Quote from THHuxleynew

6X fewer COVID deaths juts from age

Do you agree that 0 (Slovakia average a development country..) or 1 death does not work with your 6x less ??

PART 1: Dr. Robert Malone, mRNA Vaccine Inventor, on Latest COVID-19 Data, Booster Shots, and the Shattered Scientific ‘Consensus’

PART 1: Dr. Robert Malone, mRNA Vaccine Inventor, on Latest COVID-19 Data, Booster Shots, and the Shattered Scientific ‘Consensus’

“We need to confront the data [and] not try to cover stuff up or hide risks,” says mRNA ...

m.theepochtimes.com

PART 2: Dr. Robert Malone on Ivermectin, Escape Mutants, and the Faulty Logic of Vaccine Mandates

PART 2: Dr. Robert Malone on Ivermectin, Escape Mutants, and the Faulty Logic of Vaccine Mandates

In part one of this American Thought Leaders episode, mRNA vaccine inventor Dr. Robert Malone explained the latest ...

www.theepochtimes.com

The reason for this situation, is a mass psychosis. Most of this people are doing this because of --- a profound disillusionment -- an addiction to materialism.

* Go with program = riches for some, surely billions and billions are being spent

* Go with program = keep "my riches" for others, that nice paying Professorship with the ability to drink coffee without stress, and stay in respectability even though the streets could be on fire outside the Ivory Tower

* Go with program = psychological survival for many, most don't know T-cell from the T-line on a subway, they are spouting data and stats because of a terror, a profound fear that has taken over them --- this is the operating platform for most people in society -- even though they would never say they are terrorized

* Go with program = for the young, they are giving in to the delusion of being in a culture trying to save itself, when in fact, the elites have unleashed a parasite to consume the culture and draw it into the delusion

As Towne Criers, why do you engage in this? You've been deceived. Maybe you've been deceived that if you deceive others you'll stay part of the club....why not exit the club? Maybe you've been cult programmed at a young age. Maybe your programmers don't care about you? Do you feel it would break you if you had to go with the Truth?

I genuinely want to know why people on the periphery are continuing this op which is failing so badly. Maybe to be specific, the entire op is based on forcing a false reality onto others. YOU MUST TAKE THE VACCINE OR REALITY ITSELF WILL BE EXTINGUISHED. It is morally bankrupt to the core, because it PRETENDS TO CARE WHEN IT IS PARASITIC AND EVIL TO THE CORE. This entire thing cannot lead to anything stable.

A man who lies to himself and listens to his own lie comes to a point where he does not discern any truth either in himself or anywhere around him, and thus falls into disrespect towards himself and others. Dostoyevsky

Quote from Fm1

Change history

22 June 2021Editor’s Note: Readers are alerted that the conclusions of this paper are subject to criticisms that are being considered by the editors and the publisher. A further editorial response will follow the resolution of these issues

Not surprising - it was an article fishing for a mechanism which is just a list of possibles, so it can't include much.

Quote from Fm1

The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article

https://www.nature.com/articles/s41429-021-00430-5

Abstract

Considering the urgency of the ongoing COVID-19 pandemic, detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention. This evidence-based review article aims to discuss the mechanism of action of ivermectin against SARS-CoV-2 and summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications have been proposed.

Introduction

A relatively recent surge in zoonotic diseases has been noted over the past few decades. Several reasons could be responsible for this “spill-over” of disease-causing agents from animals to humans. These include an exponential rise in the global population causing man to encroach new ecological habitats in search of space, food, and resources as well as improved opportunities for rampant wildlife trade causing inter-species pathogen jumps. The 1980s was known for HIV/AIDS crisis that originated from the great apes, while the Avian flu pandemic in 2004-07 came from the birds. The pigs lead to the Swine flu pandemic in 2009 and bats were the original hosts of Ebola, Severe Acute Respiratory Syndrome (SARS), Middle Eastern respiratory syndrome (MERS), and probably Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) outbreak as well.

COVID-19 has already caused millions of deaths worldwide and has paralyzed not only the world’s healthcare system but also the political and economic relations between countries [1]. The fact that the SARS-CoV-2 virus has been thought to have originated from wildlife and may have “jumped” into humans, not only highlights future risks from animal-borne diseases but also provides an important clue to its resolution. In such a scenario, where this “jump” has been made from animal to human, it seems only logical to review a drug that has worked efficiently against a disease-causing agent and is available in a form that is safe for human consumption since the early 1980 s.

Ivermectin belongs to a group of avermectins (AVM), which is a group of 16 membered macrocyclic lactone compounds discovered at the Japanese Kitasato institute in 1967 during actinomycetes cultures with the fungus Streptomyces avermitilis [2]. This drug radically lowered the incidence of river blindness and lymphatic filariasis and was discovered and developed by William C. Campbell and Satoshi Ōmura for which they received the Nobel Prize in Physiology or Medicine in 2015 [3, 4]. Ivermectin is enlisted in the World Health Organization’s Model List of Essential Medicines [5].

Drug repurposing, drug redirecting, or drug reprofiling is defined as the identification of novel usages for existing drugs. The development risks, costs as well as safety-related failure, are reduced with this approach since these drugs have a well-established formulation development, in vitro and in vivo screening, as well as pharmacokinetic and pharmacodynamic profiles. Moreover, the first clinical trial phases of many such drugs have been completed and can be bypassed to reduce several years of development. Therefore, drug repurposing has the potential to reduce the time frame for the whole process by up to 3–12 years and carries great potential [6].

Although several drugs received Emergency Use Authorization for COVID-19 treatment with unsatisfactory supportive data, Ivermectin, on the other hand, has been sidelined irrespective of sufficient convincing data supporting its use. Nevertheless, many countries adopted ivermectin as one of the first-line treatment options for COVID-19.

With the ongoing vaccine roll-out programs in full swing across the globe, the longevity of the immunity offered by these vaccines or their role in offering protection against new mutant strains is still a matter of debate. The adoption of Ivermectin as a “safety bridge” by some sections of the population that are still waiting for their turn for vaccination could be considered as a “logical” option.

Several doctor-initiated clinical trial protocols that aimed to evaluate outcomes, such as reduction in mortality figures, shortened length of intensive care unit stay and/or hospital stay and elimination of the virus with ivermectin use have been registered at the US ClinicalTrials.gov [7]. Real-time data is also available with a meta-analysis of 55 studies to date. As per data available on 16 May 2021, 100% of 36 early treatment and prophylaxis studies report positive effects (96% of all 55 studies). Of these, 26 studies show statistically significant improvements in isolation. Random effects meta-analysis with pooled effects using the most serious outcome reported 79% and 85% improvement for early treatment and prophylaxis respectively (RR 0.21 [0.11–0.37] and 0.15 [0.09–0.25]). The results were similar after exclusion based sensitivity analysis: 81% and 87% (RR 0.19 [0.14–0.26] and 0.13 [0.07–0.25]), and after restriction to 29 peer-reviewed studies: 82% and 88% (RR 0.18 [0.11–0.31] and 0.12 [0.05–0.30]). Statistically significant improvements were seen for mortality, ventilation, hospitalization, cases, and viral clearance. 100% of the 17 Randomized Controlled Trials (RCTs) for early treatment and prophylaxis report positive effects, with an estimated improvement of 73% and 83% respectively (RR 0.27 [0.18–0.41] and 0.17 [0.05–0.61]), and 93% of all 28 RCTs. These studies are tabulated in Table 1. The probability that an ineffective treatment generated results as positive for the 55 studies to date is estimated to be 1 in 23 trillion (p = 0.000000000000043). The consistency of positive results across a wide variety of cases has been remarkable. It is extremely unlikely that the observed results could have occurred by chance [8].

Table 1 All 55 ivermectin COVID-19 trials (As per data available on 16 May 2021) divided based on stage of treatment (Early Vs Late) and the type of study

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However, a controlled outpatient trial by López-Medina et al. demonstrated that, in mild COVID-19, Ivermectin showed no improvement [9]. Misinterpretation of results were noted due to possible gaps in regards to the study quality (study design, the methodology adopted, statistical analysis, and hence the conclusion).

Ivermectin has rapid oral absorption, high liposolubility, is widely distributed in the body, metabolized in the liver (cytochrome P450 system) and excreted almost exclusively in feces [4]. Following a standard oral dose in healthy humans, it reaches peak plasma levels at 3.4 to 5 h; and plasma half-life has been reported to be 12 to 66 h [10]. Despite its widespread use, there are relatively few studies on the pharmacokinetics of Ivermectin in humans [11]. Ivermectin binds strongly to plasma proteins in healthy subjects (93.2%) [12]. Such an “avid binding” can be beneficial when administered in countries where malnutrition and hypoalbuminemia are common, leading to an increased availability of “free fraction” of ivermectin [4]. Hypoalbuminemia is a frequent finding in patients with COVID‐19 and it also appears to be linked to the severity of lung injury [13]. Therefore, Ivermectin might be useful when used in such a setting.

There is evidence supporting the use of Ivermectin in decreasing mortality figures in patients with SARS-CoV-2 infection. However, the use of ivermectin orally in an outpatient setting also requires strict and well defined guidelines to avoid any form of overdosing that could lead to toxicity. A study by Baudou, E et. al described two human ABCB1 nonsense mutations associated with a loss of function in a patient who had an adverse reaction to ivermectin after the administration of a usual dose. This finding warrants caution regarding medical prescriptions of ivermectin and other ABCB1 substrates [14].

This article aims to discuss the mechanism of action by summarizing the in vitro and in vivo evidence demonstrating the role of Ivermectin in COVID-19 as per the available literature over the years. [Table 2] A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications has been proposed. [Fig. 1]

Table 2 A list of studies demonstrating the role of Ivermectin (IVM) on SARS-CoV-2

Full size table

Fig. 1: A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications.

figure1

Ivermectin; IVM (red block) inhibits and disrupts binding of the SARS-CoV-2 S protein at the ACE-2 receptors (green). The green dotted lines depict activation pathways and the red dotted lines depict the inhibition pathways. The TLR-4 receptors are directly activated by SARS-CoV-2 and also by LPS mediated activation (seen during ICU settings) causing activation of NF-Kb pathway and MAP3 Kinases leading to increased intranuclear gene expression for proinflammatory cytokines and chemokines (responsible for cytokine storm) and NO release (responsible for blood vessel dilatation, fluid leak, low blood pressure, ARDS and sepsis). The NF-Kb and STAT-3 pathway activation is central to the pathogenesis and sequelae of COVID-19. STAT-3 physically binds to PAK-1 and increases IL-6 transcription. The annexin A2 at the cell surface converts plasminogen; PLG to plasmin under the presence of t-PA. Plasmin triggers activation and nuclear translocation of STAT-3. An upregulation of STAT-3 stimulates hyaluronan synthase-2 in the lung cells causing hyaluronan deposition leading to diffuse alveolar damage and hypoxia. STAT-3 also directly activates TGF-beta initiating pulmonary fibrosis; a typical characteristic of SARS-COV-2 lung pathology. The damaged type 2 cells express PAI-1 and an already hypoxic state also causes an upregulation of PAI (through Hypoxic inducible factor-1) along with direct stimulation by STAT-3. Simultaneous STAT-3 and PAI-1 activation inhibits t-PA and urokinase-type plasminogen activator leading to thrombi formation. Also, the SARS-CoV-2 spike protein binds to the CD147 on red blood cells and causes clumping. IVM in turn, binds to SARS-CoV-2 Spike protein and hence prevents clumping. T cell lymphopenia in COVID-19 can also be attributed to the direct activation of PD-L1 receptors on endothelial cells by STAT-3. IVM directly inhibits the NF-kb pathway, STAT-3, and indirectly inhibits PAK-1 by increasing its ubiquitin-mediated degradation. The natural antiviral response of a cell is through interferon regulatory genes and viral RNA mediated activation of TLR-3 and TLR7/8- Myd88 activation of transcription of interferon-regulator (IRF) family. For a virus to establish an infection, this antiviral response needs to be inhibited by blocking interferon production. The proteins such as importin and KPNA mediate nuclear transport of viral protein and subsequent IFN signaling. The SARS-CoV-2 proteins (ORF-3a, NSP-1, and ORF-6) directly block IFN signaling causing the surrounding cells to become unsuspecting victims of the infection. IVM inhibits both importin a-b (green) as well as the KPNA-1 receptors (brown) causing natural antiviral IFN release. IVM also inhibits viral RdrP, responsible for viral replication. IVM Ivermectin, ACE-2 angiotensin-converting-enzyme 2, LPS Lipopolysaccharide, TLR Toll-like receptor, t-PA tissue-like plasminogen activator, PLG Plasminogen, IMPab Importin alpha-beta, Rdrp RNA dependant RNA polymerase, KPNA-1 Karyopherin Subunit Alpha 1, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, Map3Kinases Mitogen-activated Kinases, PAK-1 P21 Activated Kinase 1, STAT-3 Signal transducer and activator of transcription 3, PAI-1 Plasminogen activator inhibitor-1, HIF-1 Hypoxia-Inducible Factor

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Methods

A comprehensive search of the PubMed database was conducted from January 1, 2008 up to January 30, 2021 using syntax constructed using MeSH Database as follows: (stromectol OR Ivermectin OR “dihydroavermectin”) OR (22 AND 23-dihydroavermectin B) AND (antiviral OR virus OR COVID-19 OR SARS-CoV-2). All the results obtained were manually reviewed for content, relevance and included when considered appropriate. The papers cited in the references were also reviewed and included when considered appropriate. The articles were retrieved manually to exclude any duplicates.

Results

Ivermectin as an anti-helminth

Ivermectin has been approved as an anti-helminthic [15]. It is a selective positive allosteric modulator at the glutamate-gated chloride channels found in nematodes and insects and acts by binding to these channels leading to chloride ion influx causing hyperpolarization of the cell and hence, dysfunction [16]. However, at higher concentrations, Ivermectin can also bind to host GABA receptors only when the blood-brain barrier (BBB) is “leaky”. This is not the case in healthy human beings with an intact BBB as the drug is “excluded” by a p-glycoprotein drug pump (MDR-1). Chandler et al. considered Ivermectin to be free of potential neurological adverse drug reactions, except in situations of overdose [17].

SARS-CoV-2 virus structure

SARS-CoV-2 is a sarbecovirus with structural similarity to SARS-CoV-1. Out of the four structural proteins of the SARS-CoV-2 beta coronavirus, namely: Spike (S) protein, membrane (M) protein, envelope (E) protein, and nucleocapsid (N) protein, the S protein is responsible for eliciting potent neutralizing antibody responses. The entry of SARS-CoV-2 into the host cell is mediated by the binding of the S1 subunit of its S protein (receptor binding domain) to the Angiotensin-converting enzyme 2 (ACE-2) receptors present on the host cell surface [18]. The S2 subunit is associated with a fusion protein that binds with the cell membrane after priming with Transmembrane protease, serine 2 (TMPRSS-2) and is responsible for fusion with the host cell.

The SARS-CoV-2 genome consists of ∼29.8 kb nucleotides; it possesses 14 open reading frames (ORFs) encoding 27 proteins [19]. The 5′ two-thirds of the viral genome encodes the replicase gene. It contains two ORFs: ORF1a and ORF1b. ORF1a/b encodes two polyproteins by polymerase frameshifting; these are then post-translationally cleaved into 15 non-structural proteins (nsps): nsp1–10 and nsp12–16. The rest of the genome encodes for the four structural proteins [(S protein, E protein, M protein, N protein], in addition to eight accessory proteins (3a/3b, p6, 7a/7b, 8b, 9b, and ORF14) [19]. The replicase also encodes the papain-like protease (PLpro) and the serine-type protease or main protease (Mpro) [20].

In principle, a molecule can act as an anti-viral drug if it “inhibits some stage of the virus replication cycle, without being too toxic to the body’s cells [21].”

The possible modes of action of anti-viral agents would include the following:

1.

Inactivate extracellular virus particles.

2.

Prevent viral attachment and/or entry.

3.

Prevent replication of the viral genome.

4.

Prevent synthesis of specific viral protein(s).

5.

Prevent assembly or release of new infectious virions

The role of Ivermectin against the SARS-CoV-2 virus

The targets of activity of Ivermectin can be divided into the following four groups:

A.

Direct action on SARS-CoV-2

Level 1: Action on SARS-CoV-2 cell entry

Level 2: Action on Importin (IMP) superfamily

Level 3: Action as an Ionophore

B.

Action on host targets important for viral replication

Level 4: Action as an antiviral

Level 5: Action on viral replication and assembly

Level 6: Action on post-translational processing of viral polyproteins

Level 7: Action on Karyopherin (KPNA/KPNB) receptors

C.

Action on host targets important for inflammation

Level 8: Action on Interferon (INF) levels

Level 9: Action on Toll- like-Receptors (TLRs)

Level 10: Action on Nuclear Factor-κB (NF-κB) pathway

Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae

Level 12: Action on P21 activated Kinase 1 (PAK-1)

Level 13: Action on Interleukin-6 (IL-6) levels

Level 14: Action on allosteric modulation of P2X4 receptor

Level 15: Action on high mobility group box 1 (HMGB1),

Level 16: Action as an immunomodulator on Lung tissue and olfaction

Level 17: Action as an anti-inflammatory

D.

Action on other host targets

Level 18: Action on Plasmin and Annexin A2

Level 19: Action on CD147 on the RBC

Level 20: Action on mitochondrial ATP under hypoxia on cardiac function

The direct “antiviral targets” may be useful in the early stages while the anti-inflammatory targets might be addressed in the later stages of the disease.

Direct action of Ivermectin on SARS-CoV-2

Level 1: Action on SARS-CoV-2 cell entry

A study by Lehrer S et al observed that Ivermectin docked in the region of leucine 91 of the SARS-CoV-2 spike protein and histidine 378 of the host cell ACE-2 receptor blocking its entry into the host cell [22]. In yet another study by Eweas et al., potential repurposed drugs such as Ivermectin, chloroquine, hydroxychloroquine, remdesivir, and favipiravir were screened and molecular docking with different SARS-CoV-2 target proteins including S and M proteins, RNA-dependent RNA polymerase (RdRp), nucleoproteins, viral proteases, and nsp14, was performed. Ivermectin showed the following 5 important docking properties [23]:

1.

Highest binding affinity to the predicted active site of the S glycoprotein (Mol Dock score −140.584) and protein–ligand interactions (MolDock score−139.371).

2.

Considerable binding affinity to the predicted active site of the SARS-CoV-2 RdRp protein (MolDock score −149.9900) and protein–ligand interactions (MolDock score −147.608), it formed H-bonds with only two amino acids: Cys622 and Asp760.

3.

Highest binding affinity (MolDock score −212.265) to the predicted active site of nsp14.

4.

The highest binding affinity to the active site of the TMPRSS2 protein (MolDock score −174.971) and protein–ligand interactions (MolDock score −180.548). Moreover, it formed five H-bonds with Cys297, Glu299, Gln438, Gly462, and Gly464 amino acid residues present at the predicted active site of the TMPRSS protein

5.

The free binding energy of the spike protein (open) was higher in Ivermectin (−398.536 kJ/mol) than remdesivir (−232.973 kJ/mol).

An In-silico data analysis conducted by Choudhury et al. demonstrated that Ivermectin efficiently utilizes viral spike protein, main protease, replicase, and human TMPRSS2 receptors as the most possible targets for executing its “antiviral efficiency” by disrupting binding. Since Ivermectin exploits protein targets from both, the virus and human, this could be the behind its excellent in vitro efficacy against SARS-CoV-2 [24].

The development of vaccines for SARS-CoV-2 is centered around spike protein biology (virus targeted) and the recently documented “vaccine escape strains” have been a cause of worry. In such a situation, Ivermectin, is both, virus as well as host targeted and hence could act as a potential therapeutic against these new strains that could “escape” immunity offered by the vaccine.

Level 2: Action on Importin (IMP) superfamily

Inside the cell, the nuclear transport of proteins into and out of the nucleus is signal-dependent and mediated by the Importin (IMP) superfamily of proteins that exist in α and β forms. This IMPα/β1 exists as a heterodimer with a “IBB” (IMP β-binding) site present over IMP α that binds to IMP β1 on “cargo recognition” by IMPα. The SARS-CoV-2 virus upon host cell entry tends to “load” its proteins over the host protein IMP α/β1 heterodimer (importin) to enter the nucleus through the nuclear pore complex. Once inside, the importin molecule detaches while the viral protein from the SARS-CoV-2 virus hijacks the host cell machinery and inhibits the natural cell “anti-viral” response by blocking the release of interferon (an antiviral substance released by an infected cell to alert the surrounding cells of an ongoing viral attack). As a result, the surrounding cells become “unsuspecting victims” of the virus and the infection continues with the virus escaping recognition by the immune cells [25]. Ivermectin, in presence of a viral infection, targets the IMPα component of the IMP α/β1 heterodimer and binds to it, preventing interaction with IMP β1, subsequently blocking the nuclear transport of viral proteins. This allows the cell to carry out its normal antiviral response [26]. In such a case, it should be noted that the activity of Ivermectin here is viro-static, that is, it neutralizes the virus by competing for the same receptor.

Level 3: Action as an Ionophore

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 [27]. 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 [28]. These ionophores allow neutralizing the virus at an early stage of the infection before it can adhere to the host cells and enter it to exploit their biochemical machinery for the production of other viral particles.

Action on host targets for viral replication

Level 4: Action as an antiviral

A systematic review article by Heidary, F. discussed the “anti-viral” properties of Ivermectin against other viruses including the RNA viruses such as Zika Virus (ZKV), Dengue virus, yellow fever virus (YFV), and West Nile virus (WNV), Hendra virus (HEV), Newcastle virus, Venezuelan equine encephalitis virus (VEEV), Chikungunya virus (CHIKV), Semliki Forest virus (SFV), and Sindbis virus (SINV), Avian influenza A virus, Porcine Reproductive and Respiratory Syndrome virus (PRRSV), Human immunodeficiency virus type 1 as well as DNA viruses such as Equine herpesvirus type 1 (EHV-1) and Pseudorabies virus (PRV) [29].

Level 5: Action on viral replication and assembly

An in-vitro study by Caly L et al. demonstrated that the Vero/hSLAM cells infected with the SARS-CoV-2 virus when “exposed” to 5 µM Ivermectin showed a 5000-fold reduction in viral RNA at 48 h when compared to the control group [30]. This study attracted opinions regarding the inability of Ivermectin to achieve the therapeutic effect of COVID-19 through routine dosage. Contrary to this, Arshad et al, by utilizing modeling approach, predicted lung accumulation of Ivermectin over 10 times higher than EC 50. This likelihood of attainment of higher lung tissue concentrations of Ivermectin leaves the door open for further research especially for respiratory infections [31].

An explanation for the study by Caly et al was provided in a review article: Global trends in clinical studies of ivermectin in COVID-19 by Yagisawa et al., co-authored by Prof. Satoshi Ōmura, regarding the “setting of the sensitivity for experimental systems in vitro”. As per the authors, using Vero/hSLAM cells, the antiviral activity of the test drug was reliably measured and the sensitivity of the IC50 = 2 μM set by them was appropriate as neither false positives nor false negatives occurred. Therefore, the study by Caly et al. merely indicated that ivermectin was found to have anti-SARS-CoV-2 activity in vitro—no more, no less. Also, the fact that there are in vivo infection experiments that could be used to connect in vitro experiments to clinical studies [32].

Another in-silico study by Swargiary et al. demonstrated the best binding interaction of −9.7 kcal/mol between Ivermectin and RdRp suggesting inhibition of viral replication [33]. The RdRP residing in nsp12 is the centerpiece of the coronavirus replication and transcription complex and has been suggested as a promising drug target as it is a crucial enzyme in the virus life cycle both for replication of the viral genome but also for transcription of subgenomic mRNAs (sgRNAs) [34]. Ivermectin binds to the viral rdrp and disrupts it. The highly efficient binding of ivermectin to nsp14 confirms its role in inhibiting viral replication and assembly. It is well known that nsp14 is essential in transcription and replication. It acts as a proofreading exoribonuclease and plays a role in viral RNA capping by its methyltransferase activity [35]. Moreover, highly efficient binding of ivermectin to the viral N phosphoprotein and M protein is suggestive of its role in inhibiting viral replication and assembly [23].

Level 6: Action on post-translational processing of viral polyproteins

Once gaining entry into the host cell, the viral RNA is translated by the host ribosome into a large “polyprotein”. Some enzymes break away through autoproteolysis from this polyprotein and further help other proteins to break off and carry out their function for replication. One such enzyme, 3 chymotrypsin-like proteases (3’cl pro/ Mpro) is responsible for working on this polyprotein causing other proteins to “librate” and carry out viral replication. Ivermectin binds to this enzyme and disrupts it. It also efficiently binds to both proteins, Mpro, and to a lesser extent to PLpro of SARS-CoV-2; therefore, it has a role in preventing the post-translational processing of viral polyproteins [23].

Level 7: Action on Karyopherin (KPNA/KPNB) receptors

Karyopherin-α1 (KPNA1) is essential for the nuclear transport of signal transducers and activators of transcription 1 (STAT1) [36], and the interaction between STAT1 and KPNA1 (STAT1/KPNA1) involves a nonclassical nuclear localization signal (NLS). Ivermectin inhibits the KPNA/KPNB1- mediated nuclear import of viral proteins allowing the cell to carry out its normal antiviral response [30].

Action on host targets for inflammation

Level 8: Action on Interferon (INF) levels

These virus-infected cells release interferons that bind to the IFN receptors present on neighboring cells alerting them of a viral attack. The IFN-I and IFN-III receptors then further activate members of the JAK-STAT family. The virus after gaining entry into the host cell hijacks the host cell machinery and works towards antagonizing the normal interferon-mediated host cell antiviral response. SARS-CoV-2 proteins such as ORF3a, NSP1, and ORF6 inhibit IFN-I signaling [37, 38]. As a result, the cells surrounding the SARS-CoV-2 virus-infected cell “fail” to receive “critical and protective IFN signals” causing this SARS-CoV-2 virus to replicate and spread without any hindrance. This is one of the main reasons that, at this stage, COVID-19 infection is “hard to detect” clinically [39].

Ivermectin has been shown to promote the expression of several IFN-related genes, such as IFIT1, IFIT2, IF144, ISG20, IRF9, and OASL [40].

Level 9: Action on Toll- like-Receptors (TLRs)

Upon virus entry, the intracellular pattern recognition receptors (PRRs) present on the host cells are responsible for detecting the viral attack. The virus activates one such PRR named the Toll-like receptors (TLRs). These receptors are present on various immune system cells that help them locate and bind with the pathogen. The activation of TLRs, causes oligomerization, further activating downstream interferon regulatory factors (IRFs) and nuclear factor-kappa B (NF-kB) transcription factors inducing INF production [41]. Ivermectin plays a role in the blockade of activation of NF-kB pathway and inhibition of TLR4 signaling [42].

Level 10: Action on Nuclear Factor-κB (NF-κB) pathway

Activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines [43]. Jiang et al. demonstrated that Ivermectin at its very low dose, which did not induce cytotoxicity, drastically reversed the resistance of tumor cells to the chemotherapeutic drugs both in vitro and in vivo by inhibition of the transcriptional factor NF-κB [44]. Also, Zhang et al., suggested that Ivermectin inhibits lipopolysaccharide (LPS)-induced production of inflammatory cytokines by blocking the NF-κB pathway and improving LPS-induced survival in mice [42]. Therefore, using Ivermectin would be helpful in ICU settings where there are increased chances of bacterial infections (LPS mediated).

Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae

A strong correlation exists between SARS-CoV-2 viral load, disease severity, and progression [45]. COVID-19 not only causes flu-like symptoms such as fever, dry cough but could also lead to widespread thrombosis with microangiopathy in pulmonary vessels [46], raise D-dimer levels [47], cause lymphopenia [48], raise proinflammatory cytokine and chemokine production [49] as well as lead to a significant elevation of CRP levels [50]. SARS-CoV-2 has structural similarity with SARS-CoV-1. Several SARS-CoV-1 proteins antagonize the antiviral activities of IFNs and the downstream JAK (Janus kinase)-STAT signaling pathways they activate. JAK family kinases display a wide range of functions in ontogeny, immunity, chronic inflammation, fibrosis, and cancer [51].

The host proteins, such as the members of the signal transducers and activators of transcription (STATs) and NF-κB, enter the nucleus through nuclear envelope-embedded nuclear pores mediated by the IMPα/β1 heterodimer and play a role in COVID-19 pathogenesis. Frieman et al. demonstrated that accessory SARS ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane [52]. A review article by Matsuyama et al, hinted at SARS-CoV-2-mediated inhibition of IFN and STAT 1, with the subsequent shift to a STAT 3 dominant signaling network that could result in almost all of the clinical features of COVID-19 [39].

Before discussing further, it is important to understand the link between STAT-3 upregulation and COVID-19 sequelae and the role of Ivermectin in inhibiting STAT-3. STAT-3 acts as a “central hub” that mediates the detrimental COVID-19 cascade. In the lungs, STAT-3 activates Hyaluronan synthase-2 leading to deposition of hyaluronan causing diffuse alveolar damage. The damaged type 2 alveolar cells express PAI-1 (plasminogen activator inhibitor-1). Additionally, hypoxia due to diffuse alveolar damage causes an upregulation of PAI-1 through HIF-1a. STAT-3 also directly activates PAI-1. The simultaneous activation of PAI-1 and STAT-3 inhibits t-PA and urokinase-type plasminogen activator leading to thrombi formation in the capillaries. PAI-1 also binds to TLR-4 receptors on macrophages further activating the NF-kB pathway.

The “cytokine storm” typical of severe COVID-19 involves STAT-3 mediated upregulation of proinflammatory cytokines, TNFα, and IL-6 in macrophages. Additionally, STAT-3 induces a C-reactive protein that upregulates PAI-1 levels. STAT-3 is directly responsible for activating IL-6 gene transcription which further leads to an increase in TGF-β causing pulmonary fibrosis. The PD-L1 receptors present on the endothelial cells are activated by STAT-3 causing T cell lymphopenia. Ivermectin inhibits STAT-3 through direct inhibition preventing COVID-19 sequalae [39].

Level 12: Action on P21 activated Kinase 1 (PAK-1)

The p21 activated kinase 1 (PAK1) physically binds to both JAK1 and STAT3, and the resultant PAK1/STAT3 complex activates IL-6 gene transcription responsible for cytokine storm in COVID-19 [53]. Ivermectin suppresses the Akt/mTOR signaling and promotes ubiquitin-mediated degradation of PAK-1 hence compromising STAT-3 activity and decreasing IL-6 production [54].

Level 13: Action on Interleukin-6 (IL-6) levels

A study by Zhang et al. demonstrated that Ivermectin suppressed IL-6 and TNFα production, two major components of the detrimental cytokine storm induced by SARS-CoV-2 and “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes [42, 55].

Level 14: Action on allosteric modulation of P2X4 receptor

P2X receptors are the channels selective to cation, are gated by extracellular ATP [56] and mediate several functions in health and disease [57]. From the seven subunits of P2X receptors, P2X4 is most sensitive to Ivermectin. Positive allosteric modulation of P2X4 by Ivermectin enhances ATP-mediated secretion of CXCL5 (pro-inflammatory chemokine). CXCL5 is a chemo-attractant molecule expressed in inflammatory cells in different tissues and modulates neutrophil chemotaxis and chemokine scavenging [58].

Level 15: Action on high mobility group box 1 (HMGB1)

The damage-associated molecular pattern high mobility group box 1 (HMGB1), is released by damaged cells acting as an agonist for the TLR4 receptor and hence mediating lung inflammation associated with COVID-19 [59]. Ivermectin inhibits HMGB1 [60].

Level 16: Action as an immunomodulator on Lung tissue and olfaction

In a study by DeMelo et al., the effects of Ivermectin were investigated on SARS-CoV-2 infection using the golden Syrian hamster as a model for COVID-19. Both, male and female adult golden Syrian hamsters were intranasally inoculated with 6 × 104 PFU of SARS-CoV-2. At the time of infection, animals received a single subcutaneous injection of Ivermectin (antiparasitic dose of 400 μg/kg) classically used in a clinical setting and were monitored over four days. Mock-infected animals received the physiological solution only. Interestingly, Ivermectin had a sex-dependent and compartmentalized immunomodulatory effect, preventing clinical deterioration and reducing the olfactory deficit in infected animals. This effect was sex-dependent: infected males presented a reduction in the clinical score whereas a complete absence of signs was noticed in the infected females. Regarding the olfactory performance, 83.3% (10/12) of the saline-treated males presented with hyposmia/anosmia, in contrast to only 33.3% (4/12) of IVM-treated males (Fisher’s exact test p = 0.036). No olfactory deficit was observed in IVM-treated females (0/6), while 33.3% (2/6) of saline-treated females presented with hyposmia/anosmia (Fisher’s exact test p = 0.455). Ivermectin dramatically reduced the IL-6/IL-10 ratio in lung tissue, which likely accounts for the more favorable clinical presentation in treated animals [55]. Loss of smell has been reported as one of the common symptoms in COVID-19 [61]. Interestingly, majority of patients in India regained their sense of smell after a brief anosmic period during their clinical course. Ivermectin is being used in India as one of the first-line drugs for COVID-19 treatment. It could be hypothesized that Ivermectin might have a role to play in reducing SARS-CoV-2 induced olfactory deficit.

Level 17: Action as an anti-inflammatory

The mechanism for anti-inflammatory action of Ivermectin was explained as inhibition of cytokine production by lipopolysaccharide challenged macrophages, blockade of activation of NF-kB, and the stress-activated MAP kinases JNK and p38, and inhibition of TLR4 signaling [42, 61, 62]. Moreover, Immune cell recruitment, cytokine production in bronchoalveolar lavage fluid, IgE, and IgG1 secretion in serum as well as hyper-secretion of mucus by goblet cells was reduced significantly by Ivermectin [63].

Action on other host targets

Level 18: Action on Plasmin and Annexin A2

As per study by Kamber Zaidi et al, annexin A2 may be linked to COVID-19 pathophysiology. Annexin A2 acts as a co-receptor for the conversion of plasminogen to plasmin in the presence of t-PA. Increased plasmin levels are found in co-morbid states and is also responsible for early stages of viral infection. Plasmin leads to direct activation of STAT-3 inducing detrimental COVID-19 sequelae. Ivermectin directly inhibits STAT-3 and could play a role in the inhibition of COVID-19 complications.

Level 19: Action on CD147 on the RBC

The transmembrane receptor CD147, present on the red blood cell (RBC) along with ACE-2 has been recognized as a key binding site for SARS-CoV-2 spike protein. The SARS-CoV-2 does not internalize into the RBC but such attachments can lead to clumping [65]. Ivermectin binds to the S protein of the virus making it unavailable to bind with CD147. This action might also be beneficial in advanced stages of COVID-19 presenting with clotting/thrombotic phenomena.

Level 20: Action on mitochondrial ATP under hypoxia on cardiac function

SARS-CoV-2 has been a well-known cause for acute myocardial injury and chronic damage to the cardiovascular system in active infection as well as in long haulers [66]. Nagai et al. demonstrated that Ivermectin increased mitochondrial ATP production by inducing Cox6a2 expression and maintains mitochondrial ATP under hypoxic conditions preventing pathological hypertrophy and improving cardiac function [67].

Conclusion

Considering the urgency of the ongoing COVID-19 pandemic, simultaneous detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention.

Change history

22 June 2021Editor’s Note: Readers are alerted that the conclusions of this paper are subject to criticisms that are being considered by the editors and the publisher. A further editorial response will follow the resolution of these issues

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I'd just note on this that:

• The in vivo evidence of anti-viral action is negative at achievable concentrations and therefore this experimental data trumps the speculation and in silico binding stuff for the first 10 or so (anti-viral action) suggestions in the absence of strong positive trial anti-viral results.
• The action as immunomodulatory is what could be interesting - either good or bad - and we need reliable data to find out. Currently the data does not look great, but this is still open.

There are many many drugs that have complex immunomodulatory possible actions - so this paper would really be more appropriate once we knew what action ivermectin had (if it has one). You can see from this very long lits of possibles that what precisely almost anything does to the immune system is complex and can't be determined without experimental data.

THH

Quote from Navid

As Towne Criers, why do you engage in this? You've been deceived. Maybe you've been deceived that if you deceive others you'll stay part of the club....why not exit the club? Maybe you've been cult programmed at a young age. Maybe your programmers don't care about you? Do you feel it would break you if you had to go with the Truth?

Navid - I think your judgement of people sucks.

I realise my posting here must seem to you annoying, and i guess you call me a Towne Cryer.

My motivation (which everyone except you knows because I've said it) is that

1. I thoroughly enjoy investigating the ins and outs of the science for anything like this that is not fully understood and important.

2. In addition I think some conspiracy theories (pro-Trump anti-democracy ones, antivax ones) do the world a lot of harm, and specifically at the moment antivax conspiracy theories are doing massive harm both to individual lives blighted by COVID and to economies where vaccine hesitancy increases COVID rates and finally to the world, where high COVID rates + vaccines => faster generation of new troublesome variants.

3. I get annoyed when people here who I think know better post obvious lies or make grossly misleading statements.

I am about the most difficult person to deceive - in the sense you mean - around. I see both sides of all issues. I look at details even when they are against my current position. I change position when evidence merits that. I don't accept any one research paper or view as settling things. I think independently. At age 4, on encountering Bible Stories at school from teachers, I came back and asked my parents for more context. They gave it to me being very neutral and not anti-Christian as you might expect. My reply was: I find that very diciffult (sic) to believe" I respect other people's beliefs - about religion. Otherwise the world splits into believers, and non-believers. I'm a non-believer. I, for example, am not an atheist. Militant atheists are too sure of things and have some emotional need to knock down and hurt theists that I do not like.

I suspect though that you, as a strong advocate of various conspiracy theories, are a believer: needing to have a cause you strongly support - not good at seeing both sides of issues - motivated by strong dislike of the other side whom you believe evil - rather than strong dislike of deceit. You talking about the Truth tells me you are a believer. A lot of this COVID stuff is still uncertain, though admittedly the antivax crowd jumps onto a lot of arguments that are demonstrably false.

I might be quite wrong (about the character stuff).

THH

Quote from THHuxleynew

Not surprising - it was an article fishing for a mechanism which is just a list of possibles, so it can't include much.

I'd just note on this that:

• The in vivo evidence of anti-viral action is negative at achievable concentrations and therefore this experimental data trumps the speculation and in silico binding stuff for the first 10 or so (anti-viral action) suggestions
• The action as immunomodulatory is what could be interesting - either good or bad - and we need reliable data to find out. Currently the data does not look great, but this is still open.

There are many many drugs that have complex immunomodulatory possible actions - so this paper would really be more appropriate once we knew what action ivermectin had (if it has one).

THH

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Anti viral Thomas !!!

https://www.mdpi.com/2073-4409/9/9/2100/pdf

Quote from Navid

Most of this people are doing this because of --- a profound disillusionment -- an addiction to materialism

I don't think that is true. At least not of many here, or me.

Quote from THHuxleynew

I don't think that is true. At least not of many here, or me.

its a big picklist...

Quote from THHuxleynew

Navid - I think your judgement of people sucks.

I realise my posting here must seem to you annoying, and i guess you call me a Towne Cryer.

My motivation (which everyone except you knows because I've said it) is that

1. I thoroughly enjoy investigating the ins and outs of the science for anything like this that is not fully understood and important.

2. In addition I think some conspiracy theories (pro-Trump anti-democracy ones, antivax ones) do the world a lot of harm, and specifically at the moment antivax conspiracy theories are doing massive harm both to individual lives blighted by COVID and to economies where vaccine hesitancy increases COVID rates and finally to the world, where high COVID rates + vaccines => faster generation of new troublesome variants.

3. I get annoyed when people here who I think know better post obvious lies or make grossly misleading statements.

I am about the most difficult person to deceive - in the sense you mean - around. I see both sides of all issues. I look at details even when they are against my current position. I change position when evidence merits that. I don't accept any one research paper or view as settling things. I think independently. At age 4, on encountering Bible Stories at school from teachers, I came back and asked my parents for more context. They gave it to me being very neutral and not anti-Christian as you might expect. My reply was: I find that very diciffult (sic) to believe" I respect other people's beliefs - about religion. Otherwise the world splits into believers, and non-believers. I'm a non-believer. I, for example, am not an atheist. Militant atheists are too sure of things and have some emotional need to knock down and hurt theists that I do not like.

I suspect though that you, as a strong advocate of various conspiracy theories, are a believer: needing to have a cause you strongly support - not good at seeing both sides of issues - motivated by strong dislike of the other side whom you believe evil - rather than strong dislike of deceit. You talking about the Truth tells me you are a believer. A lot of this COVID stuff is still uncertain, though admittedly the antivax crowd jumps onto a lot of arguments that are demonstrably false.

I might be quite wrong (about the character stuff).

THH

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The very first thing Christian stories should have taught is that the Empire is usually evil. We're decades into evil empire and most can't seem to string together the first connections between all of these things...thus either in the Club or thoroughly deluded. By rampant use of "Conspiracy theory" as a way to disrespect, shame, and divert conversation...there is no respect upon which to build an actual conversation.

Respect is the basis of trust in a shared humanity...and the perhaps antiquated notion that the conversation even has a point -- the point being to flex by the weight of the conversation. To change. Anyone launching into name calling in the midst of a conversation is not respectful, isn't engaging in real conversation, and is not being genuinely human.

An AI can weight ideas as "conspiracies" and spit them at you -- I wouldnt talk to an AI either.

Quote from Fm1

Anti viral Thomas !!!

https://www.mdpi.com/2073-4409/9/9/2100/pdf

https://iris.paho.org/bitstream/handle/10665.2/52025/PAHOIMSCovid19200008_eng.pdf?sequence=1&isAllowed=y

The first (most signiifcant) in vitro evidence you quote is Caly et al. Put in context here

Caly et al.¹⁰ report a 5,000-fold reduction in SARS-CoV-2 RNA levels, compared with those in controls, after infected Vero/hSLAM cells were incubated for 48 hours with 5 μM ivermectin. The ivermectin IC₅₀ for the virus was calculated at approximately 2.5 μM. These concentrations are the equivalent of 4,370 and 2,190 ng/mL, respectively, notably 50- to 100-fold the peak concentration (C_max) achieved in plasma after the single dose of 200 μg/kg (14 mg in a 70-kg adult) commonly used for the control of onchocerchiasis.¹² Pharmacokinetic studies in healthy volunteers have suggested that single doses up to 120 mg of ivermectin can be safe and well tolerated.¹³ However, even with this dose, which is 10-fold greater than those approved by the US Food and Drug Administration, the C_max values reported were ∼250 ng/mL,¹³ one order of magnitude lower than effective in vitro concentrations against SARS-CoV-2.

FLCC recommend 400ug/kg to 500ug/kg - still 25-50X lower than the EQ50 dose here.

In vitro evidence is unreliable - this does not rule it out. But it makes it look a poor bet and certainly cannot be positive evidence for it.

You might note - on the political Latin American side:

Ivermectin and COVID-19: How a Flawed Database Shaped the Pandemic Response of Several Latin-American Countries - Blog

  [Authors:  Carlos Chaccour , Assistant Research Professor at ISGlobal and BOHEMIA Chief Scientific Officer;  Joe...

www.isglobal.org

Over the last few weeks we have seen the inclusion of ivermectin in the national therapeutic guidelines for COVID-19 of Peru, mass drug administration of ivermectin to 350,000 people for treatment or prevention of COVID-19 in Bolivia, Paraguay restricting the ivermectin market and advocacy groups in Colombia aiming for national ivermectin policy. Why is this happening?

Ivermectin is an antiparasitic drug used for river blindness, lymphatic filariasis and other Neglected Tropical Diseases. It also has some antiviral effect against single-strain RNA viruses like Dengue and Yellow fever. Early in April, researchers from Australia reported that Ivermectin inhibits the replication of SARS-CoV-2 in vitro. They used concentrations that are not readily achieved in the human body but the biological plausibility opened the doors for clinical trials given the drugs excellent safety profile and lack of effective treatment for COVID-19. In this guest editorial at the American Journal of Tropical Medicine and Hygiene we call for scientific rigor and provide rationale for conducting trials. Our own trial on this subject SAINT, was launched on May 13.

However, the policy decisions in Latin-American have been largely based on the analysis presented in a pre-print posted in the SSRN repository in early April by Patel et al. Though only a pre-print, this manuscript has been very impactful: it has been downloaded 15,655 times, its abstract has been viewed 89,895 times (as of May 28, 2020).

Also - relevant to the above LA political decision - showing how poor the initila pro-ivermectin evidence was:

The authors claim to have used data from the Surgical Outcomes Collaborative (Surgisphere Corporation, Chicago, IL, USA). According to a recent publication in The Lancet (discussed below), the data included in this collaborative platform is “de-identified data obtained by automated data extraction from inpatient and outpatient electronic health records, supply chain databases, and financial records. In other words, there is some form of collaboration agreement with hundreds of hospitals using electronic records from around the world that allow this private corporation to automatically retrieve patient’s data periodically. At least in the EU, this seems to go directly against several points of the EU General Data Protection Regulation (GDPR) and the Privacy Shield EU-US collaboration scheme for the transfer of personal data.

Several concerns about this database have been raised based on the recent Hydroxychloroquine analysis published in The Lancet by the same authors of the ivermectin pre-print. These concerns are largely addressed elsewhere.

The first version of the ivermectin pre-print was posted on April 6*. This version evaluated data from 1,970 critically ill hospitalized patients diagnosed with COVID-19 with lung injury requiring mechanical ventilation from 169 hospitals across Asia, Europe, Africa, North and South America between January 1st 2020 and March 1st 2020. This included 52 patients treated with ivermectin, three of these patients (critically ill, requiring ventilation) came from African hospitals, but by March 1st, only two COVID-19 cases had been confirmed in the whole African continent.

After finding out this discrepancy, we contacted the authors via email and the answers received left our concerns unchanged. Additionally, the manuscript presented a survival analysis with serious methodological flaws (Figure 1

Figure 1

The first version was removed and substituted by a second version of this by April 19*. This new version included data from 1,408 PCR-confirmed, hospitalized patients diagnosed with COVID-19 between January 1, 2020 and March 31, 2020. The data came from 169 hospitals in three continents. Half of these patients (704) had received a single dose of ivermectin (150 mcg/kg) and were matched “exactly on age, sex, race, underlying co-morbidity including chronic obstructive pulmonary disease (COPD), history of smoking, history of hypertension, diabetes mellitus, coronary artery disease, other cardiac disease, an index of illness severity (qSOFA) as well as medication use including hydroxychloroquine, azithromycin and corticosteroids”.

The outcomes from this analysis are a 65% reduction in the need for mechanical ventilation (7.3 vs 21.3%) and an 83% reduction in the overall death rate (1.4% vs 8.5%) in patients treated with ivermectin (figure 2). There are however two problems** with these data:

• The need for mechanical ventilation in untreated patients seems quite high. As an example, in Spain, as of May 20, 2020, only 9% of all hospitalized patients (11,454 out of 124,521) have required ICU admission, a prerequisite for mechanical ventilation [Source: official statistics from ISCiii).
• The data described in the manuscript do not match the figure.

In spite of these flaws this analysis has been cited in a white paper advocating for ivermectin to be included in the national COVID-19 treatment guidelines of Peru. This was followed shortly by a ministerial level communication recommending the use of ivermectin for COVID-19, albeit recognizing the lack of evidence and requesting informed consent. This however led to a black market and alleged distribution of veterinary formulations. All in spite of some strong voices from local scientific leaders including the ex-minister of Health Patricia García.

In spite of these flaws this analysis has been cited in a white paper advocating for ivermectin to be included in the national COVID-19 treatment guidelines of Peru

Health authorities from Bolivia has followed closely and even went a step further into distributing 350,000 ivermectin doses in the city of Trinidad. In Paraguay the authorities had to restrict ivermectin sales after a surge in demand.

This off-label use of ivermectin entails several risks:

• Diversion of drug supply, causing shortages for its use in proven indications.
• The use of veterinary formulations or non-supervised doses could lead to unforeseen side effects that can harm ongoing mass treatment schemes at community. level such as the Mectizan Donation Program which managed to eradicate river blindness in Colombia just a few years ago.
• Rural regions of Latin America have a high prevalence of intestinal helminths. These parasite are known to modulate one type of immune response that favors viral clearance. Mass deworming due to ivermectin could have repercussions on the severity of COVID-19.
• Moral hazard, due to a false feeling of protection or treatment with the drug.
• Impossibility to conduct clinical trials should ivermectin become the new standard of care.

Once again, scientific rigor is needed, even in pandemic times.

Related resources

ASTMH editorial

One-hour conversation with clubes de ciencia Bolivia on this subject

Our own clinical trial, SAINT

Updates

[*06/02/2020: The first version of this text indicated that the preprint on ivermectin appeared on April 16, while it was actually April 6. The release date of the second version of the preprint has also been updated. Initially it was written that it had been published on April 21, while the correct date is April 19.]

[**06/04/2020: Initially it was stated that the second version of the preprint had three problems with the data. The second of the problems said that the mortality rate in hospitalized COVID-19 patients receiving mechanical ventilation was too low, based on a case series of 5,700 patients hospitalized with COVID-19 in New York which showed a mortality among those receiving mechanical ventilation was 88%. These data came from a paper by Richardson et al. which has been corrected. For more details, see https://jamanetwork.com/journals/jama/fullarticle/2765367]

More evidence for Ivermectin as an anti viral

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Quote from Navid

By rampant use of "Conspiracy theory" as a way to disrespect, shame, and divert conversation...there is no respect upon which to build an actual conversation.

Respect is the basis of trust in a shared humanity...and the perhaps antiquated notion that the conversation even has a point -- the point being to flex by the weight of the conversation. To change. Anyone launching into name calling in the midst of a conversation is not respectful, isn't engaging in real conversation, and is not being genuinely human.

If you are not rubbishing the collective scientific efforts of the world (the 95% who support vaccines, do not yet see evidence for ivermectin as treatment for COVID) I will withdraw my conspiracy theory statement.

If you, based on some abstraction, think all these people are distorting their findings then I think that is a fair definition of a strong conspiracy theory.

Conspiracy theories (as the phrase is used) share the view that most people (and also most experts) considering the matter have got it wrong and are deluded. Note this is different from a scientific debate where scientists take both sides but nobody is deluded and the evidence of both sides as considered and where relevant incorporated by the other. Science is often uncertain and these debates can go on a long time.

Now, occasionally such theories are correct. Obviously expects can be wrong and groupthink is possible.

Where I object to this is when the theories are patently absurd (QAnon) or whether they involve judgments made by non-expert scientists which are repeatedly and transparently refuted by experts, where I have read both sides and find the original claims have no evidence - MMR controversy, most of the post-MMR antivax stuff, most of the anti-mRNA anti-COVID-vax stuff, the anti-AGW people, would be examples.

These scientific conspiracy theories are only conspiracy theories because the science on which they depend has been repeatedly considered and found bad. in most cases the original science (e.g. as with MMR) was appallingly bad.

THH

Public Health Ontario Reports 100+ Youth Hospitalizations Involving Heart Problems Post COVID-19 mRNA Vaccination

Public Health Ontario Reports 100+ Youth Hospitalizations Involving Heart Problems Post COVID-19 mRNA Vaccination

Public Health Ontario (PHO) released a thus far largely unnoticed report aggregating COVID-19 immunization adverse events following immunization or (AEFI)

trialsitenews.com

Public Health Ontario (PHO) released a thus far largely unnoticed report aggregating COVID-19 immunization adverse events following immunization or (AEFI) in Ontario reported in the Public Health Case and Contract Management Solution. For the period of Dec. 13, 2020, to August 7, 2021, PHO reports a significant cluster of vaccine safety activity associated with the ongoing COVID-19 program. Based on vaccines associated with both Pfizer-BioNTech and Moderna, the report reveals that by August 7 106 cases of myocarditis/pericarditis were reported in Ontario residents under the age of 25, representing over fifty percent of the total incidents. Segmented by age, 31 of the total cases were reported in young people 12 to 17 years old while 75 of the total were in the 18 to 24-year-old group. Put another way 80% of the total AEFIs were young people 24 and below; 80% of the entire group were made.

Warnings Noted

While the U.S. Food and Drug Administration (FDA) recently, and controversially approved the Pfizer-BioTNech product, or as TrialSite discussed, essentially established two parallel approved and EUA pathways, the agency also reported increased risk for males over 40 for myocarditis and/or pericarditis following administration of the Pfizer-BioNTech vaccine.

The world’s regulators are on notice. An accelerated vaccine product, seemingly safe and effective, but waning in effectivity over time now becomes associated with the need for three shots (an additional booster) and now Israel’s COVID czar has come out and declared be ready for a fourth booster and perhaps even more.

What does this mean in terms of risk when so little data is known—these products are still very young. Thus, PHO issued a directive in the summer instructing public health agencies of Canada to direct surveillance efforts toward these particular conditions, with a recognition that similar AEFIs were recorded in both the United States and Israel.

Some Findings

PHO shows that rates of cases associated with myocarditis/pericarditis were higher following the second dose of mRNA vaccine than after the first dose, particularly for those receiving the Moderna vaccine as the second dose of the series (regardless of the product received for the first dose).

The Canadian public health agency furthermore conveyed that the total rate of case reports associated with the Pfizer-BioNTech vaccine was 6.4 million doses administered following the first dose and 8.7 per million doses administered following the second dose when combining age groups and gender.

Breaking out vaccines PHO reveals that the Moderna vaccine reporting rate was 6.6 million doses administered following the first dose and a noticeable spike of 28.2 per million doses administered following the second dose, for all age groups and genders combined.

One particular group—those aged 18 to 24—when receiving the second dose of an mRNA COVID-19 vaccine were more at risk with a 37.4 per million doses associated with Pfizer-BioNTech and a noticeable 263.2 per million following the Moderna vaccine as the second dose.

While these rates are high, according to the Canadian Immunization Guide a rare AEFI occurs at a frequency of 0.01% to less than 0.1%. The Canadian POH continues a march forward with a full-throttle vaccine-centric strategy discounting these cases as rare given the vaccine’s high effectiveness at preventing symptomatic infection with severe outcomes, which is also associated with the risk of myocarditis.

The key for any true risk-based effort would be to understand what the risks of myocarditis and pericarditis are associated with COVID-19 and compare that to the risks of these adverse events occurring via vaccination.

Quote from Fm1

More evidence for Ivermectin as an anti viral

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

https://portlandpress.com/bioc…fic-inhibitor-of-importin

I'm repeating myself. I agree ivermectin has been shown to be an antiviral - as are very many other drugs.

The issue is that the Caly et al result you cited showed an in vitro result, against COVID specifically, that looked much too high to be useful.

In pharmocology quantities matter. All drugs have side effects and activities. You want the desired action (as much as possible) with minimum amount of side effect.

So when you have shown that a drug does not kill COVID except at much higher concentrations than it is able to be safely prescribed it is not good identifying specific not clearly quantitative mechanisms for its antiviral action.

Quote from Fm1

One particular group—those aged 18 to 24—when receiving the second dose of an mRNA COVID-19 vaccine were more at risk with a 37.4 per million doses associated with Pfizer-BioNTech and a noticeable 263.2 per million following the Moderna vaccine as the second dose.

While these rates are high, according to the Canadian Immunization Guide a rare AEFI occurs at a frequency of 0.01% to less than 0.1%. The Canadian POH continues a march forward with a full-throttle vaccine-centric strategy discounting these cases as rare given the vaccine’s high effectiveness at preventing symptomatic infection with severe outcomes, which is also associated with the risk of myocarditis.

260 per million looks very high for Moderna.

I'm wondering what Ron Brown (TSN) is doing singling out data from one Canadian province for a vaccine that has been used throughout the world. The first step in evaluating this data would be to see whether it is consistent with data found in other places? The second step (or maybe first) would be to assess its statistical significance. How many cases was this figure based on?

Anyway, worth looking carefully at all the data, but not helpful to have this one thing singled out. Since everyone throughout the world is already aware of higher than normal myocarditis/pericarditis AEs from young men in this age group for mRNA vaccines we will get better data by looking at larger numbers.

Quote from THHuxleynew

260 per million looks very high for Moderna.

I'm wondering what Ron Brown (TSN) is doing singling out data from one Canadian province for a vaccine that has been used throughout the world. The first step in evaluating this data would be to see whether it is consistent with data found in other places? The second step (or maybe first) would be to assess its statistical significance. How many cases was this figure based on?

Anyway, worth looking carefully at all the data, but not helpful to have this one thing singled out. Since everyone throughout the world is already aware of higher than normal myocarditis/pericarditis AEs from young men in this age group for mRNA vaccines we will get better data by looking at larger numbers.

As you said, it's a good way to compare data from regions around the world. It could be environmental which would need smaller community data to compare against each. Maybe there is a trigger

Quote from Fm1

You couldn't explain India,

Leading Indian epidemiologists say they can explain the data, and they say it has nothing to do with ivermectin. They say this is the natural course of an epidemic. The curve is what you would expect from local herd immunity. The reported rates of infection and death were too low for herd immunity, but the epidemiologists conducted independent antibody tests. They found the actual infection rate was far higher than reported (I recall it was 10 to 20 times higher), and it was enough to reach herd immunity.

Quote from Fm1

ow do you explain the southern hemisphere where ivermectin is used. Vaccination rates are about 29% for the southern hemisphere

Vaccination rates in many South American countries is now higher than the US, and the infection rates have plummeted. Chile is at 76% vaccinated. Infections and deaths are close to zero.

Chile COVID: 1,641,526 Cases and 37,108 Deaths - Worldometer

www.worldometers.info

A test of ivermectin in Chile showed no effects.

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19

This randomized trial compares the effects of ivermectin vs placebo on time to symptom resolution within 21 days among patients with mild COVID-19.

jamanetwork.com

In case some question about young people

The Vaccine Versus the Virus: An Update

The virus is more dangerous than the vaccine for adolescents and young adults.

The Vaccine Versus the Virus: An Update

Editor's note:I decided to take the holiday off. Fortunately, Dr. Howard was eager and itching to go with a post to fill in for me. In fact, Dr. Howard has…

sciencebasedmedicine.org

My personal vision is that it is good, but no reason to make a war at home for young people... there are more important questions, like social life, education, depression, meeting people...

Anyway vaccines just better than the virus, that we will all catch , probably even the immunized, the formerly infected...

For me I admit it is not even a question, the virus was more deadly than my former practice of skydiving, urban bike and big wall climbing. I stopped all when dad, so same for the Virus.

My daughter is immunized, to avoid long covid and anxiety... Her most important need is living parents, good education and social life.

Best wishes to all.

Quote from JedRothwell

Chile is at 76% vaccinated.

Brazil and Uruguay are also far ahead of the U.S. in vaccinations. Cases and deaths are have fallen in both. Uruguay is close to zero. Most other countries in S. America are about the same as the U.S., but cases are falling steadily with no new wave of infections.

COVID-19 vaccine rollout: charts, maps and eligibility by country

Tracking the coronavirus vaccination rollout and who has access to a vaccine around the world

graphics.reuters.com

Venezuela is far behind, as you would expect, alas. They are mired at high rates of infection and death. They began using ivermectin last year. It is not clear how widely it is being used, but you can see it is not reducing cases or deaths.

Ivermectin: repurposing a multipurpose drug for Venezuela's humanitarian crisis - PubMed

Ivermectin (IVM) is a robust antiparasitic drug with an excellent tolerance and safety profile. Historically it has been the drug of choice for onchocerciasis…

pubmed.ncbi.nlm.nih.gov