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Saturday, 2 May 2015

Sustained Release NAC for Autism and Schizophrenia








“Pharmacokinetics” of a typical drug


Today’s post is about what should be the optimal anti-oxidant therapy for autism, schizophrenia, COPD and any other disease in which oxidative stress is present.  You will have to be able to swallow pills, to fully benefit.

NAC seems to be the most potent, safe, anti-oxidant, the only drawbacks are:-

·        Short half-life

·        Can taste/smell bad


In autism, NAC is normally given three times a day, but often it is not practical to give a drug at precise intervals throughout the day.

This is a common problem with many drugs and has been solved long ago – with the sustained release pill.

If you find that four hours after giving NAC there is an increase in irritability, anxiety or stimming, it may be that oxidative stress has already returned.  It may be that other factors have triggered a higher load of oxidative stress.  The way to be sure is just to give a small extra dose of NAC and wait 15 minutes.  If everything returns to normal, you found the problem.

Since you cannot always be present with an extra half dose of NAC, the answer is the sustained release form of NAC.

Since we have seen that oxidative stress triggers all kinds of secondary dysfunctions, the sustained release form of NAC might also help minimize them, since you could have 24 hour protection.  Oxidative stress does not go away while you sleep.

For example, I recall the Polish researcher at Harvard who suggested that oxidative stress might cause central hypothyroidism in autism (low levels of T3 in the brain).

Your body produces the pro-hormone T4 in the thyroid which then circulates throughout the body.  Special enzymes, produced locally, then convert the T4 into the active hormone called T3.  The researcher found that in the autistic brain this enzyme was reduced by oxidative stress.

Many “alternative” doctors, mainly in the US, do prescribe extra T3 hormone to people with autism and indeed other conditions.  Some older ladies across the world are buying T3 hormone, online from Mexico, since their doctor will not prescribe it.  They say it makes them feel better.

As your endocrinologist will tell you, hormones are controlled by so-called feedback loops.  So if you start adding extra T3 hormone, your thyroid will start producing less T4.  Then you need even more supplemental T3.

I did do a little experiment with a small dose of T3, to see if a short term increase in T3 affects “my” kind of autism.  It most definitely does; as does a short term spike in potassium levels.  These are useful diagnostic tests, rather than therapies.

This would suggest that minimizing oxidative stress 24 hours a day, may not just be possible, but also highly beneficial.
 

OTC Sustained Release NAC  (NAC SR)

There actually is an inexpensive Sustained Release NAC , available OTC (without prescription).

  





The problem with currently-available granulated and effervescent tablet compositions is that they release N-acetyl cysteine very rapidly. Thus, the effervescent compositions as well as the granulate compositions currently available on the market achieve a maximum blood plasma level within 1 hr from administration. One matrix tablet formulation does show a maximum blood plasma level at 2-2.5 hrs after administration, although its recipe indicates that granulation was required. The problem with granulation of acetyl cysteine is that if any dissolves, the dissolved material starts to decompose into impurities.
In accordance with the present invention, this problem of overly-rapid release is obviated by providing the N-acetyl cysteine in the form of a tablet or other article made with the rheology modifying acrylic or methacrylic acid-based polymers, or analogues, described in commonly-assigned application Ser. No. 09/559,687, filed Apr. 27, 2000. Tablets made in this manner exhibit controlled release characteristics, thereby allowing the N-acetyl cysteine active ingredient to be released over a longer period of time.

The rheology modifying polymers used in the present invention provide controlled release of the N-acetyl cysteine and other biologically active compounds contained in the inventive tablet, if any, so that when placed in water or body fluid, the polymer swells to form a viscous gel which retards diffusion of the active material.

The advanced bilayer Sustain™ tablets combine 1/3 Quick Release and 2/3 Sustained Release formats to both immediately raise and to maintain blood levels over a longer period of time.* NAC Sustain®  releases in the small intestine over a 8 hour period, compared to the 1.5 hour biological half-life of NAC in the bloodstream.*



NAC in published research

Much currently available data is from very early studies on NAC that indicated that the half-life was about 5 hours, but subsequent studies suggested it is very much shorter, perhaps just 90 minutes.

The following study is quite old, but compares the behaviour of different NAC formulations in 10 volunteers.
































Some definitions:-



A biological half-life or elimination half-life is the time it takes for a substance (drug, radioactive nuclide, or other) to lose one-half of its pharmacologic, physiologic, or radiological activity. In a medical context, the half-life may also describe the time that it takes for the concentration in blood plasma of a substance to reach one-half of its steady-state value (the "plasma half-life").
The relationship between the biological and plasma half-lives of a substance can be complex, due to factors including accumulation in tissues, active metabolites, and receptor interactions

Mean Residence Time

For the medical field, residence time often refers to the amount of time that a drug spends in the body. This is dependent on an individual’s body size, the rate at which the Drug will move through and react within the person’s body, and the amount of the Drug administered. The Mean Residence Time (MRT) in Drug deviates from the previous equations as it is based on a statistical derivation. This still runs off a steady-state volume assumption but then uses the area under a distribution curve to find the average drug dose clearance time. The distribution is determined by numerical data derived from either urinary or plasma data collected. Each drug will have a different residence time based on its chemical composition and technique of administration. Some of these drug molecules will remain in the system for a very short time while others may remain for a lifetime. Since individual molecules are hard to trace, groups of molecules are tracked and the distribution of these is plotted to find a mean residence time.



Conclusion

This post may have been more useful for adult readers, with Asperger’s, who are self-treating.  Many people with Schizophrenia also self-treat with NAC, but they probably do not read autism blogs.

For those unable (yet) to swallow, pills you can have the option of breaking the effervescent tablets in half (or even quarters) to try and maintain a more stable level of NAC.  We sometimes do this, half a 600 mg tablet at school at 11 am,  when needed.  It only seems to be really needed in the pollen allergy season, which seems to trigger more oxidative stress as well as histamine and IL-6.  It works.

One reader of this blog is doing something similar with Bumetanide, he/she is giving it in three daily doses.  Bumetanide also has a short half-life, as does Verapamil.  There is no sustained release form of Bumetanide, but there is for Verapamil.

A final point raised is whether the benefit from NAC comes from it being a precursor to Glutathione (GSH), the body' own master antioxidant, or whether it is actually NAC's own free radical scavenging properties that really matter. It would appear to be the latter, based on the short half life of NAC and the short term beneficial effect.  This would imply that just normalizing GSH is not enough. Studies have shown that normalizing the reduced levels of GSH levels found in autism is readily achievable.








8 comments:

  1. We are doing bumetanide 3 times per day. My son is an asthma/allergies kid and we also see a spike in anxiety/irrability in the spring/summer. We just started adding Verapamil which seems to be helping with this. I’m wondering are you giving your son the time released Verapamil?

    I’m also wondering what your thoughts are about Andrographis. My son used to suffer horrible colds and asthma and now when cold symptoms start to develop we dose up on this and the cold never develops. It got me thinking about what other uses it might have and discovered this. Do you think it could be helpful taken long term?

    http://jpet.aspetjournals.org/content/308/3/975.full

    Thanks for your insights!

    ReplyDelete
    Replies
    1. We use Verapamil 40 mg three times a day in the allergy season. In some countries there is a 120mg sustained release version, which might well work better.

      I have not looked at Andrographis, but it does look interesting and even shows an effect in Ulcerative Colitis. If it helps control the asthma, it might well be a good long term choice. Since it is widely sold, just look for any people talking about side effects.

      My son's asthma has disappeared as a side effect of his autism pills. He has not needed his Ventolin (Salbutamol) inhaler for many months, he just has a tiny dose of Flixotide (fluticasone). He also no longer gets colds, whereas his brother and classmates all do.

      It looks like you have adjusted your son's immune system, as we have also done.

      Delete
  2. Hello Peter, do you know what kind of antiepileptic is used for photosenstive epilepsy?my son has epileptiform discharges in the occipital lobe, i was wondering if clonazepam and valproate would be better than bumetanide and valproate.I had told you that I realized something was wrong with my son when he watched fast and colorful cartoons when he was 2. he couldnt process images properly until now, but I dont give up.

    ReplyDelete
    Replies
    1. I read that valproate is used for photosensitive epilepsy.

      I do not have any experience with epilepsy, however many of the drugs that affect autism also affect epilepsy. Even my latest interest in something called PPAR gamma, turns out to be a target drug for epilepsy.

      Bumetanide and micro-dose clonazepam both seem to have the same effect in autism (making GABA shift from excitatory to inhibitory) but the mechanism seems to be different. So one might work better for some people than for others; or you could use both.

      Clearly if the neurotransmitter GABA is working in "reverse" many other problems might then occur, including triggering seizures.

      So while nobody can tell you for sure what will work, all the drugs you mention should have an effect. Just as how Autism is not a biological diagnosis, neither is any kind of seizure diagnosis a precise diagnosis. Science and medicine do not yet have the required understanding/tools and so you are left with trial and error, or do nothing. Some people have very poorly controlled epilepsy and some seizure activity can have very serious consequences. So caution is necessary.

      Delete
  3. Do you think it would be safe to take three of these a day, each one 8 hours from each other, in order to ensure it stays in the blood constantly? Or would just two times a day be fine? I have Aspergers, some schizophrenia-like symptoms, and depersonalization disorder. I have confirmed heavy metal toxicity, immune abnormalities (heightened WBC frequently, low immunoglobulin subclass 2, etc) and medical symptoms that include peripheral neuropathy, chronic fatigue, and migraine.

    ReplyDelete
    Replies
    1. Since you have peripheral neuropathy, you might also try Alpha Lipoic Acid (ALA). ALA is very similar to NAC, but it is the choice used to treat peripheral neuropathy in countries with German or Russian based medicine.

      I think NAC sustain is the best form of NAC. We use 3 spread throughout the day.

      For sound sensitivity make a trial of potassium. You can read about hypokalemic sensory overload in this blog. This is a channelopathy.

      Many people with Asperger's, but not all, seem respond well to Baclofen.

      If you have allergy and headaches you might respond to Verapamil, which would treat a channelopathy. There is no diagnostic test.

      Delete
    2. What about Bumetanide for sensory hypersensitivity?

      "The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome."
      https://www.ncbi.nlm.nih.gov/pubmed/24488662

      In my child Bumetanide reduced sensory issues.
      My own hypersensitivity resolved fully on NAC 600-1200 mg daily. It was of different kind than hyperacusis though.

      Delete
    3. I would try all the drugs with some sound basis, that includes Bumetanide. You cannot be sure what the precise benefit will be because we are all a little different. The important thing is to go one by one through them.

      Delete

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