their role as an antiviral has been hypothesized. When two Ivermectin particles bind to each other in a head to tail fashion a basic ionophor is made. The consequence of this is an ionic imbalance that could have several deleterious effects upon the virus. If the concentration gradient is great enough osmotic lysis could occur. Covid-19 would be susceptible to this because its genetic material is protected only by a thin phospholipid layer. There are some viruses that have a proteic capsid, this gives them increased resistance to osmotic pressure and a stronger structure. Thankfully we have finally found an evolutionary advantage that the creator chose not to bestow upon Covid-19. Cation depletion may also inhibit viral protein synthesis by inhibiting key enzymes such as RNA polymerase.
It is uncertain which of these proposed theories are the true culprit and maybe in reality it is multiple mechanisms acting in concert to varying degrees. What is certain is that a year and a half into this debacle that a safe and cost-effective potential alternative therapeutic agent has been so ignored that we are unable to say with any real confidence whether it works or not due to a lack of properly powered randomized clinical trials. Meanwhile International pressure continues to stack up as it begins to get approval elsewhere in the world.
Jacob Hyatt Pharm D.
Father of three, pharmacist, Realtor, Landlord, freelance health and medicine reporter
www.pharmacoconuts.com
www.Glenallenliving.com
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Further reading and references
COVID-19 and Ivermectin: Potential threats associated with human use - PubMed (nih.gov)
Zaheer T, Pal K, Abbas RZ, Torres MDPR. COVID-19 and Ivermectin: Potential threats associated with human use. J Mol Struct. 2021 Nov 5;1243:130808. doi: 10.1016/j.molstruc.2021.130808. Epub 2021 Jun 12. PMID: 34149064; PMCID: PMC8195608.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778723/#CR10
Kaur H, Shekhar N, Sharma S, Sarma P, Prakash A, Medhi B. Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes. Pharmacol Rep. 2021;73(3):736-749. doi:10.1007/s43440-020-00195-y
Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action - PubMed (nih.gov)
Rizzo E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn Schmiedebergs Arch Pharmacol. 2020 Jul;393(7):1153-1156. doi: 10.1007/s00210-020-01902-5. Epub 2020 May 27. PMID: 32462282; PMCID: PMC7251046.
Mechanism of Ivermectin Facilitation of Human P2X4 Receptor Channels (nih.gov)
Priel A, Silberberg SD. Mechanism of ivermectin facilitation of human P2X4 receptor channels. J Gen Physiol. 2004 Mar;123(3):281-93. doi: 10.1085/jgp.200308986. Epub 2004 Feb 9. PMID: 14769846; PMCID: PMC2217454.
Layhadi JA, Turner J, Crossman D, Fountain SJ. ATP Evokes Ca2+ Responses and CXCL5 Secretion via P2X4 Receptor Activation in Human Monocyte-Derived Macrophages. J Immunol. 2018 Feb 1;200(3):1159-1168. doi: 10.4049/jimmunol.1700965. Epub 2017 Dec 18. PMID: 29255078; PMCID: PMC5784824.
The Mysterious Ways of the Chemokine CXCL5: Immunity (cell.com)
Koltsova EK, Ley K. The mysterious ways of the chemokine CXCL5. Immunity. 2010 Jul 23;33(1):7-9. doi: 10.1016/j.immuni.2010.07.012. PMID: 20643334.
Daghir Janabi AH. Effective Anti-SARS-CoV-2 RNA Dependent RNA Polymerase Drugs Based on Docking Methods: The Case of Milbemycin, Ivermectin, and Baloxavir Marboxil. Avicenna J Med Biotechnol. 2020 Oct-Dec;12(4):246-250. PMID: 33014317; PMCID: PMC7502160.
Choudhary R, Sharma AK. Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance. New Microbes New Infect. 2020 Apr 22;35:100684. doi: 10.1016/j.nmni.2020.100684. PMID: 32322397; PMCID: PMC7175902.
Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study. Chest. 2021 Jan;159(1):85-92. doi: 10.1016/j.chest.2020.10.009. Epub 2020 Oct 13. PMID: 33065103; PMCID: PMC7550891.
Cobos-Campos R, Apiñaniz A, Parraza N, Cordero J, García S, Orruño E. Potential use of ivermectin for the treatment and prophylaxis of SARS-CoV-2 infection. Curr Res Transl Med. 2021;69(4):103309. doi:10.1016/j.retram.2021.103309
