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[/quote "FDA has not approved ivermectin for use in treating or preventing COVID-19 in humans." FDA
It's been explained to you the financial motive for not approving Ivermectin for that purpose. If it were approved, it would become illegal to administer an experimental "vaccine" to the general public under an Emergency Authorization, thus denying big pharma (and everyone in big pharma's pockets) their billions in profits. Grow up. ^^^^^+1,000,000^^^^^^ ALWAYS follow the money!
"I refuse to waste my common sense on those who have been educated beyond their intelligence"
All you need to know about Democrats is they call American citizens "Deplorables" and illegal immigrants "Dreamers"!
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"FDA has not approved ivermectin for use in treating or preventing COVID-19 in humans." FDA
It's been explained to you the financial motive for not approving Ivermectin for that purpose. If it were approved, it would become illegal to administer an experimental "vaccine" to the general public under an Emergency Authorization, thus denying big pharma (and everyone in big pharma's pockets) their billions in profits. Grow up. Aren't the big "Pharma" organizations the same group producing both "cures". It's not AutoZone making and selling Ivermectin. Wise Up.
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Campfire Sage
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"FDA has not approved ivermectin for use in treating or preventing COVID-19 in humans." FDA
It's been explained to you the financial motive for not approving Ivermectin for that purpose. If it were approved, it would become illegal to administer an experimental "vaccine" to the general public under an Emergency Authorization, thus denying big pharma (and everyone in big pharma's pockets) their billions in profits. Grow up. Aren't the big "Pharma" organizations the same group producing both "cures". It's not AutoZone making and selling Ivermectin. Wise Up. Ivermectin is low profit, since its patent ran out long ago. Not so with the mRNA "vaccines." They are high profit, since protected by patent.
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Campfire Ranger
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Campfire Ranger
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I thought no one here was going to take any medical treatment not approved by the FDA for the treatment of Covid? Wow the unions have lower standards than I had previously thought. Does science scare you chunky? Do you understand how an anti viral works chunky? Do you understand replication? Do you understand what a chemical formula is chunky?
Last edited by ribka; 06/21/21.
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Campfire Regular
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I thought no one here was going to take any medical treatment not approved by the FDA for the treatment of Covid? does science scare you chunky? Actually it doesn't, neither does facts. Big strong straight gender men cause you to pee a little in your panties, ribyouhard ?
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Joined: Mar 2010
Posts: 24,425 Likes: 19
Campfire Ranger
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Campfire Ranger
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here ya go chunky. there are no pictures to color with crayons though. sorry https://link.springer.com/article/10.1007/s00210-020-01902-5Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature. Ivermectin [mixture of 22, 23-dihydroavermectin B1a (80%) and 22, 23-dihydroavermectin B1b (20%)] (Fig. 1) is a macrocyclic lactone with a broad-spectrum antiparasitic pharmacological activity (Gonzalez Canga et al. 2008). It is the safest and most effective semi-synthetic derivative of the entire class of avermectins, discovered in 1975 by Professor Satoshi Ōmura as fermentation products of the actinomycete bacterium Streptomyces avermitilis (Crump 2017) (later reclassified in S. avermectinius (Takahashi et al. 2002)). Its main pharmacodynamics is to bind some channel proteins for chlorine controlled by glutamate, typical of specific classes of invertebrates, causing a greater permeability to this electrolyte: all this causes a hyperpolarization of the cell membrane, blocking inhibitory neurotransmission in neurons and myocytes, resulting in paralysis and death (Geary 2005). Commercialized since 1981, its low cost, its high efficacy and safety, and the marked tropism for helminths (therefore with an almost zero impact on the biochemistry of human beings) have led to its inclusion in the twenty-first World Health Organization's List of Essential Medicines (World Health Organization 2019). Fig. 1 figure1 Structural formulas of ivermectin compounds Full size image Ivermectin is a versatile drug with unique characteristics, which make it interesting also for basic and applied research (in particular for drug repurposing): it seems to reveal an antibacterial (Lim et al. 2013; Ashraf et al. 2018), antiviral, and anticancer activity (Juarez et al. 2018; Intuyod et al. 2019), besides being potentially useful for the treatment of some chronic pathologies (Ashraf and Prichard 2016; Ventre et al. 2017), result of an action on a wide range of cellular targets. Regarding its role as an antiviral agent, its efficacy has been demonstrated on several viruses, both in vitro and in vivo. Among the many mechanisms by which it performs its function, the most consolidated one sees ivermectin as an inhibitor of nuclear transport mediated by the importin α/β1 heterodimer, responsible for the translocation of various viral species proteins (HIV-1, SV40), indispensable for their replication (Wagstaff et al. 2011; Wagstaff et al. 2012). This inhibition appears to affect a considerable number of RNA viruses (Jans et al. 2019; Caly et al. 2012), such as Dengue Virus 1-4 (DENV) (Tay et al. 2013), West Nile Virus (WNV) (Yang et al. 2020), Venezuelan Equine Encephalitis Virus (VEEV) (Lundberg et al. 2013), and Influenza (Gotz et al. 2016). In addition, ivermectin has been shown to be effective against the Pseudorabies virus (PRV, with a DNA-based genome), both in vitro and in vivo (Lv et al. 2018), using the same mechanism. Caly et al. (Caly et al. 2020) have recently shown that the drug also inhibits the replication of the SARS-CoV-2 virus in vitro, however not clarifying how it occurs. Since the causative agent of COVID-19 is an RNA virus, it can be reasonably expected an interference with the same proteins and the same molecular processes described above. However, ivermectin could prove to be a powerful antiviral, therefore also useful for a possible treatment of the new coronavirus associated syndrome, even from a new perspective. This could happen assuming its role as an ionophore agent, only hinted in the recent past but never fully described (Juarez et al. 2018). Ionophores are molecules that typically have a hydrophilic pocket which constitutes a specific binding site for one or more ions (usually cations), while its external surface is hydrophobic, allowing the complex thus formed to cross the cell membranes, affecting the hydro-electrolyte balance (Freedman 2012). These chemical species have historically been used to study the mitochondrial respiratory chain and ATP synthesis in eukaryotes (in this case also known as decoupling agents, such as 2, 4-dinitrophenol), and their antibiotic activity has long been appreciated (Bakker 1979). It is also hypothesized their role as antiviral drugs (Krenn et al. 2009; Sandler et al. 2020) and anticancer chemotherapeutic agents (Kaushik et al. 2018). Thinking of the structure of two of the most important ionophores, monensin A and valinomycin, respectively a polyether and a depsipeptide antibiotic, it is clear that they internally present many oxygen atoms (with related free electron doublets), indispensable for binding cations and transporting them through phospholipidic bilayers. At a first glance, the two structures that make up the ivermectin formula do not have these chemical properties, nor those mentioned above, essential for a compound to be defined as ionophore. However, it can be hypothesized that two ivermectin molecules, reacting with each other in a “head-tail” mode, can create a complex suitable to be considered such (Fig. 2). This interaction could occur spontaneously or be mediated by the binding of the same molecules to some plasma transport proteins, in particular albumin (Klotz et al. 1990), which would have the role of positioning them in the correct way to obtain the proposed configuration. Fig. 2 figure2 Possible interaction mechanism between two ivermectin molecules Full size image As it can be seen, in this way, an internal cavity is formed: the oxygen atoms (indicated in red), now present in greater number, work as Lewis bases and could therefore coordinate a series of cations (Lewis acids). On the other hand, the –OH groups are highlighted in blue and they could have a decisive role in the stabilization of the new structure, with the establishment of chemical bonds between these functional groups: one or more –O– bridges (however, it is difficult the formation of ether bonds, since acid catalysis at high temperature is not possible under normal conditions, both in vitro and in vivo) or more probably hydrogen bonds could be formed, even among more molecular complexes of this type. However, the formation of other weak and strong interactions of various kinds cannot be excluded. Otherwise, specific cations could bind the two molecules in the proposed way, creating themselves the final structure and stabilizing it: there are examples already known in literature (Abbott et al. 1979). The external part of the complex, then, would already have in itself all the hydrophobic characteristics necessary to carry ions through the viral membrane. As a consequence, it would be determined an ionic imbalance between the external and internal environment, with the recall of water and consequent osmotic lysis. This would allow to neutralize the virus at an early stage of the infection, before; therefore, it can adhere to the host cells and enter it to exploit their biochemical machinery for the production of other viral particles. However, this hypothesis would concern only viruses without a proteic capsid, a structure that shows a certain resistance to osmotic pressure, even if to a lesser extent than a bacterial, fungal, or plant cell wall (Cordova et al. 2003). The new coronavirus is one of these, presenting only a phospholipid envelope in defense of the genetic material, where its few proteins are inserted and which it acquires in the act of exiting the infected cells (Sigrist et al. 2020). This unconventional electrolyte uptake mode could also affect the potential of the viral membrane, threatening its integrity and functionality. The same goes for the viral proteins present here. Furthermore, the concentration variation of some cations, thus determined, could inhibit some key enzymes in the viral replication, such as RNA-dependent RNA polymerases (RdRp) (te Velthuis et al. 2010), already used as pharmacological targets. Another indication in favor of a possible ionophore role for ivermectin comes from the analysis of molecular similarity that can be carried out through the Drugbank database ( www.drugbank.ca). By setting a minimum similarity threshold for ivermectin equal to 0.7, about 14 results are obtained. Among the various selected molecules, the majority of which have antiparasitic and antibiotic activity (already not only on the market but also in the study and experimentation phase), a compound that has high structural similarity is nystatin (score of 0.72), an antimycotic drug with an ionophoric activity at the plasma membrane level, where it forms channels (Yamasaki et al. 2011; Stillwell 2016; Rang 2015). Immediately afterwards, with a slightly lower similarity, it can be find amphotericin B and natamycin, all pharmacological molecules of assured ionophoric activity (score of 0.71 and 0.706, respectively) (Stillwell 2016; Rang 2015; Ramos 1989; Ikehara et al. 1986). In conclusion, pending computational simulations and chemical-physical laboratory analysis, this hypothesis could be applied to other known pharmacological molecules, in order to identify compounds with probable ionophore nature to be used in research and clinical practice. References Abbott BJ, [bleep] DS, Dorman DE, Occolowitz JL, Debono M, Farhner L (1979 Dec) Microbial transformation of A23187, a divalent cation ionophore antibiotic. Antimicrob Agents Chemother. 16(6):808–812 CAS Article Google Scholar Ashraf S, Prichard R (2016 Aug 15) Ivermectin exhibits potent anti-mitotic activity. Vet Parasitol. 226:1–4 CAS Article Google Scholar Ashraf S, Chaudhry U, Raza A, Ghosh D, Zhao X (2018) In vitro activity of ivermectin against Staphylococcus aureus clinical isolates. Antimicrob Resist Infect Control. 7:27 Article Google Scholar Bakker EP (1979) Ionophore Antibiotics. In: Hahn F.E. (eds) Mechanism of action of antibacterial agents. Antibiotics 5:1 Springer, Berlin, Heidelberg Google Scholar Caly L, Wagstaff KM, Jans DA (2012) Nuclear trafficking of proteins from RNA viruses: potential target for anti-virals? Antiviral research 95:202–206 CAS Article Google Scholar Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM (2020 Apr) The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 3:104787 Article Google Scholar Cordova A, Deserno M, Gelbart WM, Ben-Shaul A (2003 Jul) Osmotic shock and the strength of viral capsids. Biophys J. 85(1):70–74 CAS Article Google Scholar Crump A (2017 May) Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo). 70(5):495–505 CAS Article Google Scholar Freedman JC (2012) Chapter 4 - Ionophores in planar lipid bilayers. In: Sperelakis N (ed) Cell Physiology Source Book, 4th edn. Academic Press, pp 61–66 ISBN 9780123877383 Geary TG (2005) Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 21(11):530–532 CAS Article Google Scholar Gonzalez Canga A et al (2008) The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J 10(1):42–46 Article Google Scholar Gotz V et al (2016) Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep 6:23138 Article Google Scholar Ikehara T, Yamaguchi H, Hosokawa K, Yonezu T, Miyamoto H (1986) Effects of nystatin on intracellular contents and membrane transport of alkali cations, and cell volume in HeLa cells. J Membr Biol. 90(3):231–240 CAS Article Google Scholar Intuyod K, Hahnvajanawong C, Pinlaor P, Pinlaor S (2019) Anti-parasitic drug ivermectin exhibits potent anticancer activity against gemcitabine-resistant cholangiocarcinoma in vitro. Anticancer Res. 39(9):4837–4843 Article Google Scholar Jans DA, Martin AJ, Wagstaff KM (2019) Inhibitors of nuclear transport. Curr Opin Cell Biol 58:50–60 CAS Article Google Scholar Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A (2018 Feb 1) The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 8(2):317–331 CAS PubMed PubMed Central Google Scholar Kaushik V, Yakisich JS, Kumar A, Azad N, Iyer AKV (2018) Ionophores: Potential use as anticancer drugs and chemosensitizers. Cancers (Basel) 10(10):pii: E360. https://doi.org/10.3390/cancers10100360CAS Article Google Scholar Klotz U, Ogbuokiri JE, Okonkwo PO (1990) Ivermectin binds avidly to plasma proteins. Eur J Clin Pharmacol. 39(6):607–608 CAS Article Google Scholar Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJ, Seipelt J (2009 Jan) Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol. 83(1):58–64 CAS Article Google Scholar Lim LE, Vilchèze C, Ng C, Jacobs WR Jr, Ramón-García S, Thompson CJ (2013 Feb) Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob Agents Chemother. 57(2):1040–1046 CAS Article Google Scholar Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, Jans DA, Kehn-Hall K (2013) Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res 100(3):662–672 CAS Article Google Scholar Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, Yan C, Yang Z, Wang X (2018) Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res 159:55–62 CAS Article Google Scholar Ramos H (1989 Jul 10) Attias de Murciano A, Cohen BE, Bolard J. The polyene antibiotic amphotericin B acts as a Ca2+ ionophore in sterol-containing liposomes. Biochim Biophys Acta. 982(2):303–306 CAS Article Google Scholar P.H. Rang, (2015). Rang and Dale’s pharmacology. Dale, M. Maureen, Flower, R. J. (Rod J.), 1945-, Henderson, G. (Graeme) (Eighth ed.). [United Kingdom]. Google Scholar Sandler ZJ, Vu MN, Menachery VD, Mounce BC (2020) Novel ionophores active against La Crosse virus identified through rapid antiviral screening. bioRxiv doi. https://doi.org/10.1101/2020.01.21.914929Sigrist CJ, Bridge A, Le Mercier P (2020 Mar 1) A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral Res. 177:104759 CAS Article Google Scholar Stillwell W (2016) Chapter 19 - Membrane Transport. In: Stillwell W (ed) An introduction to biological membranes, 2nd edn. Elsevier, pp 423–451 ISBN 9780444637727 Takahashi Y, Matsumoto A, Seino A, Ueno J, Iwai Y, Omura S (2002 Nov) Streptomyces avermectinius sp. nov., an avermectin-producing strain. Int J Syst Evol Microbiol. 52(Pt 6):2163–2168 CAS PubMed Google Scholar Tay MY et al (2013) Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res 99(3):301–306 CAS Article Google Scholar te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ (2010 Nov 4) Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 6(11):e1001176 Article Google Scholar Ventre E, Rozières A, Lenief V, Albert F, Rossio P, Laoubi L, Dombrowicz D, Staels B, Ulmann L, Julia V, Vial E, Jomard A, Hacini-Rachinel F, Nicolas JF, Vocanson M (2017 Aug) Topical ivermectin improves allergic skin inflammation. Allergy. 72(8):1212–1221 CAS Article Google Scholar Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA (2011) An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import. Journal of biomolecular screening 16(2):192–200 CAS Article Google Scholar Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA (2012) Ivermectin is a specific inhibitor of importin alpha/beta mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. The Biochemical journal 443(3):851–856 CAS Article Google Scholar World Health Organization (2019) World Health Organization model list of essential medicines: 21st list 2019. World Health Organization, Geneva Google Scholar Yamasaki M, Tamura N, Nakamura K, Sasaki N, Murakami M, Rajapakshage W, Kumara B, Tamura Y, Lim SY, Ohta H, Takiguchi M (2011 Dec) Effects and mechanisms of action of polyene macrolide antibiotic nystatin on Babesia gibsoni in vitro. J Parasitol. 97(6):1190–1192 CAS Article Google Scholar Yang SNY et al (2020) The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res 177:104760 CAS Article Google Scholar Download references Author information Affiliations Department of Prevention, Local Health Authority of Lecce (ASL Lecce), Lecce, Italy Emanuele Rizzo Italian Society of Environmental Medicine (SIMA), Milan, Italy Emanuele Rizzo Contributions All research phases (idea, drafting of the paper, and proofreading) were conducted by the only author, ER. Corresponding author Correspondence to Emanuele Rizzo. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Reprints and Permissions About this article Verify currency and authenticity via CrossMark Cite this article Rizzo, E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1153–1156 (2020). https://doi.org/10.1007/s00210-020-01902-5Download citation Received 29 April 2020 Accepted 10 May 2020 Published 27 May 2020 Issue Date July 2020 DOI https://doi.org/10.1007/s00210-020-01902-5Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Ivermectin Antiviral Ionophore COVID-19 SARS-CoV-2 Download PDF
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I thought no one here was going to take any medical treatment not approved by the FDA for the treatment of Covid? does science scare you chunky? Actually it doesn't, neither does facts. Big strong straight gender men cause you to pee a little in your panties, ribyouhard ? I forgot unions don't even require an 8h grade science or math education lmao
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Joined: Aug 2008
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Campfire Regular
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here ya go chunky. there are no pictures to color with crayons though. sorry https://link.springer.com/article/10.1007/s00210-020-01902-5Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature. Ivermectin [mixture of 22, 23-dihydroavermectin B1a (80%) and 22, 23-dihydroavermectin B1b (20%)] (Fig. 1) is a macrocyclic lactone with a broad-spectrum antiparasitic pharmacological activity (Gonzalez Canga et al. 2008). It is the safest and most effective semi-synthetic derivative of the entire class of avermectins, discovered in 1975 by Professor Satoshi Ōmura as fermentation products of the actinomycete bacterium Streptomyces avermitilis (Crump 2017) (later reclassified in S. avermectinius (Takahashi et al. 2002)). Its main pharmacodynamics is to bind some channel proteins for chlorine controlled by glutamate, typical of specific classes of invertebrates, causing a greater permeability to this electrolyte: all this causes a hyperpolarization of the cell membrane, blocking inhibitory neurotransmission in neurons and myocytes, resulting in paralysis and death (Geary 2005). Commercialized since 1981, its low cost, its high efficacy and safety, and the marked tropism for helminths (therefore with an almost zero impact on the biochemistry of human beings) have led to its inclusion in the twenty-first World Health Organization's List of Essential Medicines (World Health Organization 2019). Fig. 1 figure1 Structural formulas of ivermectin compounds Full size image Ivermectin is a versatile drug with unique characteristics, which make it interesting also for basic and applied research (in particular for drug repurposing): it seems to reveal an antibacterial (Lim et al. 2013; Ashraf et al. 2018), antiviral, and anticancer activity (Juarez et al. 2018; Intuyod et al. 2019), besides being potentially useful for the treatment of some chronic pathologies (Ashraf and Prichard 2016; Ventre et al. 2017), result of an action on a wide range of cellular targets. Regarding its role as an antiviral agent, its efficacy has been demonstrated on several viruses, both in vitro and in vivo. Among the many mechanisms by which it performs its function, the most consolidated one sees ivermectin as an inhibitor of nuclear transport mediated by the importin α/β1 heterodimer, responsible for the translocation of various viral species proteins (HIV-1, SV40), indispensable for their replication (Wagstaff et al. 2011; Wagstaff et al. 2012). This inhibition appears to affect a considerable number of RNA viruses (Jans et al. 2019; Caly et al. 2012), such as Dengue Virus 1-4 (DENV) (Tay et al. 2013), West Nile Virus (WNV) (Yang et al. 2020), Venezuelan Equine Encephalitis Virus (VEEV) (Lundberg et al. 2013), and Influenza (Gotz et al. 2016). In addition, ivermectin has been shown to be effective against the Pseudorabies virus (PRV, with a DNA-based genome), both in vitro and in vivo (Lv et al. 2018), using the same mechanism. Caly et al. (Caly et al. 2020) have recently shown that the drug also inhibits the replication of the SARS-CoV-2 virus in vitro, however not clarifying how it occurs. Since the causative agent of COVID-19 is an RNA virus, it can be reasonably expected an interference with the same proteins and the same molecular processes described above. However, ivermectin could prove to be a powerful antiviral, therefore also useful for a possible treatment of the new coronavirus associated syndrome, even from a new perspective. This could happen assuming its role as an ionophore agent, only hinted in the recent past but never fully described (Juarez et al. 2018). Ionophores are molecules that typically have a hydrophilic pocket which constitutes a specific binding site for one or more ions (usually cations), while its external surface is hydrophobic, allowing the complex thus formed to cross the cell membranes, affecting the hydro-electrolyte balance (Freedman 2012). These chemical species have historically been used to study the mitochondrial respiratory chain and ATP synthesis in eukaryotes (in this case also known as decoupling agents, such as 2, 4-dinitrophenol), and their antibiotic activity has long been appreciated (Bakker 1979). It is also hypothesized their role as antiviral drugs (Krenn et al. 2009; Sandler et al. 2020) and anticancer chemotherapeutic agents (Kaushik et al. 2018). Thinking of the structure of two of the most important ionophores, monensin A and valinomycin, respectively a polyether and a depsipeptide antibiotic, it is clear that they internally present many oxygen atoms (with related free electron doublets), indispensable for binding cations and transporting them through phospholipidic bilayers. At a first glance, the two structures that make up the ivermectin formula do not have these chemical properties, nor those mentioned above, essential for a compound to be defined as ionophore. However, it can be hypothesized that two ivermectin molecules, reacting with each other in a “head-tail” mode, can create a complex suitable to be considered such (Fig. 2). This interaction could occur spontaneously or be mediated by the binding of the same molecules to some plasma transport proteins, in particular albumin (Klotz et al. 1990), which would have the role of positioning them in the correct way to obtain the proposed configuration. Fig. 2 figure2 Possible interaction mechanism between two ivermectin molecules Full size image As it can be seen, in this way, an internal cavity is formed: the oxygen atoms (indicated in red), now present in greater number, work as Lewis bases and could therefore coordinate a series of cations (Lewis acids). On the other hand, the –OH groups are highlighted in blue and they could have a decisive role in the stabilization of the new structure, with the establishment of chemical bonds between these functional groups: one or more –O– bridges (however, it is difficult the formation of ether bonds, since acid catalysis at high temperature is not possible under normal conditions, both in vitro and in vivo) or more probably hydrogen bonds could be formed, even among more molecular complexes of this type. However, the formation of other weak and strong interactions of various kinds cannot be excluded. Otherwise, specific cations could bind the two molecules in the proposed way, creating themselves the final structure and stabilizing it: there are examples already known in literature (Abbott et al. 1979). The external part of the complex, then, would already have in itself all the hydrophobic characteristics necessary to carry ions through the viral membrane. As a consequence, it would be determined an ionic imbalance between the external and internal environment, with the recall of water and consequent osmotic lysis. This would allow to neutralize the virus at an early stage of the infection, before; therefore, it can adhere to the host cells and enter it to exploit their biochemical machinery for the production of other viral particles. However, this hypothesis would concern only viruses without a proteic capsid, a structure that shows a certain resistance to osmotic pressure, even if to a lesser extent than a bacterial, fungal, or plant cell wall (Cordova et al. 2003). The new coronavirus is one of these, presenting only a phospholipid envelope in defense of the genetic material, where its few proteins are inserted and which it acquires in the act of exiting the infected cells (Sigrist et al. 2020). This unconventional electrolyte uptake mode could also affect the potential of the viral membrane, threatening its integrity and functionality. The same goes for the viral proteins present here. Furthermore, the concentration variation of some cations, thus determined, could inhibit some key enzymes in the viral replication, such as RNA-dependent RNA polymerases (RdRp) (te Velthuis et al. 2010), already used as pharmacological targets. Another indication in favor of a possible ionophore role for ivermectin comes from the analysis of molecular similarity that can be carried out through the Drugbank database ( www.drugbank.ca). By setting a minimum similarity threshold for ivermectin equal to 0.7, about 14 results are obtained. Among the various selected molecules, the majority of which have antiparasitic and antibiotic activity (already not only on the market but also in the study and experimentation phase), a compound that has high structural similarity is nystatin (score of 0.72), an antimycotic drug with an ionophoric activity at the plasma membrane level, where it forms channels (Yamasaki et al. 2011; Stillwell 2016; Rang 2015). Immediately afterwards, with a slightly lower similarity, it can be find amphotericin B and natamycin, all pharmacological molecules of assured ionophoric activity (score of 0.71 and 0.706, respectively) (Stillwell 2016; Rang 2015; Ramos 1989; Ikehara et al. 1986). In conclusion, pending computational simulations and chemical-physical laboratory analysis, this hypothesis could be applied to other known pharmacological molecules, in order to identify compounds with probable ionophore nature to be used in research and clinical practice. References Abbott BJ, [bleep] DS, Dorman DE, Occolowitz JL, Debono M, Farhner L (1979 Dec) Microbial transformation of A23187, a divalent cation ionophore antibiotic. Antimicrob Agents Chemother. 16(6):808–812 CAS Article Google Scholar Ashraf S, Prichard R (2016 Aug 15) Ivermectin exhibits potent anti-mitotic activity. Vet Parasitol. 226:1–4 CAS Article Google Scholar Ashraf S, Chaudhry U, Raza A, Ghosh D, Zhao X (2018) In vitro activity of ivermectin against Staphylococcus aureus clinical isolates. Antimicrob Resist Infect Control. 7:27 Article Google Scholar Bakker EP (1979) Ionophore Antibiotics. In: Hahn F.E. (eds) Mechanism of action of antibacterial agents. Antibiotics 5:1 Springer, Berlin, Heidelberg Google Scholar Caly L, Wagstaff KM, Jans DA (2012) Nuclear trafficking of proteins from RNA viruses: potential target for anti-virals? Antiviral research 95:202–206 CAS Article Google Scholar Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM (2020 Apr) The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 3:104787 Article Google Scholar Cordova A, Deserno M, Gelbart WM, Ben-Shaul A (2003 Jul) Osmotic shock and the strength of viral capsids. Biophys J. 85(1):70–74 CAS Article Google Scholar Crump A (2017 May) Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo). 70(5):495–505 CAS Article Google Scholar Freedman JC (2012) Chapter 4 - Ionophores in planar lipid bilayers. In: Sperelakis N (ed) Cell Physiology Source Book, 4th edn. Academic Press, pp 61–66 ISBN 9780123877383 Geary TG (2005) Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 21(11):530–532 CAS Article Google Scholar Gonzalez Canga A et al (2008) The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J 10(1):42–46 Article Google Scholar Gotz V et al (2016) Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep 6:23138 Article Google Scholar Ikehara T, Yamaguchi H, Hosokawa K, Yonezu T, Miyamoto H (1986) Effects of nystatin on intracellular contents and membrane transport of alkali cations, and cell volume in HeLa cells. J Membr Biol. 90(3):231–240 CAS Article Google Scholar Intuyod K, Hahnvajanawong C, Pinlaor P, Pinlaor S (2019) Anti-parasitic drug ivermectin exhibits potent anticancer activity against gemcitabine-resistant cholangiocarcinoma in vitro. Anticancer Res. 39(9):4837–4843 Article Google Scholar Jans DA, Martin AJ, Wagstaff KM (2019) Inhibitors of nuclear transport. Curr Opin Cell Biol 58:50–60 CAS Article Google Scholar Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A (2018 Feb 1) The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 8(2):317–331 CAS PubMed PubMed Central Google Scholar Kaushik V, Yakisich JS, Kumar A, Azad N, Iyer AKV (2018) Ionophores: Potential use as anticancer drugs and chemosensitizers. Cancers (Basel) 10(10):pii: E360. https://doi.org/10.3390/cancers10100360CAS Article Google Scholar Klotz U, Ogbuokiri JE, Okonkwo PO (1990) Ivermectin binds avidly to plasma proteins. Eur J Clin Pharmacol. 39(6):607–608 CAS Article Google Scholar Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJ, Seipelt J (2009 Jan) Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol. 83(1):58–64 CAS Article Google Scholar Lim LE, Vilchèze C, Ng C, Jacobs WR Jr, Ramón-García S, Thompson CJ (2013 Feb) Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob Agents Chemother. 57(2):1040–1046 CAS Article Google Scholar Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, Jans DA, Kehn-Hall K (2013) Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res 100(3):662–672 CAS Article Google Scholar Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, Yan C, Yang Z, Wang X (2018) Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res 159:55–62 CAS Article Google Scholar Ramos H (1989 Jul 10) Attias de Murciano A, Cohen BE, Bolard J. The polyene antibiotic amphotericin B acts as a Ca2+ ionophore in sterol-containing liposomes. Biochim Biophys Acta. 982(2):303–306 CAS Article Google Scholar P.H. Rang, (2015). Rang and Dale’s pharmacology. Dale, M. Maureen, Flower, R. J. (Rod J.), 1945-, Henderson, G. (Graeme) (Eighth ed.). [United Kingdom]. Google Scholar Sandler ZJ, Vu MN, Menachery VD, Mounce BC (2020) Novel ionophores active against La Crosse virus identified through rapid antiviral screening. bioRxiv doi. https://doi.org/10.1101/2020.01.21.914929Sigrist CJ, Bridge A, Le Mercier P (2020 Mar 1) A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral Res. 177:104759 CAS Article Google Scholar Stillwell W (2016) Chapter 19 - Membrane Transport. In: Stillwell W (ed) An introduction to biological membranes, 2nd edn. Elsevier, pp 423–451 ISBN 9780444637727 Takahashi Y, Matsumoto A, Seino A, Ueno J, Iwai Y, Omura S (2002 Nov) Streptomyces avermectinius sp. nov., an avermectin-producing strain. Int J Syst Evol Microbiol. 52(Pt 6):2163–2168 CAS PubMed Google Scholar Tay MY et al (2013) Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res 99(3):301–306 CAS Article Google Scholar te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ (2010 Nov 4) Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 6(11):e1001176 Article Google Scholar Ventre E, Rozières A, Lenief V, Albert F, Rossio P, Laoubi L, Dombrowicz D, Staels B, Ulmann L, Julia V, Vial E, Jomard A, Hacini-Rachinel F, Nicolas JF, Vocanson M (2017 Aug) Topical ivermectin improves allergic skin inflammation. Allergy. 72(8):1212–1221 CAS Article Google Scholar Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA (2011) An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import. Journal of biomolecular screening 16(2):192–200 CAS Article Google Scholar Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA (2012) Ivermectin is a specific inhibitor of importin alpha/beta mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. The Biochemical journal 443(3):851–856 CAS Article Google Scholar World Health Organization (2019) World Health Organization model list of essential medicines: 21st list 2019. World Health Organization, Geneva Google Scholar Yamasaki M, Tamura N, Nakamura K, Sasaki N, Murakami M, Rajapakshage W, Kumara B, Tamura Y, Lim SY, Ohta H, Takiguchi M (2011 Dec) Effects and mechanisms of action of polyene macrolide antibiotic nystatin on Babesia gibsoni in vitro. J Parasitol. 97(6):1190–1192 CAS Article Google Scholar Yang SNY et al (2020) The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res 177:104760 CAS Article Google Scholar Download references Author information Affiliations Department of Prevention, Local Health Authority of Lecce (ASL Lecce), Lecce, Italy Emanuele Rizzo Italian Society of Environmental Medicine (SIMA), Milan, Italy Emanuele Rizzo Contributions All research phases (idea, drafting of the paper, and proofreading) were conducted by the only author, ER. Corresponding author Correspondence to Emanuele Rizzo. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Reprints and Permissions About this article Verify currency and authenticity via CrossMark Cite this article Rizzo, E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1153–1156 (2020). https://doi.org/10.1007/s00210-020-01902-5Download citation Received 29 April 2020 Accepted 10 May 2020 Published 27 May 2020 Issue Date July 2020 DOI https://doi.org/10.1007/s00210-020-01902-5Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Ivermectin Antiviral Ionophore COVID-19 SARS-CoV-2 Download PDF Only a sexually deviated boy from Idaho would Copy and Paste that much and expect anyone to read it, well maybe that idiot from Minnesota also. I'm starting to notice a resemblance with that kid Maser and your posts, maybe a sock puppet ?
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Only a sexually deviated boy from Idaho would Copy and Paste that much and expect anyone to read it, well maybe that idiot from Minnesota also. I'm starting to notice a resemblance with that kid Maser and your posts, maybe a sock puppet ?
Sometimes you have to know when to fold, Kentucky Chucky
Quit giving in inch by inch then looking back to lament the mile behind ya and wonder how to preserve those few feet left in front of ya. They'll never stop until they're stopped. That's a fact.
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Campfire 'Bwana
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Campfire 'Bwana
Joined: Nov 2002
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And here I thought Covid was fake news...
Conduct is the best proof of character.
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Joined: Aug 2008
Posts: 1,953
Campfire Regular
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Campfire Regular
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Only a sexually deviated boy from Idaho would Copy and Paste that much and expect anyone to read it, well maybe that idiot from Minnesota also. I'm starting to notice a resemblance with that kid Maser and your posts, maybe a sock puppet ?
Sometimes you have to know when to fold, Kentucky Chucky Only when you're playing with your own money, Crouch.
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I've read that Ivermectin has been used successfully in treating and preventing cancer. Lord knows that the medical industry doesn't want a cure for cancer.
Life is good live it while you can.
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Campfire Regular
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Campfire Regular
Joined: Aug 2008
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I thought no one here was going to take any medical treatment not approved by the FDA for the treatment of Covid? does science scare you chunky? Actually it doesn't, neither does facts. Big strong straight gender men cause you to pee a little in your panties, ribyouhard ? I forgot unions don't even require an 8h grade science or math education lmao Maybe you should try it and report back to us, let us know if it cures the gay for you. What have you got to lose? Doubt you could make it though a four year apprenticeship with IBEW. If you did you would have a two year associate degree and a four year skilled labor trade apprenticeship, what do you have to show for your vast wealth of knowledge? Why are LBGT "men" always lmao?
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Joined: Dec 2013
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Campfire Outfitter
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Campfire Outfitter
Joined: Dec 2013
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I've read that Ivermectin has been used successfully in treating and preventing cancer. Lord knows that the medical industry doesn't want a cure for cancer. Lots of money in prolonging it. Probably cause a financial collapse in the medial industry if a fast cheap cure was found.
Patriotism (and religion) is the last refuge of a scoundrel. Jesus: "Take heed that no man deceive you." Hebrew Roots Judaizer
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Joined: Dec 2005
Posts: 13,113 Likes: 13
Campfire Outfitter
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Campfire Outfitter
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If you know anything about stats, .62 at the 95 percentile is big. It’s more than moderate confidence.
"...aspire to live quietly, and to mind your own affairs, and to work with your hands, as we instructed you, so that you may walk properly before outsiders and be dependent on no one." - Paul to the church in Thessalonica.
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Campfire 'Bwana
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OP
Campfire 'Bwana
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ChuckKY, You've proven that you just can't grasp the validity of ivermectin, Or the financial motivation behind denying its effectiveness. Your argument doesn't hold water. Only Kool-Aid.
So please move on. Your body, your choice.
Slaves get what they need. Free men get what they want. Rehabilitation is way overrated. Orwell wasn't wrong. GOA member disappointed NRA member 24HCF SEARCH
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Campfire Ranger
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lol chunky try getting a degree in biochem. take 3 semesters of calc, physics, organic chem and labs, genetics, physical chem I thought no one here was going to take any medical treatment not approved by the FDA for the treatment of Covid? does science scare you chunky? Actually it doesn't, neither does facts. Big strong straight gender men cause you to pee a little in your panties, ribyouhard ? I forgot unions don't even require an 8h grade science or math education lmao Maybe you should try it and report back to us, let us know if it cures the gay for you. What have you got to lose? Doubt you could make it though a four year apprenticeship with IBEW. If you did you would have a two year associate degree and a four year skilled labor trade apprenticeship, what do you have to show for your vast wealth of knowledge? Why are LBGT "men" always lmao?
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Joined: Aug 2009
Posts: 20,824
Campfire Ranger
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Campfire Ranger
Joined: Aug 2009
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Union strong....... you go chunky...... lmao
Originally Posted by Judman PS, if you think Trump is “good” you’re way stupider than I thought! Haha
Sorry, trump is a no tax payin pile of shiit.
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Joined: Dec 2007
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Campfire Ranger
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Campfire Ranger
Joined: Dec 2007
Posts: 25,143 Likes: 2 |
Just bought some 1.87% Duravet paste.
I’m around 200#’s. What’s the Campfire approved dose?
“Life is life and fun is fun, but it's all so quiet when the goldfish die.”
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Joined: Dec 2007
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Campfire Ranger
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Campfire Ranger
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Do I need a secret union handshake to get info?
“Life is life and fun is fun, but it's all so quiet when the goldfish die.”
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