THE SEARCH FOR SILVER BULLETS
Collated posts on potential pharmacological interventions against the coronavirus. Please note: several of these hypotheses have since been validated in-silico through the research published here by myself and my co-author.
APRIL 16TH 2020
With my prediction back on February 6th 2020 of ivermectin being highly effective against COVID-19 in vitro and in patients, I feel moved to share a further set of evolving (cautious) hunches and predictions.
There is some connection between anti-parasitic mechanisms and busting COVID-19 that isn't clear, but is stacking up: (hydroxy)chloroquine, ivermectin, methylene blue.
Meanwhile, metronidazole, another broad-spectrum antibiotic, antifungal, and antiprotozoal, is suggested to potentially be useful against COVID-19.
Ivermectin blocks importin, which cells use to move proteins inside of them. This makes it harder for RNA viruses to infiltrate cells, so it makes sense that it's an effective antiviral.
However, (hydroxy)chloroquine and methylene blue (both anti-protozoans) don't appear to have this importin-related mechanism. Neither does metronidazole. Something else must be at play in these cases.
Cellular microtubules also play a role in viral infection of cells. They are another method by which viruses can attack cells.
It has been shown that SARS-CoV-2 spike proteins interact with cytoskeleton filaments (i.e. microtubules and actin) for internalization into host cells – a critical step in viral pathogenesis. I suspect that like rabies and mouse noroviruses, COVID-19 disrupts cellular microtubules by depolymerising them.
I also suspect there's a link between viral depolymerization of microtubules, and the selective preferential polymerization of parasitic tubulin or ezrin in anthelmintic drugs. Such drugs also have an effect on non-parasitic cells too, just to a lesser degree. I posit that somehow this modest alteration of microtubule polymerization within host cells can make a difference in how easily COVID-19 can attack those cells, perhaps through a hormetic eustress process.
Fenbendazole is one drug which is well documented in altering microtubule inhibition. I predict than that the deworming agent fenbendazole and its sister compounds (phenothiazine, thisabendazole, parbendazole, mebendazole, albendazole, febantel, cambendazole, oxibendazole, flubendazole, oxfendazole, cyclobendazole, thiophanate, and triclabendazole) will be useful drugs against COVID-19.
I also predict that the veterinary deworming agents moxidectin and selamectin (agonists of glutamate-gated Cl channels) are similarly applicable as ivermectin. Chlorinated derivatives of salicylanilide including niclosamide, oxyclozanide, and rafoxanide will also be useful.
Biscoclaurine alkaloids such as cepharanthine, coclobine, berbamine, and pendulin will be effective. I further predict that routine consumption of the alkaloids in Bitter Gourd may provide some limited level of prophylaxis or treatment effects for COVID-19 within South Asia and Indo-China.
I also predict that bitter plants containing oleanolic acid and other bitter glycosides (such as Marigold and Gentiana respectively) and distillates of them, will provide some limited prophylaxis or treatment value.
Plants bearing saponin glycosides and phenols, such as ginseng root and eucalyptus leaf, probably can also have some treatment value against COVID-19, as should non-steroidal saponin drugs (triterpene glycosides), particularly those with oleanane ring systems.
It has been shown for some coronaviruses that targeting the cytoskeleton with tubulin or actin inhibitors reduces viral load. I have a hunch that *parasite* tubulin or ezrin may be a valuable immune-boosting antigen to aid the body's defenses against COVID-19, perhaps even sufficient to act as a partial vaccine against COVID-19.
Finally, I predict based upon this, that the parts of the world with greater parasitical loads in the population will, all things being equal, be less likely to experience widespread symptomatic COVID-19 infection. Observation seems to support that hypothesis for now.
APRIL 23RD 2020
Cohort research suggests that smokers paradoxically may have some protection against COVID-19, which is rather counter-intuitive.
It might be some kind of hormesis effect – a small amount of damage or disruption to a system which ends up making it more antifragile long-term. Perhaps the mild hypoxia from smoking protects against the strange hypoxic effects of COVID-19.
However, I also observe that like (hydroxy)chloroquine, methylene blue, and ivermectin, nicotine is also a potent antiparasitic agent. Plants containing nicotine are sought out for use by bumblebees to control mites, and birds seem to seek out cigarette butts for similar purposes.
Nicotine was used as an anthelmintic treatment prior to the development of modern drugs.
Further, nicotine has some neuroprotective effects, which might help to prevent the invasion of neural tissue by COVID-19.
Nicotine is, of course, highly addictive, and the traditional delivery mechanisms are dangerous. But experimenting with a patch seems like a potential compromise. A French study is now investigating this delivery mechanism to note any effects.
My hypothesis is that nicotine will be found to be useful, due to its utility as an antiparasitic and its effects upon cellular microtubules and their disruption, which I believe is the mechanism that makes antiparasitics useful against COVID.
April 30th 2020
An American study (n=1408 patients) has found Ivermectin to be extremely useful in beating COVID.
For those on ventilators, deaths during the study dropped from 21.3% to 7.3% (2/3 reduction). The mortality of all patients dropped from 8.5% to 1.4% (5/6 reduction).
84% fewer deaths. Wow! Side effects of treatment were minimal, also.
This urgently needs to be (a) replicated in further research, and (b) rolled out **immediately** in all hospitals worldwide. Ivermectin is extremely safe and well tolerated and complications are likely to be rare and minor.
A study has combined HCQ with Ivermectin for a one-two punch – HCQ to try to defend against cell entry, and Ivermectin to prevent replication.
Both of these drugs are pennies per pill. If we can scale the production and distribution of them, particularly ivermectin, we have a chance to kill this pandemic once and for all by late summer.
May 19th 2020
Take this with a huge grain of salt, as it isn't even a pre-print paper yet, but the team is desperate to get the word out so further studies on this can begin immediately:
A team at Bangladesh Medical College Hospital (BMCH) experimented with a combination of ivermectin with doxycycline and allegedly got excellent results, with most patients recovering in about 4 days.
Doxycycline is another antimalarial with antibiotic properties, like ivermectin. It also has inhibitory effects on calcium channels (like ivermectin), which I have previously postulated to be the method by which anti parasite drugs such as HCQ and Methylene Blue can be effective (cellular microtubule inhibition, a process significantly regulated by calcium transport).
Interestingly, Doxycycline (and its sister minocycline, but not tetracycline) is implicated in blocking hypoxic effects, and hypoxia is also a symptom of COVID-19.
Both drugs are common, off-patent, and therefore cheap.
Again, this is almost hearsay, but I thought it an important and interesting enough anecdote to help signal boost.
[A response mentioning taking black seeds]Nigella sativa, i.e. 'Fennel flower/black cumin'? Huh, interesting. It has traditional uses for dyspnea (a sensation of shortness of breath), as well as clearing intestinal parasites.
Research suggests that it's indeed more powerful than chloroquine for killing plasmodium, mg for mg!
Thymoquinone, the principal bioactive compound within the seeds, is also a noted muscle relaxant, and appears to do this via some effect on calcium channels.
This might even potentially provide a measure of prophylaxis for cultures that frequently consume this in significant quantity.
[What can you say about Artemisia annua?]It's another antiparasitic that blocks ion channels. I would honestly be surprised if it doesn't turn out to at least have *some* value, given the pattern which appears to be emerging.
15th July 2020
Studies continue to emerge on Ivermectin, showing up to a 40% reduction in mortality for patients who are prescribed it. I am glad that my prediction bore fruit, and I hope that this life saving drug can be rolled out more thoroughly at global scale.
Further research also suggests that HCQ with ivermectin may be an effective combination.
19th August 2020
Professor Thomas Borody MB, BS, BSc(Med), MD, PhD, DSc, FRACP, FACP, FACG, AGAF, FRS(N) has described Ivermectin, in combination with doxycycline and zinc as powerful treatment that could end the pandemic in days via its 100% cure rate, and implores for its widespread deployment.
Antibiotics such as doxycycline and azithromycin can inhibit viral entry into cells.
26th August 2020
My prediction of Eucalyptus Leaf having value appears to have merit, according to the UK Armed Forces laboratories.
7TH December 2020
My prediction that parts of the globe which are regularly inoculated against parasites would experience fewer infections appears to have merit. There may also be a lasting protective mechanism even after serum levels of the drug have declined.
9th December 2020
After 1 million avoidable deaths, Dr Pierre Kory, president of the US Frontline Covid-19 Critical Care Alliance (FLCCC), has testified to the US Senate Committee on Homeland Security about early outpatient treatment in general and the importance of Ivermectin in particular. Dr Kory has also addressed the very unfortunate politicization of this topic, and the disappointing inertia of many health authorities.
20th December 2020
Glycyrrhizin, a licorice plant saponin appears to indeed have value, at least in vitro, along with a bitter alkaloid, Lycorine.
30th DECEMBER 2020
The new, more infectious strains are bringing us to a new stage in the pandemic. In fact, it's almost like a new pandemic entirely, one that will spread and grow over time like the last one, but on a greater scale.
Vaccines can help a great deal, but the challenges are increased with the new strains.
According to recent statements by Dr Anthony Fauci, vaccines will now require up to 90% of the population to receive them in order to enable herd immunity to the coronavirus.
This means that it will take a lot longer to make a population safe, perhaps 6 months longer. Therefore, a longer time until a return to living as we are accustomed, and economic recovery.
A 90% compliance rate also seems like a significant challenge, even under pressure from authorities. Countries are now admitting to keeping secret lists of citizens who decline to be vaccinated on moral, religious, or health grounds, and exchanging them between themselves.
How such blacklists may be used to deny privileges remains to be seen, but continued non-compliance may encourage authorities to cajole people with veiled threats (which will provoke civil unrest). Most frustratingly for authorities, a significant number of healthcare workers appear hesitant to receive the experimental treatment.
Moreover, it will take a long time to reach everyone, especially in rural areas, and in all parts of the globe, leading to pockets of potential infection (and potential 'vaccine escape' mutations).
The current rollout strategy appears to be based on triage of need, but this means that vaccinated people diffuse into the population. This presents more opportunities for the virus to develop resistance to the vaccine over time.
If deployment was instead done city by city, county by county, they could mitigate the risk of resistance developing, and meanwhile life could return to 'normal' at least within that zone (thanks to Roko Mijic for this idea). I very much hope that states will adopt this strategy as soon as the very most vulnerable have been addressed.
Meanwhile, the increase in transmissibility itself will cause a great deal more deaths within an unvaccinated population simply due to scale, even if the strains aren't any more deadly per se.
The replication number of the virus will increase dramatically if the purported ~55% increase in transmissibility is correct.
We could barely contain the virus even with masks, social distancing, and lockdowns. If the R number increases by a further 55%, then interventions that have been helpful before will likely cease to be effective in containing a chain reaction of infection.
Further draconian measures will not be tolerable, and various populations are already on the verge of outright revolt.
But we must try something new to reduce replication. So where do we go from here?
Almost a year ago, before the pandemic was even declared, I made a prediction about the value of Ivermectin in stopping replication.
That prediction was since been validated by clinical data.
There is even early evidence suggesting that the drug may even function as a prophylaxis, preventing viral infection per se.
The data suggests that this safe, cheap, and well-tolerated compound is reducing the rate of infection within populations that are routinely exposed to it, such as on the continent of Africa, where it is used to control parasites.
"Here, we show that countries with routine mass drug administration of prophylactic chemotherapy including ivermectin have a significantly lower incidence of COVID-19. Prophylactic use of ivermectin against parasitic infections is most common in Africa and we hence show that the reported correlation is highly significant both when compared among African nations as well as in a worldwide context."
Now that our backs are firmly against the wall due to the emergence of an unmanageable replication rate, it seems like our only hope for containment might be to deploy prophylactic ivermectin for the masses, or at the very least as a firebreak within those most likely to cause a superspreading event.
Mass deployment of Vitamin D is another intervention that evidence suggests may also be effective.
Sadly, censorship by social media companies is blocking access to serious, referenced discussion on these topics, and I am at serious risk of being zucced (like many others) simply for reiterating the published research of board certified medical professionals (this is a whole other, separate epistemic issue).
18th SEPTEMBER 2021
I’ve been working on other problems lately and haven’t been following the research much, but I stumbled across this paper that validates the treatment value of foods containing phenolic compounds, along with further research highlighting the value of glycyrrhizin/licorice, and saponins, as I had predicted.