Ivermectin Fans Have a New Champion to Root For - 3CL Protease Inhibitor Tollovid
http://www.mytollovid.com/ https://todosmedical.com/ https://ivmmeta.com/ https://www.clinicaltrials.gov/ct2/results?cond=COVID-19&term=ivermectin&cntry=&state=&city=&dist=&Search=Search https://www.nature.com/articles/s42003-020-01577-x https://www.nature.com/articles/s41593-021-00926-1 https://www.news-medical.net/news/20211027/Study-uncovers-how-novel-coronavirus-disrupts-normal-cell-defenses-to-hijack-human-host-cells.aspx https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30464-8/fulltext https://www.nejm.org/doi/10.1056/NEJMc2114907 https://www.biospace.com/article/releases/todos-medical-receives-new-fda-certificate-of-free-sale-for-tollovid-daily-including-3cl-protease-inhibitor-claim/ https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results https://www.provistadx.com/neutralization-antibody-panel?hsLang=en-us https://www.timesofisrael.com/health-minister-suggests-fourth-vaccine-dose-amid-rising-fears-of-fifth-covid-wave/ https://www.dailywire.com/news/fauci-tells-cnn-its-a-matter-of-when-not-if-definition-of-fully-vaccinated-changes https://www.dailywire.com/news/cdc-director-threat-of-suicide-drugs-flu-to-youth-far-greater-than-covid https://www.cnn.com/videos/health/2021/12/14/anthony-fauci-covid-19-omicron-hospitalizations-data-sot-vpx-nr.cnn https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19 https://pubmed.ncbi.nlm.nih.gov/31724441/ https://academic.oup.com/ofid/article/8/11/ofab358/6316214 https://www.chemistryworld.com/news/ivermectin-debacle-exposes-flaws-in-meta-analysis-methodology/4014477.article https://www.otcmarkets.com/stock/TOMDF/news/Todos-Medical-Announces-Positive-Observational-Trial-Results-for-Oral-Antiviral-3CL-Protease-MPro-Inhibitor-Tollovir?id=323148 https://www.acsh.org/news/2021/12/02/how-does-pfizers-pavloxid-compare-ivermectin-15967 https://www.ems1.com/coronavirus-covid-19/articles/understanding-ivermectin-I6HFMGuIN9stMjii/ https://reader.elsevier.com/reader/sd/pii/S1879625721000407?token=F4E7C679A61973D4C6559C8894A1A6A417B5FDF6A886A5CFA061221BC656C4968CBDA0A4B5A0466CFA597405D840DE9A&originRegion=us-east-1&originCreation=20211212021531 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817688/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751445/ https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provide-us-government-10-million-treatment-courses https://www.acsh.org/news/2021/12/02/how-does-pfizers-paxlovid-compare-ivermectin-15967 https://soseiheptares.com/uploads/Presentation%20and%20Webcast/2021/2021.08%20MPro%20Factsheet.pdf https://www.science.org/doi/10.1126/science.abl4784 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430524/ https://tollovid.myshopify.com/products/tollovid%E2%84%A2-immune-support-capsules Early in the pandemic it was pretty obvious to a lot of doctors that ivermectin seemingly worked. The issue is that there were no well controlled studies and lack of a solid protocol in clinical management. In places like Central and South America Doctors didn’t have time to do controlled studies; they simply prescribed it to all the patients as a triage to stem the overflowing hospital corridors. For many it seemingly worked because they got the drug early in the disease. When there were calls for a clinical trial, there was no control group that hadn’t already been given ivermectin so it suffered from its own success. There are over 80 clinical trials for ivermectin in just the United States right now, but based on the 3CL protease mechanism of action that is so powerful in treating COVID patients, ivermectin is unlikely to attain approval. But there is a new and improved ivermectin called Tollovid and you can buy it TODAY to have immune support. Unfortunately for ivermectin, the variants emerged and they came with a much higher viral load. This is likely why studies done later in the pandemic didn't confirm the early efficacy that the doctors witnessed. Targeting the 3CL Protease Pfizer has proved that blocking the 3CL protease is the best method for an antiviral, with its clinical results far surpassing efforts by Merck and others. What we know is that ivermectin is a weak 3CL protease inhibitor so while it might have worked well in the initial stage of the pandemic, once Alpha and Delta arrived with their much higher viral loads, ivermectin simply couldn’t compete once the virus was established in a person. The reason why is discussed later in the article. It’s also likely that ivermectin was showing really weak efficacy that can only be mined through meta analyses since it's such a weak 3CL protease inhibitor—to the point that its benefits cannot easily be measured. And some of these studies gathered through the meta analysis, particularly those showing high efficacy for ivermectin, were fraudulent or biased. Ivermectin Doubles as a 3CL Protease Inhibitor Before COVID-19 hit Ivermectin was viewed as a viral inhibitor. In vitro studies showed benefit against HIV, Dengue, West Nile, Yellow Fever, and the Zika virus. The other mechanism of action was that Ivermectin facilitated the transport of proteins to the nucleus. These proteins formed would end up signaling cytokine production to improve cellular defense and alarm to neighboring cells. People were claiming that Pfizer’s drug was a repurposed ivermectin as both drugs inhibit the 3CL protease. It was found that: “ivermectin blocked more than 85% of 3CLpro activity of SARS-CoV-2. Although the anti-viral activity of ivermectin mediated through the blocking of α/β1 importin is established, herein we report the inhibitory effects of ivermectin on 3CLpro enzyme of SARS-CoV-2, suggesting additional anti-viral mechanism of ivermectin towards SARS-CoV-2.” Since the pandemic started scientists have learned much more about the mechanisms behind inhibiting 3CL protease. There is a belief that the 3CL protease cleaves NEMO and prevents the cellular alarm signal from making it to the nucleus. In addition to this, the 3CL protease if left unchecked ends up cleaving Galectin-8 which is responsible for the cellular defense of xenophagy, which is the process of engulfing the virion and digesting them. “We discovered that the virus attaches to and deactivates an important sensor protein in the host cell called galectin-8, which protects the cell against infection. By deactivating galectin-8, SARS-CoV-2 disarms a cell's antiviral defense system and allows the virus to take over the host." - Dr. Chris Overall, study's senior author, Canada Research Chair, and principal investigator, UBC Centre for Blood Research, Life Sciences Institute and Faculty of Dentistry Ivermectin the Prophylactic Many people are using it as a prophylactic and in theory that makes sense why it would work given the many mechanisms of action, but there are trade-offs that come in the form of side effects. A report in the Lancet spelled out clinical benefits very early in the disease progression and a lessening of side effects and that the results suggested a larger trial would be needed to confirm that. Some may call this New England Journal of Medicine (NEJM) report a propaganda piece against ivermectin, but the NEJM has an impeccable reputation that put out a pretty convincing article that demonstrated that prevention and treatment using ivermectin was not a good idea due to considerable toxicity and questionable efficacy. Patient symptoms included gastrointestinal distress (nausea, vomiting, & diarrhea), confusion, weakness, hypotension, and seizures. The most common side effects for ivermectin include itching and hives, dizziness, headache, nausea, diarrhea and muscle pain. In order to achieve a large reduction in viral load to the point that it makes you feel better, large doses of ivermectin would be needed. That is clearly not a good idea because of the potential side effects whereby the cure becomes worse than the disease. There is a new 3CL protease inhibitor called Tollovid that earned its Certificate of Free Sale from the FDA. It's basically ivermectin on steroids without any side effects. Ivermectin was invented in 1975 and was so ideal for its use (killing parasitic worms) that no one has tried to improve it in close to 50 years because it was used for short periods of time and the safety profile was manageable given the circumstances. Much was learned from the recently announced Pfizer data that showed the 3CL protease is an integral part of the disease. So all the naysayers that said ivermectin didn’t work were mistaken. It’s no longer a question of whether it worked or not. Ivermectin clearly takes on the 3CL protease, but it has limitations. The controversy at the FDA level is whether or not it was taken soon enough, or whether it is potent enough to see a clinical benefit. The answer to these questions could have been quantified with viral load samples perhaps taken hourly but there is no approved test for this and the point is moot because there is an upgraded version available right now. Ivermectin Officially Defunct for Variants There are very good scientific explanations why ivermectin worked on the wild type virus and good reasons why it can work in the early stages of the disease. However, just because it worked under these sheltered conditions doesn’t give people license to claim that it works now. It should be clear it doesn't work now and that it has been replaced by Tollovid. The higher infectivity and viral load of these new variants has effectively dramatically diluted the efficacy of the drug to the point whereby no clinical benefit would be expected to be observed. It will still block 3CL protease, but the problem is that it won’t block enough of it. The level of protease inhibition is determined by looking at viral load and not even lethal levels of the drug will even get close to making a dent. Behind the Rise of Ivermectin The reason there are so many Ivermectin fans is because people were sitting there thinking how silly it was to pursue the concept of herd immunity. For decades our society has been trying to reach herd immunity for mutating viruses yet people still contract the flu. Despite these decades of experience, people that get their flu shots understand they can still contract it and that there is no herd immunity. Herd immunity is like Camelot, a perfect society that just isn't real. The flu hasn't been stamped out yet, nor will it ever be using these antiquated methods. There still isn't an answer for HIV, but politicians and that includes Fauci, assured the American people that this time with COVID, it was going to be different. Many saw through the smokescreen and asked why they weren't more focused on therapeutics. Luckily, the company that came up with Tollovid, was very focused. It's undeniable that vaccines do work and have played a major role in flattening the curve, but they just weren't used effectively. Had they been used with widespread testing and verification of antibody levels with the cPass test (FDA EUA approved neutralizing antibody test), the United States may have had a chance to mute the Delta wave. Instead, this holiday season, many Americans are burdened with the choice of seeing family and potential infection or sheltering in place. As the pandemic rages on this holiday season with the rise of the Omicron variant, Israel starting to push the 4th dose (second booster), and Fauci changing his mind once again the pandemic by suggesting a redefinement of what “fully vaccinated” means, and the health authorities pushing vaccinations for kids (who if health are at virtually no risk for COVID-19 symptoms, let alone death) Americans, especially the anti-vaxxers, are looking for their own solutions to the pandemic. Many Americans are getting tired of masks and lockdowns and therefore the only two things these people can do are stay healthy and look for treatments or prophylactic treatments. This generally means taking supplements like Vitamin D to support immune function, and either taking daily or stocking up on oral antivirals to prevent severe disease if COVID-19 is contracted. With Omicron, even the vaccinated are at risk of contracting the disease and getting hospitalized. For those that have the new ivermectin called Tollovid, there is another option of boosting the immune system while sharing time with the family. So many people have turned to ivermectin as an oral antiviral, with ivermectin prescriptions surging, but the subject of whether it works or not has been hotly debated. Dissenters citing issues with virtually all of ivermectin clinical trial designs, including small sample sizes, dosing with other drugs, heterogeneous populations, a lack of blinding, and other factors that make it difficult to draw scientifically valid conclusions from these studies. Data for Ivermectin The data for ivermectin is very confusing. There are even entire websites set up for gathering ivermectin data, whether fraudulent or not. Consumers hear about doctors prescribing ivermectin to everyone, doctors refusing to prescribe ivermectin, ivermectin being a miracle drug, and ivermectin being less than useless in fighting COVID-19. Which is it? There’s debates, generally between those who follow regulatory authorities and those who don’t trust regulatory authorities, as to what is the truth. The WHO, for instance, advises ivermectin use only for clinical trials, basically saying that the medical community needs better run trials to prove the drug’s benefit. On the other hand, the FDA is totally against it. But a review of actually well run trials (placebo controlled, randomized, blinded studies) such as this one suggest a very modest benefit if used early. The trial results suggest very slight benefits, including a trend to reduction in viral load and quicker recovery from loss of sense of smell, a far cry from reducing death. With Pfizer recently announcing an oral antiviral that proved in one well designed, randomized, placebo-controlled, blinded study, consumers of ivermectin must be wondering why it takes a meta analysis of over 30 studies to even suggest that ivermectin is efficacious for COVID-19. With a massive sample size, it’s easy to prove a therapeutic benefit, but studies are conflicting on ivermectin. Pfizer’s pill, which works by blocking a viral enzyme produced in cells called the 3CL protease, clearly works. This proves the clinical utility of blocking the 3CL protease and ivermectin fans need to take this new information into account. In fact, ivermectin has been shown to inhibit the 3CL protease, but the amount of ivermectin one needs to sufficiently block the enzyme are unattainable with a normal dose, and would result in significant toxicity if one took enough ivermectin to achieve this. Ivermectin’s inability to sufficiently block the 3CL protease could explain why various studies fail to conclusively prove its clinical benefits, and so ivermectin users should be looking for more powerful and proven 3CL protease inhibitors. As of now, there are only two pills available: Paxlovid (Pfizer’s prescription drug) and Tollovid, which is a 3CL protease inhibitor nutraceutical. These products are much more potent at blocking the 3CL protease and users should expect a much more robust clinical effect. Why Ivermectin Can’t Block 3CL Protease Like Pfizer’s Drug It’s easy to Google search a list of compounds that might block the 3CL protease. In fact, various flavonoids found in one’s normal diet can block the enzyme. However, to sufficiently block the viral replication process, there must be enough of these compounds in the body and so the question becomes: how much of the compound does one need? Unfortunately, these compounds are likely unable to sufficiently block viral replication in achievable quantities. The same goes for ivermectin. It comes down to the amount needed in the body and how much one can absorb into the body. There are various metrics to measure this but the main measurement is IC50 (inhibitory concentration required to reduce the target’s maximum activity by 50%). For translating how much of an oral compound one must take, the bioavailability and pharmacokinetics of the drug are what is important: i.e. how well the drug is absorbed and then how slowly it is eliminated from the body. Ivermectin falls short in both of these categories, and consumers need to find a 3CL protease that can deliver. A Comparison of 3CL Protease Inhibitors Different 3CL protease inhibitors such as Paxlovid, Tollovid, and ivermectin have differing levels of clinical activity. First, Pfizer recently confirmed a 88-89% hospitalization or death reduction in its phase 2/3 trial for at-risk patients and a 70% benefit for those at normal risk, as well as confirmed activity against Omicron. Ivermectin, on the other hand, was suggested to have a mortality benefit of 56% in a meta-analysis of dozens of clinical trials using the drug. However, the authors later removed various clinical trials from the analysis based on risk of bias or fraud. According to Andrew Hill, “When we take out the trials at risk of bias or fraud, we don’t see any effects of ivermectin on survival and don’t see any effects on clinical recovery” An article discussing Hill’s meta analysis concluded: “He estimates that of the 18 randomised control trials about a third are either fake or not conducted as described. ‘There’s not a single randomised control trial which reliably says ivermectin saves lives,’ says Sheldrick. A key conclusion for him is that ‘trust is toxic in research’ and that starting from a position of trust ‘is one of the biggest things that needs to change’. [...] ‘The thing that really shocked me and my co-authors is how much of it is deliberate fraud,’ says Sheldrick. ‘Things like the same 11 patients copied and pasted, over and over.’ In another example, hundreds of patients were supposedly recruited using complicated protocols in incredibly short time scales with a team of three.” There is a lack of any one high-quality trial that shows ivermectin works in treating COVID-19, and the studies that suggest robust benefit have clear evidence of fraud. This doesn’t mean that ivermectin has no benefit that will ever be proven but it makes sense given ivermectin’s properties why the benefit has not been observed; when it comes to blocking the 3CL protease, Ivermectin pales in comparison to Paxlovid and Tollovid. Ivermectin debacle exposes flaws in meta-analysis methodology Tollovid on the other hand is a newly developed all-natural nutraceutical that blocks the 3CL protease. There’s not a ton of data available on it besides the fact that it has been safely given to over 5000 people and that the company producing it is ramping up their manufacturing capacity due to demand for the product. When looking for clinical evidence, the nutraceutical has a cousin in a phase 2 clinical trial—a drug, called Tollovir, being developed by Todos Medical that has the same active pharmaceutical ingredient (API) extracted from natural sources. The phase 1/2 exploratory, observational study in hospitalized patients (as opposed to Pfizer’s study that tested people with symptoms, not those already hospitalized) showed a 100% mortality benefit as well as reductions in inflammatory biomarkers and shortened hospital stays with the treated group versus untreated. Tollovir Phase 1/2 Data There isn’t a huge number of patients tested in the clinical trial, but hospitalized patients are much more difficult to treat than outpatients and the data looks excellent with nobody taking Tollovir dying. This bodes well for consumers looking to boost their immune function with the nutraceutical, Tollovid, and these initial results look much better than anything ivermectin had to offer. The question most are facing is: If all the drugs block the 3CL protease, why would Paxlovid and Tollovid perform so much better than ivermectin? As mentioned before, it comes down to how well the 3CL protease is blocked. A short answer is that ivermectin, while blocking the 3CL protease effectively in vitro (in a petri dish), needs to be present in the body at absurd levels to block the virus. Below is a table which can be used as a rough, descriptive guide of a range of potencies and the probability of whether a compound of a given potency has a reasonable chance of being "strong" enough to be a useful drug. Values are approximate: Comparative IC50 Values for 3CL Protease Inhibitors (adapted) The key thing here is that these rule-of-thumb charts assume some sort of drug toxicity. That’s why the “potential utility as a drug” assumptions rule out drugs like ivermectin with such a poor IC50 as impossible to make into a COVID-19 drug via 3CL protease inhibition. As seen in the clinic and as noted by the New England Journal of Medicine, many patients experience toxicity and significant side effects when trying to take enough ivermectin to block COVID-19 replication. In vitro 85% inhibition of 3CL pro may sound amazing to those who don’t study drug development, but it isn’t. This is because, to block the enzyme’s activity by 85%, a concentration of 50 µM ivermectin is required. This is an extremely high concentration for a typical drug. At the approved ivermectin dose, 12 mg for the typical 60kg human, the maximum plasma concentration (cmax) of ivermectin is 47 ng/mL. When compared to the IC50 of ivermectin (21.5 µM, or 18,815 ng/mL) the cmax 1/400th of what would be required to block the enzyme. There is nowhere near enough ivermectin in a normal dose to block SARS-CoV-2 viral replication. With poison control centers reporting 2 mg/kg doses being toxic (typically that’s 120mg in tablet form), any attempt to truly make ivermectin block the 3CL protease would likely result in a trip to the emergency room. Tollovid and Paxlovid, on the other hand, appear to be doing their job at biologically tolerated levels with fantastic clinical trial data. One might ask the question of whether Tollovid/Tollovir can truly reach reasonable blood levels, but the answer is that it has a much higher dose and the natural product is so well tolerated that this plasma concentration can be achieved. Pfizer also reported low bioavailability of its other screened compounds before selecting Paxlovid as a preclinical candidate, so it's possible Tollovid has better solubility/bioavailability too. 3CL Protease Inhibitor Chart Treatment Ivermectin Paxlovid Tollovid Oral Dose 12mg/day [source] 300mg +100mg ritonavir (2x/day) [source] 900mg/day [source] IC50 21.5µM [source] 6nM-18nM [source 1, source 2, source 3] 1.2µM Binding Affinity −32 kJ/mol [source] −102 kJ/mol [source] Cmax (ng/ml) 23.5-50 [source] ~3,000 (EC90 = 292ng/ml) [source] tmax (h) 3.4-10.3 [source] ~1.5 t1/2 (elimination, h) 11.1-12.6 [source] Dose Limiting Toxicity Observed Yes Suspected No Natural Product No No Yes Time to Stock up on Tollovid The ivermectin and anti-big pharma crowds need to look into stocking up on Tollovid as an alternative to COVID-19 treatment as a replacement for ivermectin. Alternatively, for those who are convinced that ivermectin still works, Tollovid could be used as a backup in case it doesn’t do enough. After all, Tollovir was tested in the hospitalized setting successfully. Further, consumers who oppose drugs in general can buy Tollovid knowing it comes from a plant. There’s really no downside to keeping an open mind about these things, especially when visiting with at-risk family and friends during the holiday season. Nobody wants to be the one that got their beloved friend or family member sick and that person gets hospitalized or dies from COVID, but only a few options like Tollovid offer immune support. And there comes some peace of mind knowing Pfizer isn’t trying to rip everyone off by selling “Pfizermectin,” since Ivermectin can’t do what Paxlovid does. Regardless of vaccination status, everyone has the opportunity to protect their friends and family this holiday season.
