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.

Modulating Wnt Signaling in Autism and Cancer

Source: LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way

In earlier posts I have covered various signaling pathways such as Wnt, mTOR and the unusually sounding Hedgehog.

You can go into huge detail if you want to understand these pathways, or just take a more superficial view. In most cases, things only start to go wrong if you are hypo/hyper (too little/too much) in these pathways.

We saw with mTOR that most people with autism are likely to have too much activity and so might benefit from mTOR inhibition, but a minority will have the opposite status and stand to benefit from more mTOR activity.

When it comes to Wnt signaling the research suggests the same situation. Wnt signaling is likely to be aberrant, but both extremes exist.

Wnt signaling networks in autism spectrum disorder and intellectual disability

Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.

While the human genetic data is an important supporting factor, it is not the only one. There are a number of mouse genetic knockout (KO) models targeting Wnt signaling molecules, describing molecular, cellular, electrophysiological, and behavioral deficits that are consistent with ASD and ID. Furthermore, the genes involved in Wnt signaling are of significant clinical interest because there are a variety of approved drugs that either inhibit or stimulate this pathway.

There are many drugs developed and tested as modulators of Wnt signaling in the cancer field that could potentially be repurposed for developmental cognitive disorders. In cases where a reduction in Wnt signaling is thought to underlie the pathology of the disorder, usage of compounds that elevated canonical Wnt signaling could be applied. An example of this is GSK-3β inhibitors that have failed in cancer trials but may be effective for ASDs and ID (e.g., Tideglusig, ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02586935","term_id":"NCT02586935"}}NCT02586935). In cases where elevated Wnt signaling is thought to contribute to disease pathology, there are many potential options to inhibit canonical Wnt signaling using chemicals (Fig. 1) that inhibit the interaction between β-catenin and its targets (e.g., inhibiting β-catenin interaction with the TCF factors), disheveled inhibitors (through targeting of the PDZ domain which generally inhibit the Frizzled–PDZ interaction), and tankyrase inhibitors (e.g., XAV939, which induces the stabilization of axin by inhibiting the poly (ADP)-ribosylating enzymes tankyrase 1 and tankyrase 2)

As autism candidates emerge, cancer pathway rises to top

In recent years, strong autism ties have cropped up for one group of genes in particular: those that make up a well-known signaling pathway called WNT, which also has strong links to cancer. This pathway is especially compelling because some people with autism carry mutations in various members of it, including one of its central players: beta-catenin¹. What’s more, studies from the past year indicate that several of the strongest autism candidate genes, including CHD8 and PTEN, interact with this pathway.

“There might be a particular subgroup of genes associated with autism that could all be feeding into or be regulating this pathway,” says Albert Basson, reader in developmental and stem cell biology at King’s College London, who studies CHD8 and WNT. “That clearly has emerged as a relatively major theme over the last few years.”

The connection between cancer and some autism is over-activated pro-growth signaling pathways. Many signaling pathways have growth at one extreme and cell death at the other. In cancer you actually want cell death to suppress tumor growth; in much autism there is also too much growth.  

Many cancers are associated with elevated signaling of mTOR, Wnt and indeed Hedgehog.  These are targets for cancer drug therapy and so there is already a great deal known.

A complication is that in a developmental neurological condition, like autism, it also matters when these signaling pathways were/are disturbed. For example Wnt signaling is known to play a role in dendritic spines and synaptic pruning, some of this is an ongoing process but other parts are competed at an early age, so it would matter when you intervene to modulate these pathways.

Historically cancer therapies involve potent drugs, often with potent side effects, however in recent years there has been growing awareness that some safe existing drugs can have equally potent anti-cancer effects. Many of these drugs are anti-parasite drugs, but even the very widely used diabetes drug Metformin has been shown to have significant anti-cancer effects, not to forget Simvastatin.

Many autism pathways/genes play a role in cancer (RAS, PTEN) and the upstream targets considered in cancer research are also autism targets.  For example many human cancers are RAS dependent and in theory could be treated by a RAS inhibitor, but after decades of looking nobody has found one. So instead scientists go upstream to find another target that will indirectly reduce RAS. This led to the development of PAK1 inhibitors that will reduce RAS.

RAS plays a role in some types of intellectual disability and indeed autism. The collective term is RASopathy.  Logically, drugs that modulate RAS to treat cancer might be helpful in modulating RAS for some autism.

Most types of cancers are complex and so there are multiple potential targets to attack them, but also the same target can have multiple possible approaches. RAS dependent cancers can be targeted via Wnt and even Hedgehog signaling.

This may sound all very complicated but does it have any relevance to autism?

It apparently does because almost all these pathways are known to be disturbed hypo/hyper in autism.  This means that clever insights developed for cancer can be repurposed for autism.

Anti-parasite drugs and Cancer

It is indeed remarkable how many anti-parasite drugs have an anticancer effect and indeed there is a much maligned theory to justify this.

Clinical Evaluation of a New Form of Cancer Therapy Based on the Principles of Atavistic Metamorphosis

Quite possibly it is just a coincidence.

There are many ways to kill parasites, one of which involves starving them of ATP. ATP is the fuel that is produced in your mitochondria.

Cancer cells and many parasites use a very inefficient way to produce ATP that does not require oxygen. In normal human cells the process followed is known as OXPHOS, by which glucose and oxygen from the blood is converted into ATP (energy) is very efficient. Only when you run low on oxygen, like a marathon runner at the end of the race, can you run into trouble because there is not enough oxygen for OXPHOS.  What happens next is anaerobic respiration, when a different process takes over to make ATP. It is much less efficient and causes lactic acidosis which makes marathon runners' muscles hurt.

A cheap anti-parasite drug Pyrvinium targets anaerobic respiration and starves the parasite of ATP and thus kills it. Another common children’s anti-parasite drug albendazole also works by starving the parasite of ATP.

Other anti-parasite drugs work in different ways.

We already know from the autism trials of Suramin, another anti-parasite drug,  that it works via P2X and P2Y purinergic channels.

Ivermectin  binds to glutamate-gated chloride channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased permeability to chloride ions, resulting in cellular hyper-polarization, followed by paralysis and death.  Fortunately in mammals ivermectin does not cross the BBB.

Ivermectin is also a PAK1 inhibitor and a positive allosteric modulator of P2X7.

Both PAK1 and P2X7 are relevant to many cancers and so not surprisingly research shows that Ivermectin has an anti-cancer effect.

Ivermectin appears to have a positive effect in some autism, but strangely it does not cross the BBB.

Mebendazole is another extremely cheap children’s anti-parasite drug which has remarkable potential anti-cancer properties. It inhibits hedgehog signaling and, via the inhibition of TNIK, it is a Wnt inhibitor.

Unfortunately in the US the private sector has also noticed the anticancer effects of Mebendazole and albendazole and they have recently become astronomically expensive. Mebendazole (MBZ), which costs almost nothing in many countries, now costs hundreds of dollar per dose in the US under the name Emverm. Outside of the US, Mebendazole is OTC in many developed countries. In poor countries it is donated free by big pharma.

In the cancer research they consider taking advantage of the fact that cimetidine (a cheap H2 antihistamine) interacts with Mebendazole to increase its bioavailability. Cimetidine is by chance another generic drug also being considered to be repurposed for cancer.

While some anti-parasite drugs like Suramin have side effects or cannot be taken regularly like Ivermectin, others are seen as safe for continued use even at high doses (e.g. Mebendazole and albendazole).  

Anti-parasite drugs and Autism

Just as many anti-parasite drugs seem to have a positive effect on some cancers it looks likely that the same may be true for autism.  This does not mean that parasites cause either cancer or autism.

We know from Professor Naviaux that some people respond to Suramin.

Two people who comment on this blog have found their child responds to PAK1 inhibitors, one of which is the drug Ivermectin.

There are groups of people on the internet who think parasites cause autism and you will find some of them if you google “autism mebendazole”, but there are some very valid reasons why some people’s autism may respond to mebendazole, but nothing to do with little worms.

Potency of Anticancer drugs

Failed anticancer drugs are already considered as possible drugs to treat neurological conditions.

The same pathways do seem to be involved in some cancer and some neurological conditions, but the severity by which that pathway is affected may be very different, so a new drug may lack potency to treat a type of cancer but be potent enough to benefit others.

In the case of the anti-parasite drugs Ivermectin and indeed mebendazole the dosage being used in current cancer studies are very much higher than normally used.

Very little mebendazole makes its way out of your intestines and so researchers counter this by using a dose 15 times higher and even taking advantage of the interaction with the H2 antagonist cimetidine to boost bioavailability.

The standard human dose of Ivermectin is 3mg, but in the cancer trials (IVINCA trial - IVermectin IN CAncer) in Switzerland and Spain the trial dose is 12, 30 and 60 mg.

So when it comes to autism and the possible repurposing of these drugs, the cancer studies will give valuable safety information, but the likely dose required to fine-tune these signaling pathways will likely be a tiny fraction of the cancer dose.

The newly developed cancer drugs that fail in clinical trials, may have potential in autism but it is unlikely that anyone will develop them, test them and bring them to the market.

The clever thing for autism seems to be to keep an eye on the existing generic drugs considered to benefit the overlapping cancer pathways.

Conclusion

Aberrant Wnt signaling has been identified by researchers as playing a key role in autism; the Simons Foundation is among those now funding further research.

In practical terms you can be either hypo or hyper, but hyper seems more likely. It may be a case of shutting the stable door after the horse has bolted, because the ideal time to modulate Wnt signaling is probably as a baby, or before. Nonetheless some older people may indeed benefit from modulating Wnt; the Simons Foundation must also believe so.

In the case of people with hyperactive Wnt signaling, there is a case to make for the potential use of the cheap anti-parasite drug Mebendazole.

The drug Mebendazole (MBZ) can found in three states/polymorphs called Polymorph A, B or C. This is relevant because they do not cross the blood brain barrier to the same extent.

Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model  

To treat brain tumors, or indeed potentially some autism, you need MBZ-B or MBZ-C, it looks like MBZ-A does not cross the blood brain barrier.

Fortunately, MBZ-C is  the polymorph found most commonly in generic mebendazole tablets.  

Ivermectin is known not to cross the blood brain barrier but yet has been shown to show anti-tumor activity in brain cancer. The anti-cancer effect is thought to be as a PAK1 inhibitor, but this effect must be occurring outside the brain. Some people do use Ivermectin for autism.

The people using Ivermectin for autism are told they cannot use it continuously. Perhaps as the high dose cancer trials evolve the safety advice may change.

PAK inhibitors and potentially treating some Autism using Grandpa’s Medicine Cabinet

I wrote several posts about why PAK1 inhibitors should be beneficial in some autism and indeed some schizophrenia.

We also saw that PAK1-blocking drugs could be potentially useful for the treatment of neurofibromatosis type 2, in addition to RAS-induced cancers and neurofibromatosis type 1.

One problem with drugs developed for cancer is that, even if they finally get approved, they tend to be ultra-expensive.  Production volumes are low because even if they “work” they do not prolong life for so long and cancer has numerous sub-types.

Cheap drugs are ones used to treat common chronic conditions like high blood pressure, high cholesterol and indeed treatment of male lower urinary tract symptoms (LUTS), like benign prostatic hyperplasia (BPH).

A small number of readers of this blog have confirmed the beneficial effect of PAK inhibitors in their specific sub-types of autism.  The problem is that there are no potent PAK1 inhibitors suitable for long term use that are readily available.

The anti-parasite drug Ivermectin is an extremely cheap PAK1 inhibitor, but cannot be used long term, due to its other effects.

Propolis containing CAPE (Caffeic Acid Phenethyl Ester) is a natural PAK1 inhibitor, but may not be sufficiently potent as is reported by people with neurofibromatosis.

You would think somebody would just synthesize CAPE (Caffeic Acid Phenethyl Ester) artificially and then higher doses could be achieved.

PAK Inhibitors and Treatment of Prostate Enlargement

I was rather surprised that research has recently been published suggesting that PAK inhibitors could be used to treat the prostate enlargement, common in most older men. 

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

Abstract

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α₁-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.

It looks like a PAK inhibitor could potentially solve both the key problems in BPH and so replace the current therapies.

Existing Drugs for LUTS/BPH

Undoubtedly someone is going to wonder whether existing drugs for LUTS/BPH might improve autism.  This is actually possible, but totally unrelated to PAK1 inhibition and RASopathies.

Existing drugs are in two classes, 5α-reductase inhibitors and α₁-adrenoceptor antagonists.

α-adrenoceptor antagonists

Alpha blockers relax certain muscles and help small blood vessels remain open. They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure.

Because alpha blockers also relax other muscles throughout the body, these medications can help improve urine flow in older men with prostate problems.

Selective α₁-adrenergic receptor antagonists are often used in BPH because it is the α₁-adrenergic receptor that is present in the prostate.

 α ₂-adrenergic receptors are present elsewhere in the body

Alpha-2 blockers are used to treat anxiety and post-traumatic stress disorder (PTSD). They decrease sympathetic outflow from the central nervous system. Post-traumatic stress disorder is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system.

Alpha-2 receptor agonists for the treatment of post-traumatic stress disorder

So a nonselective alpha blocker, like one given to an older man with high blood pressure and BPH, might well have an effect on some kinds of anxiety.

You would think that a selective alpha 2 blocker might be interesting, how about Idazoxan?

Idazoxan is a drug which is used in research. It acts as both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in schizophrenia. Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, a brain area thought to be involved in the pathogenesis of schizophrenia.

Mirtazapine is a cheap generic drug used at high doses for depression.  It happens to be a selective alpha 2 blocker, but it has numerous other effects as well.  One reader of this blog does respond very well to Mirtazapine.

So realistically in Grandpa’s medicine cabinet there might a selective alpha 1 agonist or a non-selective alpha agonist, it is the latter type that might have an effect on some kinds of autism.

5α-reductase inhibitors

The pharmacology of 5α-reductase inhibition involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone.

Beyond being a catalyst in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC).

In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function.

These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABA_A receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT.

This, in turn, results in slight elevations in testosterone and estradiol levels. 

In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.

A new look at the 5alpha-reductase inhibitor finasteride

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.

This would suggest that a 5α-reductase inhibitor, like finasteride, that might be among Grandpa’s tablets might very well have an effect on someone with GABAa dysfunction, this includes very many people with autism, schizophrenia and Down Syndrome.

Whether the effect will be good or bad is hard to say, and may well depend on whether other drugs that target GABA or NMDA receptors are being used. Due to their other effects, 5α-reductase inhibitors are usually only used in adults.

Merck developed a lower dose form of finasteride, called Prospecia to treat baldness, usually in men.  It is 20% the normal potency used for BPH.

Side effects

The current BPH drugs cause side effects in some people.  PAK1 inhibitors may also have some side effects.

Conclusion

Going back in the days of living with your extended family might make treating many people’s autism much simpler.  It looks like many older people’s drugs can be repurposed for some types of autism (ion channel modifying diuretics, calcium channel blockers, statins, even potentially intranasal insulin in some).  Because older people’s drugs are so widely used they are well understood and inexpensive.  

Clearly the research on PAK inhibitors for LUTS/BPH is at an early stage, but there is a huge potential market.   A widely available PAK1 inhibitor might be a big help to some people with autism, neurofibromatosis, other RASopathies, not just Grandpa’s prostate.

In addition to FRAX486 and IPA3, why doesn’t someone try synthetic CAPE, i.e. without the bees, as a PAK inhibitor?

Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.

There is far more chance of a PAK1 inhibitor coming to market for LUTS/BPH, or certain cancers than for autism.  That is a fact of life.

As for 5α-reductase inhibitors, like finasteride, we know from Hardan’s study on Pregnenolone at Stanford that this hormone can have a positive effect and we know that various natural steroid metabolites will modulate GABA subunits.  So it is quite likely that finasteride is going have a behavioral effect.  Perhaps Hardan would like to trial finasteride 5mg and 1mg (Prospecia) in some adults with autism. I suspect it will make some people “worse” and others somewhat “better”; so please do not report the “average” response, highlight the nature of the positive responders.