stereomatch | 12 points | Jan 17 2021 21:24:34

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations (2017-02-15)

NOTE: The moderator asked me to post a comment on this 2017 review paper as a separate post - since while this article reviews Ivermectin from a pre-covid19 perspective (like a few other ivermectin reviews), but this article maybe more readable from a covid19 perspective.

Posting it as a link gave the message that it has been posted here before - so posting this as a text post.

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https://www.nature.com/articles/ja201711

15 February 2017

Review Article

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

Andy Crump 

The Journal of Antibiotics volume 70, pages495–505(2017)

Surprisingly, despite 40 years of unmatched global success, plus widespread intensive scientific study in both the public and private sectors, scientists are still not certain exactly how ivermectin works. Moreover, whereas ivermectin-resistant parasites swiftly appeared in treated animals, as well as in ectoparasites, such as copepods parasitizing salmon in fish farms, somewhat bizarrely and almost uniquely, no confirmed drug resistance appears to have arisen in parasites in human populations, even in those that have been taking ivermectin as a monotherapy for over 30 years.

Very interesting.

Ivermectin’s mode of action against parasites in the human body remains to be clarified. There is a substantial disparity between maximum plasma concentrations after ivermectin administration and the concentrations needed to induce paralysis in microfilariae. Support has been accumulating for the evidenced-based hypothesis that the clearance of microfilariae is governed by immunoregulatory processes.

Again, very interesting, given that is what is being said now for covid19 and ivermectin ie maybe not just killing the virus, but immunomodulatory effect.

Ivermectin treatment causes microfilariae to quickly disappear from the peripheral skin lymphatics, with long-lasting effect, the high lipid solubility of ivermectin resulting in it being widely distributed throughout the body. Following oral administration, mean peak plasma concentration occurs approximately 4 h after dosing, a second peak at 6–12 h probably arising because of enterohepatic recycling of the drug, with the plasma half-life of ivermectin being around 12 h. Dermal microfilarial loads are reduced by 78% within 2 days, and by some 98% within 2 weeks of treatment, remaining at extremely low levels for about 12 months. As lowest levels of microfilariae occur well after ivermectin administration, they are not necessarily killed when plasma drug levels are highest.

I wonder if Ivermectin lasts much longer for prophylaxis

Though we do have an upper bound from the Indian AIIMS results - where medical workers given ivermectin one time had 78pct fewer cases.

That is lower than expected for weekly - which is why the MATH+/FLCCC folks revised it to a minimal of every other week (from earlier weekly dose) recommendations.

So I suspect at least for covid19 the every 2 weeks may be the minimal effective dose - although would be interesting if it turns out it has a partial protective effect over very long term - for example if it has a protective effect against severe covid19 (AIIMS study didn't say anything about severe covid19 - since for that you need much larger study - since severe cases are few anyway - is to get large enough statistically relevant data about severe cases).

It is increasingly believed that the rapid microfilarial clearance following ivermectin dosing results not from the direct impact of the drug but via suppression of the parasite’s ability to evade the host’s natural immune defense mechanism. Immunomodulatory agents often display fewer side effects than drugs, as well as producing less opportunity for creation of resistance in target microorganisms, which helps explain the absence of drug resistance in humans.

Again, wow.

Trichinosis Globally, approximately 11 million individuals are infected with Trichinella roundworms. Ivermectin kills Trichinella spiralis, the species responsible for most of these infections.

Ivermectin is effective against trichinosis too.

What is it's effectiveness against worm infestation from raw fish ie sushi etc.

Consequently, in combination with other anti-malarial agents, ivermectin could become a useful, novel malaria transmission control tool.

Yes, posted on this earlier - WHO thinking of using for recalcitrant malaria regions.

Rosacea Although the broad-spectrum anti-parasitic effects of ivermectin are well documented, its anti-inflammatory capacity has only relatively recently been identified. Ivermectin is used ‘off-label’ to treat diseases associated with Demodex mites, such as blepharitis and demodicosis, oral ivermectin, in combination with topical permethrin, being a safe and effective treatment for severe demodicosis. Demodex mites have also been linked to rosacea, a chronic skin condition that manifests as recurrent inflammatory lesions. Long-term treatment is required to control symptoms and disease progression, with topical medicaments being the first-line choice. Ivermectin 1% cream is a new once-daily topical treatment for rosacea lesions, more effective and safer than all current options, which has recently received approval from American and European authorities for the treatment of adults with rosacea lesions.

Rosacea even ?

Asthma A 2011 study investigated the impact of ivermectin on allergic asthma symptoms in mice and found that ivermectin (at 2 mg kg−1) significantly curtailed recruitment of immune cells, production of cytokines in the bronchoalveolar lavage fluids and secretion of ovalbumin-specific IgE and IgG1 in the serum. Ivermectin also suppressed mucus hypersecretion by goblet cells, establishing that ivermectin can effectively curb inflammation, such that it may be useful in treating allergic asthma and other inflammatory airway diseases.

Asthma - didn't know about this.

EDIT: I may have actually searched for this to screen for any issues for ivermectin for asthmatic patients - but had forgotten. But this article's section on asthma caught my eye again at least.

I just asked an asthmatic who is taking ivermectin for prophylaxis (12mg per week) for last few months of he has felt a relief in his asthma, and he said yes - for this time of year he usually needs a puff of inhaler every day, but now he can go without it for a few days ie so he said yes asthma is reduced.

Epilepsy Nodding syndrome (NS) is a mysterious and problematic form of epilepsy that occurs in parts of South Sudan and northern Uganda. 

I had actually searched for ivermectin and epilepsy for an acquaintance. And the results were reasonably positive.

This article doesn't say too much about it.

But there is a purported immunological aspect to Epilepsy - for example the impact of NAC (N-acetyl cysteine) on Epilepsy.

Ivermectin has benefit for River Blindness related Epilepsy - that seems plausible:

https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007966 Ivermectin as an adjuvant to anti-epileptic treatment in persons with onchocerciasis-associated epilepsy: A randomized proof-of-concept clinical trial

https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-019-3345-7 Impact of 19 years of mass drug administration with ivermectin on epilepsy burden in a hyperendemic onchocerciasis area in Cameroon 19 March 2019

But it seems to have been used as adjuvant with other cases of Epilepsy also.

https://pubmed.ncbi.nlm.nih.gov/28929472/ [Ivermectin as an adjunct in the treatment of refractory epilepsy] 2017

Conclusion: Ivermectin has been useful as an adjuvant, achieving a significant decrease in seizures in this group of drug resistant patients

And viral - which we are aware of - dengue, partial impact on HIV etc.:

Recent research has confounded the belief, held for most of the past 40 years, that ivermectin was devoid of any antiviral characteristics. Ivermectin has been found to potently inhibit replication of the yellow fever virus, with EC50 values in the sub-nanomolar range. It also inhibits replication in several other flaviviruses, including dengue, Japanese encephalitis and tick-borne encephalitis, probably by targeting non-structural 3 helicase activity. Ivermectin inhibits dengue viruses and interrupts virus replication, bestowing protection against infection with all distinct virus serotypes, and has unexplored potential as a dengue antiviral.

And the "importin α/β-mediated nuclear transport" which was the first possible explanation given for why Ivermectin works (now there are 4 pathways suggested - which are covered by Whiteboard Doctor in his videos):

Ivermectin has also been demonstrated to be a potent broad-spectrum specific inhibitor of importin α/β-mediated nuclear transport and demonstrates antiviral activity against several RNA viruses by blocking the nuclear trafficking of viral proteins. It has been shown to have potent antiviral action against HIV-1 and dengue viruses, both of which are dependent on the importin protein superfamily for several key cellular processes. Ivermectin may be of import in disrupting HIV-1 integrase in HIV-1 as well as NS-5 (non-structural protein 5) polymerase in dengue viruses.

(continued in comment below)

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