Repurposing Anti-parasite drugs to treat Cancer and Autism?

 

I should start this post by highlighting that generally cancer and autism are not caused by parasites.

I have to be a little careful because we now know that certain types of virus and bacteria are involved in the initial trigger to initiate some types of cancer. This is why many females are now offered human papillomavirus (HPV) vaccines to minimize the chance of several different cancers. I noticed recently that in the US this vaccine is advertised on TV.  I used to know a woman who like most people had the HPV virus as a child, but did not have this vaccine.  She developed a rare oral cancer that the vaccine would have protected against and died very young. We saw in a previous post how a specific gut bacteria blocks the initiation of childhood leukemia.

The pharmaceutical industry does not seem to like the idea of repurposing existing drugs to treat a different disease.  There are some exceptions; it is OK to treat females with acne, using the diuretic drug Spironolactone.  Nobody seems to object to the treatment of intractable headaches with drugs actually approved to lower blood pressure (Verapamil, Amlodipine etc).

When investigating cancers you have to look at the specific underlying mechanisms, just as you do with autism.

As we saw long ago in this blog, it has been suggested to classify autism as either over-active pro-growth signaling pathways, or under-active pro-growth signaling pathways. Most is the over-active type.

Cancer is very clearly another example of over-active pro-growth signaling pathways, so it is not surprising that there is an overlap between therapies for autism and cancer.  The difference is that they are far more likely to be effective in autism. 

So, a cheap anti-parasite drug for kids like Mebendazole, which just happens to also be a Wnt inhibitor,  may slow down the growth of some cancers, but it is sadly not curative.  In an autistic brain where Wnt signalling might be overactive, a lower dose of Mebendazole, might well provide a long-term benefit.   

My old posts that mention Wnt signaling are here:-

https://www.epiphanyasd.com/search/label/Wnt 

Wnt signaling interestingly plays a role in how your hair will go gray/grey. If you reduce Wnt signaling, your hair will go gray and so this is an inevitable side effect of a potent Wnt inhibitor. 

Premature graying might indeed indicate reduced Wnt activity.

 

Pyrantel pamoate

Our reader Dragos recently fined tuned his adult son’s anti-aggression therapy and he recently shared his latest innovation:-

 

"you have to give him 20mg of propranolol 2-3 times a day, pyrantel pamoate 750mg in the evening for 2-3 days, and you will see that his anger will disappear, stay on propranolol. After 3 weeks repeat with antiparasitic, you will see that I was right, you don't use psychotropic drugs"

 

Propranolol is a normally used to lower blood pressure, but it does this in a way that also reduces anxiety.  At the low doses used by Dragos, it has been used to treat actors with stage fright. It can be used before exams or driving tests, to calm the person down.

Propranolol has been trialed in autism. Some people use a low dose and some use a higher dose.

Pyrantel pamoate is used to treat hookworms and other parasites that can be picked up by young children. It works by paralyzing the worms. This is achieved by blocking certain acetylcholine receptors in the worm.

As is very often the case, pyrantel pamoate likely has other modes of action that are entirely different. Is it a Wnt inhibitor like the other hookworm treatment Mebendazole?

I did a  quick search on google and it gave me the wrong pamoate. 

Pyrvinium pamoate is able to kill various cancer cells, especially CSC. The drug functions through the reduction of WNT- and Hedgehog-dependent signaling pathways (Dattilo et al., 2020). 

Pyrvinium pamoate is yet another anti-parasitic drug, but not the one Dragos is using.

So pyrantel pamoate may not be a Wnt inhibitor, unlike many anthelmintic drugs, but it is used by the “anti-parasitic re-purposer in chief” Dr Simon Wu.  He publishes his findings/thoughts, which is good to see.  He likes to combine different anti-parasitic drugs.

I did look up the effect of pyrantel pamoate on gene expression.  There is data, but you really need to see the source material to know whether anything is valid.

Inhibiting GSTP1 (glutathione S-transferase pi 1) is suggested and that is a feature in common with an anti-parasite drug class called Thiazolides (e.g.  Nitazoxanide).  That would make pyrantel pamoate a potential therapy for triple-negative breast cancer, where the cancer cells rely on vigorous activity by the enzyme glutathione-S-transferase Pi1 (GSTP1).  Cancer cells are highly vulnerable to oxidative stress, and as we know glutathione is the main way the body extinguishes it. Glutathione S-transferases P1 protects breast cancer cell from cell death.  So you want to inhibit GSTP1.

Pyrantel has many other suggested effects even reducing expression of the gene FXR2 (fragile X mental retardation,2) and increasing expression of the gene MTSS1 (metastasis suppressor 1).

Pyrantel is even suggested as an epilepsy drug.

 

Drug repositioning in epilepsy reveals novel antiseizure candidates

Epilepsy treatment falls short in ~30% of cases. A better understanding of epilepsy pathophysiology can guide rational drug development in this difficult to treat condition. We tested a low-cost, drug-repositioning strategy to identify candidate epilepsy drugs that are already FDA-approved and might be immediately tested in epilepsy patients who require new therapies.

Expanding on these analyses of epilepsy gene expression signatures, this study generated a list of 184 candidate anti-epilepsy compounds. This list of possible seizure suppressing compounds includes 129 drugs that have been previously studied in some model of seizures and 55 that have never been studied in the context of seizures. 91 of these 184 compounds are already FDA approved for human use, but not for treating seizures or epilepsy. We selected four of these drugs (doxycycline, metformin, nifedipine, and pyrantel tartrate) to test for seizure suppression in vivo.

Pyrantel tartrate is an antiparasitic agent that acts by inhibiting fumarate reductase, and by directly acting on acetylcholine receptors at the neuromuscular junction of infecting helminths. Pyrantel tartrate is FDA approved for use in domestic animals and has been used to treat human parasitic infections.73 Unlike nifedipine and metformin (for which some rodent studies and human reports relate to seizures), a March 2018 PubMed search for “pyrantel and epilepsy” and “pyrantel and seizure” found no manuscripts that studied pyrantel in seizures. Thus, pyrantel tartrate represents a truly novel antiseizure drug candidate yielded by our screen.

 

All in all it is not surprising that Dr Yu is prescribing pyrantel pamoate.

Digging any deeper is beyond the scope of a blog post.

What is clear is that pyrantel pamoate and mebendazole are unlikely to be equally effective in Dragos’ son.

Other anti-parasite drugs work very differently.

In the chart the mode of action of some common drugs  is presented.

 

Anthelminticsfor drug repurposing: Opportunities and challenges

 

Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).

  

Suramin is now quite well known as a potential autism therapy and two different groups are trying to commercialize it.  Suramin is the original anti-purinergic drug (APD), it blocks purinergic receptors that have names like P2Y2.

When I looked at PAK1 a long time ago, which was put forward as a treatment pathway for neurofibromatosis, some schizophrenia and some autism I came across Ivermectin as an existing alternative to the research drug FRAX486, or the expensive BIO 30 propolis from New Zealand.

A decade later and the world goes crazy when the idea of using Ivermectin to treat COVID 19 gets well publicized.  The good news is that now we know that regular use of Ivermectin is not as dangerous as people thought it would be.  Many people have been using the veterinary version in the US, Brazil and elsewhere. 

The supporting research:- 

Effect of Pyrantel on gene expression.

 https://maayanlab.cloud/Harmonizome/gene_set/pyrantel-5513/CMAP+Signatures+of+Differentially+Expressed+Genes+for+Small+Molecules

 

decreases expression of:-

FXR2   fragile X mental retardation, autosomal homolog 2

(and many more)

 

Increases expression of

MTSS1 metastasis suppressor 1

BNIP1 BCL2/adenovirus E1B 19kDa interacting protein 1

BRAF B-Raf proto-oncogene, serine/threonine kinase

(and many more)

 

https://maayanlab.cloud/Harmonizome/gene_set/Pyrantel+Pamoate/CTD+Gene-Chemical+Interactions

Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.

Pyrantel Pamoate Gene Set

Dataset          CTD Gene-Chemical Interactions

2 genes/proteins interacting with the chemical Pyrantel Pamoate from the curated CTD Gene-Chemical Interactions dataset.

GPR35    G protein-coupled receptor 35

GSTP1   glutathione S-transferase pi 1

 

Triple-negative breast cancer target is found

They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

  

"Inhibiting GSTP1 impairs glycolytic metabolism," Nomura said. "More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells." 

 

Anthelmintics for drug repurposing: Opportunities and challenges 

It has been demonstrated that some of the anthelmintics are able to inhibit critical oncogenic pathways, such as Wnt/β-catenin, signal transducer and activator of transcription proteins 3 (STAT3), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB; therefore, their application for cancer treatment has been considered.

 

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

 

Anthelmintics for drug repurposing: Opportunities and challenges

 

Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).

 

Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells

More research on the repurposing anti-parasite drugs: 

Antiparasitic and Antifungal Medications for Targeting Cancer Cells Literature Review and Case Studies Frederick T. Guilford, MD; Simon Yu, MD

Chronic inflammation is a new catch phrase for the explanation of all chronic degenerative diseases, from asthma, arthritis, heart disease, auto-immune disease, and irritable bowel disease to cancer. Occult infections from oncovirus, bacterial, and fungal infections as well as from lesser known parasitic infections are driving forces in the cellular evolution and degeneration of cancer cells. An approach using currently available medications that target both fungal and parasitic metabolism appears to interfere with the metabolic synergy that is associated with tumor growth and aggressiveness 

 

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs 

 

Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent 

 

Anti-Parasite drug Ivermectin shows promise against cancer 

A Pinworm Medication Is Being Tested As A Potential Anti-Cancer Drug

 Conclusion

I did suggest long ago that Mebendazole, as a Wnt inhibitor, might be a cheap and effective treatment for some autism.  I had envisaged that it would need to be given daily, as it is in the cancer trials.

Dragos’ use of pyrantel pamoate, for an average of 4 days a month is interesting.  It is cheap, safe and practical.

One key issue with antiparasitic drugs is how much is absorbed into the blood stream.  If 100% of the drug stays in the gut, its benefit will be limited.

About 20% of Mebendazole ends up in the blood stream and if you take it often this figure is reported to increase.

The combo of propranolol + pyrantel pamoate is an interesting option to treat self-injury and aggressive behavior.  It works for Dragos and undoubtedly will for some others.

Is the inhibition of Wnt signalling the reason why pyrantel pamoate is effective for Dragos’ son?  There is no evidence to support that.

Are antiparasitic drugs going to be widely adopted to treat any unrelated conditions, cancer included, I very much doubt it.

Cancer is better avoided, than treated.  It is a much more achievable objective.

The Fragile X researcher Randi Hagerman takes metformin, as her chemoprevention therapy. She is the medical director of MIND Institute at the University of California, Davis.

You can raise IQ in people with Fragile X by 10-15% using Metformin.  I guess Randi had been reading up on Metformin and came across the anti-cancer effects.

If I had to suggest an anti-parasite drug for Randi to try in Fragile X, I would suggest the PAK inhibitor Ivermectin, made (in)famous by Donald Trump and Jair Bolsonaro during Covid. The research drug FRAX 486 is called FRAX for Fragile X. It is a PAK inhibitor that never made it to market.  Ivermectin is an existing drug that is also a PAK inhibitor.  Worth a try, Randi?

I expect Dr Yu might try and increases his chances and make a combo with a second anti-parasitic drug.

Metformin is one of several anti-cancer choices, it depends which type of cancer is of concern. For RAS-dependent cancer I think Atorvastatin is the best choice. 

If you read the research, like me and Randi, chemoprevention is the obvious choice for older adults. Dementia prevention is equally obvious.

Parkinson’s prevention may be achieved by blocking Cav1.3 (amlodipine etc)

Alzheimer’s prevention may be achieved using low dose fenamates (Ponstan etc).

For vascular dementia and Alzheimer’s prevention/treatment spermidine (in the form of modified wheatgerm) is promising.

Anti-parasite drugs for cancer and autism? Yes, it sounds mad. But is it?

What is for sure is that your pediatrician will think you have gone mad!

Our reader MG in Hong Kong will have got some new ideas to think about.

Tics, Ticks, Autism - Wnt signaling & PAK1

I was interested to receive a comment from a reader of this blog who finds that the anti-parasite drug Ivermectin has a major impact on her child’s  autism, debilitating tics and OCD (Obsessive Compulsive Disorder).

Regular readers may recall that when looking at so-called PAK1 inhibitors, which look like the Holy Grail for both common cancers and autism, it turned out that two already exist.  One is an old anti-parasitic drug called Ivermectin and the other is a substance found in certain types of bee propolis from Brazil and New Zealand.

It then turned out that a handful of “alternative” practitioners in the US are already using Ivermectin for autism, but for entirely different reasons.  They believe that various parasites exist inside the children and cause/exacerbate autism.

I thought this was intriguing and quite likely another case of “the right therapy, for the wrong reason”.

Tics and Ticks

Tics are those sudden, repetitive involuntary actions that can vary from annoying to debilitating.

Ticks are tiny parasites that like to attach themselves to your skin, they can fall from trees/bushes or attach themselves to skin as you pass through long grass. Some ticks carry Lyme Disease.

Tics are common in autism, PANDAS, PANS and many forms of OCD (Obsessive Compulsive Disorder).

It seems that some “alternative” practitioners in the US are treating PANDAS and PANS on the assumption that it is caused by Lyme Disease.  Others are recommending “de-worming” for autism, on the assumption that intestinal parasites are to blame.

Here is a link to somebody writing about these alternative practitioners, for those who are curious.

My take

This all sound highly odd to me, partly because it seems that you have to keep taking the de-worming tablets for the long term.  With regular mild parasites found in developed countries, drugs therapy can eliminate the parasites.  In some tropical climates more aggressive parasites exist that are almost impossible to eradicate 100%.

So regular de-worming of humans in the United States, in 2014, sounds bizarre.

On the other hand, you cannot dispute when somebody finds their child’s tics and OCD have disappeared with the de-worming therapy and that they return when the therapy stops.

Is it, as I suggested in the early posts, that the PAK1 inhibiting properties of Ivermectin are behind its effect?  Hopefully yes, but I am not sure.  So I will take a look at Ivermectin and see if it has any other properties that could impact autism, tics and OCD.

Ivermectin - not just for your dog

Most people would only come across Ivermectin at the vet, but there is much more to it.

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

Discovered in the late-1970s, originating solely from a single microorganism isolated at the Kitasato Institute, Tokyo, Japan from Japanese soil, Ivermectin has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found.

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. The disease causes visual damage for some 1–2 million people, around half of who will become blind.

Lymphatic Filariasis, also known as Elephantiasis, is another devastating, highly debilitating disease that threatens over 1 billion people in more than 80 countries. Over 120 million people are infected, 40 million of whom are seriously incapacitated and disfigured. The disease results from infection with filarial worms

Modes of Action

Let us look at the various modes of action proposed for Ivermectin.

1.     GABA

Initially, researchers believed that Ivermectin blocked neurotransmitters, acting on GABA-gated Cl⁻ channels, exhibiting potent disruption at GABA receptors in invertebrates and mammals.

In mammals the GABA receptors occur only in the central nervous system (CNS), i.e. in the brain and the spinal cord. But mammals have a so-called blood-brain barrier (BBB) that prevents microscopic objects and large molecules to get into the brain. Ivermectin, while paralyzing body-wall and pharyngeal muscle in nematodes has no such impact in mammals.  Consequently Ivermectin is much less toxic to mammals than to parasites without such a barrier, which allows quite high safety margins for use on livestock, pets and humans.

2.     Glutamate

Subsequently, researchers discovered that it was in fact glutamate-gated Cl⁻ channels (GUCl⁻) that were the target of Ivermectin and related drugs.

3.     Reversing Immunosuppression

The growing body of evidence supports the theory that the rapid parasite 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 defence mechanism.

Researchers discover how key drug kills worms in tropical diseases

In a major breakthrough that comes after decades of research and nearly half a billion treatments in humans, scientists have finally unlocked how a key anti-parasitic drug kills the worms brought on by the filarial diseases river blindness and elephantitis

Regular readers will recall that a beneficial parasite therapy in inflammatory diseases is the TSO worm.  This worm also modulates the host’s immune system so as not to be ejected.  This calming of the over activated immune system appears to be beneficial in several conditions and possibly autism.

4.     Inhibitor of Wnt-TCF Pathway

Recent cancer research has shown the Ivermectin has a highly unexpected property; it can block a pathway called Wnt-TCF on which many cancers are dependent.

The river blindness drug Ivermectin and related macrocyclic lactones inhibit pathway WNT-TCF responses in human cancer

Wnt signaling is also a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS), in other words oxidative stress, known to cause DNA and cellular damage.

Perhaps aberrant Wnt signaling is involved in the mechanism of autism?

Well it appears to be the case.

Role of a novel Wnt pathway in autism spectrum disorders

The canonical Wnt signaling pathway in autism.

 Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism.

5.     Inhibitor of PAK1

We already know from earlier in this blog, that Ivermectin is a PAK1 inhibitor.  Blocking PAK1 should prevent several common cancers, according to researchers at MIT, who also suggest that autism cannot occur without PAK1.\

Not entirely surprisingly, if you look into the cancer research you will see that PAK and WNT are interrelated.

p21-Activated kinase (PAK) interactswith Wnt signaling to regulate tissue polarity and gene expression

Wnt signaling is mediated by three classes of receptors, Frizzled, Ryk, and Ror. In Caenorhabditis elegans, Wnt signaling regulates the anterior/posterior polarity of the P7.p vulval lineage, and mutations in lin-17/Frizzled cause loss or reversal of P7.p lineage polarity. We found that pak-1/Pak (p21-activated kinase), along with putative activators of Pak, nck-1/Nck, and ced-10/Rac, regulates P7.p polarity. Mutations in these genes suppress the polarity defect of lin-17 mutants. Furthermore, mutations in pak-1, nck-1, and ced-10 cause constitutive dauer formation at 27 °C, a phenotype also observed in egl-20/Wnt and cam-1/Ror mutants. In HEK293T cells, Pak1 can antagonize canonical Wnt signaling. Moreover, overexpression of Ror2 leads to phosphorylation of Pak1. Together, these results indicate that Pak interacts with Wnt signaling to regulate tissue polarity and gene expression.

So there at least five possible effects that Ivermectin can have.

Too much Ivermectin is not good

According to the literature in the developing world, there are 200 million people (http://onlinelibrary.wiley.com/doi/10.15252/emmm.201404084/abstract) currently taking Ivermectin, which is provided free for river blindness; some of those have been using the drug for over 20 years - so much is known about it.

It is suggested that at excessive doses, Ivermectin starts to cross the BBB and then affects the neurotransmitter GABA.  Ivermectin stimulates the release of the GABA in the presynaptic neurons and enhances its postsynaptic binding to its receptors. This increases the flow of chloride ions in the neurons, which causes hyperpolarization of the cell membranes. This on its turn disturbs normal nervous functions and causes a general blockage of the stimulus mechanisms in the CNS. The resulting cerebral and cortical deficits include mainly:

• Ataxia (uncoordinated movements)
• Hypermetria (excessive or disproportionate movements)
• Disorientation
• Hyperesthesia (excessive reaction to tactile stimuli)
• Tremor (uncoordinated trembling or shaking movements)
• Mydriasis (dilatation of the pupils); in cattle and cats also myosis (contraction of the pupils)
• Recumbency (inability to rise)
• Depression
• Blindness
• Coma

So, too much Ivermectin is not a good idea.

So why is Ivermectin good for Tics, OCD and Autism?

At low doses Ivermectin does not cross the BBB (blood brain barrier), but in autism it appears that the BBB can be more permeable than it should be.  So possibly Ivermectin produces an increase in GABA, like that caused by Valproic Acid.  Some people with autism find Valproic Acid very beneficial.

Perhaps those glutamate-gated Cl⁻ channels (GUCl⁻) play a, yet unidentified, role in autism.

Or, perhaps we got it right and PAK inhibiting property is what matters. 

Perhaps being an PAK1 inhibitor will also make it a Wnt inhibitor, or maybe not, worth checking though?

Perhaps the MIT guys got it wrong and it is Wnt rather than PAK that we should be focused on? 

I hope the blog reader that prompted this post does indeed give the bee propolis a go and see if it has the same effect as Ivermectin.

Cancer

Having said in an earlier post that I will not try and out-smart the cancer researchers, I will just say that the extremely cheap drug Ivermectin does seem to have some potent anti-cancer properties.  

I know that cancer drugs are supposed to be hugely expensive.

An earlier post mentioned Ivermectin’s positive effect on Leukemia, but it seems that the WNT-TCF Pathway is involved in very many cancers.  This is not to mention that just being a PAK1 inhibitor should be enough to prompt further interest.

Conclusion

Well it looks like Dr Wu and Dr Klinghardt have indeed got the therapy right, but I believe for entirely the wrong reasons. By promoting themselves via organisations like Autism One, they are almost guaranteed to be ignored by mainstream doctors and researchers. The therapy will therefore remain on the fringe, with the quacks and cranks.

From my perspective, what really matters is whether a therapy works.  We can always later on figure out why it works.  So thank you Dr Wu and Dr Klinghardt.

PAK1 Therapy for Autism – All packed and ready to go!

Following up on recent posts about PAK1, whose presence is required for 70% of cancers to grow and MIT have implicated in several types of autism, I have collected all the data I can find to make trials of PAK1 inhibition in autism.

  

I contacted the leading Japanese researcher who has developed PAK1 therapies for various kinds of tumor, mainly found in neurofibromatosis, but also brain tumors and even epilepsy.  He suggested the dosage of the CAPE-rich propolis from New Zealand and also suggested another drug called Fingolimod/Gilenya.  

This drug is an immunomodulating drug, approved for treating multiple sclerosis, but it is also a PAK1 inhibitor.  It appears to cross the blood brain barrier.  The downside it that Gilenya is hugely expensive, costing around $50,000 a year.

  

While Tonegawa's group at MIT continue to develop their new PAK1 inhibitors, I am concerned that they will end up with a drug costing as much as Gilenya, which will put it out of reach of most people, even if it was effective.

So that brings me back to the trials I propose.

Trial 1   -  BIO 30 Propolis

This is a natural product and as such will appeal to many of this blogs readers.  It needs no prescription from your doctor.  You can buy it over the internet from numerous pharmacies in New Zealand.

The dosage proposed for autism by the Japanese Researcher is 1-2 ml per 10 kg of body weight.

It appears that about 1% of people have an allergy to bee products.  If you are in the 99%, it is reported that even very much larger doses of BIO 30 have no side effects.

Trial 2   -  Ivermectin/Stromectol

This is the cheap drug that is used to treat parasites, but turns out to be a PAK1 inhibitor.  It was also recently shown to kill leukemia cells.

Here I will draw on the autism worm-dosage used by Dr Wu, who prescribes Ivermectin in the belief that the autistic kids’ behaviours are driven by worms.

Dr Yu is combining Ivermectin with other anti-parasite drugs.  I am assuming he “got it right for the wrong reason”, in other words the worms are not the issue, PAK1 is the issue.

Below is the dosage Dr Yu suggests in his autism presentation and one case report where there was a before and after evaluation.  Here the ATEC was used, which is a scale designed by Bernard Rimland and Stephen M.Edelson of the Autism Research Institute (the DAN people).

  

From what I could find, a single dose of Ivermectin (Stromectol) should kill the parasites.  Pets are given the same drug on a regular basis, some preventatively.

In low doses it appears to be very safe, but not in high doses.

Strongyloidiasis is a human parasitic disease caused by the nematode (roundworm).  On the site RXLIST.com the dosage for Strongyloidiasis is:-

The above is for a single dose therapy.  Dr Wu’s worms are either much more resilient, or his much higher and multiple dose therapy is actually working for entirely different reasons.

Trial 3   -   Fingolimod/Gilenya

Given the huge cost of Gilenya, I cannot imagine anybody trying it for autism.  Perhaps Novartis would like to donate some?

We did cover immunomodulatory therapy in earlier posts and it was Dr Chez who likes to write about this subject, in relation to autism.  He has published several trials and a good book.

Perhaps he should do the Gilenya trial?

The Blood Brain Barrier

I did ask the Japanese researcher if CAPE, the anti-PAK1 ingredient of the New Zealand propolis can cross the blood brain barrier, since it is claimed that Ivermectin does not.  He says that BIO30 and Fingolimod/Gilenya cross the BBB.

This brings me to a slight diversion.

Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155

In this research the aim was to confirm the mechanism behind why inflammation causes the blood brain barrier (BBB) to leak.  It has been suggested that the leaky BBB is a key part of autism.  The less leaky it is the better for autism.  Since pro-inflammatory agents like histamine and IL-6 really do make autism worse, it is highly relevant that the research shows that pro-inflammatory agents cause the BBB to let through more of the substances that it is supposed to keep out.

Perhaps the ever-present pro-inflammatory cytokines found in autism, mean that the BBB is always partially compromised.  A drug like Ivermectin might therefore pass more freely across the BBB, than would be expected in other people.

So Ivermectin might remain a cheap alternative to Gilenya.  Dr Yu’s case studies perhaps warrant some more serious attention.

Will it work?

There are good reasons why PAK1 inhibition should have a positive effect.  It is definitely not quack science, it is the serious MIT kind.

In treating Neurofibromatosis NF-1 tumors, it does seem to be more effective at stopping new tumors, rather than shrinking existing ones.   This perhaps should not be surprising, since PAK1 is needed for a tumor to grow and may not be needed for it to live.  At much higher doses, it is reported that existing tumors shrink. So with autism, maybe PAK1 is needed early on, before birth; blocking PAK1 in a 10 year old may be pointless.

The only way to find out for sure if it works in your type of autism is to try it.

If it does not work for Monty, aged 10 with ASD, we cannot say it will not work in somebody’s two year old with a different type of autism.

Also, in Monty, the PAK1 effect might already be being mitigated by his existing drugs.

It would be helpful if there was a clinical trial, but there is not.

Conclusion

Trial 1 is easy to do at home, and if you do it for a month, you would need two bottles of propolis, costing $50 including shipping from New Zealand.

Since the Nobel Laureate from MIT tells us that autism requires PAK1 and that, in mouse models of autism, PAK1 inhibitors are effective treatments, it seems odd nobody has tried it.  In PAK1-driven Neurofibromatosis, there are now many people claiming BIO30 to be effective.  In this condition you can measure/count the tumors, so I guess they should know if it works.

The MIT-inspired drugs, like Tonegawa’s FRAX486 will not be available for many years, and who knows how much they will cost.

In the case of Ivermectin, somebody really should look at the toxicology data and see how safe regular usage would be in humans.  The Leukemia researchers proposed this drug be actively developed, but nothing seems to have happened.  Just for a few days, Trial 2 would not seem to be too risky.

We agree to leave trial 3 to Dr Chez, in Sacramento.