Readers may be wondering at what point Peter will run out of things to write about. I do sometimes wonder the same thing. I was going to also write about Loperamide (Imodium), but the post would have been too long. Next time!
Pentoxifylline
Pentoxifylline
has been in use to treat autism for 50 years. The original studies did suggest
its effect was greatest among small children.
I have been in some discussions with a US psychiatrist, Dr Powell, who
is a big fan of the off-label use of this drug to affect the brain in adults. He has even written a book on the subject.
My previous posts on Pentoxifylline can be found here:
https://www.epiphanyasd.com/search/label/Pentoxifylline
Dr Powell’s patients with autism tend to be older children, not the toddlers who did well in clinical trials in Japan in the 1970s. He sees significant improvement in many, but not all, of his patients with autism. The parents report improved social interactions and having higher-level discussions with their child.
What
is notable is that he uses frequent dosing, 4 times a day, always after food to
avoid the GI side effects.
Pentoxifylline
is inexpensive, but its effect does not last long, hence the frequent
dosing. Some people take taking this
drug 5-6 times a day.
Pentoxifylline
has multiple modes of action, it should increase blood flow to the brain and it
is broadly anti-inflammatory. It is a
non-selective PDE inhibitor, normally used treat muscle pain in people with
peripheral artery disease. It increases red blood cell flexibility and it
reduces the viscosity of blood.
There
are PDEs 1 to 11. It all gets quite complicated, for example PDE1 subtype A2
has a potential role in neurodegenerative diseases, including:
· Parkinson's disease
· Axonal neurofilament degradation
· Motorneuronal degradation
· Neuronal ischemia
· Alzheimer's disease
· Epilepsy
Recall
that PDE4 inhibitors are used to treat asthma and COPD. We can potentially repurpose
those to improve myelination in MS, or autism, and at specific low doses they
can improve cognition.
cGP (from Black Currants)
I did write quite a lot in this blog about growth factors and autism. The familiar ones are BDNF, NGF and IGF-1, but there are many more.
My previous posts on IGF-1 can be found here:
https://www.epiphanyasd.com/search/label/IGF-1
We know that growth signaling in autism is disturbed, but it is not simple. As the disease progresses (the fetus develops, the baby is born and grows into a toddler) the imbalance in growth signaling changes. This means that what would be helpful in a 6 month old baby might well be inappropriate in a 6 year old. This is a good example of what I call the what, when and where of treating autism. Here it is the “when” that matters.
Some
people lack BDNF while others have too much. Very possibly, this changes over
time in the same child.
One
possible therapy for autism is injections of IGF-1 (Insulin-like Growth Factor
1). IGF-1 plays an important role in
childhood growth.
A
synthetic analog of IGF-1 is used in children for the treatment of growth failure. This
drug called Mecasermin
was used in autism trials and in Rett syndrome trials.
In Rett
syndrome the search has been on for an oral therapy.
Trofinetide
(NNZ-2566) is a potential therapy
for Rett
syndrome being developed by Neuren Pharmaceuticals in Australia.
Trofinetide is derived from IGF-1.
Trofinetide got to phase 2 trials as a therapy for Fragile-X in
2015.
The second product in development at Neuren is NNZ-2591. It is aimed at normalizing the level of
IGF-1.
This is in the pipeline to treat:
- Phelan-McDermid syndrome (Shank3 gene and others not working)
- Angelman syndrome (UBE3A gene not working)
- Pitt Hopkins syndrome (TCF4 gene not working)
- Prader-Willi syndrome (MAGEL2 gene and others not working)
https://www.neurenpharma.com/irm/content/product-development-pipeline.aspx?RID=483&RedirectCount=1
What is NNZ-2591?
It is
an analogue (modified version) of cyclic glycine proline (cGP)
Cyclic
glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective through
improving IGF-1 function.
There
is also research focused on Parkinson’s and Alzheimer’s where it seems that cGP
is reduced.
In New
Zealand they found that supplementation of Blackcurrant anthocyanins (pigments)
increased cGP in the spinal fluid of patients with Parkinson’s.
This
also led the way to the idea of increasing cGP as means of protecting the brain
during aging. There is now a commercial OTC product in New Zealand to do just
this.
Our
reader Daniel, who has a daughter with Rett syndrome, is assessing the benefit
of cGP, using the OTC product cGPMAX. The results so far are promising.
Rett
is very specific because we know for sure that IGF-1 and NGF are disturbed.
Is
cGP going to be beneficial in broader autism?
May be yes, but we come back to the what, when and where. It may well depend on when a specific person
takes it. We have both hypoactive
pro-growth signalling autism and hyperactive pro-growth signalling autism.
Unfortunately, what the clever researchers who came up with the above concept did not consider is that you may start out hyper in the womb and switch to hypo a few short years later.
Conclusion
Frequently
dosed Pentoxifylline looks like a potentially interesting therapy for many with
autism, including some with high IQ.
Take note our Aspie readers.
Daniel’s
idea to look at the Neuren’s non-Rett therapy as a Rett therapy is
interesting. In effect you do not need
to wait for the Australian drug, you can hop across the Tasman Sea to New
Zealand and use their cGP supplement, developed for protection against
dementia.
You would also think that parents of
children with:
- Phelan-McDermid syndrome (Shank3 gene and others not working)
- Angelman syndrome (UBE3A) gene not working)
- Pitt Hopkins syndrome (TCF4 gene not working)
- Prader-Willi syndrome (MAGEL2 gene and others not working)
might want to follow Daniel’s lead.
As you can see, there is a lot of trial and error in
science. Back in 2009 NNZ-2566 was in clinical trials for the
treatment of cognitive deficits following traumatic brain injury. That must not have worked out. Fragile-X did not work out and now it is
phase 3 for Rett girls, which seems to be going well.
IGF-1 for old
people
The
same growth factor IGF-1 that is key during development also plays a key role
in aging. Dr Jian
Guan made a world first discovery. She discovered that cGP (cyclic
Glycine-Proline) was responsible for controlling the IGF-1 hormone in our body.
Thus by increasing the level of cGP in our body, the cGP will essentially
command the IGF-1 to build more blood vessels.
Dr Jian Guan, was then recognised as the world-wide
authority on cGP. In 2017 she discovered that New Zealand blackcurrants
contained high volumes of natural cGP which could regulate optimum levels of
IGF-1 in the body.
So now we have Antipodeans/Kiwis fending
off dementia, and potentially metabolic syndrome, by taking their locally made
cGPMax.
Will it help you case of autism? Who
knows, but if it does not, just give the leftover pills to Grandma, Granddad or
take them yourself!
All the supporting papers from New Zealand.
Hi Peter
ReplyDeleteSorry if this is slightly off topic I`ve been giving my son Calcium Folinate (brand Folinoral) for a little while now, we have been delaying giving him ADHD drugs but now believe they may help him, the pediatrician recommended Methylphenidate.
I`ve tried looking for drug interactions with the two combined and nothing on google, although Folinoral is not really a drug as its more of a vitamin.
Have you heard of Calcium Folinate whether Leucovorin or Folinoral been taken with adhd drugs?
The are no interactions that I can see listed. I have not heard of any such problems. If Calcium Folinate has been well tolerated, adding Methylphenidate should not cause a problem, according to the available information.
DeleteYes, I'm amazed how you find new interventions time after time! This one looks interesting, but is not cheap. If Daniel reads this it would be very informative to hear about his experience so far (treated symptoms + dosing + timeline). Thanks!
ReplyDelete/Ling
Ling, the comments are in this post:
Deletehttps://www.epiphanyasd.com/2013/10/its-small-world-igf-1-and-nnz-2566-in.html?showComment=1663138581337&m=1#c806227770567415140
Hi Ling,
DeleteWe have been on 2 capsules a day. After 4 months our daughter is less foggy, She does things with a clear purpose, improved fine and gross motor skills.
Over the weeks we experienced an increase in hyperactivity, alertness and difficulty getting sleep. When we stop cGP She quickly resumes hyperactivity and gains are more obvious.
My girl is a 47-month-old Classical Rett.
A few days ago it was the first time that my daughter accepted me to caress her calmly on the sofa. What’s incredible is that She then also caressed me.
I now can find more ways to stimulate her, I now can do minor movements like playing castanet and She tries to repeat it like He did when She was two. The fine motor skills had regressed a lot since She was 2 but now it seems She’s recovering some and more importantly She is recovering the intention to copy me.
I can now also play puppets and get some very nice smiles, humor sense is back!
Gross motor skills in the playground have clearly improved.
Are these improvements cGP? Who knows… but there’s sufficient scientific evidence to believe it could be so.
Also, the fact that cGP is overexciting her might be a sign that cGP is crossing BBB and having some effect there.
For what I have researched this excitation could be related to some cholinergic action and/or Na,K-ATP pump or anything else.
Just be aware that if your son has autism you have to pay a lot of attention to the increase of excitability. Especially if He is susceptible to seizures.
In any case, I now clearly can see that we need to shift Gaba excitability with Bumetanide and I would recommend you to start trying Bumetanide before trying cGP. It will help your son to deal easier with cGP’s excitability.
Thank you for the long answer, very helpful!
DeleteIt is great to hear that you have found something that helps you daughter, congratulations to that!
I know the gene we deal with is related to MecP2, but not exactly where and how. So anything for Rett is always interesting!
/Ling
My 10 year old has been toilet trained since the age of 4 years.All if a sudden since Jan he has completely regressed peeing.He pees in his pants very often .Cannot hold his pee for 30 min.Has constant urge to go pee.Dr did all the blood test and urine test.No UTI .He drinks regular amount of water.Dr has recommened timed voiding.We have been doing it for the ladt 8 monghs.No success.Can you recommend what we could do?
ReplyDeletePolyuria, the constant need to pee, and urinary incontinence are symptoms of PANS. Find a doctor who treats PANS PANDAS and get him checked out.
DeleteI'd like to second Peter's first guess - for my daughter, urinary regression was almost the only symptom of PANS for a while. Not many doctors know PANS can present with partial symptoms. In our case, naproxen helped it mostly (as per dr. Andrew Baumel).
DeleteIs there something that can help with urinary incontinence? My son has Pans
DeleteThis should be something that the PAMS doctor can answer, since it must be a common issue.
DeleteYou could ask about Desmopressin. In theory when you have controlled PANS all the symptoms should fade away.
Dr said no Pandas or Pans.Any other possibility?
ReplyDeleteIt is very hard to diagnose PANS.
DeletePolyuria has a long list of possible causes, even low potassium. Diabetes is a common cause.
You probably need to consider any other symptoms that have appeared and any drugs or supplements being taken.
Potassium,glucose,calcium and the basic metabolic panel has been done All normal .I have started him on AZO for bladder control.It is fir adults but I have no choice right now.It is pumpkin seed extract.Dr here are saying it is behavioral and not doing anything much.
ReplyDeleteIt could be behavioral, but for such acute onset there would have to have been an acute trigger. Death, divorce, change of school, moving house are examples. If there was no such event then it must be biological not behavioral.
DeleteIt started soon after he was dragged on a rug at school by his aide.The scar from the dragging was so bad that it looked like someone had burnt his butt.The doctor and the child protective service got involved.Could you please take a look at AZO for bladder control and let me know if it can harm a child?
ReplyDeleteThe producer says not to give to children or pregnant women.
DeleteI suggest you ask the doctor for Desmopressin. This is used to prevent bed wetting in children and may also improve symptoms of autism. It is a synthetic version of the human hormone Vasopressin.
Little bit similar situation, but my son had urinary accidents for couple of years. He was never diagnosed with PANS or PANDAS, but it was sudden onset and started when he got sick. ABA helped little bit initially, but he got better after giving him a small dose of Mirica (PEA).
ReplyDeleteThis comment has been removed by the author.
ReplyDeleteAs many here know, my daughter has been on IVIG and other treatments for Pans for a while now with good success. Her condition is pretty stable and we decided it was time for a change. Since IVIG can’t be a life long therapy for practical and financial reasons, we wanted to try out Alpha 1 Thymosine which was recommended by Dr A. from Italy. The idea was to use october and november as months with both low allergens and low seasonal illness to try it out without risking a challenge by a great immune disruption such as allergies or flu. So our last ivig was sept 2. I was in the process of ordering the injections and they have notnyet arrived. Her ivig effect has lapsed by now. she got a cold which was running through her school. The illness itself she did fine, but once the fever went down, the Pans exploded. For two days, she was in ‘urgent ivig needed’ territory with tics losw attention span aggression etc. The third day I was able to give her the alpha 1 thymosine but in pills (locally available). The effect was as weirdly instantenous as Ponstan - as if those two days had never happened. She is on it right now for 5 days and I can vouch that it replaces IVIG at least to 90%. I don’t know whether it would be helpful for other Pans cases and our neuroimmunologist insisted we remove viruses before we start it, so its obviously not a ‘lets just try it’ therapy, but it certainly is effectful for us.
ReplyDeleteTatjana, what effects do you see from Ponstan and how long do they last? What is your dosage?
DeleteI have been giving 250mg once a day for a few months. The original reason was to overcome extreme sound sensitivity, but I think the benefits go further.
The original idea of Knut's had nothing to do with sound sensitivity it was very broad to block damaging brain developments that produce severe non-verbal autism in toddlers.
Good luck with alpha 1 thymosine.
Which dose of thimosyne alpha are you using?
DeleteI see the effects as sound sensitivity but just as you, I also think they go further. Its a subtle broad effect rather than some big one thing (apart from the sound). I have to say we are currently pretty lucky with interventions and have come to a very good place. We are using ponstan, bumetanide (both just 1/2 in the morning), a very thorough mito complex, valtrex, some diflucan a few times a week, the proinsulin c spray and now the alpha thymosine. She is superhappy, superstable and very communicative in intent. I think also her speech is coming along but its not some explosion.
ReplyDeleteHi Peter
ReplyDeleteIs there any link to buy the recommend cGP supplement
Thanks
The best product seems to be.
DeleteCgpmax.com
It seems to help some people but have no effect in others