Ivermectin for COVID 19

Ivermectin which belongs to the avermectin (a macrocyclic lactone 22,23-dihydroavermectin B produced by the bacterium Streptomyces avermitilis [1]) family, is a drug discovered over 50 years ago by Satoshi Omura and William Campbell (more information.) Ivermectin is one of the safest drugs available. It is on the World Health Organization’s List of Essential Medicines, is FDA-approved as an antiparasitic agent, has been given 3.7 billion times around the globe, in addition to winning the Nobel prize in 2015 for its global and historic impacts in eradicating endemic parasitic infections in many parts of the world.

Ivermectin has been used on humans for decades to treat various parasites including head lice, scabies, and traditionally other human diseases caused by roundworms of ectoparasites. It’s also been used extensively in animals to treat parasitic infections like heartworm, acariasis, and others.

If your family member is in the hospital in critical condition with COVID-19 infection please skip to this section

Please Note: This article is subject to change, and is updated with new studies, articles or data as it becomes available.

• 11-6-2021 Added Information from Dr. Theresa Anne Lawrie – Added new BIRD IICC videos
• 11-8-2021 Added worldcouncilforhealth.org At-Home Early Treatment Guidelines for COVID-19 – Added data_is_louder Indonesia and Ivermectin use twitter post – Added aapsonline.org Guide to Home-Base COVID Treatment
• Added section showing Ivermectin as a protease inhibitor, and so is Pfizers new SARS-CoV-2 drug
• Improved section on Ivermectin and COVID-19 in Africa

“There are few drugs that can seriously lay claim to the title of ‘Wonder drug’, penicillin and aspirin being two that have perhaps had greatest beneficial impact on the health and wellbeing of Mankind. But ivermectin can also be considered alongside those worthy contenders, based on its versatility, safety and the beneficial impact that it has had, and continues to have, worldwide”

“Ivermectin proved to be even more of a ‘Wonder drug’ in human health, improving the nutrition, general health and wellbeing of billions of people worldwide“

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Source c19ivermectin.com

History of Ivermectin

The highly potent bioactivity of a fermentation broth of an organism isolated by the Kitasato Institute in Tokyo, which had been sent to Merck’s research laboratories in 1974. Ivermectin was officially identified in 1975, It’s role in human medicine effectively began in April 1978 inside the Merck company, several years before the drug emerged on the Animal Health market.

The results, obtained in November 1978, showed that ivermectin was “highly effective in preventing patent infections with both O. gibsoni and O. gutturosa”. Ivermectin was marketed successfully from 1981 for parasitic infection indications in animals, and then approved for human use for activity against onchocerciasis (river blindness) in 1987.

It has since been used successfully to treat a number of human parasitic worm infestations causing river blindness/filariasis, strongyloidiasis/ascariasis, ectoparasites causing scabies, pediculosis (lice infestation), rosacea [1, 3]. As well as treatment of onchocerciasis, cutaneous larva migrans, Gnathostomiasis and Trichuriasis. More recent applications include to control insect mediators of infection, such as malaria [1 , 3 , 4 , 5]

Ivermectin and Onchocerciasis (River Blindness)

The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms.

A single annual dose of 150 µg/kg of ivermectin, given orally, can reduce the level of skin microfilariae to zero and, by interfering with worm embryogenesis, can delay the build-up of new microfilariae for a period of up to two years.

In the early-1970s, the disease was endemic in 34 countries: 27 in Africa; 6 in the Americas; and 1 in the Arabian Peninsula. The World Health Organization (WHO) later estimated that 17.7 million people were infected worldwide, of whom some 270,000 were blind, and another 500,000 severely visually disabled.

By 1973, Onchocerciasis had been recognized by the then head of the World Bank, Robert McNamara, as a major disease of massive health and socioeconomic importance. Four United Nations agencies, including the World Bank, launched the Onchocerciasis Control Programme in West Africa (OCP). The programme covered 1.2 million km², protecting 30 million people in 11 countries from River Blindness.

In January 1980, Merck decided to proceed independently to Phase I (safety) trials. Clinical trials of ivermectin began in 1981, with a Phase I trial in 32 patients in Senegal followed by another trial in Paris among 20 West African immigrants. The studies found that a single dose of ivermectin, 30 µg/kg, substantially decreased the number of skin microfilariae. It also established that the effect lasted for at least 6 months, with no serious adverse events being observed.

A UN-based Special Programme for Research & Training in Tropical Diseases (TDR) was established in 1975 essentially offering funds and resources to push the search for drugs against tropical diseases; donating several million to that end. Some 10,000 compounds, many supplied by leading pharmaceutical companies as coded samples, passed through the screening network set up by TDR. TDR reactions to the initial data about ivermectin were rather muted. When Merck officials visited TDR and OCP in 1982 to present the results from the Phase I trials, each side recognised the immense potential and collaboration in earnest began.

Following the registration of ivermectin (produced under the brand name Mectizan^®) for human use in 1987, in a hitherto unprecedented move and with unheralded commitment, Mectizan^® was donated by the manufacturing company, Merck & Co. Inc., to treat onchocerciasis in all endemic countries.

Ivermectin began to be distributed in 1988, with operations being organized through the independent Mectizan Donation Program (MDP) established and funded by Merck. Thereafter, OCP control operations changed from exclusive vector control to larviciding combined with ivermectin treatment or, in some areas, to ivermectin treatment alone. 

Ivermectin proved to be virtually purpose-built to combat Onchocerciasis, and swiftly became the drug of choice for the treatment of Onchocerciasis due to its unique and potent microfilaricidal effects, the absence of severe side effects and its excellent safety.

 It is now the sole tool being used in disease elimination campaigns in the 16 other African countries where the disease exists, orchestrated by the African Programme for Onchocerciasis Control (APOC) launched in 1996. OCP ceased operations in 2002 after virtually eliminated disease transmission of Onchocerciasis.

Ivermectin and other filarial diseases

In the mid-1980s, well before ivermectin was approved for human use to treat onchocerciasis, Merck were also undertaking trials of ivermectin to measure its impact against lymphatic filariasis and to find optimal treatment dosages. [36] Ivermectin even at low dose, proved even especially effective, decreasing microfilarial density by 99% after one year and 96% after two years

In late-1998, following registration of the drug for lymphatic filariasis, Merck extended its ivermectin donation programme to cover lymphatic filariasis in areas where it co-existed with Onchocerciasis. Subsequently, in 1999/2000, the WHO launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF).

Ivermectin Safety and Awards

Ivermectin has an established safety profile for human use (Gonzalez Canga et al., 2008; Jans et al., 2019; Buonfrate et al., 2019), and is FDA-approved for a number of parasitic infections (Gonzalez Canga et al., 2008; Buonfrate et al., 2019). The World Health Organization has long included ivermectin on its WHO Model List of Essential Medicines.

Over 3.7 Billion human beings have been treated with Ivermectin for parasitic diseases, which has resulted in less than 5695 reports, and only 20 deaths (approx. as of 9-15-21) in total have resulted from Ivermectin treatment, according to WHOs own database VigiBase.

“It is one of the safest medications ever made. It is safer then Aspirin! More people have died from Aspirin, than from Ivermectin”

Dr. Paul Marik

Standard doses of ivermectin (0.2 mg/kg x 1–2 days) have a nearly unparalleled safety profile historically among medicines as evidenced by the following findings:

1. WHO Guidelines for Scabies: “the majority of side effects are minor and transient”
2. Prof Jacques Descotes, Toxicologist, Expert on Safety of Ivermectin: “severe adverse events are unequivocally and exceedingly rare”
3. LiverTox Database: Not considered toxic to the liver
4. Nephrotox Database: Not considered toxic to the kidney
5. PneumoTox: Not considered toxic to the lungs

“Ivermectin is one of the world’s safest, cheapest and most widely available drugs,”

Dr. Kory head of FLCCC

“Ivermectin has continually proved to be astonishingly safe for human use. Indeed, it is such a safe drug, with minimal side effects, that it can be administered by non-medical staff and even illiterate individuals in remote rural communities, provided that they have had some very basic, appropriate training.“

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

NIH Table 2e. Characteristics of Antiviral Agents That Are Approved or Under Evaluation for the Treatment of COVID-19 | Ivermectin Approved by NIH

If you go to the NIH (National Institute of Health) website covid19treatmentguidelines.nih.gov and scroll to the bottom you will find Ivermectin listed as an NIH approved drug for treatment of COVID 19 near the bottom of Table 2e. Characteristics of Antiviral Agents That Are Approved or Under Evaluation for the Treatment of COVID-19 (see below.)

WHO Model List of Essential Medicines – Ivermectin

Ivermectin has been on the the WHO Model List of Essential Medicines for roughly 35 years, originally added to the database 1987. It is currently classified under anti-infective medicines.

Ivermectin was first approved for human use in the United States back in 1996. The U.S. Food and Drug Administration (FDA) declared it to be a safe and effective remedy for treating two parasitic infections: strongyloidiasis and onchocerciasis.

The list is available by electronic search using the WHO Electronic EML or access the latest hard copy of the WHO Model List of Essential Medicines PDF by scrolling down on the main page or searching “list of essential medicines 22nd” (22nd is the 2021 publication, which at the time of writing this article is the latest, but you can replace 22 with the correct number for future publications ie: 23 for 2022, 24 for 2023, etc) and click the dropdown that appears to show search results before pressing enter.

WHO Model List of Essential Medicines Ivermectin Search | Video Guide

WHO Model List of Essential Medicines 2021 PDF

WHO Pharmacological Vigilance DataBase | VigiBase

Established by the WHO, VigiBase is the WHOs global database of reported potential side effects of medicinal products. It tracks side effects and deaths of medications for the last 25 years; however it is only accessible to health care practitioners. Public access of VigiBase is available through VigiAccess, a non profit site established by WHO.

“VigiBase is the unique WHO global database of individual case safety reports (ICSRs). It is the largest database of it’s kind in the world, with over 25 million reports of suspected adverse effects of medicines, submitted since 1968, by member countries of the WHO Programme for International Drug Monitoring. It is continually updated with incoming reports“

VigiAccess

Ivermectin Search on VigiAccess

If you search “Ivermectin” on VigiBase the results show that in the 25+ years the database has existed, and with over 3.7 Billion humans treated worldwide with ivermectin, there is a total of 20 Deaths. When you search COVID-19 Vaccine it lists 11,536 deaths as of Oct 6 2021 and the COVID-19 vaccines have only been available for roughly a year.

Ivermectin Deaths vs COVID-19 Vaccine Deaths on WHO VigiBase | Video

Argument “These numbers are useless because we don’t know how many people took Ivermectin; probably a magnitude less than those who received COVID-19 vaccines!!!!

According to WHO VigiBase database covers all reports from all member countries of the WHO PIDM, and is kept up to date. So according to WHO the stats from their database include, every single person that has taken ivermectin and had an Adverse reaction, who is a member of the WHO PIDM.

Ivermectin has been used to treat over 3.5 billion people over 25+ years and according to WHOs own database that has resulted in less than 5695 reports submitted into their database, with a total of only 20 deaths from Ivermectin. These statistics including the last two years 2020-2021 where Ivermectin has seen widespread use, and more people self administering the drug, due to COVID-19.

So why are health authorities banning Ivermectin on the premise that is not safe? That’s a darn good question…a big part of it is greed.

The 2014 Gairdner Global Health Award for Ivermectin

“The 2014 Gairdner Global Health Award was conferred for discovery of the unique microorganism that is the sole source of the endectocidal avermectins, and the Public sector/Private sector Partnership that developed innovative biopharmaceuticals with immeasurably beneficial impact on public health worldwide. Ivermectin is already labelled a ‘wonder drug’, essential for campaigns to eliminate two disfiguring and devastating tropical diseases. New uses for it are identified regularly, including possible antibacterial, antiviral, and anticancer potential. Hundreds of millions of people are taking ivermectin to combat various diseases and afflictions, and mass administration of ivermectin in polyparasitised poor communities around the world is increasingly recognized as a mechanism to easily and cost-effectively improve overall health and quality of life for everyone.”

Ivermectin: panacea for resource-poor communities?

Fast forward to 1:04:00 for the speech regarding Ivermectin.

The 2014 Gairdner Global Health Award Award Ceremony | Video

Nobel Prize awarded to Ivermectin in 2015 | Video

“the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases”.

 The Nobel Prize in Physiology or Medicine 2015″

Ivermectin: panacea for resource-poor communities? | Review

A review published Sep 2014 titled Ivermectin: panacea for resource-poor communities? showed how Ivermectin is one of the worlds most successful and promising medicines. From it’s award winning discovery, to the over 300 million people given Ivermectin annually as a treatment for a variety of diseases from river blindness to elephantiasis.

• Gairdner Global Health Award given for discovery, development, and use of ivermectin.
• Ivermectin is one of the world’s most successful and promising biomedical compounds.
• Administration of ivermectin to entire communities improves health and social welfare.
• Donated ivermectin use will soon eliminate river blindness and elephantiasis globally.
• Over 300 million poor people take ivermectin annually to treat a range of diseases.
• Ivermectin has significant promise to combat a variety of diseases of global concern.
• Extensive research is needed to clarify the potential use of ivermectin in human health.
• Multidisciplinary, international partnerships hold the key to better public health.

Ivermectin 20 years on: maturation of a wonder drug | Review

An article published Nov 2005 titled Ivermectin 20 years on: maturation of a wonder drug showed how Ivermectin “revolutionized the treatment of nematode and arthropod parasites in animals and has provided hope for the control or even eradication of filariases in humans.”

Ivermectin: 25 years and still going strong | Review

A review posted Feb of 2008 titled Ivermectin: 25 years and still going strong outlines the anti viral properties of Ivermectin after 25 years of use, and billions treated.

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective |Review

A review published in 2011 titled Ivermectin, ‘Wonder drug’ from Japan: the human use perspective, analyzed human use of Ivermectin.

Safety of High Dose Ivermectin

As of 10-23-2021 there are dozens upon dozens of studies, and also several accepted meta-analysis of studies on ivermectin, which show it’s safety and efficacy against COVID-19 (please visit ivmmeta.com for a more updated list).

Safety of high-dose ivermectin: A systematic review and meta-analysis

A meta-analysis published Apr 2020 titled Safety of high-dose ivermectin: a systematic review and meta-analysis analyzed data from 6 studies on higher Ivermectin doses ≥200 and ≥400 μg/kg and compared adverse events by severity and organ system effected. The study found no differences in adverse events even for much higher doses of Ivermectin.

“no differences in the number of individuals experiencing adverse events. A descriptive analysis of these clinical trials for a variety of indications showed no difference in the severity of the adverse events between standard (up to 400 μg/kg) and higher doses of ivermectin.”

Safety of high-dose ivermectin: a systematic review and meta-analysis

“In all the studies included in this review, the safety profile of ivermectin was reported to be favorable.”

Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis

Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects | Clinical Trial

A Clinical Trial published Oct 2002 tested the Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects to discern weather higher or more frequent doses of ivermectin, than approved for human use (at the time), were safe. Patients were evaluated in a double-blind, placebo-controlled, dose escalation study. The study found Ivermectin was well tolerated even at doses 10 times the DFA doze of 200ug/kg.

“This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.”

Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects

Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo)

1. 30 mg (three times a week) – The 30 mg panel (range: 347–594 μg/kg) also received a single dose with food after a 1-week washout
2. 60 mg (three times a week)
3. 90 mg (single dose)
4. 120 mg (single dose)

Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis (pupil dilation), accurately quantitated by pupillometry (measurement of pupil diameter or width.)

“Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 μg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose.”

Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects

Safety of High dose Ivermectin for COVID-19

In COVID-19, particularly in regard to the emerging variants of concern, viral loads are higher and viral replication is thought to be prolonged. Given that ivermectin has demonstrated a strong dose-response relationship in terms of viral clearance, higher doses have not only been required, but have demonstrated clinical efficacy.

“the evidence provided by our systematic review and meta-analysis, with risk of bias assessment and grading of the certainty of the evidence represents the highest level of evidence that is used under normal circumstances and goes beyond the level of evidence required by NICE to make a recommendation on ivermectin during a pandemic.”

“I reiterate that the evidence in support of using ivermectin for treatment of covid-19 is far stronger than the evidence on any other medicine given emergency use authorization to treat covid-19”

Written Evidence Submitted by Dr. Theresa Anne Lawrie, Director, The Evidence based Medicine Consultancy Ltd (CLL0115)

“Some doctors argue that toxicity shows up at the higher dose required for COVID-19, and cite cases of neurotoxicity and other effects such as:

• Coma
• Paralysis
• Speech disabilities
• Motor deficits
• Modify gut bacteria – can change metabolism and immunity
• Hinder immunity to COVID
• Reduce ability to mount effective response to vaccine
• Viral resistance

However many doctors who support IVN (Ivermectin) state it is one of the safest medicines available (even at the high doses required for COVID-19), with a wide therapeutic window of safety. And that the very few cases of neurotoxicity, are very rare and isolated incidences. Ivermectin does not cross the BBB (Blood Brain Barrier) and therefore it’s nearly impossible for it to cause neurotoxicity.”

“(Ivermectin) has proven to be safe. Doses up to 10 times the approved limit are well tolerated by healthy volunteers

Prof. Chris Whitty – UK Government Chief Scientific Officer

“The higher dosage (1200 µg/kg for 5 days) showed no safety
concerns, as no SADR were observed”

High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

As you will see below the evidence for the safety of High dose Ivermectin for prophylaxis and treatment (different doses respectively) is insurmountable.

“Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 μg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose.”

Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects

“no differences in the number of individuals experiencing adverse events. A descriptive analysis of these clinical trials for a variety of indications showed no difference in the severity of the adverse events between standard (up to 400 μg/kg) and higher doses of ivermectin.”

Safety of high-dose ivermectin: a systematic review and meta-analysis

“recent reviews and meta-analysis indicate that high dose ivermectin has comparable safety as the standard low-dose treatment”

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

“IVM (Ivermectin) doesn’t cross the blood brain barrier in vertebrates, owing to its high specificity in targeting the the glutamate- chloride ion channels of neurons”

COVID-19 and Ivermectin: Potential threats associated with human use

FLCCC List of Studies & Clinical Trials analyzing Side Effects of High dose Ivermectin for COVID-19

1. Randomized controlled trial of ivermectin in COVID using 0.6mg/kg x 5 days reported no differences in side effects.
2. Randomized controlled trial, with 3 arms; one arm treated with 1.2 mg/kg for 5 days, and another treated with 0.6mg/kg for 5 days with no differences in side effects
   another treated with 0.6mg/kg for 5 days with no differences in side effects
3. A report by the State Health Minister on 3,000 patients in La Pampa, Argentina who were part of a “test and treat” program were given 0.6 mg/kg daily for 5 days. Liver function tests and significant side effects were closely monitored and none were reported.
4. A report by the Health Minister in Misiones, Argentina, also using 0.6 mg/kg for 5 days with no significant adverse events reported.

High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial | Study

A preprint of a randomized study posted Sep 6 2021 titled High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial aimed to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals. The study evaluated the highest doses ever tested for SARS-CoV-2 treatment.

The study utilized Randomized, double-blind, multicentre, phase II, 48 dose-finding, proof-of-concept clinical trial performed in outpatients in Italy.

“This study confirms that ivermectin at high dose can be considered safe“

“no major neurological signs were observed, asreported previously in cases of serious ivermectin toxicity”

“We also show that high doses of ivermectin are safe, but tolerability is reduced compared to usual doses”

High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

The study analyzed adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Participants were assigned according to a randomized permuted 53 block procedure to one of the following arms with allocation ratio 1:1:1

1. (arm A – 32) – placebo
2. (arm B – 29) – single dose 54 ivermectin 600 μg/kg plus placebo for 5 days
3. (arm C – 32) – single dose ivermectin 1200 μg/kg for 5 days

“The higher dosage (1200 µg/kg for 5 days) showed no safety concerns, as no SADR were observed”

High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

Researchers stated high-dose ivermectin was safe but didn’t prove efficacy in viral load reduction.

Personal analysis of study data | High Dose Ivermectin for the Early Treatment of COVID-19 Study data

On a personal note while reviewing the study I did notice they mentioned 4 participants disease worsened enough to cause hospitalization and of that 3 were in arm C (high dose IVM). Now the researchers state that there was no statistical difference in viral load between arm A, arm B, and arm C. But let’s take a closer look.

Since the amount of patients in the study was so low, the study lacks quantity of data to test” a range of age groups, there was no controls for dietary differences, and they stated the majority were European but we don’t know what ethnicities they were (or what mixes of what ethnicities), these are all factors that play an important role in immune system function, susceptibility to COVID-19 severity and mortality rates.

The majority 83/87 (95%) participants experienced lessening disease severity. With such a small sample size of patients, how do we know that patients in the arm A (placebo) or arm B (lower dose IVM) weren’t of a healthier disposition or otherwise less prone to infection severity, due to other factors such as ethnicity or diet? The lack of numbers makes the data less credible. In addition I believe it was a grave mistake that the study did not perform sufficient controls of other variables variables including diet, which play a massive role in immune system function and thus influence COVID-19 severity and mortality.

Ivermectin for COVID-19 | Studies and Clinical Trials

Ivermectin, a widely used anti-parasitic medicine with known anti-viral and anti-inflammatory properties and is proving a highly potent and multi-phase effective treatment against COVID-19 in multiple clinical trials and laboratory studies.

“If it was universally distributed at a dose that costs ten American cents in India and about the cost of a Big Mac in the United States, he said, Ivermectin would save countless lives, crush variants, eliminate the need for endless big pharma booster shots, and end the pandemic all over the world.”

Dr. Pierre Kory – The Drug that Cracked COVID

In the last two years numerous, controlled clinical trials from multiple centers and countries worldwide, are reporting consistent, large improvements in COVID-19 patient outcomes when treated with ivermectin.

“The widespread use of ivermectin resulted in a significant reduction in cases and mortality rates that approached pre-pandemic levels in these areas.”

Kory P FLCCC

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines | Meta-Analysis

A review published in the American Journal of Therapeutics titled Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines preformed a meta-analysis of 24 RCTs (Randomized Controlled Trials) involving 3406 participants, found that ivermectin reduced risk of death compared with no ivermectin.

“Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n 5 2438; I2 5
49%; moderate-certainty evidence)”

“Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%)”

“Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.”

“Ivermectin is likely to be an equitable, acceptable, and feasible global intervention against COVID-19. Health professionals should strongly consider its use, in both treatment and prophylaxis.”

“Given the evidence of efficacy, safety, low cost, and current death rates, ivermectin is likely to have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with an unknown safety profile. It is a WHO “Essential Medicine” already used in several different indications, in colossal cumulative volumes. Corticosteroids have become an accepted standard of care in COVID-19, based on a single RCT of dexamethasone. If a single RCT is sufficient for the adoption of dexamethasone, then a fortiori the evidence of 2 dozen RCTs supports the adoption of ivermectin.“

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

The study also showed low certainty findings that there may be no benefit with ivermectin for “need for mechanical ventilation”.

Main Findings | Results

“Twenty-two trials (2668 participants) contributed data to the comparison ivermectin treatment versus no ivermectin treatment for COVID-19 treatment.”

“ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces the risk of COVID-19 infection by an average of 86%””

“We restricted the included studies to the highest level of evidence, that is, RCTs, as a policy. This was despite there being numerous observational but nonrandomized trials of ivermectin, which one could argue could also be considered in an emergency.”

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

• Total 24 RCTS (including 3 quasi-RCTs) involving 3406 participants were included
• 22 trials in treatment and 3 trials in prophylaxis met review inclusion
• 16 evaluated ivermectin among participants with mild to moderate COVID-19
• 6 trials included patients with severe COVID-19
• Most compared ivermectin with placebo or no ivermectin; 3 trials included an active comparator (Table 1)
• 3 RCTs involving 738 participants were included in the prophylaxis trials
• Most trials were registered, self-funded, and undertaken by clinicians working in the field. 
• There were no obvious conflicts of interest noted, with the exception of two trials. [85 , 139]

All Cause Mortality
Meta-analysis of 15 trials, assessing 2438 participants, found that ivermectin reduced the risk of death by an average of 62% compared with no ivermectin treatment. Risk of death 2.3% versus 7.8% among hospitalized patients in this analysis, respectively.

“The effect on reducing deaths was consistent across mild to moderate and severe disease subgroups. “

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Table 1. – Summary of study characteristics.

Table 2. – Summary of findings table of ivermectin versus no ivermectin for COVID-19 treatment in any setting.

Secondary Outcomes

Secondary outcomes provided low certainty evidence that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” favored ivermectin (Figures 12-14 Slide below).

“Low-certainty findings suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,”

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

In other words moderate quality evidence shows that Ivermectin can help reduce the viral load and improve mortality in COVID-19. However some people due to multiple factors in their inherent biology including: health, genetics, etc may be more susceptible to severe COVID-19 infection, and may be more prone to need mechanical ventilation as the disease progresses, in which case Ivermectin may not be as effective as a treatment for those individuals in helping lessen the severity of disease at it’s later stages.

Adverse Events Risk

“Meta-analysis of 11 trials, assessing 1533 participants, found that there was no significant difference between ivermectin and control in the risk of severe adverse events”

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Ivermectin Prophylaxis vs no Ivermectin Prophylaxis

“Three studies involving 738 participants evaluated ivermectin for COVID-19 prophylaxis among health care workers and COVID-19 contacts. Meta-analysis of these 3 trials, assessing 738 participants, found that ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces the risk of COVID-19 infection by an average of 86%“

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Discussion

“The findings indicate with moderate certainty that ivermectin treatment in COVID-19 provides a significant survival benefit.”

“Overall, the evidence also suggests that early use of ivermectin may reduce morbidity and mortality from COVID-19.”

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

• Low-certainty evidence on improvement and deterioration also support a likely clinical benefit of ivermectin.
• Low-certainty evidence suggests a significant effect in prophylaxis.
• The more favorable effect estimates were for mild to moderate disease compared with severe disease for death due to any cause.

“We restricted the included studies to the highest level of evidence, that is, RCTs, as a policy. This was despite there being numerous observational but nonrandomized trials of ivermectin, which one could argue could also be considered in an emergency”

“We adhered to PRISMA guidelines and the WHO statement on developing global norms for sharing data and results during public health emergencies.”

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

WHO Recently Updated Therapeutic Guidelines

“The recently updated WHO therapeutics guidelines included 7 trials and 1419 people in the analysis of mortality. Reporting a risk reduction of 81%“

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Evidence from Systematic Reviews and other Observational Studies

“In addition to the evidence from systematic reviews, the findings of several controlled observational studies are consistent with existing evidence and suggest improved outcomes with ivermectin treatment. [55 , 57 , 59] Similarly, with respect to ivermectin prophylaxis of frontline workers and those at risk, controlled observational studies from Bangladesh and Argentina (the latter which involved 1195 health care workers) have shown apparent reductions in COVID-19 transmission with ivermectin prophylaxis, including in some reports total protection (zero infections) where infection rates in the control group exceeded 50%. [122 , 123] A very large trial of ivermectin prophylaxis in health care workers in India [124] covered 3532 participants and reported risk ratios not significantly different from this meta-analysis (Ivermectin showing a positive prophylaxis outcome).

“A standard indication for ivermectin in the elderly is scabies. We identified 2 recent reports suggesting that ivermectin may be efficacious as prevention and treatment of COVID-19 in this age (seniors) group. [50 , 127] A letter on positive experience in 7 elder care facilities in Virginia covering 309 patients was sent to NIH [127] and has recently been submitted for publication.”

Evidence from Countries where Ivermectin has been Implemented

“There is also evidence emerging from countries where ivermectin has been implemented. For example, Peru had a very high death toll from COVID-19 early on in the pandemic. [128] Based on observational evidence, the Peruvian government approved ivermectin for use against COVID-19 in May 2020. [128] After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. [128] Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30+ days and of 75% at 45+ days. [129] However, factors such as change in behavior, social distancing, and face-mask use could have played a role in this reduction.”

Evidence from Ongoing Clinical Trials

“There are numerous emerging ongoing clinical trials assessing ivermectin for COVID-19. The trade-off with policy and potential implementation based on evidence synthesis reviews and/or RCTs will vary considerably from country to country. Certain South American countries, Indian states, and, more recently, Slovakia and other countries in Europe have implemented its use for COVID-19. [129 , 131 , 132 , 133 , 134]”

Evidence from other reviews

“At least 5 other reviews of ivermectin use for COVID-19 have been published, including one coauthored with Nobel Laureate Professor Satoshi Ōmura, discoverer of ivermectin, [9 , 10 , 118 , 119 , 120] but only 3 have been peer-reviewed [9 , 118 , 120] and only 2 attempt full systematic review. [10 , 119] We applied AMSTAR 2 [121] a critical appraisal tool for systematic reviews of health care interventions, to the 2 non peered systematic reviews [10 , 119] and both were judged to be of low quality (Table 5). However, there was also a suggestion that ivermectin reduced the risk of death in treatment of COVID-19 in these reviews.

Study PDF Download

Original Source American Journal of Therapeutics

Complimentary list of Ivermectin Studies Organized by Country

Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use? | Meta-analysis

A meta-analysis of studies was published on may 8 2021 titled Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use? which concluded through review of multiple studies that Ivermectin reduced mortality among hospitalized patients with COVID-19.

“In the present meta-analysis of RCTs, administration of ivermectin reduced mortality among patients hospitalized for COVID-19.”

Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use?

The study stated that in addition to the direct activity of Ivermectin against SARS-CoV-2, another factor dexamethasone, could have played a roll in the positive outlook for mortality among COVID-19 patients.

“may involve Strongyloides hyperinfection, an uncommon complication of dexamethasone administration, [6] which is overprescribed worldwide in COVID-19 patients”

Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use?

In other words…by replacing ineffective and dangerous medications including dexamethasone with Ivermectin, simply by avoiding the damages caused by those medications, could improve COVID-19 mortality in hospitalized patients.

The review concluded although modern medicine must have ironclad evidence, that mounting evidence in it’s efficacy against COVID-19; especially clinical trials combined with an emergency situation are reasonable grounds to use a medication, especially a cheap and safe medicine like Ivermectin.

“While modern medicine cannot do without ironclad evidence, in an emergency situation the use of a cheap medication without major side effects may be reasonable even if strong verification of its efficacy is still lacking”

Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use?

NIH Revises Treatment Guidelines for Ivermectin for the Treatment of COVID-19

One week after Dr. Paul Marik and Dr. Pierre Kory—founding members of the Front Line Covid-19 Critical Care Alliance (FLCCC)— along with Dr. Andrew Hill, researcher and consultant to the World Health Organization (WHO), presented their data before the NIH Treatment Guidelines Panel, the NIH has upgraded their recommendation on ivermectin, making it an option for use in COVID-19.

This new designation upgraded the status of ivermectin from “against” to “neither for nor against”, which is the same recommendation given to monoclonal antibodies and convalescent plasma, both widely used across the nation.

The BiRD Recommendation on the Use of Ivermectin for COVID-19

The B.I.R.D. (British Ivermectin Recommendation Development) panel recommends Ivermectin for the prevention and treatment of COVID-19 to reduce morbidity and mortality associated with COVID-19 infection and to prevent COVID-19 infection among those at higher risk.

BiRD Ivermectin Handout Flyer | Spread the word

BiRD First International Ivermectin for COVID Conference

There is a separate post with all the videos from the BiRD International Ivermectin for COVID Conference (see below). The conference was attended exclusively by physicians, scientists and other professionals. Each speaker has a separate video, with their picture and credentials, along with a synopsis of their lecture.

International Ivermectin for COVID Conference – BiRD IICC

Why some doctors argue against Ivermectin treatment for COVID-19, while others support It

Those against Ivermectin say the efficacy and safety of Ivermectin is not established based on randomized clinical trials (RCTs), therefore it’s effectiveness in prevention or treatment of COVID-19 has no evidence to support it. However many doctors state there is mountains of evidence including studies for the effectiveness of Ivermectin in COVID-19 prophylaxis (prevention) and treatment.

The WHO (World Health Organization) seems to agree, because according to their own database VigiBase there has been just over 5k reports filed and only 20 deaths from Ivermectin treatment in the 25 years that the database has existed, and considering Ivermectin has been used to treat over 3.5 billion people, it would indeed prove that Ivermectin is one of the safest medicines available in the history of the world.

There are two groups of doctors
A) doctors who are against administering Ivermectin as a treatment for COVID-19, which only accept the purest, homogenous selection for meta-analysis of RCTs as valid data
B) Doctors who support Ivermectin treatment and accept a more heterogeneous selection of RCTs, observational studies & clinical trials reflective of practical realities.

Dr. Pierre Kory Testifies before the Senate Committee | Video

“The world has gone mad,” … All over the world, people [are] fighting for their lives not only against the coronavirus but against their national public health societies, their most respected hospitals and long-trusted doctors for the right to use the little generic pill that cracked COVID-19.”

Dr. Pierre Kory – The Drug that Cracked COVID

“We have a solution to this crisis. There is a drug that is proving to be of miraculous impact. When I say miracle, I do not use that term lightly. And I don’t want to be sensationalized when I say that. It’s a scientific recommendation based on mountains of data that has emerged in the last three months…from many centers and countries around the world showing the miraculous effectiveness of Ivermectin. It basically obliterates transmission of this virus. If you take it, you will not get sick.”

Dr. Pierre Kory – The Drug that Cracked

From the transcript:

“… We now have data from over 20 well-designed clinical studies, ten of them randomized, controlled trials, with every study consistently reporting large magnitude and statistically significant benefits in decreasing transmission rates, shortening recovery times, decreasing hospitalizations, or large reductions in deaths. This clinical data is also supported by multiple basic science, in-vitro and animal studies. Our manuscript, completed one week ago, is already out of date due to the near daily emergence of new, positive ivermectin studies. The manuscript has been posted on the medical pre-print server OSF (Open Science Foundation) and can be downloaded here https://osf.io/wx3zn/ or on our organization’s website, www.flccc.net. A more updated meta-analysis and review authored by a group of Ph.D. researchers and scientists includes all ivermectin studies as of December 4th, 2020 and can be found on the c19study.com website here: https://ivmmeta.com/.

“These data show that ivermectin is effectively a “miracle drug” against COVID-19. … Our group held a press conference this past Friday, December 4th at the United Memorial Medical Center in Houston, issuing a “Call to Action.” We made a formal request to our national and global health care agencies and leaders to rapidly assess the growing scientific evidence on ivermectin and update treatment guidelines accordingly. We noted that the last treatment recommendation on Ivermectin is from August 27th where on the NIH website, they recommended that Ivermectin only be used in clinical trials and they based that recommendation as “expert opinion” only given the lack of clinical studies at the time. There is now a wealth of studies reporting efficacy of ivermectin. In that press conference, we called for a rapid and updated review of this evidence in the hopes a treatment recommendation could be made and thus saving many thousands of lives, quickly. The press conference was broadcast via the Associated Press and Univision to nearly every country globally. The Health Ministry of the Government of Uganda is currently reviewing our manuscript with the intent of incorporating our treatment protocol into a national treatment guideline. It is now 48 hours later and, although it has been shared widely, we have not heard from:

“• Any national news radio, newspaper or television station.
• Any single member of any U.S health care agency.
• One notable exception is the interest shown by the Health Ministry of the Government of Uganda as they are currently reviewing our manuscript with the intent of incorporating our treatment protocol into a national treatment guideline.
We know of no similar effort by any US health care agency at this time. (This point can be omitted if necessary)

“This is unacceptable as we have documented evidence that leading members of Operation Warp Speed, including Janet Woodcock had planned to watch our press conference as have multiple members of the CDC and military as well as journalists from major national news outlets who watched. Again, 48 hours later and no contact from any health official or major news outlet. We are still hopeful to hear soon from the government and media.”

Dr. Ardis Talks about Ivermectin and why Remdesivir is deadly

Dr Paul Marik Talks about Ivermectin | Video

Philippine-American Academy of Science and Engineering (PAASE) | Episode 19 Ivermectin: PROS and CONS in LIGHT OF COVID in the Philippines

The Philippine-American Academy of Science and Engineering (PAASE) has a summary of data and analysis on IVN posted on its website: www.paase.org. These were presented by MDs and PhDs in two PAASE “fireside chats” on the pros and cons of IVN on March 31 and April 9. The chats were attended by hundreds of MDs and lay persons on Zoom and thousands of people on YouTube.

PAASE also conducted an online survey on IVN where 553 MDs responded. Results showed that more MDs are in favor of prescribing IVN for prevention and treatment than MDs who are opposed or undecided. An even greater number of MDs favor conducting clinical trials on IVN for prevention and treatment of COVID-19. Almost all MDs want more information on IVN. Results are posted on the PAASE website.

Discussion Guide

1. Clinical and epidemiological studies: safety and efficacy of Ivermectin for prevention & treatment of COVID-19 (Specifically regarding prophylaxis and treatment of COVID-19)
2. Mechanisms of action: biomolecular or biochemical data
3. Ethical issues for Ivermectin use
4. Regulatory issues for Ivermectin use
5. Ways Foward

Ivermectin: The evidence from Literature

Lecture by Jacinto Blas V. Mantaring III, MD, MSc – Department of Clincal Epidemiology, UP College of Medicine.

Please note Dr. Jacinto has 0 experience; has never worked with or treated and COVID-19 patients.

• Chair of the Department of Clinical Epidemiology
• Chair of the UPMREB (Manila Research Ethics Board) and the DOH-SJREB (Single Joint Research Ethics Board)
• Not an infectious disease specialist
• Not representing any interest group
• No interests in any company that sells or manufactures any product related to the management of COVID.

Why patients improve

• Effect of treatment(s) – differences in treatment, dose, duration, co-interventions
• Host factors – Immunology, resistance, general health, genetics, nutrition
• Disease factors – virulence, dose of the virus, natural progression of the disease
• Environmental factors
• Socio-economic Factors
• Differences in patient outcomes and manner of outcome assessment

Advantages to Randomized Controlled Trial (RCT)

• Randomization
  • Provides an equal chance for all eligible participants to be allocated to treatment or no treatment
  • Equalizes baseline characteristics for known (and unknown) factors that may influence the outcome.
  • Controls for co-intervention
  • Standardizes treatment dose, duration
  • Standardizes outcome and outcome assessment

Ivermectin RCT (Randomized Controlled Trials) Summary

Filtered through 218 studies, removed duplicates, results in initial screening yield of 18, 9 of which were excluded due to not being RCT. 4 additional trials were later added for a total of 11 RCTs included in the lecture summary.

Characteristics of studies

• 4 trials published and 7 pre-published (prevents computation bias = comprehensive search)
• Ivermectin vs Placebo – 3 studies
• Ivermectin vs Ivermectin + Doxycycline vs Placebo – 1 study
• Ivermectin vs no Ivermectin – 3 studies
• Ivermectin of different doses – 2 studies
• Ivermectin vs Hydroxychloroquine – 2 studies

• Methodologic quality
  • Open label – 3 studies
  • No mention of blinding – 2 studies
  • Double blind – 6 studies
  • Good study quality – 3 trials

Characteristics of participants

• Characteristics of participants
  • All adult RT-PCR confirmed, 1 study included 14 year old (Elgazzar 2020)
  • Mild covid – 4 studies
  • Mild to moderate – 6 studies
  • Moderate – 1 study
• Outcomes
  • Virologic clearance or load reduction – 8 studies
  • Improvement of symptoms – 2 studies
  • Duration of hospitalization – 1 study
  • Time to resolution of symptoms – 1 study

Results

Duration of Symptoms

• Ahmed 2020 (Median days)
  • Ivermectin 9.6 days (7.7-11.7)
  • Ivermectin + doxycycline 10.1 days (8.5-11.8)
  • Placebo 9.7 days (8.1-11)
• Lopez – Medina 2020 (Resolution by day 21)
  • Ivermectin 164/200 (82%) vs Placebo 156/198 (79%)

Viral Clearance

• Chaccour 2020 (proportion RT-PCR (-) at day 7 | Not statistically significant
  • Ivermectin 12/12 (100%) vs 11/12 (91%) RR 0.92 (0.77-1 0.09, p = 1.0)
• Ravikirti 2020 (RT-PCR (-) at day 6) | Showed approx. 7% improvement for IVM group – still Not statistically significant
  • Ivermectin 18/57 (31.6%) vs Placebo 13/55 (23.6%) RR-0.78 (0.41-1.38)
• Krolewicki 2020 | Not statistically significant
  • There was no difference in viral load reduction between groups
• Pott-Junior 2020 (Proportion with 2 negative SARS-CoV-2 RT-PCR tests within 7 days) | Showed 4% improvement for 200 mcg/kg IVM group – still Not statistically significant
  • No 2/3 (66.7)
  • IVM 100 mcg/kg – 3/6 (50%)
  • IVM 200 mcg/kg – 10/14 (71.4%)
  • IVM 400 mcg/kg – 4/7 (57.1%)

Bukari 2020 (Viral clearance at days 3, 7 and 14) | Showed statistically significant reduction in viral load.

Resolution of symptoms

Dr. Pierre Korey of FLCCC speaks before the Philippine Congress

Ivermectin and the Soul of Medicine

An article published by Dr. Justus R. Hope titled Restoring the Soul of Medicine outlines Dr. Scott Jensen’s efforts during the pandemic to save lives, by spreading the word about his success with Hydroxychloroquine and later Ivermectin.

“This kindly family doctor was voted the Physician of the Year, and he went on a mission to save humanity from the pandemic. He teamed up with Yale’s Dr. Harvey Risch to tell the world about Hydroxychloroquine – and later about Ivermectin. He traveled to the Senate to inform the public that there was a better way.”

Restoring the Soul of Medicine

Because he supported treatments against the mainstream narrative, Dr. Scott Jensen came under attack. A perfect example why so many doctors continue to stay silent, or risk ridicule, and even risk losing their license. However in the end Dr. Scott Jensen was vindicated of all accusations and free to continue his campaign of saving lives during the COVID-19 pandemic.

“Despite saving many lives, the State Medical Board threatened him. His license to practice was jeopardized, not because of poor care but because his actions threatened corporate profits. He went far above and beyond what was required. And as with many men of courage, this doctor’s actions were rewarded, and he was vindicated.”

“If this could happen to me, my view is it could happen to anybody.”

Restoring the Soul of Medicine

Dr. Scott Jensen feels a solemn theological obligation to offer his best to end the pandemic and corruption that have plagued medicine. He supports both Ivermectin and Hydroxychloroquine, but does so at great personal risk, simply because what he advocates goes against the mainstream narrative.

Who is Dr. Jensen

Dr. Jensen is a graduate of the University of Minnesota School of Medicine, where he also taught; a religious man. He won his state’s Physician of the Year award, was selected Minnesota’s 2016 Family Physician of the Year by the Minnesota Academy of Family Physicians, and is author of Relationship Matters: The Foundation of Medical Care is Fracturing.

Dr. Jensen was elected to the Minnesota State Senate in 2016. Senator Jensen served patient interests while a member of the legislature. He co-authored bills involving lowering prescription drug prices, improving opioid safety, telemedicine, and mental health. Dr. Jensen is currently running for Governor of Minnesota.

Written Evidence Submitted by Dr. Theresa Anne Lawrie, Director, The Evidence based Medicine Consultancy Ltd (CLL0115)

In a committee document titled Written Evidence Submitted by Dr. Theresa Anne Lawrie, Director, The Evidence based Medicine Consultancy Ltd (CLL0115) Dr. Theresa Anne Lawrie pleads with the UK parliament advocating early treatment protocols including Ivermectin. To that end Dr. Theresa preformed an official meta-analysis study of the available Ivermectin studies, which concluded that Ivermectin was very effective in prevention and early treatment of COVID-19.

“Following my evaluation of the evidence, I concluded that ivermectin was an essential drug to reduce the morbidity and mortality from covid-19”

“the evidence provided by our systematic review and meta-analysis, with risk of bias assessment and grading of the certainty of the evidence represents the highest level of evidence that is used under normal circumstances and goes beyond the level of evidence required by NICE to make a recommendation on ivermectin during a pandemic.”

“Ivermectin, if it had been implemented when the evidence was presented, could have proven to be a very useful tool that, in combination with other measures, could have substantially ameliorated the devastating impact of Covid-19 on the population, NHS staff, the economy, etc.”

“We have been urging the British government to consider the rapid implementation of ivermectin for the prevention and treatment of Covid-19.”

“the UK could have prevented tens of thousands of deaths if it had only taken a close look at the evidence on ivermectin that we repeatedly brought to the attention of government, health and regulatory agencies”

Written Evidence Submitted by Dr. Theresa Anne Lawrie, Director, The Evidence based Medicine Consultancy Ltd (CLL0115)

Email | URGENT – Ivermectin for COVID-19 will save lives and prevent COVID-19 infection

“I emailed my report on ivermectin to Mr. Hancock, Mr. Ashworth, Mr. Rees Mogg (my MP based on my home address) and Mrs. Wera Hobhouse (my MP based on my business address).”

Written Evidence Submitted by Dr. Theresa Anne Lawrie, Director, The Evidence based Medicine Consultancy Ltd (CLL0115)

Report Summary (Pg. 16)

“This review and meta-analysis confirms that ivermectin substantially reduces the risk of a person dying from COVID-19 by probably somewhere in the region of 65% to 92% according to RCT data. The uncertainty in the evidence relates to the precise extent of the reduction, not in the effectiveness of ivermectin itself. Similarly, when ivermectin is used as prophylaxis among health care workers and contacts, it is clear that ivermectin substantially reduces COVID-19 infections, probably somewhere in the region of 88% (82% to 92%). Data from numerous currently active RCTs will help to determine the precise extent of its protective effect in these at-risk groups.
Despite the FLCCC’s strong recommendation that ivermectin should be implemented globally to save lives from COVID-19, most governments and health professionals still appear to be unaware of this profoundly effective COVID-19 treatment. Not only is ivermectin a safe, effective and well-known medicine, at an estimated cost of less than 10 pence per person treated with a 12 mg tablet, it does indeed seem like a miracle drug in the context of the current global COVID-19 situation. Guidance and protocols on using ivermectin for COVID-19 can be found on the FLCCC website https://covid19criticalcare.com.”

Written Evidence Submitted by Dr. Theresa Anne Lawrie, Director, The Evidence based Medicine Consultancy Ltd (CLL0115)

Questions to Science and Technology Committee

I therefor ask the members of the Science and Technology Committee to please answer the following questions:

1. Why has no one from the UK government, health and regulatory agencies engaged with me to discuss the evidence on ivermectin?
2. Why did the Therapeutics Taskforce not engage with the evidence we sent them, and invite Dr. Tess Lawrie to testify before the relevant entities?
3. Why have novel treatments approved (e.g. remdesivir) based on less evidence, when they are less effective, more expensive and with a worse safety record?
4. Why did the government ignore its own instructions for developing guidelines during the pandemic, as set out in March 2020 in NICE’s document entitled “Interim process and methods for developing rapid guidelines on Covid-19”?
5. In ignoring the systematic review and meta-analysis, as well as the real-world data, observational studies and expert opinion, overwhelmingly favoring ivermectin against Covid-19, was the government aware of the tens of thousands of lives it could have saved?
6. Given the safety record of ivermectin at a range of dosage regimes, why was the government so reluctant to trial ivermectin when the worst that could have happened was that trial participants would have been rid of any parasites they may have had?
7. Finally, and most importantly, why is ivermectin not part of the toolkit for clinicians against Covid19?

PDF Download

How Studies are manipulated to deceive the public

You may be asking…how can there be so many studies in support of Ivermectin, and yet those against it manage to show RCTs that propound the Ivermectin’s ineffectiveness in the prophylaxis and treatment of COVD-19. Below is an excellent example of how easy it is for a study to mislead the general public.

When you spend as much time as I do mulling through studies, you begin to see more clearly how some studies tailor or structure data to enforce a specific narrative; which can easily mislead the public. To that end they will often manipulate and obfuscate certain points of data, or even draw conclusions that aren’t congruent with the studies results.

The average joe isn’t going to read through, nor understand much of the content in a medical study. A basic understanding of medical terminology, and methods of analysis is required in order to analyze and critically think about the data being presented; this makes it easy to mislead a public who lacks those essential skills…

Celebrity doctors and how the media spoon feeds the public a narrative

The public only has one source of hearing about studies or science, and that is from a celebrity doctor and / or a newspaper; they aren’t going to survey medical journals for 3 hours a day.

A study is usually published, some celebrity doctor or news reporter shows a chart or infographic relating to the study, then parrots a few of quotes from researchers…voila the public at large now knows everything about that study and “the science” that they need to…right? Actually that is dangerous, because your allowing one fallible potentially unethical human being to dictate to you the totality of your knowledge on a subject, you are letting laziness and lack of education become your excuse for ignorance, and this is why you will be taken advantage of. This is why critical thought and the effort at least to get seperate opinions from differing sources, is so important.

Look through the study below and before reading my explanation, tell me what exactly is wrong with this study, that makes it completely invalid for showing the efficacy of Ivermectin in the Treatment of COVID-19.

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

A study was published Jul 2 2021 titled Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial which found Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19.

However the study had several issues that make the study invalid to analyze the effect of Ivermectin on COVID-19; mainly related to the dose (see below)

“Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes.”

Results

“The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes.“

Why is this study is invalid for showing the efficacy of Ivermectin on treatment of COVID-19?

In order to answer this question, you will have to scroll far down to the bottom of the study to the “Discussion” section, and several paragraphs you will find a single sentence telling you why this study is invalid for studying the effectiveness of Ivermectin in the treatment and prophylaxis of COVID-19

“This study has several limitations. Firstly, the percentage of events in relation to the primary outcome was below the estimate, so this trial was under powered. Secondly, the mean dose of ivermectin was 192.37 μg/kg/day (SD ± 24.56), which is below the doses proposed as probably effective [20, 33].”

“Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days.“

Do you know what the average dose of Ivermectin is in studies where Ivermectin was shown as highly effective for treatment of COVID-19? It’s 400-1200 µg/kg administered often for 5 days or more!

1. The dose given in this study is half or 1/3 of the lowest dose proven in other studies, to be required for effective treatment of COVID-19.
2. They administered the dose for only 2 days, which is also well below the schedule duration required; according to other studies, for treatment of COVID.19

If you are not a doctor, or don’t know by memory the effective dosing amount of Ivermectin used in other studies, which proved Ivermectin was effective for prophylaxis or treatment of COVID-19; you would have no idea that this study is entirely useless, for analyzing the effectiveness of Ivermectin, against COVID-19 Infection.

The average person gets their science from a doctor on TV, which in the case of this study, means you could have been deceived by the validity of this study without even being aware of it…This is just one of the many ways studies are designed to drive a narrative, which easily misleads the public; but not so much statisticians or doctors.

Ivermectin for Prophylaxis of COVID-19

The conclusion of many studies is that Ivermectin’s anti-viral properties lend it to be most effective when administered either in prophylaxis of COVID-19, or in the early stages of infection. Known as early treatment, this allows maximum effectiveness of Ivermectin to prevent the viral replication of COVID-19 and it’s mutations including SARS-CoV-2, by keeping the viral load low so the body’s innate immune system can mount a full response.

“where a host-directed agent can be a “game-changer” in treating viral infection may well be in the initial stages of infection or even prophylactically to keep the viral load low so that the body’s immune system has an opportunity to mount a full antiviral response [11 , 17].”

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

“Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86%“

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

“Pseudorabies (PRV) mouse challenge model which showed that dosing (0.2 mg/kg) 12 h post-infection protected 50% of mice, which could be increased to 60% by administering ivermectin at the time of infection“

Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo

“Clinical data published in preliminary form for the phase III trial in Thailand [40] indicate antiviral activity; daily dosing (0.4 mg/kg) was concluded to be safe, and have virological efficacy, but clear clinical benefit was not reported, potentially due to the timing of the intervention. The authors concluded that dosing regimen modification was required to ensure clinical benefit [40]. This study both underlines ivermectin’s potential to reduce viral load in a clinical context, and highlights the complexities of timely intervention and effective dosing regimens to achieve real clinical benefit”

Definition and Types of Prophylaxis

“Prophylaxis is a measure that is applied to preventing an infection or disease from developing1,2. Prophylaxis is usually given after exposure to an infectious agent. There are 2 types of prophylaxis depending on whether the drug is administered before or after exposure to the infectious agent:

1. POST-EXPOSURE PROPHYLAXIS (PEP)
2. PRE-EXPOSURE PROPHYLAXIS (PrEP)

Post-Exposure Prophylaxis (PEP) is aimed at preventing the development of an infection and disease after exposure to an infectious agent1,2 had already occurred. The WHO, PAHO, the US Department of Health and Human Services (HHS), and other recognized organizations recommend PEP for HIV infection1,2,3, Hepatitis B and C3 and Tuberculosis4. In the case of diseases transmitted primarily through the respiratory tract, such as pulmonary tuberculosis4, prophylaxis is mainly given to Contacts of confirmed cases of the disease. In the context of COVID-19, the WHO defines a confirmed case of COVID-19 as a person with a SARS CoV-2 infection confirmed by laboratory tests5,6″

COVID-19: IVERMECTIN PROPHYLAXIS IN ADULT CONTACTS. First Report on Health Personnel and Post-Exposure Prophylaxis

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study

A peer reviewed cohort study was published Aug 21 2021 titled Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study.

The study analyzed 542 (271 each in Ivermectin and Placebo groups) healthcare personnel who adhered to the PrEP program with ivermectin at a weekly oral (PO) dose of 0.2 mg/kg. The study was carried out in two medical centers: Centro Medico Bournigal (CMBO) in Puerto Plata and Centro Medico Punta Cana (CMPC) in Punta Cana.

“In our study, the hazard ratio (HR) of 0.26 was achieved in the ivermectin group, which translates into a 74% lower risk of contagion with SARS-CoV-2.”

“These results suggest that compassionate use of weekly ivermectin could be an option as a preventive method in healthcare workers”

“There were no severe side effects reported from the use of ivermectin, only minor side effects such as dizziness (3.7%), headache (1.5%), stomachache (1.4%), pruritus (1.1%), nausea (1.1%) and diarrhea (0.7%).”

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study

Outcome / Endpoint

1. Primary outcome was to measure the number of healthcare workers with symptomatic SARS-CoV-2 infection and a positive reverse transcription polymerase chain reaction (RT-PCR) COVID-19 test in the ivermectin group and in the control group
2. Secondary outcome was to measure the number of sick healthcare workers with a positive RT-PCR COVID-19 test whose condition deteriorated and required hospitalization and/or an Intensive Care Unit (ICU), or who died, in the ivermectin group and in the control group.

Results

In total 542 participants (271 each in Ivermectin and Placebo groups) were settled. The groups were left without significant differences in the measured variables.

“The mean age of the study was 35.19 years (±10.02), composed mainly of females (79.0%). Regarding the profession or role, physicians represent 10.3%, nurses 25.8%, medical assistants 11.6% and administrative personnel and others 52.2%. More than half of the personnel had medium and high exposure to COVID-19, corresponding to 29.9% and 25.1%”

“In 28 days of follow-up, significant protection of ivermectin preventing the infection from SARS-CoV-2 was observed”

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study

Primary and secondary outcomes

1. Ivermectin Group – 271 Health Care Workers – weekly oral (PO) dose of 0.2 mg/kg of Ivermectin) – PrEP with ivermectin was associated with a statistically significant reduction in SARS-CoV-2 infection
   1. 1.8% Infected (chi-square homogeneity test)
   2. 74% reduced risk of COVID-19 infection, compared to control group. (Cox regression analysis)
2. Placebo (control) Group – 271 Health Care Workers – no ivermectin
   1. 6.6% Infected (chi-square homogeneity test)

Kaplan-Meier Risk Analysis

“The first four days after starting the study, a slightly higher number of positive COVID-19 infections was seen in the control group compared to the ivermectin group. Then, from the fifth day, the number of positive COVID-19 infections was the same in both groups. At day 10, a difference between the two groups began to be noticed, which increased over the course of the days until reaching day 28, where the protection of ivermectin achieved significant statistics (p-value = 0.006). Between days 16 and 28 (12 days), the ivermectin group did not present any contagion (Figure 2).”

Conclusion

“Pre-exposure prophylaxis (PrEP) for COVID-19 with a weekly oral dose of ivermectin 0.2 mg/kg was statistically significant in exposed healthcare personnel at the CMBO and CMPC after 28 days of follow up, with only 1.8% of the physicians and health collaborators developing SARS-CoV-2 infection versus 6.6% in the control group (p-value = 0.006). Ivermectin reduced the risk of contagion with COVID-19 by 74% compared to the control group (HR 0.26, 95% CI [0.10, 0.71]). These results suggest that compassionate use of weekly ivermectin could be an option as a preventive method in healthcare workers and as an adjunct to immunizations, while further well-designed randomized controlled trials are developed to facilitate scientific consensus.”

Discussion and Rebuttle | Comments

In the comment section, avid gene therapy vaccine followers immediately attacked the veracity of the study (specifically a Robert Hildalgo) calling it a “conspiracy theory” connected with “Pro-Ivermectin sect followers” which is used to “perpetuate a very deadly anti-vaccine narrative, and that it showed a “lack of ethical compliance”. He also presented some arguments:

1. He accused a “reliable source” said the study researchers ran out of Ivermectin and then used the veterinary formulation in humans.
   1. Jose responded “In our country, the Dominican Republic, the use of IVM has been, and still is, very common in medical practice, for more than 30 years; there are at least two pharmacological laboratories that produce, commercialize and export it to other countries; especially to Central America. Its acquisition is easy, very cheap, available and does not require a physician prescription. We DO NOT HAVE TO USE A VETERINARY IVM compounds because the formulation for humans is absolutely accessible.“
2. He accused an “important Dominican newspaper the official Dominican Ethics Council (CONABIOS – the official ethics entity in DR) issued a very compelling letter directed to you Jose Natalio Redondo, reproaching your study and lack of compliance with expected ethical standards”
   1. “our institution approved, authorized and sponsored the study presented here after several months of having applied, voluntarily and with each individual signed informed consent, a prophylactic treatment with Ivermectin in our health resources. The work of data collection and statistical analysis was done, as well described in the published study. Furthermore, months later, it was subjected to a strict biostatistician research protocol on an observational fact. (An experience)”

The argument continues on with Mr. Hildalgo not citing any of his credentials, while attacking the study methods, validity of the study and integrity of the researchers outright. While Doctors replied to his comments starting data and facts.

Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers | Cohort study

A cohort study was published Aug 2021 titled Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers which aimed to demonstrate the prophylactic role of oral ivermectin in preventing SARS-CoV-2 infection among HCWs, at the All India Institute of Medical Sciences (AIIMS) Bhubaneswar.

“Participants who took ivermectin prophylaxis had a lower risk of getting symptoms suggestive of SARS-CoV-2 infection (6% vs 15%).”

“Two doses of oral ivermectin (300 μg/kg/dose given 72 hours apart) as chemoprophylaxis among HCWs reduced the risk of COVID-19 infection by 83% in the following month. Safe, effective, and low-cost chemoprophylaxis has relevance in the containment of pandemic alongside vaccine.”

Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers

The study analyzed 3892 Healthcare workers in total. All staff members of the India Institute of Medical Sciences (AIIMS) formed the study cohort, which included the clinical staff engaged in inpatient care activities, administrative staff, and students. HCWs were provided the oral ivermectin according to the bodyweight in the form of multiple of tablets

1. Dose (Exposure criteria) – uptake of two doses of oral ivermectin (300 μg/kg/dose at a gap of 72 hours, followed by a once-monthly dose on the 30th day from the last dose.). The ivermectin uptake was 62.5% for two doses and 5.3% for single dose
2. Primary outcome – COVID-19 infection in the following month of ivermectin consumption testing by RT-PCR (reverse transcriptase polymerase chain reaction.

Participant Demographics

• Over half of the study participants were less than 30 years of age (53.4%) and one-third (32.3%) were in the 30- to 39-year age group.
• The majority of participants were male (67.6%).
• Approximately three-fourths (72.7%) of the participants were involved in the direct management of COVID-19 patients.
• Administrative staff and students comprised 13.9% and 13.4%, respectively. Among the 2567 participants, who were involved in COVID-19 patient care, 812 were doctors, 717 were nursing officers, and 1038 were supporting staff.
• The strengths of our study are the large sample size, minimal loss to follow-up, and the establishment of temporality.

Results

1. Participants who took ivermectin prophylaxis had a lower risk of getting symptoms suggestive of SARS-CoV-2 infection (6% vs 15%).
2. HCWs who had taken two doses of oral ivermectin had a significantly lower risk of contracting COVID-19 infection during the following month (ARR 0.17; 95% CI, 0.12-0.23).
3. Only 1.8% of the participants reported adverse events, which were mild and self-limiting.
4. Out of 331 participants, who had symptoms suggestive of SARS-CoV-2 infection, 200 (60.4%) participants were from the group who had not taken ivermectin prophylaxis

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study.

An India peer reviewed article was published Feb 16 2021 titled Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study, which aimed to explore the association between ivermectin prophylaxis and the development of SARS-CoV-2 infection among healthcare workers.

Researchers analyzed 372 patients (186 matched pairs) with a mean age of 29 (most under 30), in a hospital-based matched case-control format. The mean difference in date of diagnosis between cases and control was 3.8 days. The study was carried out among healthcare workers of AIIMS Bhubaneswar, India, from September to October 2020.

“Our study has shown that two doses of ivermectin prophylaxis at a dose of 300 μg/kg given 72 hours apart was associated with a 73% reduction of SARS-CoV-2 infection among HCWs for the following month”

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study

Highlights

• Two doses of ivermectin prophylaxis at a dose of 300 μg/kg given 72 hours apart was associated with a 73% reduction of SARS-CoV-2 infection among HCWs for the following month
• Single-dose ivermectin prophylaxis at a dose of 300 μg/kg, HCQ prophylaxis, and vitamin-C prophylaxis are not associated with preventing SARS-CoV-2 infection
• Engaging in physical activity for more than one hour daily, which is taken for lack of physical distancing, was an independent risk factor for SARS-CoV-2 infection
• Single-dose prophylaxis has no association with a reduction of SARS-CoV-2 infection, and two-dose of ivermectin (300 μg/kg) was associated with a reduction of SARS-CoV-2 infection 
• We did not find any association between vitamin-C prophylaxis and prevention of SARS-CoV-2 infection
• Strengths of our study are the adequate sample size, completeness of the data collection and verification from subjects. All the HCWs received ivermectin procured from a single manufacturer and belonged to the same batch for each strength

Materials and methods

1. Cases were HCWs who were diagnosed as positive for COVID-19 by Reverse Transcription Polymerase Chain Reaction (RT-PCR).
2. Controls were defined as HCWs who were diagnosed as negative for COVID19 by RT-PCR with a similar risk of exposure toSARS-CoV-2.

“For every enrolled case, a control was selected from the existing line list. Individual matching was carried out for profession, gender and age. In addition, an attempt was made to match the date of diagnosis….In the majority of cases, it was within a week. The average number of days for a difference in date of diagnosis was 3.8 days between cases and controls.”

“Exposure was defined as the prophylaxis viz., ivermectin and/or (HCQ) and/or vitamin C and/or other agent taken for the prevention of COVID-19”

Consensus Statement to provide all HCW’s with Ivermectin for prophylaxis

“On 17th September 2020, a decision to provide all HCWs with ivermectin for prophylactic use was announced, based on a consensus statement that was released at the institute”

Results

In total 372 patients were in involved. “Profession, gender, age and date of diagnosis were matched for 186 case-control pairs. Cases and controls were healthcare workers who tested positive and negative, respectively, for COVID-19 by RT-PCR“

“The majority of the participants (60.75%) were below 30 years of age. Nearly two-thirds of participants (67.2%) were male. More than half of the participants (57.26%) were involved in COVID-19 patient care in the outpatient department (OPDs) and/or inpatient department (IPDs) and/or intensive care unit (ICU) in the last one month. Most participants (82.26%) were not doing any physical activity during the study period.”

“Out of 372 participants, 171 participants (101 from cases and 70 from controls) took any form of prophylaxis. 117 (31.4%) participants had a history of ivermectin prophylaxis-76 from controls and 41 from cases, 67 (18.01%) participants had a history of vitamin-C prophylaxis-38 from controls and 29 from cases, 19(5.11%) participants had a history of HCQ prophylaxis-12 from controls and seven from cases (Table 2). Four participants were taking home-based remedies for the prevention of COVID-19. Ninety-one (24.46%) participants had a history of two-dose ivermectin prophylaxis (300 μg/kg at Day 1 and Day 4). However, 17 (4.57%) participants took only one dose (300 μg/kg), and 9 (2.42%) participants continued the same dose for three or more days. Out of 67 participants, who took vitamin-C prophylaxis, 54 participants took a dose of 500 mg once daily, and 13 participants took vitamin-c 500 mg twice daily. The majority of participants took vitamin-C for less than one month; however, 27 participants were continuing vitamin-C prophylaxis for more than one month. HCQ prophylaxis was practiced 400 mg once a week. Out of 19 participants who took HCQ prophylaxis, ten participants took for three or more weeks, five participants took for two weeks, and four participants took for a week.”

Matched Pair Analysis

Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial | Study Preprint

A Study preprint was posted May 31 2021 titled Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial which aimed to assess whether ivermectin can shorten the viral shedding in patients at an early-stage of COVID-19 infection.

“There were significantly lower viral loads and viable cultures in the ivermectin group, which could lead to shortening isolation time in these patients.”

Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial

The study analyzed 89 eligible non-hospitalized COVID-19 patients (47 in ivermectin and 42 in placebo arm) with a medium age of 35 yrs, utilizing a double blinded, randomized, placebo controlled format.

Females accounted for 21·6%, and 16·8% were asymptomatic at recruitment. Median time from symptom onset was 4 days.

1. Arm A – Ivermectin dose of 0·2 mg/kg for 3 days
2. Arm B – Placebo group

“RT-PCR from a nasopharyngeal swab was obtained at recruitment and then every two days. Primary endpoint was reduction of viral-load on the 6^th day (third day after termination of treatment) as reflected by Ct level>30 (non-infectious level). The primary outcome was supported by determination of viral culture viability.”

Day 2 -6 Cultures

1. Arm A Ivermectin – Day 2-6 Cultures – 3 out of 23 (13.0%) were positive
2. Arm B Placebo – Day 2-6 Cultures – 14 out of 29 (48.2%) were positive

Day 6 Endpoint

1. Arm A Ivermectin Day 6 – 34 out of 47 (72%) patients reached endpoint (non-infectious)
2. Arm B Placebo – Day 6 – 21 out of 42 (50%) patients reached endpoint (non-infectious)

In a multivariable logistic-regression model, the odds of a negative test at day 6 was 2.62 time higher in the ivermectin group.

Prophylactic Ivermectin in COVID-19 Contacts | Study Preprint

Preliminary results from a recently completed study Titled Prophylactic Ivermectin in COVID-19 Contacts (NCT04422561) examined asymptomatic family close contacts of confirmed COVID patients, and showed that two doses of ivermectin 72 h apart result in only 7.4% of 203 subjects reporting symptoms of SARS-CoV-2 infection, in stark contrast to control untreated subjects, of whom 58.4% reported symptoms.

The study had 340 participants, 16 Years to 70 Years of age, who had family contact of confirmed COVID-19 case. Primary Outcome was Development of Symptoms ( Fever ,Cough, Sore Throat, Myalgia,Diarrhea, Shortness of Breath).

The participants were separated into two groups.

1. Group A – Ivermectin group had 203 participants and were given two doses of Ivermectin tablets 72 hours apart
2. Group B – Control group had 101 participants who were given nothing.

As you can see above 15 (7.4%) of the Ivermectin group became symptomatic, while 59 (58.4%) of the control group (no ivermectin) were symptomatic upon examination. This shows clear and concrete evidence that Ivermectin is quite effective in prophylaxis (prevention) of COVID-19.

A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin | Study

A study published Nov 2020 titled A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin found that “countries with routine mass drug administration of prophylactic chemotherapy including ivermectin have a significantly lower incidence of COVID-19.”.

The study compared the incidence of COVID-19 among countries with different PCT campaigns and those countries in which PCT is non-existent. Initial study results were collected April 15 2020, but because at the time SARS-CoV-2 was still being detected in new countries on a daily basis, they continued to monitor the situation to see if if the correlation (ivermectin and lower Infection rates) would become less significant. After adding more data and updating calculations throughout May 2020 to June 2020, researchers noticed that the observed association between Ivermectin MDA and lower COVID-19 incidence in fact grew stronger as more data came in.

“there is a very strong negative correlation between the use of PCT—especially involving ivermectin—and COVID-19 proliferation. This, paired with ivermectin’s proven inhibitory effect on SARS-CoV-2 replication in vitro, leads us to the hypothesis that the drug may have a—likely indirect—prophylactic effect and thereby reduce the spread of the disease.”

A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin

“It is important to note that the hypothesis that ivermectin might have a prophylactic effect against SARS-CoV-2 is merely based on a rather strong correlation. On the other hand, this correlation has grown increasingly stronger in the worldwide data set earlier this year and then been independently replicated within the African data set later in the summer. Both remain highly significant, suggesting that there may be a causal connection, which is also suggested by other recent findings reported in literature.“

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

information from the FLCC Alliance and covid19criticalcare.com

Source American Journal of Therapeutics

Study of the Efficacy and Safety of Topical Ivermectin + IotaCarrageenan in the Prophylaxis against COVID-19 in Health Personnel | Clinical Trials

A study published titled Study of the Efficacy and Safety of Topical Ivermectin + Iota Carrageenan in the Prophylaxis against COVID-19 in Health Personnel, sought to assesses whether a combination of topical nasal carageenan and oral ivermectin can reduce SARS-CoV-2 infection in Health Care Workers when administered prophylactically. The study outlined a pilot study, followed by a larger study utilizing even more participants.

Pilot Study

In the pilot study A total of 229 health personnel were recruited for this study;

1. 98 within the control (PPE alone) group
2. 131 received IVECAR treatment in addition to their wearing of PPE – This group was matched for age, demographics, past medical history, work environment including hours worked and possible exposure to CoVid 19 positive patients within the hospital.

All HCW’s were healthy with no Covid-19 symptoms and negative swabs for the virus immediately prior to enrollment in the study

“Combination therapy (IVECAR) consisted of 1 spray of topical Carrageenan (Cert. No. 57,232, ANMAT (National Administration for Drugs, Food and Medical Technology) 100 ml, 0.9 g of sodium chloride and 0.17 g of carrageenan) into each nostril and four sprays of topical Carageenan into the oral cavity, followed 5 minutes later by 1 drop of ivermectin (Cert. Nº 58.382, ANMAT 100ml Ivermectin drops (0.6 mg / ml) to the tongue 5 minutes later. This dosage schedule was repeated 5 times a day (every 4 hours) for 14 days with food and liquids avoided 1 hour before and after treatment [12-15].”

“Patients in the PPE group and IVECAR groups were evaluated at 7 and 14 days completing symptom questionnaires ( including the reporting of any adverse effects from the treatment), physical examinations and CoVid-19 testing of nasopharyngeal secretions (PCR or rapid test) at each time point. Both groups continued to adhere to standard PPEs and were evaluated at 7, 14, 21 and 28 days from the commencement of the study. Infection rates were reported for each group, with 11 contagions among those not treated, and no contagions in the treated group [22-26].”

“None of the health personnel treated with IVERCAR tested positive for CoVid19 during the 14 day treatment period. Furthermore none returned positive swabs in the 3 weeks post completion of their initial treatment. Eleven health personnel (11.1%) in the comparator PPE group yielded positive swabs.”

Multi-center study

In the larger multi-center study a total of 1,195 health care workers were recruited from 4 major hospitals in Argentina.

The study period was from June 1 2020 – August 1 2020. A modification of the initial protocol was performed for ease of medication delivery. Carageenan application was reduced to 4 x a day at the same total dose, and Ivermectin was administered as once per week dose of 12mg. Each of the 4 centers used the same dosing protocol.

1. 407 within the control (PPE alone) group
2. 788 received IVECAR treatment in addition to their wearing of PPE

“The overall infection rate in health care workers recruited for this study was 20% with 237 testing positive for CoVid 19 during the 3 month study recruitment. Of those infected, all patients were from the comparator group of using PPE alone. This represented an overall infection rate of 58.2% ( 237 of 407) in the PPE group. No patients of the 788 treated with IVERCAR tested positive for CoVid 19 during the study“

Covid 19 and Ivermectin Prevention and Treatment Update

the use of ivermectin as a preventive of COVID 19 should not be limited only to Health Agents, but should be extended to the Security Forces, to all Essential Personnel who must be transferred in mass media, to population groups in confinement and / or overcrowded conditions (geriatric, psychiatric, prison, orphanage, slums, etc.), their cohabitating contacts and people with comorbidities

Covid 19 and Ivermectin Prevention and Treatment Update

Ivermectin in Prevention

1. Ivermectin should be used at a rate of 200 micrograms per kilogram of weight, in a weekly dose, which will be repeated in the same period, up to 8 weeks. After these two months, the adipose tissue will have accumulated enough ivermectin for its protective effect to last for another four months [9]. Those four “extra” months can be covered with carrageenan, which may have been used since the beginning of prevention or just added in the ninth week, since its use can be prolonged indefinitely [10].

The I.D.E.A. Protocol has been replicated in several Provinces (Corrientes, Jujuy, Salta, Tucumán) and is being incorporated in many others (Misiones, Santa Fe, Chubut, etc.). Several amendments have been added, due to the results obtained and new concepts that have emerged since the completion and elevation of the protocols in June 2020 [11]. They are detailed below:

1. The doses are repeated weekly, as many weeks as necessary in each individual case, until the patient is free of disease and / or risk.
2. The weekly schedule can be shortened to every 5 days, if the patient’s condition so requires
3. Bromhexine has been associated with success, outside of the original protocol, since it adds a blocking factor on TMPRSS2 receptors that is not achieved with other medications [12]
4. Carrageenan can be added –also outside the original protocol- in order to reduce the dissemination by aerosols of patients, minimize endogenous reinfection, and the risk of the Health Personnel in charge of their care [13].
5. Once the patient is released, the immune response achieved through “natural active immunization” should be measured, which means having contracted the disease. This immunity is inconsistent at the humoral level, and there is still no infrastructure to massify the search for cellular immunity [14,15]. For this reason, we consider that if the patient has not elevated the specific IgG in a qualitatively/ quantitatively satisfactory way, he should continue with the prophylaxis scheme, once externalized.

Covid 19 and Ivermectin Prevention and Treatment Update PDF

A RANDOMIZED TRIAL – INTENSIVE TREATMENT BASED IN IVERMECTIN AND IOTA-CARRAGEENAN AS PRE-EXPOSURE PROPHYLAXIS FOR COVID- 19 IN HEALTHCARE AGENTS | Preprint

Early results of a new study were published in medRxiv preprint server for health sciences on Mar 20 2021, titled A RANDOMIZED TRIAL – INTENSIVE TREATMENT BASED IN IVERMECTIN AND IOTA-CARRAGEENAN AS PRE-EXPOSURE PROPHYLAXIS FOR COVID- 19 IN HEALTHCARE AGENTS, which focused on evaluating “the protective effect of the combination Ivermectin / Iota58 Carrageenan (IVER/IOTACRC), intensive treatment with repeated administration in 59 oral- and nasal-spray, respectively, as a prophylaxis treatment prior to exposure to 60 SARS-CoV-2, in health personnel at Public Healthcare Centers.”

“The intensive preventive treatment (short-term) with IVER/IOTACRC was able to reduce the number of health workers infected with COVID-19. This treatment had also effect in preventing the severity of the disease, since all patients treated were mild”

“Consequently, people with treatment decrease their chance of contracting COVID-19 by 87%.”

“Through this study, it was possible to show a prophylactic effect of IVER/IOTACRC against COVID-19 disease. “

A RANDOMIZED TRIAL – INTENSIVE TREATMENT BASED IN IVERMECTIN AND IOTA-CARRAGEENAN AS PRE-EXPOSURE PROPHYLAXIS FOR COVID- 19 IN HEALTHCARE AGENTS

The study analyzed 234 Health personnel belonging to the Tucumán State Health System, with a mean age of 39.6 (+-9.5yrs) in the EG group and 38.4 (+-7.4) in the control group, from October 2020 to December 2020. No subject had Covid-19 disease diagnosed by negative RT-PCR. Subjects were analyzed in a Randomized controlled clinical trial (1:1) format. No subjects had compatible COVID-19 signs, and all were diagnosed with negative RT-PCR before beginning the trial.

“The people who agreed to participate in the study gave their informed consent before starting the study (Research Ethics Committee / Health Research Directorate, file number 52/2020). The clinical trials registry number is NCT04701710“

1. EG (Experimental Group – 117 participants) – received Ivermectin orally 2 tablets of 6 mg = 12 mg every 7 days, and 66 Iota-Carrageenan 6 sprays per day for 4 weeks.
2. CG (Control Group – 117 participants) – received no prophylactic treatment. Used biosecurity measures (PPE – Personal protective equipment)

Primary and secondary outcomes, security definitions and Statistics | Objective

1. Reduction of the infections rate for COVID-19 disease in healthcare agents.
2. Reduction in symptoms numbers presence, and protection against the appearance of severe stages for COVID-19 disease.

“we founded that the protective power of ivermectin is conserved in both sex groups “

A RANDOMIZED TRIAL – INTENSIVE TREATMENT BASED IN IVERMECTIN AND IOTA-CARRAGEENAN AS PRE-EXPOSURE PROPHYLAXIS FOR COVID- 19 IN

• COVID-19 cases were classified according to the WHO definitions of COVID-19 cases [22].
• Adverse Event (AE) was defined as any medical event, signs, symptoms, or disease temporarily associated with the use of the medication, which could occur in the subjects enrolled in the study [23].
• Pearson’s Chi-square and proportions test, as appropriate, were used to analyze the statistical differences between the qualitative variables of each group.

Intervention Protocol

“A post-control follow-up was carried out at 14 days (remote clinical telemedicine follow-up) at the end of which an RT-PCR test was performed. EG and CG patients were evaluated every 7 days in 4 visits from the beginning of the study. Enrolled subjects completed symptom questionnaires (including reporting any adverse effects of treatment), physical examinations, and COVID-19 nasopharyngeal secretion tests (RT-PCR) at each time. Also in the visit, in person, was supplied the corresponding dose for the week. Cases will be classified according to the WHO definitions of COVID-19 cases22.”

Results

“it’s necessary point out that the comorbidities or risk factor such as hyper-tension, DBT, obesity or over 60 years old were similar in both groups (Table 1). So, the results above mentioned, cannot be attributed to presence to comorbidities in the CG.”

Clinical report and COVID-19 case in EG vs. CG

“most of the symptoms, all related to COVID-19, were reported in the CG (p-Value <0.05). The most frequent symptoms were fever (21), taste and / or smell disturbance (19), and headache (19). With intermediate frequency of symptoms, cases with polymyoarthralgia (9), diarrhea (9), abdominal pain (8), and low oxygen saturation (SpO₂) (6) were reported”

“Nineteen patients had mild classification for COVID-19, n= 4 in EG, and n= 15 in CG (p-Value = 0.001). Seven subjects were moderate, and 3 with severe diagnostics, all them were in CG. In addition, it was found that in the EG people who contracted COVID-19 only 1/4 had any symptoms, while the CG 24/25 (p-Value = 1.10⁻⁵).”

“On the other hand, the probability of contracting COVID-19 was dependent on the patient’s preexisting comorbidity. People with comorbidities had a greater chance of contracting COVID-19, Odds Ratio 5.58, 95% 2.20 to 14.16, p-Value = 1.10⁻⁵ (Odds Ratio >1).”

Discussion

“We interpret that a double viral barrier would be formed that would enhance its action and allow to increase the protective effect in the following way:

1. The first barrier for viral protection would be at the entry of the virus into the nasal cavity where the carrageenan would behave as a mucolytic agent in the barrier of sulfacted polysaccharides with negative charge [28]
2. The other action of ivermectin is to decrease the viral load based on its systemic cellular action [29]”

“Secondary outcome found was that IVER/IOTACRC not only prevents the infections rate, but also has a protective effect on reduction in symptoms number’s presence, and protection against the appearance of severe stages for COVID-19 disease (Figure 2). As can be seen in Figure 2B, the EG only had mild cases, while the CG had mild, moderate and severe cases, the differences between both groups being significant.”

COVID-19: IVERMECTIN PROPHYLAXIS IN ADULT CONTACTS. First Report on Health Personnel and Post-Exposure Prophylaxis | Preprint

A study preprint was published Jul 20 2020 titled COVID-19: IVERMECTIN PROPHYLAXIS IN ADULT CONTACTS. First Report on Health Personnel and Post-Exposure Prophylaxis aimed to analyze Ivermectin prophylaxis in a clinical setting.

“The result of the present study finds utility in the use of Ivermectin as prophylaxis for COVID-19.”

“none of the 33 (out of 40) participants developed the disease during the 21 days of follow-up after Ivermectin was given”

COVID-19: IVERMECTIN PROPHYLAXIS IN ADULT CONTACTS. First Report on Health Personnel and Post-Exposure Prophylaxis

The PEP study is a descriptive and interventional study, which analyzed 33 people (40 enrolled, but 7 tested COVID-19 positive and so were excluded). Enrolled participants had to be asymptomatic and test negative for COVID-19 on a lab test.

Materials and Methods – Inclusion & Exclusion Criteria

Participant requirements were as follows:

1. Be over 20 years old
2. Be a contact of a person with a COVID-19 diagnosis confirmed by laboratory test
3. Have a negative Laboratory Test for SARS CoV-2 in the last 48 hours prior to taking Ivermectin doses.

In addition anyone with known allergies to Ivermectin (or history of side effects), or anyone with COVID-19 symptoms in the first 3 days of Ivermectin being administered; confirmed with a lab test was excluded.

Prophylaxis Protocol

• Day 1- Ivermectin dose 0.2 mg/Kg of body weight
• Day 2 or 3 – Men over 45 yrs old – Additional Ivermectin dose 0.2 mg/Kg of body weight

“all persons who qualified as Contacts and tested negative for SARS CoV-2 in the laboratory were given a dose of Ivermectin of 0.2 mg per kilogram of body weight on day one. Additionally, in the men over 45 years of age it was indicated to evaluate giving a second dose of Ivermectin on day 2 or 3, this would be done in case other people in the home or place of residence present characteristic symptoms of COVID-19.”

“The form of presentation of Ivermectin used was from a 0.6% Dropper Bottle, which is the presentation available in Peru. According to the insert contained in bottle, each drop contained 0.2 mg (or 200 mcg) of Ivermectin.“

Results

In the study “none of the 33 participants developed the disease during the 21 days of follow-up after Ivermectin was given“

“During the clinical evaluation process of the first 3 days, no person with symptoms of COVID-19 was identified. Therefore no molecular laboratory testing was performed on any participant, no second doses of Ivermectin were indicated, and no participants were excluded from the study. Daily clinical follow-up was continued for 21 days after taking Ivermectin, and none of the participants exhibited symptoms, nor did they develop COVID-19 disease.“

Personal thoughts on Ivermectin for Prophylaxis of COVID-19

As I sift through dozens of Studies on Ivermectin, I’ve noticed a common trend among them…Ivermectin inhibits cell replication of the virus as already proven with Influenza (and many other viruses) through it’s ability to block the imp alpha/beta1 transport mechanism, this prevents the virus from injecting its proteins into the cell nucleus, which disables the cell’s immune response. On the basis of those mechanisms through which Ivermectin functions, it should be clear that Ivermectin is especially effective given pre or post infection for the prophylaxis of COVID-19 infection, but also when administered in the early stages of COVID-19 disease progression, so that it can stop viral replication before the virus has already proliferated damage throughout the lungs and body at large.

“where a host-directed agent can be a “game-changer” in treating viral infection may well be in the initial stages of infection or even prophylactically“

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

This would also explain why some studies suggest little effectiveness of Ivermectin in reducing the need for a Ventilator; because the virus has already replicated and preformed extensive damage throughout the lungs, leading to the viral replication prevention properties of Ivermectin, to be less useful. There is some data in this article to provide evidence for that conclusion, but I want to make it clear this is my personal review of studies and subsequent hypothesis, and I have not preformed my own studies to verify this hypothesis. I do want to note that Ivermectin is also a anti-inflammatory, and inflammation is one of the primary mechanisms through which COVID-19 inflicts damage, specifically as it relates to the cytokine storm, and it’s release of Inflammatory cytokines.

Other Studies on Ivermectin for Prophylaxis of COVID 19

Controlled trials studying the prevention of COVID-19 (8 trials completed)

• 3 RCT’s with large statistically significant reductions in transmission rates, a total of 774 patients
• 5 OCT’s with large statistically significant reductions in transmission rates, a total of 2,052 patients

source One-page summary of the scientific review on ivermectin –FLCCC (Frontline COVID-19 Critical Care Alliance)

Ivermectin for Treatment of COVID 19

“The FLCCC Alliance, based on the totality of the existing evidence, supports an A-I recommendation (NIH rating scheme; strong level, high quality evidence) for the use of ivermectin in both the prophylaxis and treatment of all phases of COVID-19.”

One-page summary of the scientific review on ivermectin –FLCCC (Frontline COVID-19 Critical Care Alliance)

“Hundreds of thousands, actually millions, of people around the world, from Uttar Pradesh in India to Peru to Brazil, who are living and not dying” are alive and well thanks to ivermectin…ivermectin is a virtual wonder drug for treating and curing flu/covid.”

Noted journalist and author, former Philadelphia Inquirer/Miami Herald reporter, six-time Pulitzer Prize nominee, two-time National Book Award nominee, National Headliner Award winner Michael Capuzzo in “The Drug that Cracked (Flu) COVID”

Controlled trials in the treatment of both early and hospitalized COVID-19 patients (19 trials completed)

• 5 RCT’s with large, significant reductions in time to recovery or hospital length of stay, a total of 774 patients
• 1 RCT with a large, statistically significant reduction in rate of deterioration/ hospitalization, total of 363 patients
• 2 RCT’s with significant decreases in viral load, days of anosmia, cough, or time to recovery, a total of 85 patients
• 3 RCT’s with large, significant reductions in mortality, a total of 695 patients
• 3 OCT’s with large, statistically significant reductions in mortality, a total of 1,688 patients

source One-page summary of the scientific review on ivermectin –FLCCC (Frontline COVID-19 Critical Care Alliance)

Number of studies and patients among the Existing Clinical Trials of Ivermectin in COVID-19

• 27 controlled trials, including a total of 6,612 patients have been completed using well-matched control groups
• 16 trials, including over 2,500 patients, are prospective, randomized, controlled studies
• 11 of the 27 trials have been published in peer-reviewed journals, 3,900 patients, remainder are in pre-print

One-page summary of the scientific review on ivermectin –FLCCC (Frontline COVID-19 Critical Care Alliance)

Even restricting analysis to just the 16 randomized controlled trials (totaling over 2,500 patients), the majority report a statistically significant reduction in transmission or disease progression or mortality. Further, a meta-analysis recently performed by an independent research consortium calculated the chances that ivermectin is ineffective in COVID-19 to be 1 in 67 million.

Patrick Holford – Flu Fighters Series – Other Approaches to COVID | Podcast

In this Podcast author of the Book Flu Fighters, Patrick Holford discusses with experts, Vitamin D and Ivermectin in prevention and early treatment of COVID-19.

Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis | Meta-Analysis

A meta-analysis was published in 2020 titled Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis which conducted a systematic review and meta-analysis to assess the currently available data on the therapeutic potential of ivermectin for the treatment of COVID-19 as add on therapy.

The analysis covered 4 studies, including RCT (Randomized Control Trials) and observational studies totaling 629 patients; all tested COVID-19 RT PCR positive and showed a statistically significant reduction in all-cause mortality.

All the 3 studies included in the meta-analysis reported clinical improvement as assessed by the need for respiratory support until the available follow-up period. Adding ivermectin led to significant clinical improvement compared to usual therapy.

“ivermectin led to significant clinical improvement compared to usual therapy”

Therapeutic potential of ivermectin as add on treatment in COVID 19: A systematic review and meta-analysis

1. In the study by Gorial et al, the meantime of hospital stay was significantly lower in the ivermectin group than the non-ivermectin group

Most of the patients had one or more comorbidities like diabetes, hypertension, and bronchial asthma. The dose of ivermectin varied from 150 to 200 μg/kg body weight administered as a single dose. In the study by Rajtor et al, 13 patients also received the 2nddose of ivermectin.

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19 | Editorial

An Editorial was published May 20 2020 titled Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. The review pointed out studies which show Ivermectin exhibited broad spectrum anti-viral activity against multiple RNA and DNA viruses, including SARS-CoV-2 which is an RNA virus.

“Ivermectin exerts broad-spectrum antiviral activity against several animal and human viruses, including both RNA and DNA viruses. As SARS-CoV-2 is an RNA virus, the antiviral activity of ivermectin may be mediated through the inhibition of importin α/β-mediated nuclear transport of viral proteins.“

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

“This broad-spectrum endo/ecto-parasiticide has exhibited potent antiviral effects against several ribonucleic acid (RNA) viruses, such as Zika virus [7], influenza A virus [8], Venezuelan equine encephalitis virus [9], West Nile virus [10], porcine reproductive and respiratory syndrome virus [11], Newcastle disease virus [12], chikungunya virus [13], human immunodeficiency virus (HIV-1) [14], yellow fever virus, dengue virus, Japanese encephalitis virus, and tick-borne encephalitis virus [15]. However, the in vivo antiviral potential of ivermectin has only been reported against the West Nile virus [10] and Newcastle disease virus [12].”

“In the study by Caly et al., Vero-hSLAM cells were treated with ivermectin after 2 h of SARS-CoV-2 infection, resulting in ~5000-fold reduction in viral RNA after 48 h”

A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness | RCT Study

A study published Feb 2021 titled A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness analyzed 72 patients hospitalized in Dhaka, Bangladesh in a A randomized, double-blind, placebo-controlled trial. The study found Ivermectin was safe and effective in treating adult patients with mild COVID-19 symptoms.

“A 5-day course of ivermectin was found to be safe and effective in treating adult patients with mild COVID-19. “

A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness

The 72 hospitalized patients in Dhaka, Bangladesh, were assigned 24 each, into one of three groups:

1. Oral ivermectin alone (12 mg once daily for 5 days)
2. Oral ivermectin in combination with doxycycline (12 mg ivermectin single dose and 200 mg doxycycline on day 1, followed by 100 mg every 12 h for the next 4 days)
3. Placebo control group.

Patients underwent a physical examination for COVID-19-related symptoms and their vital signs were recorded.

• Nasopharyngeal swabs were obtained to confirm the presence of SARS-CoV-2 by rRT-PCR on the day of enrolment, and then on days 3, 7, and 14. After day 14, patients were followed-up weekly until found to be test-negative.
• Venous blood was collected for blood parameters on enrolment and on day 4 (complete blood count, creatinine, alanine aminotransferase, Random Blood Sugar).
• A chest X-ray and ECG were assessed on enrolment and on day 3.
• Blood biomarkers were measured on enrolment and on day 7 (C-reactive protein (CRP), ferritin, lactose dehydrogenase (LDH), and procalcitonin).
• RNA was tested for SARS-CoV-2 by rRT-PCR targeting ORF1ab- and N-gene specific primers and probes following the protocol of the Chinese Center for Disease Control and Prevention;
• Other information collected included demographic data and details of any co-morbidity, medication use, and previous hospitalization as part of the medical history.

COVID-19 Symptoms were comparable in all 3 groups. Kaplan–Meier survival analysis revealed that the proportion of patients at risk of SARS-CoV-2 was significantly reduced in the 5-day ivermectin group.

“Virological clearance was earlier in the 5-day ivermectin treatment arm when compared to the placebo group”

“Virological clearance in the 5-day ivermectin group was significantly earlier compared to the placebo group on days 7 and 14”

A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness

There were also no severe adverse drug reactions to ivermectin, in the study.

“There were no severe adverse drug events recorded in the study.”

A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness

The Use of Compassionate Ivermectin in the Management of Symptomatic Outpatients and Hospitalized Patients with Clinical Diagnosis of Covid-19 at the Centro Medico Bournigal and at the Centro Medico Punta Cana, Grupo Rescue, Dominican Republic, from May 1 to August 10, 2020 | Clinical Trial

A clinical trial was published Nov 3 2020 titled The Use of Compassionate Ivermectin in the Management of Symptomatic Outpatients and Hospitalized Patients with Clinical Diagnosis of Covid-19 at the Centro Medico Bournigal and at the Centro Medico Punta Cana, Grupo Rescue, Dominican Republic, from May 1 to August 10, 2020.

The trial analyzed 3,099 patients infected with COVID-19 between May 1-Aug 10 2020, at the Centro Medico Bournigal (CMBO) and the Centro Medico Punta Cana (CMPC), with the objective of showing that Ivermectin reduces mortality from COVID-19 infection; prevents viral replication in early stages, therefore slows disease progression, decreases the number of hospitalizations and the number of deaths.

The study found that in 99.3% of outpatients treated with Ivermectin COVID-19 infection did not progress, and mortality for outpatients and hospitalized was reduced by over 50%.

“99.3% of the outpatients who were treated with Ivermectin, the establishment of early treatment, was effective since the infection did not progress“

Total mortality adding up outpatients and hospitalized patients treated with Ivermectin was 1.2%, well below the average 3% reported in most series and overall mortality worldwide”

The Use of Compassionate Ivermectin in the Management of Symptomatic Outpatients and Hospitalized Patients with Clinical Diagnosis of Covid-19 at the Centro Medico Bournigal and at the Centro Medico Punta Cana, Grupo Rescue, Dominican Republic, from May 1 to August 10, 2020.

Abstract

Discharged for Outpatient Treatment

• A total of 2,706 (87.3%) were discharged for outpatient treatment, all with mild severity of the infection.
• In 2,688 (99.33%) with outpatient treatment, the disease did not progress to warrant further hospitalization and there were no deaths.
• In 16 (0.59%) with outpatient treatment, it was necessary their subsequent hospitalization to a room without any death.
• In 2 (0.08%) with outpatient treatment, it was necessary their admission to the Intensive Care Unit (ICU) and 1 (0.04%) patient died.

Hospitalized

• 411 (13.3%) patients were hospitalized
  • 300 (9.7%) patients were admitted to a COVID-19 room with moderate disease
    • 3 (1%) of whom died
  • 111 (3.6%) were hospitalized in ICU with severe to critical disease
    • 34 (30.6%) of whom died

Methods – Retrospective observational study

• All trial recipients were tested COVID-19 positive either by rt-PCR (Polymerase Transcription) test or had “a highly probable diagnosis” due to the presence of 1 major and 3 major COVID-19 symptoms (Table 1).
• All trial recipients received compassionate treatment with Ivermectin and Azithromycin.

Scale of Severity

1. Grade1 (mild): Patients with arterial oxygen saturation greater than 93% room air, heart rate less than 125/minute, respiratory rate less than 24/minute, no decompensated organs and no deterioration of comorbidities (Table 1).
2. Grade 2 (moderate): Sustained arterial oxygen saturation (3 minutes) equal to or less than 93% room air, dyspnea, respiratory rate greater than 24/minute, heart rate greater than 125/minute.
3. Grade 3 (severe): Sustained arterial oxygen saturation (3 minutes) equal to or less than 80% ambient air, arterial hypotension.
4. Grade 4 (critical): Patients Grade 3 who does not respond to support measures and require mechanical ventilation, administration of vasopressors or hemodialysis.

1. Grade 1 patients were treated on an outpatient basis and followed up by our medical staff, with instructions to return immediately to the ER if they had disease progression.
2. Grade 2 patients were hospitalized in isolation rooms in the COVID-19 area.
3. Grade 3 and 4 patients were hospitalized in the Intensive Care Unit (ICU) in the COVID-19 area

1. Outpatients were administered Ivermectin at 0.4 mg/Kg, orally (PO) in a single dose and Azithromycin 500mg PO per day for 5 days, with follow-up.
2. Hospitalized patients were administered Ivermectin PO at 0.3mg/kg, days 1 and 2, and the dose was repeated on days 6 and 7. They were given Azithromycin 500 mg PO daily, for 7 days.
   1. If they presented a D-dimer greater than 1,000 mg/ml or an increase of 50% from te initial value, they were started with Enoxaparin at 1 mg/kg subcutaneously, every 12 hrs
   2. Patients with an elevated D-dimer, but less than 1,000 mg/ml received Enoxaparin at 1 mg/kg subcutaneously, every 24 hours. Enoxaparin was not administered if there was thrombocytopenia less than 50,000 [17]
   3. Patients who required oxygen received Dexamethasone at 0.1 mg/kg PO per day, maximum 10 mg per day, for 10 days (or Methylprednisolone at an equivalent dose) [18]
   4. Critically ill patients with suspected cytokine cascade syndrome were administered Interleukin 6 blockers, of the Tocilizumab type, 400 mg intravenously and the dose was repeated after 24 hours if there was no clinical improvement. If Tocilizumab was not available, they were administered Methotrexate, a Jak /Stat blocker at 1 mg/kg on days 1, 2 and 3 intramuscularly or intravenously. At 48 hours after the last dose of Methotrexate, Folic Acid 15 mg daily was started PO for 7 days [19,20]

Results and Conclusion

• 99.3% of the outpatients who were treated with Ivermectin, the establishment of early treatment (on average 3.6 days from the onset of symptoms), was effective since the infection did not progress, they did not merit subsequent hospitalization and had no deaths.
• Total mortality adding up outpatients and hospitalized patients treated with Ivermectin was 1.2%, well below the average 3% reported in most series and overall mortality worldwide

Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19

A study was published Sep 24 2020 titled Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19 analyzed the effect of Ivermectin against COVID-19, in hospitalized patients.

“Ivermectin, a US FDA-approved anthelminthic, has garnered enormous interest for treating COVID-19 as it is safe and cheap and has strong antiviral activities against board ranges of viruses including SARS-CoV-2 in vitro. [8 , 9 , 10]”

“This study shows that ivermectin is safe in COVID-19 patients and efficient at rapidly clearing SARS-CoV-2 from nasal swabs. This was much shorter than in the COVID-19 patients receiving only SC (15 days) or receiving a combination of three antiviral drugs (7–12 days [13]).”

“Ivermectin induced rapid virological clearance that we observed in this study indicating that the preclinical efficacy of the drug against SARS-CoV-2⁹ may be mirrored in patients.”

Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19

The study analyzed 325 patients in SK hospital a division of Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh, from April to June 2020, who were diagnosed with SARS-CoV-2 Infection via a PCR (polymerase chain reaction) test.

Of those the present study included 248 adult COVID-19 patients free from any other serious pathological conditions. median age of the patients was 35 (IQR 30–43) years and 60% were men. Remaining 77 patients who were under 18 years of age or transferred from other facilities were excluded from the analysis for various reasons (see study).

The study was approved by MMCH and informed consent was obtained from all patients or their relatives before starting treatment.

1. Ivermectin Group 115 patients received ivermectin at dose of 12 mg within 24-h after hospital admission, plus standard care (SC)
2. Control (no Ivermectin)133 patients received only SC

SC (Standard Care) included: antipyretics for fever, anti-histamines for cough, and antibiotics to control secondary infection.

The two groups were compared in terms of:

1. time to SARS-CoV-2 negativity
2. disease progression (develop pneumonia to severe respiratory distress)
3. duration of hospital stays
4. mortality rate.

At the time of admission, all patients had:

1. Comparatively mild/moderate disease with cough, headache, sore throat, anosmia, breathing difficulty, and pneumonia in different proportions.
2. Some patients in both groups had underlying comorbidities like hypertension, diabetes mellitus, asthma, and hyperlipidemia.
3. About 13% of the patients were current smokers.
4. About 58% had higher d-dimer and CRP levels, 51% had lymphopenia, and 47% had eosinopenia.

However, at the time of admission, there were no significant differences in the patient profiles, presenting symptoms, comorbidities and hemato-biochemical parameters of the two treatment groups

Results

*Of the ivermectin-treated patients, 61 were randomly assigned for follow-up assessment 10 and 20 days after discharge; none of them reported any complications.

“None of the ivermectin-treated patients showed progressive pathology, such as pneumonia or cardiovascular complications“

“in terms of developing respiratory distress leading to ICU admission and the final outcome (discharge/death), we observed a significant clinical benefit of ivermectin in COVID-19 patients. In fact, with ivermectin, we observed quick hospital discharge (median 9 days) in 114 out of 115 patients; the remaining patient arrived with advanced disease.”

“The treatment did not produce any aberrant symptoms related to ivermectin use.”

Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19

Viral Shedding ad communicability of COVID-19

“Such rapid clearing of SARS-CoV-2 (median 4 days); this is much shorter than the median duration (20 days) of viral shedding in patients with COVID-19, [14] indicate that ivermectin could limit the viral spreading.”

Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19

Conclusion

“In conclusion, in addition to rapid SARS-CoV-2 clearance, ivermectin seems to control the course of the disease in patients with COVID-19.”

“ivermectin can be considered as a first-line treatment for containing SARS-CoV-2 to prevent severe irreversible respiratory complications and community transmission.”

Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19

Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study

A study was published Oct of 2020 titled Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study which sought to answer the question: does ivermectin benefit hospitalized coronavirus disease in COVID-19 patients?

“Ivermectin treatment was associated with lower mortality during treatment of COVID-19, especially in patients with severe pulmonary involvement.”

“In this multihospital retrospective cohort study, we observed a significant association of ivermectin with improved survival for patients admitted with COVID-19. This association also was seen in the subset of patients with severe pulmonary disease. These findings were confirmed after multivariate adjustment for comorbidities and differences between groups, and also in a propensity score-matched cohort.”

Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study

The study analyzed 280 patients hospitalized in four Broward Health Hospitals in Florida with confirmed COVID-19 between March 15 and May 11, 2020 who were treated with or without ivermectin. Results showed that Ivermectin inhibited severe acute respiratory syndrome coronavirus 2 replication.

• Group #1 (Ivermectin) – 173 treated with Ivermectin (received at least one oral dose of ivermectin at 200 μg/kg in addition to usual clinical care. A second dose could be given at the discretion of the treating physician at day 7 of treatment.)
• Group #2 (no-Ivermectin) –107 without Ivermectin
• Most patients in both groups also received hydroxychloroquine, azithromycin, or both.

Primary and Secondary Outcomes

1. Primary outcome was all-cause in-hospital mortality. A patient was considered a survivor if he or she left the hospital alive or if his or her status in the hospital changed from active care to awaiting transfer to a skilled facility. Two consecutive nasopharyngeal swab specimens showing negative results for SARS-CoV-2, collected ≥ 24 h apart, were necessary for a patient to be accepted to the local skilled nursing facilities.
2. Secondary outcomes included mortality in patients with severe pulmonary involvement, extubation rates for mechanically ventilated patients, and length of stay (Length of stay was calculated from day of admission to either the day of discharge or to patient death.)

Result

1. Univariate analysis showed lower mortality in the ivermectin group (15.0% vs 25.2%; OR, 0.52; 95% CI, 0.29-0.96; P = .03)
2. Mortality also was lower among ivermectin-treated patients with severe pulmonary involvement (38.8% vs 80.7%; OR, 0.15; 95% CI, 0.05-0.47; P = .001)
3. No significant differences were found in extubation rates (36.1% vs 15.4%; OR, 3.11; 95% CI, 0.88-11.00; P = .07) or length of stay
4. After multivariate adjustment for confounders and mortality risks, the mortality difference remained significant
5. One hundred ninety-six patients were included in the propensity-matched cohort. Mortality was significantly lower in the ivermectin group (13.3% vs 24.5%; OR, 0.47; 95% CI, 0.22-0.99; P < .05), an 11.2% (95% CI, 0.38%-22.1%) absolute risk reduction

SARS-CoV-2 Structure and Stages of Infection

1. Binding and cell entry
2. Replication and Viral Assembly – virus production
3. Inflammation and cytokine storm

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

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

Ivermectin Mechanisms of Action | Anti-viral Properties

Ivermectin exerts broad-spectrum antiviral activity against several animal and human viruses, including both RNA and DNA viruses, through multiple mechanisms. Since 2012, multiple in vitro studies have demonstrated that Ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue and others (Mastrangelo et al., 2012;Wagstaff et al., 2012;Tay et al., 2013;Götz et al., 2016;Varghese et al., 2016;Atkinson et al., 2018;Lv et al., 2018;King et al., 2020;Yang et al., 2020).

1. Ivermectin inhibits the replication of many viruses, including SARS-CoV-2, influenza, and others
2. Ivermectin has potent anti-inflammatory properties with multiple mechanisms of inhibition
3. Ivermectin diminishes viral load and protects against organ damage in animal models
4. Ivermectin prevents transmission of COVID-19 when taken either pre- or post-exposure
5. Ivermectin hastens recovery and decreases hospitalization and mortality in patients with COVID-19
6. Ivermectin leads to far lower case-fatality rates in regions with widespread use.

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

1. A. Direct action on SARS-CoV-2
   1. Level 1: Action on SARS-CoV-2 cell entry
   2. Level 2: Action on Importin (IMP) superfamily
   3. Level 3: Action as an Ionophore
2. B. Action on host targets important for viral replication
   1. Level 4: Action as an antiviral
   2. Level 5: Action on viral replication and assembly
   3. Level 6: Action on post-translational processing of viral polyproteins
   4. Level 7: Action on Karyopherin (KPNA/KPNB) receptors
3. C. Action on host targets important for inflammation
   1. Level 8: Action on Interferon (INF) levels
   2. Level 9: Action on Toll- like-Receptors (TLRs)
   3. Level 10: Action on Nuclear Factor-κB (NF-κB) pathway
   4. Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae
   5. Level 12: Action on P21 activated Kinase 1 (PAK-1)
   6. Level 13: Action on Interleukin-6 (IL-6) levels
   7. Level 14: Action on allosteric modulation of P2X4 receptor
   8. Level 15: Action on high mobility group box 1 (HMGB1)
   9. Level 16: Action as an immunomodulator on Lung tissue and olfaction
   10. Level 17: Action as an anti-inflammatory
4. D. Action on other host targets
   1. Level 18: Action on Plasmin and Annexin A2
   2. Level 19: Action on CD147 on the RBC
   3. 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.

“Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host’s antiviral response.^4,5 In addition, ivermectin docking may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to the human cell membrane.⁶ Ivermectin is thought to be a host-directed agent, which may be the basis for its broad-spectrum activity in vitro against the viruses that cause dengue, Zika, HIV, and yellow fever.^4,7-9 Despite this in vitro activity, no clinical trials have reported a clinical benefit for ivermectin in patients with these viruses. Some studies of ivermectin have also reported potential anti-inflammatory properties, which have been postulated to be beneficial in people with COVID-19.^10-12“

NIH (National Institutes of Health) COVID-19 Treatment Guidelines – Ivermectin

“The antiviral activity of ivermectin is also found to be related to other mechanisms. Ivermectin has been reported to suppress the replication of the pseudorabies virus by inhibiting the nuclear import of UL42 (an accessory subunit of DNA polymerase) [16]. A similar mechanism of inhibition was reported for another DNA virus, bovine herpesvirus 1 [18]. Ivermectin inhibits the nuclear localization signal-mediated import of capsid protein (Cap) of porcine circovirus 2 [17].”

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

Ivermectin Mechanisms of Action Against Parasitic Infections

The primary mechanism of action for ivermectin is that it interferes with the ability of microfilariae to evade the human immune system, resulting in the host’s own immune response being able to overcome the immature worms and so kill them. Growing evidence now shows that rapid microfilarial clearance following ivermectin treatment results not from the direct impact of the drug but via suppression of the ability of the parasite to secrete proteins that enable it to evade the host’s natural immune defense mechanism.

“ivermectin inhibits nuclear import not only by preventing signal recognition by IMPα, but also by ensuring that the IMPα/β1 complex essential to mediate subsequent transport through the nuclear pore is prevented from forming“

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Ivermectin is a Protease Inhibitor and so is Pfizers NEW Oral Antiviral therapeutic DRUG for SARS-CoV-2 treatment

Although Ivermectin is villified by the media…one of the primary mechanisms through which Ivermectin operates against COVID-19 is as a protease inhibitor (study); Speaking of protease inhibitors…so is Pfizer’s new drug entering undergoing phase 1 study as a SARS-CoV-2 treatment.

Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug

A study published Aug 2012 titled Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug showed clear evidence that Ivermectin is effective at inhibiting viral infection of cells in yellow fever virus as well as several other flaviviruses including but not limited to: dengue fever, Japanese encephalitis and tick-borne encephalitis viruses.

“Ivermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of YFV replication (EC₅₀ values in the sub-nanomolar range). Moreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, Japanese encephalitis and tick-borne encephalitis viruses. Ivermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral RNA synthesis, as expected for a molecule that specifically targets the viral helicase.“

“The potential inhibitory effects of the identified molecules on in vitro replication of different flaviviruses (YFV, DENV and WNV) were evaluated. Among the three compounds, only ivermectin inhibited the replication of the selected viruses. In particular, highly potent inhibition of YFV replication was observed.

“Ivermectin proved less active against DENV in the CPE reduction assay (EC₅₀ >1 μM, not shown), although inhibition in virus yield reduction assays was observed (EC₅₀ 0.7 μM, quantified by qRT–PCR; Table 1). Ivermectin inhibited the production of infectious WNV, although with an EC₅₀ of 4 μM (Table 1).”

“Mining of epidemiological records in tropical regions where flaviviruses are endemic and where ivermectin has been administered for decades during population-wide onchocerciasis eradication programmes may offer first insights into the protective roles offered by the new application of this old drug.”

Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug

Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin | Study

A study published Sep 2010 titled Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin showed clear evidence that “Nuclear import inhibitor, Ivermectin, blocks DENV1–4 replication.”

“The small-molecule inhibitor Ivermectin was inhibitory towards both DENV 1 and 2 NS5 interaction with its nuclear transporter importin α/β in vitro, and protected against infection from DENV1–4″

Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin

Ivermectin Mechanisms of Action Against COVID-19 SARS-CoV-2 and Other Viruses

The antiviral potential of ivermectin against various viruses is mediated via the following the targeting of the following:

1. importin α/β-mediated nuclear transport of HIV-1 integrase and NS5 polymerase
2. NS3 helicase
3. nuclear import of UL42
4. Nuclear localization signal-mediated nuclear import of Cap

“There are two mechanisms of action already described that explain IVM ways of preventing COVID 19 activity. The first one is outside host cells, by provoking ionophores along the viral nucleocapside, thus allowing OH compounds in. This deconstructs the virus structure. The other mechanism is inside the host cell, preventing the virus to use the alpha and beta1 importing as carriers to reach the cell nucleus.”

Covid 19 and Ivermectin Prevention and Treatment Update

“The proposed anti-SARS-CoV-2 action of ivermectin involves the binding of ivermectin to the Impα/β1 heterodimer, leading to its destabilization and prevention of Impα/β1binding to the viral proteins. This prevents viral proteins from entering the nucleus, thereby reducing the inhibition of antiviral responses and leading to an efficient antiviral response”

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

“Ivermectin was previously found to inhibit flavivirus replication by specifically targeting the activity of non-structural 3 helicase (NS3 helicase) in vitro. It is a potent inhibitor of the yellow fever virus and a weak inhibitor of other flaviviruses, such as Japanese encephalitis, dengue, and tick-borne encephalitis viruses [15]. Ivermectin was also found to inhibit the nuclear accumulation of HIV-1 integrase and the non-structural protein 5 (NS5) polymerase of the dengue virus, a phenomenon that is dependent on importin α/β nuclear transport [14].”

Ivermectin a new candidate therapeutic against SARS-CoV-2 COVID-19

Ivermectin as a Broad-Spectrum Host-Directed Anti-viral: The Real Deal? | Review

A review of multiple studies titled Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal? analyzed in great deal Ivermectin: efficacy as an anti-parasitic agent, it’s mechanism of action as an IMPα targeting agent (and the multi-faceted ways in which it operates to that end), application as an anti-viral in a clinical setting, and specifically how these topics relate to COVID-19 treatment.

Note: Due to just how comprehensive and detailed this scientific review is….I’ve decided to include the entire review in this blog post. Important points are highlighted in bold, and all reference links are imported to this article (modified to open study in a new page when clicked).

2. Ivermectin as a US Food and Drug Administration-Approved Anti-Parasitic Agent

It is difficult to overestimate the impact of ivermectin as a therapeutic agent to control various parasitic diseases [1 , 2 , 3 , 4 , 5 , 6]. It is administered as a single oral yearly dose (e.g., 150 or 200 μg/kg, respectively) to treat onchocerciasis and strongyloidiasis. Lymphatic filariasis is similarly treated in endemic areas with a once-yearly dose (300–400 μg/kg), or alternatively bi-yearly dosing (150–200 μg/kg) [23]. Ivermectin’s documented antiparasitic mode of action is through potentiating GABA-mediated neurotransmission, and by binding to invertebrate glutamate-gated Cl⁻ channels to effect parasite paralysis and death [24]. Selectivity comes from the fact that ivermectin does not readily penetrate the central nervous system (CNS) of mammals, where GABA functions as a neurotransmitter [24].Doses up to 2000 µg/kg are well tolerated in patients with parasitic infections [23, 25], with analysis of the first 11 years of mass global ivermectin (Mectizan) administration indicating a cumulative incidence of one serious adverse side effect case per million [4, 26]. Similarly, although drug resistance can occur in animals, no resistance in humans has yet been confirmed in over 25 years. Based on this weight of evidence, ivermectin is unquestionably a safe, potent antiparasitic agent likely to be used as such long into the future [1, 4].”

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

3. Ivermectin as an IMPα Targeting Agent with Anti-viral Activity

“Transport into and out of the nucleus is central to eukaryotic cell and tissue function, with a key role to play in viral infection, where a common strategy used by viruses is to antagonize the cellular antiviral response [14 , 27]. The targeting signal-dependent mediators of this transport are the members of the IMP superfamily of proteins, of which there are multiple α and β forms [14 , 27]. The pathway mediated by the IMPα/β1 heterodimer is the best characterized pathway by which host proteins, including members of the signal transducers and activators of transcription (STATs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor families, enter the nucleus through nuclear envelope-embedded nuclear pores. A large number of viral proteins (e.g., [27 , 28]) also use this pathway (see Figure 1), where IMPα within the IMPα/β1 heterodimer performs the adaptor role of specific targeting signal recognition, while IMPβ1 performs the main nuclear roles of binding to/translocation through the nuclear pores, and release of the nuclear import cargo within the nucleus (Figure 1) [27].”

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

“ivermectin inhibits nuclear import not only by preventing signal recognition by IMPα, but also by ensuring that the IMPα/β1 complex essential to mediate subsequent transport through the nuclear pore is prevented from forming“

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Figure 1. Schematic showing IMPα’s role in nuclear transport of host and viral proteins, and mechanism of inhibition by ivermectin. (a) Host proteins, such as members of the STAT or NF-κB transcription factor families, localize in the nucleus through the action of the IMPα/β1 heterodimer, where the “IBB” (IMPβ-binding) region of IMPα (green curved line) is bound by IMPβ1 to enable cargo recognition by IMPα within the heterodimer; IMPβ1 subsequently mediates transport of the trimeric complex through the nuclear pore (NPC, nuclear pore complex) embedded within the nuclear envelope (NE) into the nucleus. This is followed by release within the nucleus to enable the transcription factors to carry out normal function in transcriptional regulation, including in the antiviral response. IMPα can only mediate nuclear import within the heterodimer with IMPβ1. (b) In viral infection, specific viral proteins (e.g., NS5 in the case of DENV, ZIKV, WNV) able to interact with IMPα utilize the IMPα/β1 heterodimer to access the nucleus and antagonize the antiviral response [14,27,28]. This is critical to enable optimal virus production as shown by mutagenic and inhibitor studies. Which SARS-CoV-2 proteins may access the nucleus in infected cells has not been examined (see Section 3). (c) The IMPα targeting compound ivermectin binds to IMPα (binding site shown as red lozenge) both within the IMPα/β heterodimer to dissociate it, and to free IMPα to prevent it binding to IMPβ1, thereby blocking NS5 nuclear import [11]. GW5074 (see Table 1) has been shown to exhibit a similar mechanism [29].

“The importance of nuclear targeting of viral proteins to the nucleus in the infectious cycle has been demonstrated for a number of viruses. Mutagenic analyses, for example, show that specific recognition by IMPα is critical to nuclear localization of various viral proteins, such as DENV non-structural protein (NS) 5 [30]; significantly, DENV, which shows the same reduced interaction of NS5 with IMPα is severely attenuated, underlining the importance of the NS5-IMPα interaction for dengue infection. As has since been shown using a range of different small molecules, the critical importance of this interaction to dengue infection is the basis for the fact that multiple distinct small molecules that disrupt IMPα recognition of dengue NS5 are able to limit dengue infection [7 , 8 , 11 , 29 , 31 ]. In the case of ivermectin, this activity extends to a large number of different viruses (see below) [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17], including SARS-CoV-2 [18]. Which SARS-CoV-2 proteins may access the nucleus in infected cells has not been examined in detail but, in terms of related coronaviruses, ORF6 (Open Reading Frame 6) protein from SARS-CoV-1 has been shown to bind IMPα [32], and ORF4b from MERS-CoV (Middle Eastern Respiratory Syndrome Coronavirus) is known to access the nucleus in NLS-dependent fashion [33]. Ongoing research will establish which of the SARS-CoV-2 ORFs may play comparable roles, and be potential targets of the impact of ivermectin on IMPα. We identified ivermectin in 2011 in a proof-of-principle, high-throughput screen using recombinantly-expressed proteins and a 1200 compound library for inhibitors of HIV-1 Integrase (IN) recognition by IMPα/β1 [34]; specific inhibitors targeting IMPα/β1 directly (such as ivermectin) and not IN (such as budenoside) were identified using a nested counterscreen strategy [34 , 35]. Of several compounds subsequently confirmed to be active against IMPα/β1 and possess antiviral activity as a consequence [7 , 14 , 29 , 36], ivermectin has been the best characterized in this regard, and shown to have broad-spectrum activities, a number of which are summarized in Table 1. It was initially shown to inhibit nuclear import not only of IN, but also of simian virus SV40 large tumour antigen (T-ag) and other IMPα/β1-dependent (but not IMPβ1-dependent) cargoes, consistent with the idea that IMPα (not IN) is the direct target [34 , 35]. Subsequent work has confirmed this, with ivermectin’s ability to inhibit the nuclear accumulation of various different host, including NF-kB p65 [37] and viral proteins demonstrated in transfected and infected cell systems (see Table 1) [14 , 34]. Ivermectin’s ability to inhibit binding of IMPα to the viral proteins NS5 and T-ag has also been confirmed in a cellular context using the biomolecular fluorescence complementation technique [11]. Although targeting of IMPα by ivermectin was clearly supported by many years of research (see also below), direct binding to IMPα was only recently formally demonstrated using a set of biophysical techniques, including thermostability, analytical ultracentrifugation, and circular dichroism (CD) [11]. Importantly, the CD/thermostability studies indicate that binding of ivermectin by IMPα induces a structural change, which is likely the basis of IMPα’s inability to bind viral nuclear import cargoes. Strikingly, the structural change also appears to impair heterodimerisation of IMPα with IMPβ1 [11]; IMPα alone cannot mediate nuclear import, only within the heterodimer with IMPβ1. Thus, ivermectin inhibits nuclear import not only by preventing signal recognition by IMPα, but also by ensuring that the IMPα/β1 complex essential to mediate subsequent transport through the nuclear pore is prevented from forming. Interestingly, GW5074 (see Table 1) appears to have a close to identical mechanism to that for ivermectin in binding to IMPα to induce structural changes that prevent both cargo recognition and specific interaction with IMPβ1 [29]; there is no such data for GSP (see Table 1), which is believed to impact the NLS-binding site of IMPα and prevent cargo recognition more directly (manuscript in preparation).

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

4. Ivermectin as an Anti-viral

“Consistent with the fact that many viruses are known to rely on IMPα/β1-dependent nuclear import of specific viral proteins for robust infection [14 , 27 , 28], ivermectin has been confirmed in a body of in vitro studies to be active in limiting infection by a range of different RNA viruses [10 , 14], including HIV-1 [7], DENV (all four serotypes) and related flaviviruses [8 , 11 , 12], influenza, and alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and chikungunya [9 , 15 , 16] (see Table 1); it is also active against DNA viruses [18 , 19 , 20]. Recent studies indicate it is a potent inhibitor of SARS-CoV-2 [17]. A striking aspect of this antiviral activity is that, where determined, the EC₅₀ for viral inhibition as assessed by a range of different techniques is in the low μM range (see right column, Table 1), interestingly aligning perfectly with its activity in inhibiting recognition of viral nuclear import cargoes by IMPα (see top of left column, Table 1). The clear implication is that the mechanism of inhibition of infectious virus production in the case of all of the viruses listed in Table 1 is largely through targeting IMPα to prevent its role in nuclear import, and of viral proteins in particular (see Figure 1). Significantly, two other small molecules (GW5074 and gossypol) that appear to target IMPα in a very similar way to prevent its nuclear import function [29] have comparable antiviral properties [13 , 29 , 36], consistent with the idea that the host protein IMPα is a key contributor to infection by a number of medically important viruses.”

5. Ivermectin as an Anti-viral in the Clinic

“One of the greatest challenges in antiviral research, as in many other disciplines, is to transition from laboratory experiments to preclinical/clinical studies, with the question of dosing challenging [6]. However, it is important to stress the obvious in this context: that the antiviral activities of ivermectin documented in Table 1 have been derived from laboratory experiments that largely involve high, generally non-physiological, multiplicities of infection, and cell monolayer cultures, often of cell lines such as Vero cells (African green monkey kidney, impaired in interferon α/β production) that are not clinically relevant. Clearly, the results in Table 1 for low μM EC₅₀ values should not be interpreted beyond the fact that they reveal robust, dose-dependent antiviral activity in the cell model system used, and it would be naïve to strive for μM concentrations of ivermectin in the clinic based on them. A key consideration in any clinical intervention using ivermectin is its host-directed (IMPα-directed) mechanism of action. Host-directed agents that impact cellular activities that are essential to healthy function must be tested with caution; although ivermectin has an established safety profile in humans [23 , 25], and is US Food and Drug Administration-approved for a number of parasitic infections [1 , 3 , 5], it targets a host function that is unquestionably important in the antiviral response, and titration of a large proportion of the IMPα repertoire of a cell/tissue/organ likely to lead to toxicity. With this in mind, where a host-directed agent can be a “game-changer” in treating viral infection may well be in the initial stages of infection or even prophylactically (see Section 6) to keep the viral load low so that the body’s immune system has an opportunity to mount a full antiviral response [11 , 17].Ivermectin’s real potential as an antiviral to treat infection can, of course, only be demonstrated in preclinical/clinical studies. Preclinical studies include a lethal Pseudorabies (PRV) mouse challenge model which showed that dosing (0.2 mg/kg) 12 h post-infection protected 50% of mice, which could be increased to 60% by administering ivermectin at the time of infection [18]. Apart from the many clinical trials currently running for SARS-CoV-2 (see below), the only other study thus far reported relates to a phase III trial for DENV infection [40]. Almost 70% of the world’s population in over 120 countries is currently threatened by mosquito-borne flaviviral infections, with an estimated 100 million symptomatic DENV infections and up to 25,000 deaths each year from dengue haemorrhagic fever [41 , 42], despite sophisticated large-scale vector control programs. As for the closely related ZIKV (cause of large outbreaks in the Americas in 2015/2016), the dearth of antiviral treatments and challenges in developing efficacious vaccines hamper disease control. Clinical data published in preliminary form for the phase III trial in Thailand [40] indicate antiviral activity; daily dosing (0.4 mg/kg) was concluded to be safe, and have virological efficacy, but clear clinical benefit was not reported, potentially due to the timing of the intervention. The authors concluded that dosing regimen modification was required to ensure clinical benefit [40]. This study both underlines ivermectin’s potential to reduce viral load in a clinical context, and highlights the complexities of timely intervention and effective dosing regimens to achieve real clinical benefit in the field.”

6. Ivermectin A Viable Treatment for SARS-CoV-2

“Despite efforts in multiple domains, the current SARS-CoV-2 pandemic has now eclipsed the porcine flu epidemic in terms of numbers of infections (rapidly nearing 30 million) and deaths (>930,000) worldwide. The search for antivirals for SARS-CoV-2 through repurposing existing drugs has proved challenging (e.g., see [43 , 44 , 45 , 46 , 47]), one important aspect of repurposing being the perceived need to achieve therapeutic levels in the lung. Published pharmacokinetic modelling based on both the levels of ivermectin achievable in human serum from standard parasitic treatment dosing and robust large animal experiments where lung levels of ivermectin can be measured, indicates that concentrations of ivermectin 10 times higher than the c. 2.5 μM EC₅₀ indicated by in vitro experiments (Table 1) are likely achievable in the lung in the case of SARS-CoV-2 [48]; modelling based on different assumptions predicts lower values, but stresses the long-term stability of ivermectin in the lung (for over 30 days) based on data from animals [49]. It should also be noted that liquid formulations for intravenous administration of long-acting ivermectin have been described, with aerosol administration also in development, to enable ivermectin administration to achieve even higher concentrations to tackle SARS-CoV-2, whilst the use of ivermectin in combination with other agents may enhance efficacy at lower doses.

“There are currently more than 50 trials worldwide testing the clinical benefit of ivermectin to treat or prevent SARS-CoV-2 (see Table 2). These include variations on combination therapies (see [51 , 52]), dosing regimens, and prophylactic protocols. With respect to the latter, preliminary results from recently completed study NCT04422561 (Table 2, no. 22), that examines asymptomatic family close contacts of confirmed COVID patients, show that two doses of ivermectin 72 h apart result in only 7.4% of 203 subjects reporting symptoms of SARS-CoV-2 infection, in stark contrast to control untreated subjects, of whom 58.4% reported symptoms, underlining ivermectin’s potential as a prophylactic. It is to be hoped that the results from the rigorous randomized clinical trials listed in Table 2 will emerge in the next few months to document ivermectin’s credentials as “the real deal” for COVID-19 infection or otherwise. In this context, it is noteworthy that ivermectin has already been approved for the treatment of SARS-CoV-2 in humans by the Republic of Peru [53] and in the Northeastern Beni region of Bolivia [54].”

7. Conclusions

“An instinctive response in developing antiviral agents is to strive for high specificity, making the idea of virus-targeted agents specific to a particular viral component or function attractive, since, ideally, they circumvent the possibility of impacting host function. However, the high propensity of viral genomes, and particularly those of RNA viruses, to mutate and evolve means that selection for resistance can be all too prevalent (e.g., for HIV). Importantly, the high specificity of an agent to a particular virus also inevitably means that its utility against a distinct virus may be limited or non-existent. Thus, it is not surprising that repurposed antivirals active against influenza or HIV, for example, may prove in efficacious against distantly related flaviviruses or coronaviruses. In contrast, antivirals that are host-directed can be repurposed more easily, as long as the viruses in question rely on the same host pathway/functions for robust infection, simply because the host pathway/function targeted is the same [14 , 28]. Although potential complication here is the viral tissue tropism (e.g., blood or lung in the case of systemic or respiratory viral infections) and accompanying pharmacokinetic considerations, selection for viral resistance is largely circumvented in this scenario. As long as toxicity is not an issue, host-directed agents thus have the potential to be genuinely broad-spectrum agents against various different viruses that rely on a common host pathway. The fact that so many viruses rely on IMPα/β1-dependent nuclear import for robust infection ([14 , 27 , 28] and see above) means that agents targeting this pathway have true potential to be broad-spectrum antivirals. After decades of use in the field, ivermectin clearly “fits the bill” here in terms of human safety, but whether it turns out to be the molecule that proves this principle will only begin to be established unequivocally, one way or another, in the ensuing months with respect to SARS-CoV-2.”

“These include variations on combination therapies (see [51 , 52]), dosing regimens, and prophylactic protocols. With respect to the latter, preliminary results from recently completed study NCT04422561 (Table 2, no. 22), that examines asymptomatic family close contacts of confirmed COVID patients, show that two doses of ivermectin 72 h apart result in only 7.4% of 203 subjects reporting symptoms of SARS-CoV-2 infection, in stark contrast to control untreated subjects, of whom 58.4% reported symptoms, underlining ivermectin’s potential as a prophylactic. It is to be hoped that the results from the rigorous randomized clinical trials listed in Table 2 will emerge in the next few months to document ivermectin’s credentials as “the real deal” for COVID-19 infection or otherwise. In this context, it is noteworthy that ivermectin has already been approved for the treatment of SARS-CoV-2 in humans by the Republic of Peru [53] and in the Northeastern Beni region of Bolivia [54].”

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro | Study

A study was published June 2020 titled The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro which found that Ivermectin reduced replication of SARS-CoV-2, thus reducing the viral load on individuals from infection.

“Similarly a 99.8% reduction in cell-associated viral RNA (indicative of unreleased and unpackaged virions) was observed with ivermectin treatment. By 48 h this effect increased to an ~5000-fold reduction of viral RNA in ivermectin-treated compared to control samples, indicating that ivermectin treatment resulted in the effective loss of essentially all viral material by 48 h.”

“these results demonstrate that ivermectin has antiviral action against the SARS-CoV-2 clinical isolate in vitro, with a single dose able to control viral replication within 24–48 h”

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

• Ivermectin is an inhibitor of the COVID-19 causative virus (SARS-CoV-2) in vitro.
• A single treatment able to effect ~5000-fold reduction in virus at 48 h in cell culture.
• Ivermectin is FDA-approved for parasitic infections, and therefore has a potential for repurposing.
• Ivermectin is widely available, due to its inclusion on the WHO model list of essential medicines.

Researchers hypothesized that the anti-viral effects are through inhibiting IMPα/β1-mediated nuclear import of viral proteins as shown for other RNA viruses (Tay et al., 2013; Wagstaff et al., 2012; Yang et al., 2020; Lv et al.,2018; King et al., 2020) which is known to mediate nuclear import of various viral proteins and key host factors.

They concluded that Ivermectin could be the most effective in it’s anti-viral action if given to patients in the very early stages of infection. This makes sense because at a later stage the virus has already replicated and progressed to a more severe infection, which would make the anti viral properties of ivermectin much less useful.

“Ultimately, development of an effective anti-viral for SARS-CoV-2, if given to patients early in infection, could help to limit the viral load, prevent severe disease progression and limit person-person transmission.”

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial | Study

A study published in the esteemed LANCET on June 17 2021 titled Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial, analyzed 45 participants (30 to IVM and 15 controls) between May 18 and September 9, 2020.

The study reported no major side effects in the Ivermectin group nor the control group. However other than 1 case, the only adverse event in the IVM group was a rash (all mild, self-limited and gone in approx. 24hrs) vs in the control group (no IVM) where there were reported single events of abdominal pain, dizziness, anxiety, anguish, and hyperglycemia.

 “18 (40%) of the 45 patients, 13 (43%) in the IVM group and 5 (33%) in the control group. The most frequent adverse event and the only experienced by more than 1 case in the IVM group was rash in 3 (10%) cases (all mild, self-limited and lasting approximately 24 h); in the control group, single events of abdominal pain, dizziness, anxiety, anguish, and hyperglycemia (all mild) were reported“

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

The study found a significant reduction in viral load for those in the Ivermectin group for those with >160ng/mL blood levels of Ivermectin

“When mean plasma IVM concentration levels were analyzed in relation to reduction in viral load, a significant positive correlation was identified, with those patients achieving higher mean plasma concentrations of IVM reaching higher reductions in viral load“

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

They also noted that a lowering of the viral burden by Ivermectin may reduce viral shedding and infectivity and could even help the innate immune system to defend epithelial cells. Stating ultimately that Ivermectin can be used to reduce viral entry or viral replication mechanisms in host cells and assist the innate system in it’s antiviral activity.

” lowering viral burden might influence infectivity, although there is conflicting data regarding the relationship between burden of viral shedding and infectivity [[33]]. The proposed antiviral mechanism of IVM is through its ability to inhibit the nuclear import of viral proteins mediated by IMPα/β1 heterodimer [[4]], and it has also been suggested that IVM could promote defense mechanisms such as pyroptosis in infected epithelial cells [[34]]. Drugs such as ivermectin can be used to target viral entry or viral replication mechanisms in host cells, as well as to modulate the innate immune responses, to achieve indirect antiviral activity”

The study concluded that Ivermectin is effective against SARS-CoV-2 but it’s effectiveness is dose dependent.

“our findings support the hypothesis that IVM has a concentration dependent antiviral activity against SARS-CoV-2″

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer

A study was published May 2020 titled The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer which found the following:

• The FDA-approved broad spectrum antiviral small molecule ivermectin targets host importin α/β1 heterodimer.
• Ivermectin can dissociate the host importin α/β1 heterodimer/prevent re-association.
• Ivermectin can inhibit not only DENV, but also WNV and ZIKV, all of which are major burdens for human health.
• Ivermectin is a compelling prospect as a therapeutic for infection by flaviviruses and other pathogenic viruses.

“Infection by RNA viruses such as human immunodeficiency virus (HIV)-1, influenza, and dengue virus (DENV) represent a major burden for human health worldwide. Although RNA viruses replicate in the infected host cell cytoplasm, the nucleus is central to key stages of the infectious cycle of HIV-1 and influenza, and an important target of DENV nonstructural protein 5 (NS5) in limiting the host antiviral response. We previously identified the small molecule ivermectin as an inhibitor of HIV-1 integrase nuclear entry, subsequently showing ivermectin could inhibit DENV NS5 nuclear import, as well as limit infection by viruses such as HIV-1 and DENV. We show here that ivermectin’s broad spectrum antiviral activity relates to its ability to target the host importin (IMP) α/β1 nuclear transport proteins responsible for nuclear entry of cargoes such as integrase and NS5. We establish for the first time that ivermectin can dissociate the preformed IMPα/β1 heterodimer, as well as prevent its formation, through binding to the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity. We show that ivermectin inhibits NS5-IMPα interaction in a cell context using quantitative bimolecular fluorescence complementation. Finally, we show for the first time that ivermectin can limit infection by the DENV-related West Nile virus at low (μM) concentrations. Since it is FDA approved for parasitic indications, ivermectin merits closer consideration as a broad spectrum antiviral of interest.”

The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer

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

I first want to address the retraction of this review by quoting the explanation as to why it was retracted…

“The Editor-in-Chief has retracted this article. Following publication, concerns were raised regarding the methodology and the conclusions of this review article. Post publication review confirmed that while the review article appropriately describes the mechanism of action of ivermectin, the cited sources do not appear to show that there is clear clinical evidence of the effect of ivermectin for the treatment of SARS-CoV-2. The Editor-in-Chief therefore no longer has confidence in the reliability of this review article. None of the authors agree to this retraction. The online version of this article contains the full text of the retracted article as Supplementary Information.”

In other words the article was completely accurate in covering it’s topic regarding Ivermectin, but the “experts” decided the evidence wasn’t enough to prove effectiveness of Ivermectin against COVID0-19 according to their standards. Therefore they retracted the article against the wishes of the reviews authors. This is classic censorship, and dangerous to the survival of the scientific process.

Here is a quote from the review that I think played a role in the scientific review being involuntarily retracted…

“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 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.“

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

That statement alone would result in my ban from several social media platforms…When you make statements that put at risk the billion dollar COVID-19 vaccine industry, you can be assured, your review will be removed and stricken from the annals of history and in many cases they will also personally attack your credibility, and try their best to ruin your career, as a lesson not to pick a fight with the pharmaceutical conglomerates.

Because the article was retracted, all downloads of the publication were deleted. I’ve managed to use the waybackmachine to access an archived copy of the article and printed it into PDF format to ensure it is preserved and accessible to readers. Please read on for information from the study.

The Study

A review was published June 15 2021 titled The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article which aimed to discuss the mechanism of action of Ivermectin against SARS-CoV-2.

Please Note: I copied and highlighted the majority of this review due to it’s detail and relevance. The majority is quoted to show text is an exact copy from the study. Some portions of the study not relevant to this article were omitted.

“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.”

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

If you want a comparison…the odds of winning the US Powerball lottery in a single ticket is 1 in 292,201,338 (292 million) and odds of winning the Lotto 6/49 jackpot in Canada are 1 in 13,983,816 (13 million) for every single ticket. The review went on to list multiple studies and clinical trials which show Ivermectin effective in the prevention and treatment of COVID-19.

“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 (unfortunately the table was deleted). 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].”

They also pointed out the role Hypoalbuminemia plays in COVID-19 infection, which Ivermectin is potentially useful for.

“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.”

The review did warn caution should be applied in using Ivermectin in an outpatient setting

“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].”

Ivermectin Mechanisms of Action

“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 ubiquitinmediated 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 angiotensinconverting- 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 Mitogenactivated 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”

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].

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

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

1. A. Direct action on SARS-CoV-2
   1. Level 1: Action on SARS-CoV-2 cell entry
   2. Level 2: Action on Importin (IMP) superfamily
   3. Level 3: Action as an Ionophore
2. B. Action on host targets important for viral replication
   1. Level 4: Action as an antiviral
   2. Level 5: Action on viral replication and assembly
   3. Level 6: Action on post-translational processing of viral polyproteins
   4. Level 7: Action on Karyopherin (KPNA/KPNB) receptors
3. C. Action on host targets important for inflammation
   1. Level 8: Action on Interferon (INF) levels
   2. Level 9: Action on Toll- like-Receptors (TLRs)
   3. Level 10: Action on Nuclear Factor-κB (NF-κB) pathway
   4. Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae
   5. Level 12: Action on P21 activated Kinase 1 (PAK-1)
   6. Level 13: Action on Interleukin-6 (IL-6) levels
   7. Level 14: Action on allosteric modulation of P2X4 receptor
   8. Level 15: Action on high mobility group box 1 (HMGB1)
   9. Level 16: Action as an immunomodulator on Lung tissue and olfaction
   10. Level 17: Action as an anti-inflammatory
4. D. Action on other host targets
   1. Level 18: Action on Plasmin and Annexin A2
   2. Level 19: Action on CD147 on the RBC
   3. 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.

A. Direct Action on Sars-CoV-2 – Level 1: Action on SARS-CoV-2 cell entry

1. 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].
2. 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.
3. 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).
4. Choudhury et al. demonstrated in an In-silico data analysis 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].

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:

1. RNA viruses
   1. Zika Virus (ZKV),
   2. Dengue virus
   3. Yellow fever virus (YFV)
   4. West Nile virus (WNV)
   5. Hendra virus (HEV),
   6. Newcastle virus
   7. Venezuelan equine encephalitis virus (VEEV)
   8. Chikungunya virus (CHIKV),
   9. Semliki Forest virus (SFV)
   10. Sindbis virus (SINV)
   11. Avian influenza A virus
   12. Porcine Reproductive and Respiratory Syndrome virus (PRRSV)
   13. Human immunodeficiency virus type 1
2. DNA viruses
   1. Equine herpesvirus type 1 (EHV-1)
   2. Pseudorabies virus (PRV)

Level 5: Action on viral replication and assembly

1. Caly L et al. in-vitro study 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.
2. 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].
3. Yagisawa et al., A review article titled Global trends in clinical studies of ivermectin in COVID-19 co-authored by Prof. Satoshi Ōmura, offered an explanation for the study by Caly et al 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].”
4. Swargiary et al. in-silico study 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 SARSCoV-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 × 10 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 salinetreated 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 SARSCoV- 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.”

Studies on the other anti-viral actions of Ivermectin

Ivermectin: A Positive Allosteric Effector of the α7 Neuronal Nicotinic Acetylcholine Receptor

An article was published titled Ivermectin: A Positive Allosteric Effector of the α7 Neuronal Nicotinic Acetylcholine Receptor which found that Ivermectin is also a positive allosteric modulator of α7 nAChR.

Ivermectin “strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human α7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells.”

“ivermectin acts as a positive allosteric effector.”

Ivermectin: A Positive Allosteric Effector of the α7 Neuronal Nicotinic Acetylcholine Receptor

RNA Viruses and Ivermectin’s Anti-Viral Properties | Other studies

“This broad-spectrum endo/ecto-parasiticide has exhibited potent antiviral effects against several ribonucleic acid (RNA) viruses, such as Zika virus [7], influenza A virus [8], Venezuelan equine encephalitis virus [9], West Nile virus [10], porcine reproductive and respiratory syndrome virus [11], Newcastle disease virus [12], chikungunya virus [13], human immunodeficiency virus (HIV-1) [14], yellow fever virus, dengue virus, Japanese encephalitis virus, and tick-borne encephalitis virus [15]. However, the in vivo antiviral potential of ivermectin has only been reported against the West Nile virus [10] and Newcastle disease virus [12].”

“The broad-spectrum antiviral potential of ivermectin against several RNA viruses is due to its ability to specifically inhibit importin α/β-mediated nuclear transport, which in turn blocks the nuclear trafficking of viral proteins [20]. Several RNA viruses depend on Impα/β1 during the process of infection [21]. SARS-CoV-2, is an RNA virus, is expected to show a similar mechanism of action. The proposed anti-SARS-CoV-2 action of ivermectin involves the binding of ivermectin to the Impα/β1 heterodimer, leading to its destabilization and prevention of Impα/β1binding to the viral proteins. This prevents viral proteins from entering the nucleus, thereby reducing the inhibition of antiviral responses and leading to an efficient antiviral response [1].”

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

1. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus
2. A Wonder Drug in the Arsenal against COVID – 19: Medication Evidence from Ivermectin
3. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin
4. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication
5. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import
6. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer
7. Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V
8. Inhibitors of nuclear transport
9. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses
10. Identification of novel antivirals inhibiting recognition of Venezuelan equine encephalitis virus capsid protein by the Importin α/β1 heterodimer through high-throughput screening
11. Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

DNA Viruses and Ivermectin’s Anti-viral Properties | Other studies

“Ivermectin has also exhibited antiviral activity against deoxyribonucleic acid (DNA) viruses, such as the pseudorabies virus [16], porcine circovirus 2 [17], parvoviruses [6], and bovine herpesvirus 1 [18]. However, the in vivo antiviral potential of ivermectin has only been reported against the pseudorabies virus [16] and parvoviruses [6].”

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo

A study published Nov 2018 showed that Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo.

1. Ivermectin inhibits PRV proliferation in BHK-21 cells.
2. Ivermectin inhibits PRV DNA polymerase accessory subunit UL42 entrance into cell nucleus.
3. Ivermectin inhibits UL42 entrance into cell nucleus by targeting NLS of UL42.
4. Ivermectin alleviated PRV infection caused gross lesions and mortalities in mice.

“Ivermectin is a specific inhibitor of importin-α/β-dependent nuclear transport and shows antiviral potential against several RNA viruses by blocking the nuclear localization of viral proteins. Since the replication of DNA viruses is in the nucleus, ivermectin may be functional against DNA virus infections if the DNA polymerase or other important viral proteins enter the nucleus via the importin-α/β-mediated pathway“

“ivermectin treatment inhibits PRV infection in cells in a dose-dependent manner. Treatment of PRV-infected cells with ivermectin significantly suppressed viral DNA synthesis and progeny virus production. Ivermectin disrupted the nuclear localization of UL42 by targeting the nuclear localization signal of the protein in transfected cells. Ivermectin treatment increased the survival rates of mice infected with PRV and relieved infection“

Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo

Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry | Study

A study published Jan 2015 titled Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry explored the role of Nuclear Localization Signal (NLS) located on the minor capsid proteins VP2 and VP3 during infection, against BK Polyomavirus, a ubiquitous nonenveloped human virus that can cause severe disease in immunocompromised populations and which little is known about how it enters the cell nucleus.

The study also showed that since NLS typically leads to nuclear import through interaction with the transporter proteins importin α/β, that Ivermectin could play a role in that pathway during infection.

• Polyomaviruses must deliver their genome to the nucleus to replicate.
• The minor capsid proteins have a well-conserved nuclear localization signal.
• Lysine 319 on VP2 and lysine 200 on VP3 are critical for nuclearlocalization of the minor capsid proteins
• Mutation of this NLS diminishes, but does not completely inhibit, infection.

“Site-directed mutagenesis of a single lysine in the basic region of the C-terminus of the minor capsid proteins abrogated their nuclear localization, and the analogous genomic mutation reduced infectivity. Additionally, through use of the inhibitor ivermectin and knockdown of importinβ1, we found that the importinα/βpathway is involved during infection“

Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry

“Because BKPyV VP2 and VP3 share homology with SV40,especially in the basic C-terminal amino acids important for nuclear localization of the SV40 proteins (Gharakhanian and Kasamatsu, 1990; Gharakhanian et al., 1987)(Fig. 1A), we hypothesized that VP2 and VP3 of BKPyV would also possess a nuclear localization signal that mapped to these residues. To test this, we expressed VP2 or VP3 alone in RPTE cells by transfection of expression plasmids. In RPTE cells, both VP2 and VP3 showed nuclear localization (Fig. 1B). We next determined the amino acids necessary to confer this nuclear localization. It has been previously shown that lysine 202 on SV40 VP3 and the same amino acid at residue 320 of VP2 was vital for nuclear localization of the SV40minor capsid proteins (Gharakhanian and Kasamatsu, 1990).Therefore, we targeted the homologous lysine in BKPyV, K319 ofVP2 and K200 of VP3, for mutagenesis (Fig. 1A, arrow). Site-directed mutagenesis was used to convert the lysine to a threonine, and the mutant constructs were transfected into RPTE cells to test localization of the proteins. Indeed, the mutants VP2K319Tand VP3K200T no longer localized to the nucleus (Fig. 1C).For SV40, co-expression of VP1 allows for nuclear import of nuclear localization-defective minor capsid proteins (Ishii et al.,1994; Kasamatsu and Nehorayan, 1979). To test whether this was also the case for BKPyV, we co-transfected a VP1 expression vector with each of the VP2K319T and VP3K200T expression vectors. The presence of VP1 led to nuclear localization of both VP2K319T andVP3K200T (Fig. 1D). This observation suggests that the nuclear localization signal on VP1 enables import of VP1-VP2 or VP1-VP3 complexes. These results also suggest that assembly of capsids, which takes place in the nucleus, should not be affected by the presence of a mutation in the minor capsid protein NLS.

Importinβ-mediated nuclear import Is involved during infection

“A number of observations point to an alternative nuclear entry pathway existing along with import through the nuclear pore. The BKPyV NLS mutation only led to attenuated infectivity, and both ivermectin treatment and importin β1 knockdown led to about a 50% decrease in early gene expression.”

“Since ivermectin treatment inhibited the mutant to a similar extent as the wildtype virus, this suggests that the mutant can somehow still use the canonical import pathway, supporting the use of another viral NLS.”

“The inhibitory effect of ivermectin on BKPyV infection further supports the use of active transport through the nuclear pore complex by polyomaviruses for gaining access to the nucleus“

“Since a classical NLS usually leads to nuclear import through interaction with the transporter proteins importin α/β,we first evaluated the role of this pathway during infection through the use of the inhibitor ivermectin, which specifically inhibits the importinα/βnuclear import pathway without affecting other nuclear import pathways (Wagstaff et al., 2012). RPTE cells were infected with wildtype BKPyV and treated with 10mM ivermectin. Early gene expression of wild type BKPyV was evaluated by measuring TAg protein by western blot and mRNA levels by RT-qPCR. TAg protein levels were much lower in the treated lysates compared to those treated with the vehicle butanol (Fig. 3A). Since the TAg protein itself normally undergoes importinα/β-mediated nuclear import, TAg mRNA levels were also measured to verify that the inhibitor was not simply causing instability of the TAg protein by preventing its nuclear localization. Quantitative RT-PCR demonstrated that TAg mRNA levels were also decreased in the inhibitor-treated samples (Fig. 3B), suggesting that the decrease in TAg protein was due to less viral gene expression from inhibition of BKPyV entry into the nucleus. Interestingly, the mutant virus was also sensitive to ivermectin treatment, as there was a decrease in TAg mRNA expression from the mutant, suggesting that the mutant virus retains the ability to use the nuclear import pathway, albeit at a reduced level. To further address a potential role for an importin-mediated nuclear entry pathway in BKPyV infection, we knocked down importin β1 protein levels through siRNA silencing. One day after siRNA transfection, RPTE cells were infected with wild type BKPyV, and protein or RNA was harvested at 24 hpi. Western blotting for importin β1 protein showed an approximately 50% knockdown (Fig. 3C, middle row). TAg levels measured by western blotting were decreased in the knockdown samples compared to those treated with a non-targeting siRNA, and TAg mRNA was also decreased (Fig. 3D). These data provide additional support for the role of the importin α/β canonical nuclear import pathway.“

Results from Countries that have adopted Ivermectin for prevention and/or treatment of COVID-19

Ivermectin has been recommended in 39 countries, about 28% of the world’s population. Some states with vastly greater geographical and population challenges than Canada or the USA, are treating COVID-19 with Ivermectin, and achieving great success across the board.

Perhaps because many of these positive results for ivermectin are from LMIC (poorer) countries, their learnings aren’t perceived as valuable as those from Western countries. Keep up to date here: www.ivmmeta.com

Please Note: most of the countries below have been selected here for analysis, because the vaccination rates are often quite low around 5-20% of the population; unless otherwise stated, and especially low compared to utilization of Ivermectin by those countries. This means the results of declines in things like mortality, hospitalizations, ICU admissions, and death, which coincide with the dates where Ivermectin use was authorized or became more widespread, can be attributed primarily to Ivermectin rather then Vaccination rates; which at such low rates are not a large contributing factor.

Countries that administer Ivermectin for human use see dramatically lower COVID deaths

Various city mayors and regional health ministries within South American countries initiated “ivermectin distribution” campaigns to their citizen populations in the hopes the drug would prove effective. The tight, reproducible, temporally associated decreases in case counts and case fatality rates in each of those regions compared to nearby regions without such campaigns, suggest that ivermectin may prove to be a global solution to the pandemic. This was further evidenced by the recent incorporation of ivermectin as a prophylaxis and treatment agent for COVID-19 in the national treatment guidelines of Belize, Macedonia, and the state of Uttar Pradesh in Northern India, populated by 210 million people

Ivermectin use in Mexico for prevention and early treatment of COVID-19

Mexico also released early treatment kits using Ivermectin and aspirin as the primary medicines, immedaitely afterwards COVID-19 mortality plummeted. Delta variant showed a small spike, then deaths plummeted again.

Ivermectin and COVID-19 in Africa

Africa has been one of the countries least impacted by the pandemic despite having some of the lowest vaccine rates in the world. Many attribute Africa going through the pandemic relatively uneffected, to the fact that Ivermectin has been widely distributed throughout Africa even before the pandemic, in programs designed to flush out parasitic infections across Africa.

• AP News dubiously claimed that “scientists are mystified and wary (about why) Africa avoid(ed) (flu/covid) disaster (sic).”
• In its weekly reports, the WHO calls Africa “one of the least (flu/covid) affected regions in the world.”

COVID-19: The Ivermectin African Enigma | Comparative Study

A study was published Dec 30 2020 titled COVID-19: The Ivermectin African Enigma researched why in come countries in Africa; which participated in an intensive Ivermectin mass campaign (carried out to control onchocerciasis), have an unprecedented low frequency of SARS-CoV-2 COVID-19 cases and deaths and if these two incidences are related.

The study pulled data from 19 countries that participated in the WHO sponsored APOC (African Programme for Onchocerciasis Control) from 1995-2015, found that APOC countries, showed a 28% lower mortality and 8% lower rate of infection due to COVID-19. And ultimately that the widespread Ivermectin campaign of the African countries against onchocerciasis, may have inadvertently also served as a mass public health preventive campaign against COVID-19.

“The incidence in mortality rates and number of cases is significantly lower among the APOC countries compared to non-APOC countries. That a mass public health preventive campaign against COVID-19 may have taken place, inadvertently, in some African countries with massive community ivermectin use is an attractive hypothesis.”

COVID-19: The Ivermectin African Enigma

Methods

The study took data from 19 countries that participated in the World Health Organization (WHO) sponsored African Programme for Onchocerciasis Control (APOC), from 1995 until 2015, and compared it with 25 (Non-APOC) countries, that were not included. Information was obtained from https://www.worldometers.info/coronavirus

“South Africa, a non-APOC country and the most populated country in our dataset with 5 million inhabitants 5 , contributed with largest number of cases and deaths. In South Africa, expected deaths and infections were 5.70 and 3.15 times higher (p <0.001) than the non-APOC countries.“

COVID-19: The Ivermectin African Enigma

The study also stated that “Different quality of health services could be an explanation for the differences in infection (detection) of cases and of mortality.” However I find that very hard to believe as the US has some of the best health care facilities in the world, and also some of the highest COVID-19 infection and death rates.

They also said it could be an issue of underreporting in the non-APOC countries. However in a study Mbow et al. 12 , analyzed the low morbi-mortality by COVID-19 in Africa compared to European countries and US, concluded that it is unlikely that it may be due to race, quality of reporting and death registration, different population age composition, lockdown stringency or other sociocultural aspects.

Ivermectin use in Indonesia sees cases and deaths plummet

Data analysis by @Data_is_Louder published on Twitter shows Ivermectin extremely effective in Indonesia for Prevention and early treatment of COVID-19. Account was suspended by twitter shortly after publishing this evidence.

Here is what brought down @Data_is_Louder. Per Jack Nicholson, @Twitter, “You can’t handle the truth.” #Ivermectin pic.twitter.com/Kdj7esHYWO

— Mary Beth Pfeiffer (@marybethpf) November 2, 2021

Ivermectin reduces COVID infection and death in India

Within may of 2021, India began widespread ivermectin treatment protocols for both prophylaxis (prevention) and treatment of COVID-19 infection. As soon as India began the Ivermectin treatments, a massive statistical drop in COVID infections and death was evident (see image below).

The Amazing Uttar Pradesh Turnaround—The Ivermectin-based Home Medicine Kits

India’s press posted an article titled 33 districts in Uttar Pradesh are now Covid-free: State govt. In the article 33 districts were pronounced COVID-19 free and Uttar Pradesh; India most populous state with about 230 million people was nearly COVID-free as well, with a mere 11 new COVID-18 cases and zero deaths reported in the last 24hrs (at the time the article was published).

To contrast this miraculous reduction in COVID-19 cases and mortality…By March 19, 2021, Uttar Pradesh with a population larger than Brazil, reported 380 cases—however, by April 24, the number of COVID-19 cases skyrocketed to 37,944. This was a public health emergency, and Ivermectin played a key role in completely turning it around.

“There are no active cases of the coronavirus disease (Covid-19) in 33 districts of Uttar Pradesh, the state government informed on Friday. About 67 districts have not reported a single new case of the viral infection in the last 24 hours, the government said, noting the steady improvement of the Covid-19 situation in the state.”

33 districts in Uttar Pradesh are now Covid-free: State govt.

The amazing reduction in COVID infections and mortality in Uttar Pradesh was attributed to a combination of organized, proactive testing, early care; which included Ivermectin home health care kits, and quarantines which all contributed.

The large-scale home prophylactic delivery program led by Dr. Anshul Pareek; General Medical and Health Services for the state of Uttar Pradesh, was probably the largest of its kind worldwide. Specifically utilizing Ivermectin for a) close contacts of COVID-19 patients, b) health workers, and c) general care of COVID-19 patients. Uttar Pradesh accounted for nearly 75% of all COVID-19 recoveries nationwide following the program.

Healthcare workers made constant visits to homes across the state, proactively testing and treating COVID-19 of infected individuals and household contacts, in the early stages, including utilizing medicine kits which included Ivermectin, RAT (Rapid Antigen Tests) and other medicines; Ivermectin is especially effective in early treatment of COVID-19 infection by inhibiting viral replication. Throughout the program Ivermectin was shown to be instrumental in combatting the virulent and transmissible strain of SARS-CoV-2.

The inclusion of Ivermectin in India’s early treatment protocol, was instigated by findings from Monash University which showed Ivermectin inhibits SARS-CoV-2 in lab in vitro (in lab cell culture), as well as research from Bangladesh headed by Dr. Tarek Alam and other places.

“Uttar Pradesh was the first state in the country to introduce large-scale prophylactic and therapeutic use of Ivermectin. In May-June 2020, a team at Agra, led by Dr. Anshul Pareek, administered Ivermectin to all RRT team members in the district on an experimental basis. It was observed that none of them developed Covid-19 despite being in daily contact with patients who had tested positive for the virus.”

Vikssendu Agrawal, Uttar Pradesh State Surveillance Officer

WHO praised the prophylactic health care program but omitted the inclusion of Ivermectin in it’s publications of the story. Censorship continued across India and the world with little western media coverage (except TrialSite), and guarded publication of events within India; few of which mentioned Ivermectin, despite it’s key role in the program.

More stories on Uttar Pradesh’s Ivermectin COVID-19 Miracle

1. Uttar Pradesh Health Officials on Record: Ivermectin as Prophylactic Has Lowered COVID-19 Infection Rate & Death Rates
2. Unprecedented Pandemic Turnaround in Uttar Pradesh with Dramatic Decline in Cases
3. Northern Indian State of Uttar Pradesh Drops Hydroxychloroquine & Replaces with Ivermectin for COVID-19 Patients

Columbia Effectiveness of one solitary public announcement

The mayor of Santiago de Cali, one of the most populous cities in southwest Columbia announced in early Jul of 2020 because of studies showing Ivermectin was effective in treating COVID-19.

Immediately the mayor was under attack by the Ministry of Health, the Columbian President and the FDA, who all released statements against use of Ivermectin in Columbia against COVID-19.

“It’s prescription is not recommended because its effectiveness has not been detected.”

Ministry of Health

“There is no scientific evidence yet to show that the drug is helpful in controlling the disease.”

Columbia President

“There is no scientific evidence that demonstrates the efficacy and safety of the use of antiparasitics such as Ivermectin for the prevention or treatment of SARS-CoV-2 infection”

FDA

Regardless interest of Ivermectin by Columbians grew immensely throughout the country and the mayor provided assurance that many studies show Ivermectin is both safe and effective to treat COVID-19. In Columbia Ivermectin can be easily obtained over the counter without a prescription making it easy for citizens to purchase and self-administer the medicine. Results nation wide showed a statistically significant difference in case fatality rates after Ivermecitn use in Columbia increased.

CFR Change by grouped states

The data below is a comparison of case fatality ratio in Group A where ivermectin sales were the highest per capity july-aug 2020 and Group B where ivermectin sales were lowest per capita for the same period.

Please Note: It’s important to understand that the data in the image below, does not account for variabilities such as comorbities, or demographic variables such as standard of living, access to health care, proximity to infected individuals, etc It does not include whether purchases translated to administration of Ivermectin. The data does not include weather Ivermectin was used in prevention or in the early stages of infection, where it is shown to be most effective, nor whether the dose and duration of administration met the criteria for prevention or treatment of COVID-19 according to other studies and proper clinical trials, Therefore the data in the below image is very low certainty evidence, and should not be used to ascertain the effectiveness of Ivermectin against COVID-19. What the data in the image does provide is a very generalized idea of how even a small portion of regional increases of high Ivermectin use combined with smaller increases in other regions, can still result in statistically significant lower case fatality ratios across the board, even when factoring in millions of people who are not taking Ivermectin or may not be administering it in the appropriate dose / regiment for COVID-19.

The data does show a statistically significant drop in CFR in Group A where IVM sales were highest, which is a trend not shown in Group B where IVM sales were lowest.

Mexico: How a “Test and Treat” strategy is changing COVID-19 figures

On Jan 22 the Head health official in Mexico City Oliva Lopez, announced in a press conference, that they have been using Ivermectin to treat COVID patients since Dec 29 2020. In addition two different health officials, as well as head of the IMSS confirmed that they were also using Ivermectin to treat COVID-19.

The chart below essentially shows that as 2021 progressed it took more tests for each confirmed case of COVID-19, essentially this means there was less people testing positive for COVID-19. This 2% positivity rate is the second lowest in comparison with neighboring countries.

Excess deaths reached normal levels in Mexico city and in the rest of the country starting early March following the Ivermectin “Test and Treat” program launch. Excess deaths in Chiapas also saw dramatic decreases.

Slovakia: Results in a European country open to treating COVID-19 with Ivermectin

Slovakia became the first EU Nation to formally approve Ivermectin for COVID-19 treatment. The Slovakia Republic’s Minister of Health has formerly registered Ivermectin as an approved prophylaxis and treatment for SARS-CoV-2, the virus behind COVID-19 on Jan 26.

Cases in Slovakia have been dropping sharply since the end of Febuary, reoughly 1 month after ivermectin was authorized nationwide.

A rise starting in late February shows positivity rates in Slovankia decline to numbers among the lowest compared to neighboring countries.

COVID-19 hospitalizations in Slovakia show sharp decline starting in late early mar (slide 1). And COVID-19 deaths also saw dramatic decrease; a 7-fold reduction in deaths (slide 2).

A discrepancy in report of COVID-19 deaths between the official daily reports and an actual analysis of the data brings into question the validity of official reporting.

The mismatch is due to The daily increments (presented also on korona.gov.sk) are from the Coroner’s office – the number of newly processed deaths (increment of processed from the previous day irrespective of when the person has died).

“Lately the coroner’s office has received many reports form Jan-Mar after they pushed the hospitals to step up their reporting.”

Misik Matej, Director of the Institute for healthcare analyses at the Slovak Ministry of Health

We know in the US many people that are admitted to the hospital for non-covid related symptoms, are often marked down as COVID-19 if they test positive. In addition according to the vaccine manufacturers you are not considered vaccinated until roughly 14 days post-vaccine, and many vaccine related deaths are being labeled as COVID-19 deaths citing insufficient proof of vaccine causality. Remdesivir can cause many of the more severe symptoms attributed to COVID-19; how many of COVID-19 deaths in the hospital are a result of hospital treatment protocols that refuse to offer Ivermectin treatment. With poor data collection practices, and corrupt reporting; we may not be able to find out until this corruption is purged from the system.

Thanks to the effectiveness of Ivermectin in Slovakia, we see news reports of easing of restrictions across the nation.

• Slovak shops to reopen for some in easing of COVID-19 restrictions
• Slovakia to open restaurant terraces, gyms in further lockdown easing

I did find some recent conflicting articles warning of a rise in COVID-19 infeciton rates in Slovakia

• Slovakia’s daily COVID-19 cases hit new peak since early March
• Slovakia reports spike in COVID cases, mainly among unvaccinated

But the thing to note here is that Ivermectin is primarily utilized in early treatment of COVID-19 which means although infections may be higher, infection severity, hospitalizations, and mortality can be lower across the board. COVID-19 infection rates are not an accurate measure of the effectiveness of a drug like Ivermectin against COVID-19 mortality, when it is largely used once an Individual is already infected, as an early treatment protocol. However the general public can not discern the difference, and reports like this can easily mislead the public into thinking that Ivermectin is not effective, when it’s effectiveness in early treatment is less measured by infection rates, and more by disease severity and mortality rates.

Czech Republic. Results in a European country open to treating COVID-10 with Ivermectin

Cases in the Czech Republic have been dropping sharply since the end of February, a roughly 78% reduction in cases from Mar 1 2021 to late april.

Following Ivermectin administration positivity rate in Czech republic is lower then Germany Hungary, Poland and Ukraine.

Since February Czech also saw a drastic drop in hospitalized COVID-19 patients, and patients in ICU. As well as deaths of the entire population and when separated those younger then 70 as well. It’s important to note that in Czech the rate of COVID-19 vaccination is quite high, which makes it impossible to rule out vaccination as a possible contributing factor to the reduced hospitalizations, ICU admissions and deaths; although vaccine involvement is not implicit either.

Ivermectin and Patient Recoveries from COVID-19 | Studies, Testimonials and Articles

Dr. Syed Halder successfully treats 4000 patients with Ivermectin with 0 deaths

https://twitter.com/DrSyedHaider/status/1451285955743207427?t=_MUg71lkplvaTNOd8tDZNA&s=19

A Family Sues to administer Ivermectin for their mother dying of COVID-19 | The Drug that Cracked COVID by Michael Capuzzo

In The Drug That Cracked Covid,4 author Michael Capuzzo relates the story of the family of Judy Smentkiewicz, who were forced to obtain a court-order to compel the hospital to give her Ivermectin, as she lay dying of Covid in late December, 2020.

Her doctors administered Remdesivir to Judy; Manufactured by Gilead Sciences, one of the world’s largest pharmaceutical companies, Remdesivir costs $3,000 a dose. However according to Michael Smentkiewicz, remdesivir had “absolutely no effect” on his mother. But he wasn’t ready to give up that easily, I’m stubborn, I’m pushy, I’m the loudest guy in the room,” he says. But by now the Smentkiewiczs believed they needed a miracle. 

Finally, Judy’s son Michael watched the video of Dr. Pierre Kory speaking at a US Senate Hearing, advocating the life saving potential of Ivermectin against COVID. Michael said Kory was “incredible,” with top credentials, “and his passion is crazy.” Within minutes, “I called the ICU and told the attending physician, ‘We want my mother to be on this medication.’”

“The doctor said no. Ivermectin wasn’t approved for COVID-19, and “we don’t experiment on our patients.” But Michael pushed harder. “I’m a bull,” he said. After several back and forths, a hospital administrator gave approval for one dose, 15 milligrams of Ivermectin. Less than twenty-four hours later, “Mom is off the ventilator.”

“The nurses were shocked. Michael was jubilant. The next day his mother was sitting in a chair talking to him on Zoom. But then Judy regressed. They moved her to a cardiac floor, her heart was racing, and “she was going downhill,” Michael says, and he asked the doctor for another dose of Ivermectin. This time the “no” from the doctor and administration was final. That day the family retained Buffalo lawyer Ralph Lorigo, who studied Kory’s video and the FLCCC website and sued the hospital to give their mother more Ivermectin.

“Judge Henry Nowak of the New York State Supreme Court agreed to hear the case on an emergency basis as “a matter of life and death.” He ruled that a woman was dying in the middle of a pandemic with no known treatment for COVID-19 and a safe, long-established drug had affected her “miraculous turnround,” and ordered the Millard Fillmore Suburban Hospital to immediately start Judith Smentkiewicz on four more doses of Ivermectin, per her family doctor’s prescription.

“The hospital refused to carry out the judge’s order. The hospital’s lawyer insisted on a hearing to make his case that no patient has the right to choose their own medicine. The debate ensued as Judy lay dying.

Michael Capuzzo Issues Plea to Fellow Journalists (may 21 2021) | Video

Daughter posts story on Tik Tok of fathers miraculous recovery with Ivermectin

TikTok Jessetacoronte elderly mother with comorbidities tests positive for covid and recovers with Ivermectin

TikTok @Jessetacoronte’s mother with multiple co-morbidities tests positive for COVID, takes monoclonal antibodies and Ivermectin and only experiences fever and sore throat.

COVID patient in Coma Gets Ivermectin After Court Order

A 68 year old woman was in intensive care for severe COVID-19 infection, and was put in a COMA. The family fought in court to administer Ivermectin citing several reports by the Front Line COVID Critical Care Alliance that ivermectin has antiviral and anti-inflammatory benefits that help people infected with COVID-19. Finally the courts decided in favor of the family, preventing the hospital from rejecting Ivermectin treatment of the senior.

“A 68-year-old woman with COVID-19, who has been in intensive care in an Illinois hospital for a month, started receiving the controversial drug ivermectin (Stromectol) this week after her family sued the hospital to have someone administer it, according to a report in the Chicago Tribune.

Nurije Fype’s daughter, Desareta, filed suit against Elmhurst Hospital, part of Edward-Elmhurst Health, asking that her mother receive the treatment, which is approved as an anti-parasite drug but not approved for the treatment of COVID-19. Desareta Fype has been granted temporary guardianship of her mother.”

However the hospital persisted to try and refuse Ivermectin Treatment…

“On Friday, DuPage County Judge James Orel ruled Fype should be allowed to get the treatment.

Three days later, according to the Daily Herald, the lawyer for the hospital, Joseph Monahan, argued the hospital could not find a hospital-affiliated doctor to administer the ivermectin.”

“In a follow-up hearing on Tuesday, Monahan told Orel that the hospital asked 20 doctors and 19 other health care workers, including nurses and pharmacists, to administer the medication and they all declined”

“Orel denied a request from Desareta Fype’s lawyer to order the hospital’s nurses to administer further doses.”

COVID Patient in Coma Gets Ivermectin After Court Order

The family had to end up finding their own doctor to administer the life saving Ivermectin treatment.

“When Fype’s doctor was unable to administer it, the legal team found another doctor, Alan Bain, DO, to do it. Monahan said Bain was granted credentials to work at the hospital so he could administer it Monday evening.“

COVID Patient in Coma Gets Ivermectin After Court Order

Ivermectin was administered by Alan Bain on Monday and by the following Tuesday the old woman’s condition already drastically improved

“She looks calm, comfortable, and I’m happy with her monitor numbers so far. They are kind of stable.”

COVID Patient in Coma Gets Ivermectin After Court Order

Ivermectin wins in court | miraculous recovery of severe covid patients

from the desertreview.com

“Ralph Lorigo is the lawyer who now has won three court orders forcing New York hospitals to administer Ivermectin to dying patients. Incredibly, these three hospitals and their lawyers fought against the patients, arguing they did not have the right to receive the drug despite a valid prescription written by their doctors. In essence, the argument was that they did not have the right to try a potentially life-saving medication.

“This lady was on a ventilator, literally on her deathbed, before she was given this drug. As far as we’re concerned, the judge’s order saved this woman’s life.”

from the desertreview.com

In each of the three cases, the New York State Supreme Court Justices sided with the patient, and in each of the three cases, the patients made near-miraculous recoveries after the Ivermectin was given. In each case, these patients were in the Intensive Care Unit on ventilators, unable to breathe on their own, and universally, after the drug was given, they rapidly improved and were able to breathe on their own.”

Practicing physician recovers within 24hrs after taking ivermectin regiment

“As a practicing physician, general internist, I contracted Covid about 2 weeks ago. Started right away with hydroxychloroquine, zinc and Z-Pak. After lying in bed for 1 week without much clinical improvement. I subsequently started on ivermectin regiment per Dr. Pierre Kory, MD from FLCCC. Within 24 hours, I felt better. And after the second dose, I was 80% back to baseline. Without ivermectin, I would certainly be admitted to the hospital and who knows what happened after that. Trust me, while laying in bed fighting for your life, you get to read a lot of research. This one saved mine. Thank you.”

John Reed says ivermectin “saved his life”

John Reed is one of those patients. He’s recovering at Broward Health Medical Center after being treated with the cocktail including Ivermectin. 

“I’m blessed with God, I’m blessed surely with my doctor, I’m definitely blessed with my nurses because they are wonderful staff and I’m blessed with that medicine because I didn’t know it was gonna happen…It saved my life, trust me it saved my life.””

Reed via via FaceTime from his hospital bed in Broward Health Medical Center

Judith Smentkiewicz goes to court to for ivermectin treatment and saves 80yr old mother diagnosed with covid

Family members of an 80-year-old woman, Judith Smentkiewicz, did their own research after their mother was diagnosed with COVID and put on a ventilator, where she was only given a 20% chance to live.

They read about Ivermectin and convinced one of the doctors in the ICU of Millard Fillmore Suburban Hospital to let her try it. Their mother began to make a miraculous recovery with Ivermectin treatment.

Shortly after their mother was moved to another section of the hospital where new doctors refused to continue ivermectin treatment. Amazingly, the hospital did not back down even when faced with a fight in court. They defended their right to deny this woman life-saving medication so they could effectively kill her!

We did a lot of our own research, we read about Ivermectin … The results sounded very promising, and we decided we had to try something different,” Michael Smentkiewicz said. “We pressured the doctor in the ICU to give it to her. He finally agreed.

On Jan. 2, Smentkiewicz was given her first dose of Ivermectin, and according to court papers filed by her family, she made “a complete turnaround.

In less than 48 hours, my mother was taken off the ventilator, transferred out of the Intensive Care Unit, sitting up on her own and communicating,” Kulbacki said in a court affidavit.

But after her mother was transferred to another hospital wing away from the ICU, doctors in that unit refused to give her any more doses of the drug, and her condition quickly declined, the family said in court papers.

We were astounded when they refused to give her any more doses,” Michael Smentkiewicz said. That’s why I called Ralph Lorigo and we took the hospital to court.

Kaleida Health, which operates the hospital, opposed the family’s request in court. Lorigo said Kaleida attorney Michael J. Roach argued to Judge Nowak that doctors – and not the courts – should be making decisions about medical care.

On Jan. 8, Nowak ordered the hospital to “immediately administer the drug Ivermectin” to Smentkiewicz, court papers show.

But the judge also told us verbally that Judith’s family doctor would have to write a prescription for Ivermectin, which he did,” Lorigo said. “In 46 years as an attorney, I’ve never seen another case where a family had to get a court order to continue a treatment that had already been started by a hospital.

This lady was on a ventilator, literally on her deathbed, before she was given this drug,” Lorigo told The Buffalo News about Smentkiewicz, a Cheektowaga resident. “As far as we’re concerned, the judge’s order saved this woman’s life.

After judge orders hospital to use experimental Covid-19 treatment, woman recovers.

South African Revolt leads to permission from Ministry of Health in Zimbabwe to treat COVID-10 patients with Ivermectin and Deaths Plummet

In South Africa, where use of Ivermectin was criminalized, civil rights activists hung posters with Kory’s data urging revolt, and a group of physicians won permission from the Ministry of Health in Zimbabwe on January 27, 2021 to treat COVID-19 with Ivermectin; case fatalities dropped in one month from seventy a day to two a day, “and our hospitals are virtually empty,” said Dr. Jackie Stone, who was subsequently taken in for questioning for her use of a controversial drug. In Phnom Penh, Cambodia, a doctor trained in Milwaukee, Wisconsin, was using Kory’s data to persuade the Ministry of Health of Ivermectin’s efficacy and was making a personal appeal to the king.

Jeff Smith of Cincinnati begins recovery after wife gets court order to administer ivermectin. Hospital fights life saving treatment, takes Jeff off Ivermectin; 10 days later Jeff dies.

“Smith tested positive for Covid-19, was hospitalized and admitted to the intensive care unit July 15, reports Desert Review, in a summary of the case. He was put on the hospital’s Covid-19 protocol consisting of the antiviral drug, Remdesivir, along with plasma and steroids—the near universal treatment of Covid in U. S. hospitals.

On July 27, Smith’s condition began to decline, and he was then sedated and intubated, and placed on a ventilator. Jeff’s wife, Julie Smith, casting about for a miracle to save her husband, discovered the existence of ivermectin on her own.

She connected with Dr. Fred Wagshul, a Dayton, Ohio pulmonary specialist, head of Lung Center of America, who in addition to office visits with patients, counsels hundreds of callers a day in tele-health consultations.

Dr. Wagshal is also one of the founders of FLCCC, who reports having treated over 2,000 Covid patients with ivermectin, with a remarkable record of no hospitalizations or visits to the ER.

In an interview, Dr. Wagshul recounted that after a lengthy conversation with Mrs. Smith, he reviewed her husband’s medical records and medical history and prescribed the drug, but the hospital refused to administer it.

Devastated, Julie hired an attorney, Ralph Lorigo and his team, who sued the hospital. By then it was August and her husband was “at death’s doorstep,” she wrote in an affidavit filed with the lawsuit. “His chances of survival have dropped to less than 30%,” she wrote. “He has no other options.”

Judge Gregory Howard ordered the hospital, West Chester, to honor the family’s request to treat Jeff Smith with Ivermectin. He approved Dr. Fred Wagshul’s prescription of Ivermectin, 30 mg daily, for three weeks.

Over the next thirteen days, as Smith faithfully received the Ivermectin, he began to take slow steps toward recovery, said Dr. Wagshul, according to Desert Review. “They were planning to begin weaning him off the ventilator,” related Lorigo, who was daily appraised of Smith’s progress.

And then, on day 13 of the treatment, a shocking thing happened. An appellate judge, Michael Oster, sided with the hospital’s appeal of the earlier court order, and ruled that the hospital could take Smith off the ivermectin. They promptly did so, over the pleas and protests of Smith’s wife, family and Dr. Wagshul.

Ten days later, Smith died.“

Source yated.com

Hospital fervently fights Ryan Drock to refuse Life saving Ivermectin for his wife, after he used it to recover from COVID-19.

In another life and death Covid lawsuit drama, this one involving a 47-year-old patient clinging to life while her attorney sought a court order to force the hospital to give her ivemectin, the hospital was accused of breaking a promise to the woman’s husband.

Attorney Jake Huxtable said hospital officials had agreed to give Tamara Drock the drug but negotiations broke down over the dosage of Ivermectin she should receive, he told Circuit Judge James Nutt during a hearing.

“We were under the impression she was going to get her first dose yesterday,” Huxtable said. “My client has the freedom of choice,” he said of Drock’s husband, Ryan, who has legal guardianship of Tamara. “He has the right to give his wife any last chance to live, including this drug, Ivermectin. And time is running out.”

Both husband and wife had contracted Covid.  Ryan recovered with the help of ivermectin, he told USA Today, but Tamara was admitted to Palm Beach Gardens Medical Center and moved to the hospital’s Intensive Care Unit, where she was placed on high flow oxygen.

Court records say doctors treated her through the hospital’s Covid-19 protocol, which includes remdesivir, steroids and antibiotics. However, on Sept. 20, her condition worsened, and she was sedated, intubated, and placed on a ventilator.

After no sign of improvement, Ryan Drock requested that his wife be treated with ivermectin, but health officials refused. Court records show he offered to sign a waiver so that the hospital would not be held liable if the treatment didn’t work or caused other problems, but hospital authorities still declined.

“My wife is dying, she has no other option,” Ryan pleaded. According to his account, he was asked to sign a confidentiality agreement, promising to not tell anyone that the hospital would give his wife ivermectin.

Once he did so, hospital officials refused to give her a meaningful dose of the medication, Drock’s lawyer told Judge James Nutt.

In a statement, Ryan Drock said he was “appalled and disgusted” by the hospital’s actions. “So now, I am left with no choice but to go through the court system. This hospital should be ashamed of itself.”

Drock also accused the hospital of thwarting efforts to be served formally with court papers, further delaying his wife’s chances of getting a correct dosage of the medication.

Broward Hospitals Use Ivermectin to Battle Covid-19

Huxtable argued that other hospitals in South Florida, including those run by Broward Health, are using Ivermectin to help patients battle Covid-19.

He cited a 2020 study of 280 patients at Broward Health’s four hospitals. It found fewer COVID-19 patients died after being treated with Ivermectin. The drug was particularly potent in patients with “severe pulmonary involvement,” noted researchers, among them Dr. Jean-Jaques Rajter, whom Yated interviewed several weeks ago on this same topic.

[Dr. Rajter agreed that ivermectin is a remarkably efficacious drug, particularly beneficial in patients with severe respiratory complications.]

“Severe pulmonary involvement is precisely what Mrs. Drock has,” Huxtable told Nutt, noting his client would be an excellent candidate for the drug.

The Florida Supreme Court devised a procedure so families of terminally ill patients have the right to have expedited hearings to decide whether life-sustaining measures are justified. But Judge Nutt seemed reluctant to get involved in the case.

He indicated he might schedule a hearing “over the weekend” to delve into the specifics of the case, not seeming to grasp that every passing hour intensified the patient’s crisis.

“This woman is on her deathbed,” Huxtable protested. “She flatlined a couple of days ago and they revived her. But the hospital is out of options.”

Drock’s attorney tried to persuade Nutt to hold the hospital to its previous promise to administer the drug. He said he wanted the judge to order the hospital to give Tamara a higher dose, the amount recommended by physicians who use ivermectin to treat Covid.

But the judge resisted, saying he wasn’t sure a judge should make a decision that requires medical expertise.

Nightmare Continues

As the nightmare continued to unfold, Attorney Isaac Ruiz-Carus, who represents the medical center, drove the stake deeper by submitting a statement from a Palm Beach Gardens hospital pharmacist, saying he would refuse to fill a prescription for ivermectin because the FDA “hasn’t authorized its use for treating Covid-19 patients.”

Huxtable countered that an emergency room physician along with others at the hospital agreed to prescribe the drug to Tamara. A pharmacy is available that would fill the prescription, he added.

Ryan Drock “isn’t asking for his wife to be treated with an illicit drug, such as heroin,” the attorney argued. “He simply wants to give his wife a chance to recover by receiving a standard dose of the medicine that some researchers said has proven effective in combating Covid-19.”

As of this writing, the case is still at a nightmarish stalemate, with Tamara barely clinging to life, the hospital unyielding in its refusal to give her ivermectin, and the judge supporting that refusal.

The case marked the second time in less than two weeks that a Palm Beach County judge has been asked to decide whether an area hospital should be ordered to give a gravely ill Covid patient ivermectin.

In the second case, however, Bethesda Hospital East in Boynton Beach chose a more humane route, agreeing to give the drug to 65-year-old Glenn Stephanos. The accord was reached after Circuit Judge John Kastrenakes asked hospital officials and Stephanos’s wife to try to settle the case out of court.”

Source yated.com

Why the media campaign against Ivermectin?

Why are some doctors stating Ivermectin is unsafe, and health authorities prohibiting it from COVID-19 treatment? What is the primary driving factor for why Ivermectin is not being prescribed in hospitals and saving lives of COVID-19 patients right now? Greed…

Ivermectin isn’t as profitable as a Vaccine

Up until the pandemic Ivermectin was pennies on the dollar. Due to demand prices for Ivermectin has went up in the last two years, however it is still a fraction of the price compared to COVID vaccine doses.

Typically mRNA vaccines sell upwards of $150USD, however under a special “pandemic supply deal” contract Pfizer has reduced that charge to around $19.50 per dose. Similar prices for the other mainstream COVID vaccines at $15 for Moderna’s shot, $16 for Novavax’s, $10 for Johnson & Johnson’s vaccine and $4 for AstraZeneca’s.

Hospitals being bribed by CMS.gov for prescribing Remdesivir

Source CMS.gov Centers for Medicare & Medicaid Services

CMS.gov is an official website of the United States Government and they are bribing hospitals with bonuses for prescribing Remdesivir. Original source link above; I copied the page into a pdf incase it disappears off their website.

AMA Code of Medical Ethics

American doctors via the American Medical Association, have a code of medical ethics which many doctors and health care practitioners seem to have forgotten about…So what is the punishment when most doctors violate multiple sections; if not most of their code of ethics (see highlighted slideshow)?

Remember that a crime of omission is still a crime. If you bend to the status quo and fail to stand up to exercise your better judgement, due to your own knowledge or experience…then you are as guilty those health care professionals doing the harm…

Pictures are screenshots of the American Medical Association AMA Code of Medical Ethics website directly. Some are available in PDF format.

Engineering Delivery systems for Ivermectin to reduce cytotoxicity and improve relative systemic availability

Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin

A study published May 8 2016, titled Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin pointed out that use of Ivermectin is somewhat hampered in it’s application by issues such as low solubility and high cytotoxicity. In the study researchers were able to reduce cytotoxicity and improve anti-viral activity, by engineering different compositions of liposomes as ivermectin carriers.

“We demonstrate that ivermectin, when delivered through liposomes, reduced cytotoxicity up to 5 times. They can effectively inhibit DENV replication with EC₅₀ values in the same range of ivermectin alone and even improve its activity in several formulations. The possibility of dissolving ivermectin into an aqueous solution thanks to the use of liposome as drug carriers is a new step towards the solution of its pharmacokinetics problems, in particular its high cytotoxicity. This could also amplify the spectrum of ivermectin activities.”

Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin

The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution

A study published Nov 1988 in the European Journal of Clinical Pharmacology analyzed the The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution and found that Ivermectin administered tablets, capsules, and alcoholic oral solution had almost twice the availability, when compared to the solid forms of ivermectin.

“Administration of 12-mg doses of ivermectin (H₂B1a) to 12 healthy volunteers in the form of tablets, capsules, and alcoholic oral solution showed the solution to have approximately twice the systemic availability as either of the solid forms, as evidence both by the maximum concentrations of drug attained in plasma and by the corresponding areas under the plasma concentration vs time curves. However, the two solid formulations showed similar systemic availability.

The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution

I.D.E.A Protocol

The I.D.E.A. Protocol has been replicated in several Provinces (Corrientes, Jujuy, Salta, Tucumán) and is being incorporated in many others (Misiones, Santa Fe, Chubut, etc.). Several amendments have been added, due to the results obtained and new concepts that have emerged since the completion and elevation of the protocols in June 2020 [11]. They are detailed below:

1. The doses are repeated weekly, as many weeks as necessary in each individual case, until the patient is free of disease and / or risk.
2. The weekly schedule can be shortened to every 5 days, if the patient’s condition so requires
3. Bromhexine has been associated with success, outside of the original protocol, since it adds a blocking factor on TMPRSS2 receptors that is not achieved with other medications [12]
4. Carrageenan can be added –also outside the original protocol- in order to reduce the dissemination by aerosols of patients, minimize endogenous reinfection, and the risk of the Health Personnel in charge of their care [13].
5. Once the patient is released, the immune response achieved through “natural active immunization” should be measured, which means having contracted the disease. This immunity is inconsistent at the humoral level, and there is still no infrastructure to massify the search for cellular immunity [14,15]. For this reason, we consider that if the patient has not elevated the specific IgG in a qualitatively/ quantitatively satisfactory way, he should continue with the prophylaxis scheme, once externalized.

Ivermectin and the Math+ Protocol | A treatment for Hospitalized COVID-19 Patients

From the beginning of the pandemic, the hospitals that Marik and Varon led had COVID-19 beat. They achieved remarkably high survival rates at their hospitals at a time when 40 to 80 percent of patients in the U.S. and Europe were dying from the disease. Their success was achieved with the group’s now-famous MATH+ protocol for hospitalized COVID-19 patients.

“Marik, Kory, Varon, Meduri, and Iglesias became heroes of the pandemic to intensivists around the globe who used their protocols to save thousands of lives, and to practitioners at many hospitals in the U.S., including the St. Francis Medical Center in Trenton, New Jersey, where Dr. Eric Osgood posted the MATH+ protocol on a private Facebook group for thousands of ICU doctors after it stopped the dying in his hospital.“

“The cocktail of safe, cheap, FDA-approved generic drugs—the steroid Methylprednisolone, Ascorbic Acid (Vitamin C), Thiamine (Vitamin B1), and the blood thinner Heparin—was the first comprehensive treatment using aggressive corticosteroid and anti-coagulant treatments to stop COVID-19 deaths. Both were novel approaches strongly recommended against by all national and international health care agencies throughout the world, but later studies made both therapies the global standard of hospital care. In addition, Kory, Marik, et. al published the first comprehensive COVID-19 prevention and early treatment protocol (which they would eventually call I-MASK). It is centered around the drug Ivermectin, which President Trump used at Walter Reed hospital, unreported by the press, though it may well have saved the president’s life while he was instead touting new big pharma drugs.” (See page image above.)

“Two manuscripts reviewing different aspects of both the scientific rationale and evolving published clinical evidence in support of the MATH+ protocol were published in major medical journals at two different time points in the pandemic (Kory et al., 2020;Marik et al., 2020). The most recent paper reported a 6.1% hospital mortality rate in COVID-19 patients measured in the two U.S hospitals that systematically adopted the MATH+ protocol (Kory et al., 2020). This was a markedly decreased mortality rate compared to the 23.0% hospital mortality rate calculated from a review of 45 studies including over 230,000 patients (unpublished data; available on request).

Although the adoption of MATH+ has been considerable, it largely occurred only after the treatment efficacy of the majority of the protocol components (corticosteroids, ascorbic acid, heparin, statins, Vitamin D, melatonin) were either validated in subsequent randomized controlled trials or more strongly supported with large observational data sets in COVID-19 (Entrenas Castillo et al., 2020;Horby et al., 2020;Jehi et al., 2020;Nadkarni et al., 2020;Rodriguez-Nava et al., 2020;Zhang et al., 2020a;Zhang et al., 2020b). Despite the plethora of supportive evidence, the MATH+ protocol for hospitalized patients has not yet become widespread.”

Doctor from Muzaffarpur, Bihar in India, Praises Dr. Pierre Kory’s Math+ Protocol for saving hundreds of lives.

A Doctor from a small locale in India sent a letter to Dr. Pierre Kory after Applying the Math+ protocol to patience in the hospital of his poor community:

“Dear Dr Marik I am from a remote place(Muzaffarpur,Bihar) in India. People are not that rich and can’t effort costly treatment. I used your MATH PLUS protocol in TOTO to save hundreds of life at very low cost. Since there is limited govt facility I have managed pts with SPO2 of even 72% at room air with home oxygen, proning and MATH PLUS. I don’t have words to thank you for this. You deserve to get Nobel Prize for your protocol. Words are not supporting me enough to thank you. Dr Vimohan Kumar“

COVID-19 Patient-Survivors on the MATH+ Protocol

Watch this 10-minute video—which was produced as evidence in the legal case to obtain a temporary restraining order against Sentara Hospital System in Virginia. That is where Dr. Paul Marik, one of the most highly published Critical Care Intensivists in the world, is being prohibited from giving his critically ill ICU patients the medicines he believes will save their lives.

Ivermectin Supplementation | Where can I get Ivermectin?

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].

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

Consult your doctor first

It is always best to consult your health care practitioner before administering any medication. Your doctor has access to your medical history, and can advise you on what dose is appropriate for you. They can also advise you against use if you have allergies or health conditions, that could pre-dispose you harm from certain drugs or medications. You should not use ivermectin if you are allergic to it.

To make sure ivermectin is safe for you, tell your doctor if you have:

• liver or kidney disease; or
• cancer, HIV or AIDS, or other conditions that can weaken your immune system.
• Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Tell your doctor if you are breast-feeding a baby as Ivermectin can pass into breast milk and may harm a nursing baby.
• Ivermectin should not be given to a child who weighs less than 33 pounds (15 kg).

Ivermectin side effects

It is common for Ivermectin may make you feel dizzy. To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.

Get emergency medical help if you have signs of an allergic reaction to ivermectin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• eye pain or redness, puffy eyes, problems with your vision;
• severe skin rash, itching, or rash with pus;
• confusion, change in your mental status, balance problems, trouble walking;
• fever, swollen glands, stomach pain, joint pain, swelling in your hands or feet;
• fast heart rate, trouble breathing;
• loss of bladder or bowel control;
• neck or back pain, seizure (convulsions); or
• a light-headed feeling, like you might pass out.

Common ivermectin side effects may include:

• headache, muscle aches;
• dizziness;
• nausea, diarrhea; or
• mild skin rash.

Some of the serious side effects include low blood pressure, inability to breathe and can also lead to liver damage.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Ivermectin side effects (more details).

Ivermectin drug interactions

Other drugs may interact with ivermectin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using. View Ivermectin drug interactions for more information.

Can you consume ivermectin for animals?

Ivermectin used for veterinary application is usually the same as ivermectin provided over the counter for human use; however some veterinary Ivermectin products may contain other medicines or additives. Over the counter human use Ivermectin is readily available and cheap; there are multiple online pharmacies that will provide Ivermectin for human use in Read This List.

Using Ivermectin for animals may not harm you, but you should ensure the product doesn’t contain other medicines or additives (which some intended for parasite removal may) and ideally it should only be used as a last resort if your circumstances are dire, and you have exhausted all over avenues of obtaining Ivermectin intended for human use.

You also will need to understand different measurements to ensure you are taking the correct dose, as veterinary Ivermectin may have higher concentrations or different units of measurement on the package.

It is always recommended to consult your health care practitioner, prior to self-administering ivermectin for the treatment of a condition, this will also ensure you get the correct dose.

Ivermectin dose for prophylaxis of COVID-19

The required dose of ivermectin depends on your unique biology including body weight, and the condition you are attempting to treat. It is best to contact a health care practitioner to be advised on correct dosage, especially if you have comorbidities (other health conditions).

Ivermectin should be used at a rate of 200 micrograms per kilogram of weight, in a weekly dose, which will be repeated in the same period, up to 8 weeks. After these two months, the adipose tissue will have accumulated enough ivermectin for its protective effect to last for another four months [9]

Covid 19 and Ivermectin Prevention and Treatment Update

• Take ivermectin on an empty stomach, at least 1 hour before or 2 hours after a meal.
• Ivermectin is usually given as a single dose. Take this medicine with a full glass of water.
• Never take ivermectin in larger amounts, or for longer than recommended by your doctor. Follow all directions on your prescription label.

How to administer ivermectin

Ivermectin is traditionally taken orally (by mouth) for internal parasites, or applied to the skin for external infestations. Most ivermectin for animals is flavored and can be consumed just as you would food.

How do I get a prescription for Ivermectin?

1. reliablerxpharmacy.com– NO Doctor RX NEEDED for Ivermectin and HCQ
2. alldaychemist.com – No Doctor, license or prescription required. Cheap and available in bulk
3. myfreedoctor.com
4. riverpharmacy.ca
5. synergyhealthdpc.com – TeleMedicine
6. drstellamd.com – Telehealth services
7. canadianhealthcarepharmacymall.com – Canada Pharmacy
8. canadianpharmacyking.com – Canada Pharmacy (Prescription required)
9. FLCCC Extended list of Doctors available here (to get Ivermectin prescription)
10. FLCCC Extended list of Pharmacies that will prescribe Ivermectin (some may require prescription)

If selecting your own medical provider always check

• reviews from other patients
• pricing for services upfront
• contact multiple providers for comparison
• In the USA Check the state medical board to see if the provider has a disciplinary record. visit: https://www.checkbook.org/national/doctors/articles/License-and-Disciplinary-Actions-3181

Guides for Home treatment protocols

1. World Council for Health worldcouncilforhealth.org
2. Association of American Physicians and Surgeons aspsonline.org

HELP!! MY LOVED ONE IS IN THE HOSPITAL WHAT DO I DO??? (READ HERE)

How to legally force hospitals to provide ivermectin for your loved one, with COVID-19 Infection

When advocating for a loved one to receive treatment from older drugs such as ivermectin, the best way is to get a prescription from your family doctor. By obtaining a prescription from your family doctor the ivermectin treatment becomes 100% legal and the hospital cannot legally refuse treatment because by law medical physicians are allowed to prescribe drugs for “off-label” use.

If you obtain a prescription from your family doctor, bring that along with any documentation on COVID ivermectin treatment (see below). If your doctor or hospital refuses to administer Ivermectin treatment, print off the documents below and give them your doctor or hospital doctors.

Every US hospital has a Medical Ethics Committee, you can also request of any hospital in the US, to have a medical ethics committee consult, and they are obligated to arrange that, weather they like it or not.

Documents to print off and show it to your doctor and the hospital

1. Fill out and bring the Medical Directive to Physician Form (Original from thedrardisshow.com)
2. NIH.gov Table 2e. Characteristics of anti viral agents approved or under evaluation for covid 19 treatment
3. British Ivermectin Recommendation Development (BIRD) Group Ivermectin Flyer
4. CMS.gov Centers for Medicare and Medicaid Services – New COVID-19 Treatments Add-On Payment (NCTAP) showing CMS.gov bribing hospitals with prescribing lethal Remdesivir
5. IVMMETA.com Stats on Ivermectin Studies (updated frequently), which show Ivermectin is effective for Prophylaxis and Treatment of COVID-19 (click PDF on the top of the page and Print off the PDF)
6. FLCCC Frontline Critical COVID 19 Care Alliance – Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
7. If the doctor refuses to administer treatment, find a new physician who will, then fill out and print off the Medical Power of Attorney Form and give that to the doctor refusing treatment.

“If your loved one is coherent, tell them to demand verbally and record it if possible, to STOP all Remdesivir treatments immediately. If they resist and continue or attempt to do it again tell your loved one to threaten that they will call the police and file battery charges against the doctor.”

Dr. Ardis theardisshow.com

The Right to Try Act in the USA

The right to try act was signed into law in May 2018 by then President Donald Trump. This law is another way for patients who have been diagnosed with life-threatening diseases or conditions who have tried all approved treatment options and who are unable to participate in a clinical trial to access certain unapproved treatments. The right to try act is federal law, which means it’s valid across all states in the USA.

The FDA also has a page explaining the Right to Try act along with a helpful Question & Answer section.

Who Qualifies for Right to Try?

To be eligible for Right to Try, a patient must meet the following conditions:

• Be diagnosed with a life-threatening disease or condition;
• Have exhausted approved treatment options;
• Be unable to participate in a clinical trial involving the eligible investigational drug, as certified by a doctor, who is in good standing with her licensing organization and will not be compensated directly by the manufacturer for so certifying; and
• Give written informed consent regarding the risks associated with taking the investigational treatment.

Ivermectin and the Right to Try Act

Does a treatment that is already FDA-approved for something else qualify for Right to Try?

“Doctors may already prescribe treatments ‘off-label.’ Off-label means prescribing an FDA approved treatment for a condition, dose, or population other than what the FDA approved. Therefore, no special permission is needed for a physician to prescribe treatments that are approved for other conditions. Right to Try applies to treatments that are being given to patients in clinical trials but are not already FDA approved.”

righttotry.org

Other Useful Documents and Articles

1. Blog: How to speak to friends, colleagues and loved ones about ivermectin

Other medicines for the prevention and treatment of COVID-19

Ivermectin Combination Therapy with Hydroxychloroquine

It has also been hypothesized that combination therapy using hydroxychloroquine and ivermectin may exert a synergistic inhibitory effect on SARS-CoV-2. In this combination, hydroxychloroquine acts by inhibiting the entry of SARS-CoV-2 into the host cells, whereas ivermectin further enhances the antiviral activity by inhibiting viral replication [22].

Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

A study was published on Jun 5 2020 titled A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications which aimed to better understand the patho-physiology of COVID-19 and the issue of inter-individual variability for the susceptibility to infection. Specifically focusing on the relationship between Nicotine and ACE2 as it relates to cardiovascular and pulmonary diseases and the following two conditions:

1. In outpatients with favorable outcome : neurological/psychiatric disorders, especially loss of sense of smell which is specific of the disease
2. In hospitalized older patients with a poor prognosis : systemic hyperinflammatory syndrome with increased levels of circulating cytokines and atypical acute respiratory distress syndrome with loss of neurological control of lung perfusion regulation and hypoxic vasoconstriction [3]

“There is structural evidence supporting the hypothesis that SARS-CoV-2 virus is a nicotinic agent.”

“observation supports the hypothesis that SARS-CoV-2 virus itself is a nAChR blocker.”

“Nicotine may be suggested as a potential preventive agent against Covid-19 infection. Both the epidemiological/clinical evidence and the in silico findings may suggest that Covid-19 infection is a nAChR disease that could be prevented and may be controlled by nicotine. Nicotine would then sterically or allosterically compete with the SARS-CoV-2 binding to the nAChR.”

“we plan a therapeutic assay against Covid-19 with nicotine (and other nicotinic agents) patches or other delivery methods (like sniffing/chewing) in hospitalized patients”

“Accordingly, in the ACE/ANG II/AT1R arm, nicotine increases the expression and/or activity of renin, ACE and AT1R, whereas in the compensatory ACE2/ANG-(1–7)/MasR arm, nicotine down regulates the expression and/or activity of ACE2 and AT2R, thus suggesting a possible contribution of acetylcholine receptors in ACE2 regulation”

Researchers also pointed out that there is strong evidence for a neurotropic action of SARS-CoV-2 infection, specifically analyzing other β-coronaviruses…

“It has been demonstrated that β-coronaviruses to which the SARS-CoV-2 belongs, do not limit their presence to the respiratory tract and have been shown to frequently invade the CNS [10]. This propensity has been convincingly documented for the SARS-CoV-1, MERS-CoV and the coronavirus responsible for porcine hemagglutinating encephalomyelitis (HEV 67N). In light of the high similarity between SARS-CoV-1 and SARS-CoV-2, it is quite likely that SARS-CoV-2 also possesses a similar potential.”

They cited other studies showing that Neuroinfection can contribute to pathophysiology and may play a role in the respiratory failure of COVID-19 patients.

“Neuroinfection has been proposed to potentially contribute to the pathophysiology and clinical manifestations of Covid-19 [10] with the neuroinvasive potential of SARS-CoV-2 suggested to play a role in the respiratory failure of Covid-19 patients [11, 12]. “

They stated that if the virus enters through the olfactory system neurons an/or through the lung it could lead to different clinical features and possibly even a different outcome for COVID-19 infection.

“Our nicotinic hypothesis proposes that the virus could enter the body through neurons of the olfactory system and/or through the lung leading to different clinical features with different outcome, and contrasts with the currently accepted view that ACE2 is the principal receptor of SARS-CoV-2 for its entry into cells.”

In addition they said the time between first symptoms of infection and intensive care may be a sufficient latency period for the virus to enter the nervous system, invade the brain stem and affect the medullary neurons of the respiratory centers. But that a variability in neurological signs suggests a diversity in the mode of proliferation and / or progression of the virus.

“Based on an epidemiological survey on Covid-19, the median time from the first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to the intensive care was 8.0 days [15]. Therefore, the latency period may be adequate for the virus to enter the nervous system, invade the brain stem and affect the medullary neurons of the respiratory centers. However, variability of the neurological signs was observed with patients having anosmia, showing in general a mild evolution without pulmonary attack, in contrast with those without anosmia suggesting a diversity in the mode of proliferation and /or progression of the virus.“

Researchers cited studies of other RNA viruses such as RABV (Rabies Virus) , and their similar actions to snake toxins, specifically in showing high affinity and exquisite selectivity to some brain receptors; can give scientists insights into COVID-19 propagation in the brain and that evidence suggests a strong role of nAChR in the disorder.

“The nAChR pathway is hypothesized to be engaged in the Covid-19 inflammatory syndrome. The nervous system, through the vagus nerve, can significantly and rapidly inhibit the release of macrophage TNF, and attenuate systemic inflammatory responses [28]. This physiological mechanism, termed the ‘cholinergic anti-inflammatory pathway’ has major implications in immunology and in therapeutics. The cytokine production of macrophages—one of the main cell types found in the bronchoalveolar fluid—is under the physiological control of auto/paracrine acetylcholine through their nAChRs [29]. Following dysregulation of macrophage nAChRs, the profile of cytokines massively secreted include Il1, Il6, TNF et Il18. This cytokine profile shows striking analogies with the cytokine storm syndrome, leading to the hyperinflammatory syndrome described in a subgroup of Covid-19 patients [30]. Systemic coagulopathy with venous and arterial thrombosis is one of the critical aspects of the morbidity and mortality of Covid-19. In line with our hypothesis, one should note that hematopoietic α7-nAChR deficiency increases platelet reactive status, which could explain the thrombogenic presentation of Covid-19 [31]. Although selective cytokine blockers (eg, IL1-receptor antagonist anakinra or anti-IL6 tocilizumab) have been proposed for the control of Covid-19 cytokine storm, their efficacy is still to be explored. Interestingly, α7 agonists, including nicotine, have proven to be effective in reducing macrophage cytokine production and inflammation in animal models of pancreatitis [32] and peritonitis [33]. In this setting, a nicotinic treatment that might possibly antagonize the blocking action of SARS-CoV-2 on the AChR through a possible modulation of the ACE2 – nAChR interaction, would act earlier than anti-cytokine therapies. nAChR modulation by Covid-19 might tentatively account for the hyperinflammatory features observed in a subgroup of Covid-19 patients, mimicking bona fide the macrophage activation syndrome.”

I found it interesting they also suggested their hypothesis may explain why the more severe forms of COVID-19 are present in obese and diabetic individuals.

“Of note, our hypothesis could explain the high prevalence of obesity and diabetes mellitus observed in severe forms of Covid19. The diminished vagus nerve activity previously described in these two illnesses could be potentiated by the Covid-19 elicited nicotinic receptor dysregulation, leading to a hyperinflammatory state often reported in obese patients [29].”

“nAChRs are present in the lung epithelium. The non-neuronal cholinergic system contributes to the regulation of cell functions such as cell-cell interaction, apoptosis, and proliferation and it is well established that human bronchial epithelial cells contain nAChRs. The airway epithelium expresses α3, α4, α5, α7, α9, β2, and β4-nAChRs subunits [34, 35, 36, 37] and their contribution has been discussed in the framework of airway epithelial basal cell proliferation-differentiation and their alteration in lung cancers [38]. These nAChRs are mentioned here as possible targets of Covid-19 infection of the lung, which would take place concomitantly with, and/or as a consequence of, the neuro-infection. Additionally, nAChRs are involved in lung perfusion regulation, which seems to be disrupted in the atypical acute respiratory distress syndrome reported in Covid-19 patients [3].”

And also that some evidence may show smoking is a protective factor against SARS-CoV-2.

“Thus, current smoking status appears to be a protective factor against the infection by SARS-CoV-2…these data are consistent with the hypothesis that its protective role takes place through direct action on various types of nAChRs expressed in neurons, immune cells (including macrophages), cardiac tissue, lungs, and blood vessels.”

Now that doesn’t mean you want to run out and by a pack of smokes… Researchers stated the chemistry of smoke is complex and the age and sex of consumers is also a factor. They also remind people that nicotine is a drug of abuse responsible for smoking addition which has severe pathological consequences and remains a danger for health, but undeer clinical settings it could help treat acute infecitons such as COVID-10.

“Nicotine may be suggested as a potential preventive agent against Covid-19 infection. Both the epidemiological/clinical evidence and the in silico findings may suggest that Covid-19 infection is a nAChR disease that could be prevented and may be controlled by nicotine. Nicotine would then sterically or allosterically compete with the SARS-CoV-2 binding to the nAChR. This legitimates the use of nicotine as a protective agent against SARS-CoV-2 infection and the subsequent deficits it causes in the CNS. Thus, in order to prevent the infection and the retro-propagation of the virus through the CNS, we plan a therapeutic assay against Covid-19 with nicotine (and other nicotinic agents) patches or other delivery methods (like sniffing/chewing) in hospitalized patients and in the general population.

In conclusion, we propose, and try to justify, the hypothesis that nAChRs play a critical role in the pathophysiology of SARS-CoV-2 infection and as a consequence propose nicotine and nicotinic orthosteric and/or allosteric agents as a possible therapy for SARS-CoV-2 infection. Interestingly, ivermectin, which has been recently shown to inhibit the replication of SARS-CoV-2 in cells in vitro [53], is a positive allosteric modulator of α7 nAChR [54]. The nicotinic hypothesis might be further challenged by additional clinical studies and by experimental observations determining whether SARS-CoV-2 physically interacts with the nAChR in vitro, for instance by electrophysiological recordings, high resolution EM and by animal model studies. Further work should also specify the still enigmatic relationships between ACE2 and nAChRs in the nervous system.”

Budesonide

“Inhaled budesonide is a safe, generic, inexpensive prescription medication. It is used by” millions of people who suffer from asthma every day. It can be prescribed by any doctor or nurse practitioner for respiratory symptoms (FDA-approved). Budesonide is so safe that it is in some over-the-counter nasal sprays such as Rhinocort.”

budesonideworks.com

“If I had not seen the video of Dr. Bartlett‘s success and if I had not had the wherewithal to fight, to advocate, and finally to demand that I be prescribed the budesonide, I believe that I would have been in the hospital on a ventilator and probably would not be writing this letter.”

James Lloyd, Covid survivor

Effect of nebulized budesonide on respiratory mechanics and oxygenation in acute lung injury/acute respiratory distress syndrome: Randomized controlled study

“Budesonide is an inhaled glucocorticoid which inhibits a variety of inflammatory cells, reduces the production of inflammatory mediators and consequently has a significant anti-inflammatory effect. It also induces vasoconstriction, inhibits mucosal edema, reduces cell exudation, and prevents airway remodeling. [13]”

More information available on Budesonide at budesonideworks.com

In 1027 A study was published in the Saudi Journal of Anesthesia titled Effect of nebulized budesonide on respiratory mechanics and oxygenation in acute lung injury/acute respiratory distress syndrome: Randomized controlled study which proved that nebulized budesonide will stop the release of cytokines from the lungs and improve their oxygenation, which is exactly what’s putting people in the hospital with COVID-19, Acute Respiratory Distress Syndrome (ARDS).

This study was conducted on 60 adult patients admitted to the ICU of Qena University Hospital either directly or referred from chest department.

“Nebulized budesonide improved oxygenation, peak, and plateau airway pressures and significantly reduced inflammatory markers (TNF-α, IL-1β and IL-6) without affecting hemodynamics.”

“The results of this study showed that budesonide nebulization significantly improved peak and plateau airway pressures and oxygenation in the form of increased PaO₂/FiO₂ ratio together with significant anti-inflammatory effect manifested by reducing the values of inflammatory cytokines (IL-1β, IL-6 and TNF-α) in patients with early ALI/ARDS.”

Effect of nebulized budesonide on respiratory mechanics and oxygenation in acute lung injury/acute respiratory distress syndrome: Randomized controlled study

“Nebulized budesonide administration had led to significant decrease in peak (P = 0.021) and plateau (P = 0.032) airway pressures when compared with the other placebo group [Table 2].

Oxygenation index (PaO₂/FiO₂) showed improvement in budesonide group (239 ± 15) compared with the placebo group (207 ± 12) with statistically significant difference (P = 0.023) [Table 2].

Regarding serum concentration of cytokines, budesonide group showed statistically significant decrease in the levels of TNF-α, IL-1β, and IL-6 compared with placebo group (TNF-α 28 ± 24 vs. 49 ± 30, IL-1β 31 ± 43 vs. 43 ± 51, and IL-6 386 ± 215 vs. 563 ± 314, respectively; P < 0.05) [Table 3].”

Common asthma treatment reduces need for hospitalization in COVID-19 patients, study suggests | Pre-print

A randomized study was published on the medRxiv pre-print server titled Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial which analyzed 146 people led by Professor Mona Bafadhel of the University’s Nuffield Department of Medicine.

The trial was inspired by the fact that, in the early days of the pandemic, patients with chronic respiratory disease, who are often prescribed inhaled steroids, were significantly under-represented among those admitted to hospital with COVID-19.

“There have been important breakthroughs in hospitalized COVID-19 patients, but equally important is treating early disease to prevent clinical deterioration and the need for urgent care and hospitalization, especially to the billions of people worldwide who have limited access to hospital care.”

“Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.”

“I am heartened that a relatively safe, widely available and well studied medicine such as an inhaled steroid could have an impact on the pressures we are experiencing during the pandemic.'”

Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial

1. Group 1 (half) took 800mcg of Budesonide 2x daily
2. Group 2 (half) were administered standard care (no budesonide)

Results suggest that inhaled budesonide reduced the relative risk of requiring urgent care or hospitalization by 90% in the 28-day study period. Participants allocated the budesonide inhaler also had a quicker resolution of fever, symptoms and fewer persistent symptoms after 28 days.

“I am encouraged to see the reduction in persistent symptoms at 14 and 28 days after treatment with budesonide. Persistent symptoms after the initial COVID-19 illness have emerged as a long-term problem. Any intervention which could address this would be a major step forward.”

Prof Bafadhel, a Respiratory Consultant also working at the Oxford University Hospitals NHS Foundation Trust

How to get a prescription for Budesonide

• Synergy Health – licensed in multiple states and provider full service (preventive, early, urgent care, etc.). They can even send supplement oxygen to your home. Book appointments on line.
• Stotland Medical– a new provider in our network and is licensed in all 50 states and D.C. Telemedicine for prophylactic, early treatment and urgent care. You can book online for appointments.
• International Providers: We do not know of any doctor who has stepped up in Canada or anywhere outside the US. You can try https://www.exstnc.com/ as they have providers listed worldwide.
• Additional resources: If you cannot find a provider to help you, try this resource: https://c19protocols.com/physicians-facilities-offering-early-treatment/. There are many telehealth providers listed there that should be able to help you. 
• If you are confused and do not know what kind of help you need, schedule a call with a Covid Coach.

Ineffectiveness of other approved medicines against COVID-19

“A wave of recently published results from therapeutic trials done on medicines thought effective for COVID-19 which found a lack of impact on mortality with use of remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, and mono-clonal antibody therapy (Agarwal et al., 2020;Consortium, 2020;Hermine et al., 2020;Salvarani et al., 2020). 4 One year into the pandemic, the only therapy considered “proven” as a life-saving treatment in COVID-19 is the use of corticosteroids in patients with moderate to severe illness (Horby et al., 2020)”

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

“Hydroxychloroquine, lopinavir/ritonavir and azithromycin have been extensively used attempting to prevent or cure Coronavirus Disease 2019 (COVID-19) during the first wave. However, during the last few months, large clinical trials demonstrated the lack of efficacy of the abovementioned treatments [1 , 2, 3].”

Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use?

Comparison of Ivermectin Vs Molnupiravir

Source birdgroup.org

Lorazepam and Midazolam ARE DANGEROUS!!!

Both Lorazepam and midazolam are extremely lethal and dangerous drugs. DONT LET DOCTORS OR HOSPITALS PRESCRIBE THEM TO YOUR YOU OR YOUR LOVED ONES!

Additional Studies | Ivermectin and COVID-19

For an up-to-date overview of all published studies on ivermectin in the treatment and prevention of COVID-19 we recommend visiting c19ivermectin.com; in addition, a meta-analysis of all studies can be found at  ivmmeta.com (up to date).

Many of these studies (until January 12, 2021) were included in the FLCCC comprehensive  Review of the Emerging Evidence Supporting the Use of Ivermectin in the Prophylaxis and Treatment of COVID-19, and a brief summary of the studies at that time can be found in the accompanying One-page summary of the scientific review on ivermectin.

List of additional studies – Table 2 | Ivermectin and COVID-19

Resources to keep up-to-date on Ivermectin stats, clinical trials and studies

1. Ivermectin Clinical Trials – ClinicalTrials.gov (constantly updated – Search Ivermectin)
2. Global ivermectin adoption for COVID-19 – ivmstatus.com (constantly updated)
3. Ivermectin Deaths by WHO Database – VigiAccess.org (constantly updated – Search Ivermectin)
4. Database of all ivermectin COVID-19 studies – c19ivermectin.com (constantly updated)
5. UK General Information, news, studies, treatment protocols, etc – bird-group.org
6. US General Information news, studies, treatment protocols, etc – FLCCC (Frontline COVID-19 Critical Care) Alliance – covid19criticalcare.com (constantly updated)
7. Dr. Ardis Info on: where to get ivermectin, what supplements to take to prevent COVID-19 infection, how to make doctors and hospitals prescribe Ivermectin, lawyer interviews on how to take sue hospitals to save your loved ones or get compensation and more – https://thedrardisshow.com/
8. Studies and stats on Ivermectin in early treatment of COVID-19 – c19early.com (constantly updated)

How to become Involved | Spread the word!

Here are some ways you can help save lives, by spreading information about the safety and efficacy of Ivermectin, for the prophylaxis and treatment of COVID-19.

Please note: it is very likely any post on social media that supports ivermectin, or shows studies on the dangers of these experimental vaccines; regardless of how credible the data, will result in censorship, de-monetization, deletion of your posts and ultimately a ban from multiple social media platforms. So please be aware of the risks:

Repercussions may include but are not limited to:

• Facebook fact checks, reduction of your posts by search algo in search results, temporary ban
• YouTube demonetization and removal of videos
• In Reddit an instant permanent ban from multiple sub-reddits, deletion of posts
• Twitter temp and permanent account ban
• Ridicule from pro-gene therapy peers include hate, threats of violence, death threats, posts on r/HermanCainAward (they celebrate non-vaccinated people dieing); if you get sick and more.

In other words you will be systematically censored, banned, and prevented from participating in social media and become a pariah in society, if you make a habit of sharing any information against experimental vaccines or for treatments not explicitly promoted by the FDA or NIH.

With that being said, here are ways you can get involved:

1. Share a link to this Article – Share it on Reddit, Facebook and twitter.
2. Share the link in the comments section of videos from: Youtube, rumble, bitchute, odyssey, etc
3. Share the link on comments, other forums, anywhere someone calls Ivermectin “Horse paste”, or gets into an argument about it’s safety or efficacy.
4. Print out this Ivermectin Flyer from the UK BIRD group and give copies away at work, school, in mailboxes, tape to lamp posts, tape on doors, slide in newspapers if you hand them out, etc
5. If you are in Canada E-mail or post a letter to your MP with your own thoughts, feel free to cite any of the studies on this article
   1. Canada: ourcommons.ca House of Commons Canada – Members of Parliament Search
   2. Addresses for current Canada members of parliament
6. If you are in USA write a comment on regulations.gov
7. Contact or write a letter to your doctor and share the documents below
8. Donate funds to FLCCC, BIRD Group or Here to WokeGuruORG, which goes towards printed media, more blog posts, stickers, letters, etc

Groups and Alliances you can join

1. FLCCC Alliance Join Here – subscribe to mailing list and donate
2. BIRD Group Here – subscribe to mailing list and donate
3. World Council for Health Here – subscribe to mailing list and social media

Ivermectin Flyers and Documents

Q&A – Questions and answers about Ivermectin for COVID-19

Can Ivermectin become Resistant to mutants?

Ivermectin is still effective against COVID-19 mutants because the same primary mechanisms of viral infection apply, regardless of the mutation.

Medical Disclaimer

This website was created for informational purposes only and has no ties to any drug company or physician. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. In addition, no one involved in this website has financial ties to any of the suggested therapies. We are merely patient advocates, trying to save lives and fight medical censorship.