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Wednesday 18 December 2019

Will Anavex for “Autisms” be worth the wait and the price, compared to Russian OTC Afobazole?





US-Russia cooperation has long been possible in Space, but not so often in Medicine. NASA reportedly pays Russia $85 million per astronaut to go the International Space Station (ISS).  The US Space Shuttle program ended in 2011, leaving a Russian Soyuz rocket the only way to the ISS.


This post comes ahead of the dietary autism post, awaited by Tanya.  It really is just a brief follow-on from the previous post. I have only just come across Anavex, which does add weight to the first post on sigma-1R.
                                                                                                               
Hundreds of millions of dollars are being spent in the US to develop a safe sigma-1R agonist (Anavex 2-73). This drug is being trialed in various autisms (Rett, Fragile X and Angelman syndromes), Parkinson’s and Alzheimer’s.

In the last post I wrote about a cheap OTC anxiety drug from Russia, called Afobazole, that appears to be a safe sigma-1R agonist.  This drug has also recently been trialed in autism and Parkinson’s - the same targets as Anavex.

I did make the point in my original sigma-1 post that I am interested in existing therapies, rather than potential ones, so I did not include Anavex, or any other research drug, in that post. Anavex is nonetheless interesting, because their research studies further support the suggestion that targeting ER stress via sigma-1 is an interesting avenue to pursue.  

ERStress and Protein Misfolding in Autism (and IP3R again) and perhaps what to do about it - Activation of Sigma-1 Chaperone Activity by Afobazole?



Anavex is claiming precision medicine, but in fact sigma-1R agonists appear more like the opposite, at least in terms of who you target.  The majority of both common and rare neurological disorders look like they should benefit from reducing ER Stress (from whatever cause); it is a shared feature.  So it looks more like a shotgun approach; that is actually a good thing, if it were to drive the price down.

What is needed is an affordable, effective, mass market drug; not an ultra expensive pill just for Rett Syndrome and perhaps a different colour version for Angelman's Syndrome.

Which will prove effective - Anavex or Afobazole? Or perhaps neither.

Having already made the case for Soyuz in my earlier post, here is the case for NASA, and for those with NASA-sized budgets, courtesy of  https://www.anavex.com/





















Treatment with Anavex 2-73 was seen to improve motor skills, acoustic responses and visual acuity in a mouse model of Rett syndrome, supporting ongoing Phase 2 studies in patients.
Its use also helped to lessen abnormal movements and ease breathing in these mice, its researchers said.
Anavex 2-73 (blarcamesine) is an oral investigational therapy developed by Anavex Life Sciences that works by activating the sigma-1 receptor (S1R), a protein involved in the correct folding of other proteins.
S1R activation results in reduced toxic accumulation of misfolded proteins, as well as lesser dysfunction in mitochondria (a cell’s “powerhouse”), oxidative stress and neuroinflammation, all involved in Rett syndrome. (Oxidative stress is an imbalance between the production of free radicals — potentially harmful molecules associated with a number of diseases — and the generation of antioxidant defenses.)
Researchers at Anavex, assisted by PsychoGenics, evaluated the potential treatment’s specific effects on Rett symptoms in a validated mouse model.
They assessed motor function (balance, motor coordination, locomotion, and abnormal movements or stereotypies), sensory function (reflex responses to sound stimuli and visual clarity), and respiratory function.
Motor and sensory functions were assessed in younger mice, while visual acuity and breathing were measured in older animals.
Results showed that Anavex 2-73 significantly eased motor dysfunction, and deficits in acoustic and visual responses compared to mice given a placebo.
Anavex 2-73 also induced a significant reduction in two distinctive features of Rett syndrome found in these mice: hind-limb clasping (an abnormal posture comparable to hand stereotypies in people with Rett), and apnea (involuntary breath-holding) that is the most concerning breathing abnormality in Rett syndrome, the researchers said. These improvements were mainly dependent on treatment dose and duration.
“In conclusion, the data demonstrate that [Anavex 2-73] is effective in ameliorating multiple neurobehavioral phenotypes in [Rett] mice,” the researchers wrote. “In line with previous animal and human studies [in other neurodegenerative diseases], [Anavex 2-73] also showed a good safety profile,” they added.
These data served as a proof-of-concept for an ongoing safety and efficacy Phase 2 trial called RS-001 (NCT03758924, still enrolling) in the U.S., and for the Phase 2 AVATAR study (NCT03941444) in Australia. These trials together will evaluate Anavex 2-73 in up to 51 women with Rett syndrome.











Conclusion

It may be that Anavex is far superior to the cheap Afobazole. Like the space shuttle was far more advanced than the Soyuz. 

But what if the cheap Afobazole is quite good enough?  Like the cramped, but reliable Soyuz rocket.

Anavex/Afobazole will not cure any severe neurological condition, just improve it, so it will need to be part of a polytherapy. That means the patient will need to be able to afford multiple drugs, somehow.

Coming back to those autisms, what if your daughter has Rett Syndrome, or son has Fragile-X Syndrome ?  Wait a few years for Anavex and for someone else to pay for it? or make do with some cheap Afobazole?











22 comments:

  1. Hi Peter,

    Hope all is well and thanks for another great post!

    Peter, an effect you have noted a few times may finally have an explanation, via a fascinating article / paper:

    https://medicalxpress.com/news/2019-12-infections-autism-symptoms.html

    Researchers just noted today that IL-17a may be the reason why some children with fever appear to improve.

    What is interesting to me is that they injected IL-17a directly into the brains of Shank3, Cntnap2, and Fmr1 mice and their behaviours improved, so this effect looks like it may be relevant to many divergent causes of ASD.

    They are also looking at gut bacterial that may result in the production of IL-17a.

    Have a great day Peter!

    AJ

    ReplyDelete
    Replies
    1. AJ, it is interesting but still not fully understood. IL-17a is a key pro-inflammatory cytokine driving conditions like psoriasis.

      "It was amazing to discover that the same immune molecule, IL-17a, could have dramatically opposite effects depending on context: Promoting autism-like behaviors when it acts on the developing fetal brain and ameliorating autism-like behaviors when it modulates neural activity in the adult mouse brain. This is the degree of complexity we are trying to make sense of," Huh says.

      From the paper itself:

      “Discussion
      Previous data in mice have suggested that increased production of IL-17a in pregnant mothers may present as a risk factor for neurodevelopmental disorders in offspring. On the basis of our current findings, we propose that in adult MIA offspring the same cytokine is beneficial and ameliorates sociability phenotypes during episodes of inflammation. Treatment with LPS led to an increase in IL-17a levels in the blood selectively in MIA offspring—but not in other monogenic mutant mice. This suggests that the inflammatory responses may result in beneficial effects only for individuals who have their immune systems primed by prenatal exposure to immune activation, or by other environmental factors. A better understanding of the role of a primed immune system among patients with neurodevelopmental disorders may help to identify those patients whose behavioural symptoms are likely to improve after exposure to fever-associated inflammation. Furthermore, elucidating the mechanisms by which IL-17a can induce two opposing behavioural outcomes depending on when its upregulation occurs (during embryonic brain development or in the adult brain) may provide opportunities to devise therapeutic as well as preventive treatments for the behavioural symptoms associated with ASD.”

      I think again we have a situations where sub-types of autism will be opposites.

      In some people inhibiting IL-17 improves their autism. These are the people who have comorbid auto-immune conditions (asthma, eczema, IBS, mast cell problems etc). These people need an IL-17 inhibitor, of which there are now many. DMF, recently added to my Polypill, inhibits IL-17.

      Also, in humans, they replicated the fever effect using hot tubs which does contradict this mouse study.

      https://www.sfari.org/funded-project/hyperthermia-and-the-amelioration-of-autism-symptoms/

      Delete
    2. Hi Peter,

      Thanks for your insights as always!

      As it always does, it really does come to what is going on with each individual, since as you noted, what may help one person may not help another or even be detrimental to another.

      This is where getting a good sense of what is causing one's issues becomes so important. And even then, it's still a challenge.

      Have a great day Peter!

      AJ

      Delete
  2. Peter,
    where do you get the dmf and how do you dose it?
    thanks

    ReplyDelete
    Replies
    1. I am using Fumaderm Initial, from Germany, it contains 30mg of DMF. From 1 tablet I make 6 doses of 5mg DMF which are placed in enteric capsules. DMF is a stomach irritant and must be taken with an enteric coating.

      You can also Skilarence or Tecfidera, which are also effectively just DMF.

      You will need a prescription to get Fumaderm, Skilarence or Tecfidera. They are expensive in Europe and ultra expensive in the US.

      You can even buy DMF as a chemical, which is cheap.

      Delete
  3. Hi Peter, I greatly appreciate all your recent posts and the video is excellent.
    Peter, sigma 1 receptor agonists are definitely helpful for cognitive rigidity I do not intend to quit.
    Afobazole had a clear cognitive effect on my son from the very first pill. He had finished the fourth month course and there was an additional benefit but then reached a plateau. It is not addictive at all.
    I wonder is afobazole a potent sigma 1 receptor agonist? According to my experience when neurotransmitters become too disturbed then you really need a potent one like fluvoxamine. I first read about fluvoxamine on the anavex page where there is supporting research on sigma 1 receptor agonists.
    Petra

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    Replies
    1. Hi Petra, nice to hear from you again.

      I would love to know more about how your son responded to Afobazole.

      What dose are you using?

      Was the objective to reduce anxiety? How does he describe the effect, both on anxiety and cognition?

      I think Afobazole is only moderately effective at treating anxiety, that is why it is OTC in Russia. I think you need to target serotonin receptors (with SSRIs) or GABA receptors (with Benzodiazepines) to have a big effect on anxiety, but these drugs are not suitable for most people, due to side effects/addiction. Beta blockers like Propranolol are effective for some people's anxiety.

      Some SSRIs are also sigma-1R agonists, it is not clear how much of their effect comes from which mode of action.

      I see Afobazole as potentially improving a core defect (ER stress leading to protein mis-folding) that your son may not have, seeing that he is high IQ. But the anxiety effect may be very helpful. It is clear that many Aspies seem to benefit from 5HT2A agonists, to improve mood. This may be different to classic autism.

      Delete
  4. Hi Peter, hope you are well.
    When I decided to use afobazole for my adult son my objective was to improve his executive functios. Anxiety for Aspergers is a complicated thing and lots of it comes through miscommunication and realisation of their disability to function properly, so I doubt there is a single pill to fix this short of anxiety.
    Afobazole at 20mg dose was not anxiolytic in a gabaergic inhibitory manner, nor mood stabilizer. It is not sedative and doesn't help with sleeping disorders. It's really mild and I agree it should be used as a part of a polypill. It can help with concentration and learning somehow like a stimulant. It can also be useful in movement coordination. That mechanism affecting dopamine may bring arousal that's why you don't want to up the dose too much.
    ER stress might as well affect my son according to pharmacogenetic tests. His serotonin short allele shows that he cannot bind serotonin effectively and drd2 Taq A1/A2 polymorphism shows low density being at risk of several serious mental and neurological illnesess and diabetes.
    I used Propranolol in the past but didn't seem to work, probably because he doesn't have performance anxiety.
    5ht2a looks normal, genotype 5ht2ar 102tt, but if you can find specific details about this please let me know, however you can never know the mechanism you get the help from.
    My son looks much better when he gets more than 100% dietary vitamin A and beta carotene daily possibly through an increase in drd2 density which normalises dopamine binding.
    If I missed something about afobazole you needed to know please ask again. I still have some packets of afobazole in case you don't have an easy access.
    My best wishes
    Petra

    ReplyDelete
    Replies
    1. Petra, thanks for all the information. I have already received my Afobazole from Russia, it came very quickly.

      Happy Christmas

      Delete
    2. Merry Christmas Peter and all the readers of your blog.
      My Russian Afobazole costs 425.00p, which is about 7 euros.
      When I ordered from UK I paid 50 euros for two packets shipping included. Both options not expensive.
      I have some reasons to suspect Afobazole is a cox2 inhibitor but I am not sure if this is due to sigma 1 or 2 receptor activation.
      Cox2 inhibitors have been found to be effective in suppressing inflammatory neurodegenerative pathways in mental illness.
      Petra

      Delete
  5. Hi Petra, hope you are well, I will make a trial of Afobazole in my son, he is in some place, between Aspergers and HFA, he has problemas with dopamine and anxiety and will start High School in almost 3 months. Do you think that afobazole could be useful for HIM? Don't know if your son is still taking it.
    Valentina

    ReplyDelete
  6. Hi Valentina, nice hearing from you. Valentina, Afobazole is like taking a mild painkiller and hope your son responds with no side effects.
    The fact that is being trialled for autism shows that it may be useful.
    Merry Christmas Valentina.
    Petra

    ReplyDelete
    Replies
    1. Thanks Petra,treating anxiety is not easy,will see how will he do with it. Merry Christmas to you and everyone!
      Valentina

      Delete
  7. Hi Peter, Friends, and community,

    I just wanted to wish everyone and your families a very Merry Christmas!!!

    Here's to having 2020 will bring each of us some great news.

    AJ

    ReplyDelete
    Replies
    1. My warmest well-wishes to all of you in the community, I hope you get the best of the season!

      Peter-sensei, thank you for yet another amazing year with your blogposts. You have changed my way of thinking.
      2019 was the year when I embraced your favourite quote 'anything is possible'. Set some things in motion, curious of where it will lead. :)

      I'm looking forward with a very positive feeling for 2020, expecting great news like you AJ but also planning strategies to create some myself.

      /Ling

      Delete
  8. Hi Peter

    I have written to you earlier regarding my 12 years old son who has ADHD and autism and he also carries clic2 mutation. With further investigating we have found that his symptoms shows extra calcium leakage.


    Can you please suggest me theraphy,drug, or any supplements which can help him.

    Regards
    Pramilla

    ReplyDelete
    Replies
    1. Pramilla, Chloride intracellular channel 2 (CLIC2) protein's only known function is the regulation of ryanodine receptor (RyR) intracellular Ca2+ release channels.

      RyR3 is expressed in the brain.

      You can look up RyR3 to see if there are any known substances that either increase of decease its effect.

      https://www.genecards.org/cgi-bin/carddisp.pl?gene=RYR3

      It lists:
      Caffeine - Activator, antagonist
      Dantrolene - Antagonist
      Calcium citrate - Transporter, substrate
      Calcium Phosphate - Transporter, substrate
      Calcium phosphate dihydrate - Transporter
      Magnesium
      ATP - Activator
      ryanodine - Activator
      Ca2+ - Activator, Antagonist
      Mg2+ - Antagonist
      Ruthenium Red - Channel blocker
      Calcium
      Chlorocresol - Activator


      Your choice would be to activate RyY3 or block it, you do not know for sure which effect is needed. There is a wide choice of activators.

      If you need an activator of CLIC2, I would choose caffeine. Some studies have found that caffeine can boost concentration for people with ADHD. So it may help regardless of RyR3.

      If you need to block it, the only substance listed, Ruthenium Red is a lab chemical used as a dye. It has potent other effects even at tiny concentrations. It is not used in humans.

      There is a condition called int22h1/int22h2-Mediated Xq28 Duplication Syndrome.
      https://www.mdpi.com/2073-4425/12/6/860/pdf

      In this syndrome 6 genes are duplicated, FUNDC2, MTCP1, BRCC3, VBP1, RAB39B, and CLIC2.

      In milder cases the symptoms include autism, ADHD and sleep problems.

      It is suggested that CLIC2 is the main problem gene in this syndrome. You might find a researcher interested in this 6 gene syndrome has something useful to tell you. In the above paper you will find the contact details.

      Delete
    2. Thankyou Peter,
      For your reply on this I will work on the above.


      Delete
  9. Hi Peter and community! Thank you for your blog. I am a Rett caregiver.

    Here explained in detail the Sigma-1r endogenous agonist action of coline:

    https://www.cell.com/cell-reports/pdfExtended/S2211-1247(18)31981-8

    I will higlhy appreciate any feedback.

    Highlights:
    • Choline, but not its metabolites, binds to Sigma-1 receptors
    • Choline potentiates IP3-evoked Ca2+ release by activating Sigma-1 receptors
    • Bradykinin stimulates Ca2+ release by stimulating formation of IP3 and choline
    • Choline uptake by a specific transporter potentiates IP3-evoked Ca2+ release

    ReplyDelete
  10. Choline is already shown effective in models of Rett Syndrome.

    Choline Rescues Behavioural Deficits in a Mouse Model of Rett Syndrome by Modulating Neuronal Plasticity
    https://link.springer.com/article/10.1007/s12035-018-1345-9

    Choline is a widely used supplement in children with autism and there ares studies like this one from 2019.

    Improvement of Language in Children with Autism with Combined Donepezil and Choline Treatment
    https://pubmed.ncbi.nlm.nih.gov/31230222/

    It would be simple to make a trial and see if it provides a benefit in your specific case.

    Good luck!

    ReplyDelete
    Replies
    1. Thank you Peter!

      I have been reading deeper about Afobazol and coline. Due to the need to activate Simar-1 in a significant way it looks like Afobazol might be safer indeed than coline itself.

      Afobzol looks quite safe and I have already ordered it from Amazon US to try it myself first in variable doses. It looks like it could help me revert my Prediabetes and prevent dementia indeed.

      A link to a nice study of different Sigmar-1 agonists:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232171/

      Kind regards,

      Delete
  11. As found there:
    Epidemiological studies have suggested that choline supplementation may improve cognitive performance, and for this application citicoline may be safer and more efficacious.

    Huperzine-A is a compound extracted from the herbs of the Huperziceae family. It is known as an acetylcholinesterase inhibitor, which means that it stops an enzyme from breaking down acetylcholine which results in increases in acetylcholine.

    There seems to be repported some benefit for Rett.

    ReplyDelete

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