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Wednesday, 27 May 2015

Diamox & Bumetanide, Ion Channels Nav1.4 and Cav1.1, HypoPP, Autism and Seizures









Today’s post links together subjects that have been covered previously.

It does suggest that there are multiple therapies that may be effective in the large sub-group of autism that is characterized by the neurotransmitter GABA being excitatory (E) rather than inhibitory (I).  The science was covered in the earlier very complicated post:-



The growing list of potential therapies is:-

·        Bumetanide (awaiting funding for Stage 3 clinical trials in humans)
·        Micro-dose Clonazepam (trials in mouse models of autism)
·        Diamox (off-label use in autism)
·        Potassium Bromide  - to be covered in a later post (in use for 150 years)


Not surprisingly, all of these drugs also have an effect on certain types of seizure.

The optimal therapy in people with this E/I imbalance will likely be a combination of some of the above.



Periodic paralysis

Periodic paralysis (Hypokalemic periodic paralysis or HypoPP) is a rare condition that causes temporary paralysis that can be reversed by taking potassium.  A similar condition is hypokalemic sensory overload, when someone becomes overwhelmed by lights or sounds, but after taking potassium all goes back to normal. Autistic sensory overload, experienced by most people with autism, can also be reduced by potassium.

Though rare, we know that HypoPP is caused by dysfunction in the ion channels Nav1.4 and/or Cav1.1.

For decades one of the treatments for HypoPP has been a diuretic called Diamox/Acetazolamide.

Other treatments include raising potassium levels using supplements or potassium sparing diuretics.

Bumetanide is a diuretic, but rather than raising potassium levels, it does the opposite.  So I always thought it was odd that bumetanide would have a positive effect on HypoPP.  But the research showed a benefit.


Autism and Channelopathies

We know that autism and epilepsy are associated with various ion channel and transporter dysfunctions (channelopathies).  In a recent post I was talking about Cav1.1 to Cav1.4.

Today we are talking about Cav1.1 and Nav1.4.

We know that Nav1.1 is associated with epilepsy and some autism (Dravet syndrome).


Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain

Nav1.1 expression increases during the third postnatal week and peaks at the end of the first postnatal month, after which levels decrease by about 50% in the adult.

We saw with calcium channels that a dysfunction in one of Cav1.1 to Cav1.4 can cause a dysfunction in another dysfunction in another one of Cav1.1 to Cav1.4.

We also so that in autism the change in expression of NKCC1 and KCC2 as the brain matures failed to occur and so in effect they remain immature and therefore malfunction.

So it is plausible that sodium channels may also malfunction in a similar way. 
  



Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant neuromuscular disorder characterized by episodes of flaccid skeletal muscle paralysis accompanied by reduced serum potassium levels. It is caused by mutations in one of two sarcolemmal ion channel genes, CACNA1S and SCN4A1-3 that lead to dysfunction of the dihydropyridine receptor or the alpha sub-unit of the skeletal muscle voltage gated sodium channel Nav1.4. Seventy to eighty percent of cases are caused by mutations of CACNA1S and ten percent by mutations of SCN4A4. 

There are no consensus guidelines for the treatment of hypoPP. Current pharmacological agents commonly used include potassium supplements, potassium sparing diuretics and carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide). Dichlorphenamide is the only therapy for hypoPP to have undergone a randomized double blind placebo controlled cross over trial. This trial showed a significant efficacy of dichlorphenamide in reducing attack frequency but the inclusion criteria were based on clinical diagnosis of hypoPP and not genetic confirmation.

  


Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene




Nav1.4

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.



Ranolazine

Ranolazine is an antianginal and anti-ischemic drug that is used in patients with chronic angina. Ranzoline blocks Na+ currents of Nav1.4. Both muscle and neuronal Na+ channels are as sensitive to ranolazine block as their cardiac counterparts. At its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na+ channels. Ranolazine block of open Na+ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate.


Muscle channelopathies:does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis?


Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis
Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations.







Mode of action

The research does state that nobody knows why Diamox is effective in many cases of hypoPP.

My reading of the research has already taken me in a different direction.  While researching the GABAA receptor that is dysfunctional in some autism, it occurred to me that in addition to targeting the NKCC1 receptor with bumetanide, another way of lowering chloride levels within the cells might well exist.

I suggested in an earlier post that Diamox could be used to target the AE3 exchanger.


What Diamox (acetazolamide) does is lower the pH of the blood in the following way.


Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:




hence lowering blood pH, by means of the following reaction that carbonic acid undergoes


In doing so there will be an effect on both AE3 and NDAE, below.  This will change the intracellular concentration of Cl-, and hence give a similar result to bumetanide.

This would also explain the phenomenon cited below that pH affects the excitability of the brain.

Over excitability of the brain is the cause of some of the effects seen as autism and clearly Over excitability of the brain will be the cause of some people’s seizures/epilepsy.

Not surprisingly, then one of the uses of Diamox is to avoid seizures.





  




Anion exchanger 3 (AE3) in autism

Anion exchange protein 3 is a membrane transport protein that in humans is encoded by the SLC4A3 gene. It exchanges chloride for bicarbonate ions.  It increases chloride concentration within the cell.  AE3 is an anion exchanger that is primarily expressed in the brain and heart

Its activity is sensitive to pH. AE3 mutations have been linked to seizures


Bicarbonate (HCO3-) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system.


Abstract

Chloride influx through GABA-gated Cl channels, the principal mechanism for inhibiting neural activity in the brain, requires a Cl gradient established in part by K+–Cl cotransporters (KCCs). We screened for Caenorhabditis elegans mutants defective for inhibitory neurotransmission and identified mutations in ABTS-1, a Na+-driven Cl–HCO3 exchanger that extrudes chloride from cells, like KCC-2, but also alkalinizes them. While animals lacking ABTS-1 or the K+–Cl cotransporter KCC-2 display only mild behavioural defects, animals lacking both Cl extruders are paralyzed. This is apparently due to severe disruption of the cellular Cl gradient such that Cl flow through GABA-gated channels is reversed and excites rather than inhibits cells. Neuronal expression of both transporters is upregulated during synapse development, and ABTS-1 expression further increases in KCC-2 mutants, suggesting regulation of these transporters is coordinated to control the cellular Cl gradient. Our results show that Na+-driven Cl–HCO3 exchangers function with KCCs in generating the cellular chloride gradient and suggest a mechanism for the close tie between pH and excitability in the brain.



Abstract

During early development, γ-aminobutyric acid (GABA) depolarizes and excites neurons, contrary to its typical function in the mature nervous system. As a result, developing networks are hyperexcitable and experience a spontaneous network activity that is important for several aspects of development. GABA is depolarizing because chloride is accumulated beyond its passive distribution in these developing cells. Identifying all of the transporters that accumulate chloride in immature neurons has been elusive and it is unknown whether chloride levels are different at synaptic and extrasynaptic locations. We have therefore assessed intracellular chloride levels specifically at synaptic locations in embryonic motoneurons by measuring the GABAergic reversal potential (EGABA) for GABAA miniature postsynaptic currents. When whole cell patch solutions contained 17–52 mM chloride, we found that synaptic EGABA was around −30 mV. Because of the low HCO3 permeability of the GABAA receptor, this value of EGABA corresponds to approximately 50 mM intracellular chloride. It is likely that synaptic chloride is maintained at levels higher than the patch solution by chloride accumulators. We show that the Na+-K+-2Cl cotransporter, NKCC1, is clearly involved in the accumulation of chloride in motoneurons because blocking this transporter hyperpolarized EGABA and reduced nerve potentials evoked by local application of a GABAA agonist. However, chloride accumulation following NKCC1 block was still clearly present. We find physiological evidence of chloride accumulation that is dependent on HCO3 and sensitive to an anion exchanger blocker. These results suggest that the anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons.
 



Conclusion

So the science does confirm that “chloride accumulation following NKCC1 block was still clearly present”.  This means that bumetanide is likely only a partial solution.

We also see that “anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons” and “that chloride accumulation that is dependent on HCO3”.

This is a subject of some research, but it is still early days.

  
I suggest that Diamox, via its effect on HCO3, may affect anion exchanger AE3 and further reduce chloride accumulation within cells.  This may have a further cumulative effect on GABA.

As we saw earlier, bumetanide does indeed shift GABA from excitatory to inhibitory in people who neurons remain in an immature state (like those of a typical two week old baby).  To my surprise, the use of micro-dose Clonazepam, as proposed by Professor Catterall, but in addition to Bumetanide, has a further effect on GABA’s excitatory/inhibitory imbalance.

Taken together this would highlight the possible further benefit of Diamox.

Normal blood pH is tightly regulated between 7.35 and 7.45.  I do wonder if perhaps in some people with autism, the pH of their blood is slightly elevated (alkaline), this would contribute to excitability of the brain.

Since Diamox increases the oxygen carrying capacity of the blood, I further wonder if this additional oxygen may also be beneficial in some cases.  Since some people are adamant that hypobaric oxygen therapy has beneficial (although not sustained) effects in autism, surely a better treatment would be Diamox?

Since the body is controlled via so-called feedback loops, perhaps in a small subset of people with autism who respond to extra O2, they actually have blood pH that is higher than 7.45.  In which case measuring blood pH would be a biomarker of who would respond to hypobaric oxygen therapy.  Not surprisingly then, trials of hypobaric oxygen therapy in autism fail, because most of the trial subjects do not have elevated blood pH.
  
So there are many reasons that Diamox should be trialed in autism.  I did find one (DAN) doctor currently using it, but they do not really explain why.

Biomedical Treatment of the Young Adult with ASD








54 comments:

  1. Hi Peter, i woul like to know if diamox can be used instead of bumetanide, if it has the same effect, becuase i can get it here in my country, do you think that i could try diamox instead of bumetanide and do the same with valproate?regards,
    Valentina

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    1. Valentina, I would also like to know if Diamox has the same effect as Bumetanide. I think it very well may do. I have not tried Diamox; it is not available where I live. Diamox is used in children. It is usually available as a 250 mg tablet. There is child dosage information on the internet, but not of course for autism. Yesterday I thought about the dosage and concluded that one quarter of a tablet (about 60mg) twice a day, would be a fair dose to try. Since Bumetanide can take three weeks to show effect, the same may be true for Diamox, since both should work by lowering chloride concentration within the cells. It is well worth a try.

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    2. Valentina, there are two other diuretics that work just like bumetanide, by affecting NKCC1. They are furosemide and piretanide. Perhaps they are available in your country? In people responsive to bumetanide, they should also be effective, just the dose would be different.

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    3. Diamox calls Diural 250 mg and I found also furosemide 40 mg. I couldnt find piretanide. Which would be better? valentina

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    4. I thought it would be helpful to note that it appears that Thiamine may be as effective as acetazolamide at inhibiting carbonic anhydrase:

      http://www.ncbi.nlm.nih.gov/pubmed/22145674
      http://www.tandfonline.com/doi/pdf/10.3109/14756366.2011.637200

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    5. Thanks that is interesting. Thiamine (vitamin B1) is not well absorbed and there are analogues with higher bioavailablity. One mentioned in this blog previously is Benfotiamine.

      Benfotiamine is being investigated to treat diabetic retinopathy. This condition is associated with the protein Carbonic anhydrase I. Perhaps this is why Benfotiamine is effective?


      Current and future approaches in the prevention and treatment of diabetic retinopathy
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693984/

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    6. In addition:

      (the information below was taken from a discussion on https://raypeatforum.com/community/threads/thiamine-is-a-carbonic-anhydrase-inhibitor-as-effective-as-acetazolamide.6833/ hence the quotes)

      "Thiamine activates pyruvate dehydrogenase and inhibits pyruvate dehydrogenase kinase. This optimizes glucose metabolism into CO2.

      2. Thiamine inhibits carbonic anhydrase about as effectively as acetazolamide, which means that not only it stimulates CO2 production but it also inhibits its degradation. I don't know of another drug that does both of these things.

      3. In similar doses, thiamine can substitute for acetazolamide in those people that do not have access to acetazolamide or are unwilling to take a prescription drug. In addition, thiamine and acetazolamide are synergistic as mentioned in the studies on mental health I posted earlier today, so in theory one could get away with much lower doses when using both substances together. For instance, there is some data showing that 250mg acetazolamide + 300mg thiamine is as effective as 750mg - 1,000mg acetazolamide in terms of raising CO2.

      4. The highest concentration of thiamine is required to inhibit hCA I and it is 380nM/L. This figure from a human study on the pharmacokinetics of thiamine shows that this concentration is achievable using a 1,500mg dose. Th concentration required to inhibit the other isoenzymes of hCA were 85nM and 62nM, which are easily achieved with a thiamine dosage of 300mg - 500mg. In order for acetazolamide to inhibit hCA I, the concentration required is not far off of that for thiamine. This would explain that doses of 2g acetazolamide daily, which given the long half life of the drug will likely reach the concentrations required to inhibit hCA I. But more importantly, a 1,500mg of oral thiamine has been shown to be well tolerated and without any serious side effects. In fact, an human study on Alzheimer treatment with thiamine used 1,500mg doses up to 5 times a day and did not observe any toxicities. But given the synergism of thiamine and acetazolamide, one can probably get the full effects by taking lower doses of both substances together. Alternatively, if only partial inhibition of hCA is OK for your goals then 300mg - 500mg of thiamine should suffice. These lower doses are in line with Peat's recommendations of taking 300mg thiamine every 4 hours if a person has degenerative conditions."



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    7. Many people respond well initially to particular B vitamins, but then the effect turns negative. Read the comments on this post on benfotiamine.

      https://epiphanyasd.blogspot.com/2016/03/benfotiamine-for-autism.html#comment-form

      There are known side effects that regularly occur after a few weeks to most B vitamins taken at large doses. Some people have no side effects at all.

      Most chatter on the internet is based on what happens after a day or two. Much more interesting is what happens after months or years. Most people seem to give up pretty quickly.

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    8. There is an old trial of acetazolamide 2g + thiamine 1.5 g daily treatment for adults with refractory schizophrenia with significant improvement reported in 50% of them:

      "Acetazolamide and thiamine: an ancillary therapy for chronic mental illness."
      https://www.ncbi.nlm.nih.gov/pubmed/2669002

      Long term treatment without issues was also reported in this paper.

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    9. Interestingly, it seems that in about 30% of cases 100mg of thiamine three times a day stops people stuttering. No formal studies, just informal ones by people with this problem. They suggest trying it for two weeks.

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    10. This is all so very interesting, that many of the B vitamins seem to work synergistically with interventions followed by us on this blog. We used 80mg of Benfotiamine for quite a while with no discernible effect. Whereas, 60mg twice a day of Acetazolamide has been brilliant. What could account for this?

      I already have the Pantethine to add on to the Ketogenic diet, and the p5p. Would it be worth adding this in also? I also wonder if the lack of benefit in the past was because of the doses being too low.

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    11. To anonymous: thanks for sharing the info on thiamine as effective alternative to diamox - esp. for those who have sulfa drug allergies like my son. I need to go back to giving the benfo a try at a higher dose. I wonder how effective this would have been for him a yr ago when it seemed his dysautonomia/mast cell symptoms were raging. Holding breath that we aren't seeing those bad flares now - likely could be that stress was/is his biggest trigger for those episodes - but good to know of benfo alternative.

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    12. Please help my non-scientific, no chemistry/biology background history degree brain understand this - in terms of diamox substitutes would potassium bicarbonate help in this area? what about re-breathing techniques / buteyko method to increase CO2? or am I getting this backwards?

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    13. Tanya, it looks like some people may be using the wrong analogue of thiamine.

      The research below clearly states that benfotiamine, though well absorbed, does not increase thiamine levels in the brain.

      Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives.

      https://www.ncbi.nlm.nih.gov/pubmed/18549472

      “CONCLUSION:
      Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain.”

      However there is another OTC analogue of thiamine, truly lipophilic, called Sulbutiamine that does cross the blood brain barrier and has been shown to increase thiamine in the brain.

      So Benfotiamine is not a good alternative to Diamox/Acetazolamide for neurological purposes.

      Either use thiamine at a high dose or Sulbutiamine at a lower dose.

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    14. thanks Peter for the clarification

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    15. I think you are right about messing up with B vitamins, Peter.
      I do like to be guided by my child symptoms, rather than the studies themselves.
      She has benefits of folate (modes dose: 400-800 mcg/d).
      There are reasons for this:
      Every summer she used to have some sort of regression. It was worse on holiday, at the sea. First couple of days she would be relatively good, and than become foggy, full of fears, sensory overloaded. She used to get something like acnes on her face. Her skin around the nose and hair was dry, greasy in flakes.
      (hair dandruff was cured with Head and shoulders shampoo).
      I've found this article (vitamin D):
      UV exposure found to lower folate levels in young women
      https://www.sciencedaily.com/releases/2014/03/140321095240.htm
      And this (vitamin A):
      Decreased Vitamin B12 and Folic Acid Concentrations in Acne Patients After Isotretinoin Therapy: A Controlled Study
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248518/
      All has gone in couple of weeks.
      Everything is in balance.

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    16. Peter,
      Does allithiamine crosses blood brain barrier?

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    17. https://autismrc.com/2016/04/16/autism-research-connections-3-a-conversation-with-dr-derrick-lonsdale/
      Dr.Lonsdale recommends only allithiamine because it crosses blood brain barrier or for something else?

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    18. Lonsdale has a deep interest in Thiamine and has various hypotheses.

      A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1375232/

      He has not convinced many others and his autism study was not replicated.

      There clearly are dysfunctions linked to thiamine. Thiamine has various modes of action. It has quite a following among those who stutter, and to help with that you would think it would have to cross the blood brain barrier. Some adults seeking to improve their cognitive function do use Sulbutiamine and I suppose that is where the OTC market is.

      Benfotiamine does seem to help some people with diabetes.

      Allithiamine is supposed to cross the blood brain barrier.

      You do not find many people using thiamine long term for autism. I found one lady who found it very effective but she used thiamine itself and found Benfotiamine had little effect. Nobody else on that forum had the same positive result. Probably her child has some rare undiagnosed dysfunction.

      Delete
  2. 1mg bumetanide is equivalent to 40mg of furosemide. So the likely dose for autism would be 40mg twice a day. You should add a potassium supplement.

    The only way to know which is best is to try them. Diamox is used for some epilepsy.

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    Replies
    1. Hi Peter,

      With hypokalemic sensory overload, I've read that symptoms are triggered by not only lights and sound but also by food - especially carbohydrates, salt. This is where it gets interesting in our A-type.

      Our child is profoundly triggered by the food he eats but he doesn't like/eat sweets whatsoever, yet carbs he does. It's virtually all he'll eat, with savoury items, so his intake of sodium is high. After eating, he becomes hyperactive and overstimulated to a profound degree. It is pronounced.

      He is at his very best when he is on an empty stomach?

      What dosage of Potassium supplements should we try? Is there a preferred form? Should we compliment with magnesium?

      PS. Our child's fasting glucose level is in the normal range.

      Thanks Peter.

      Regards,
      D&G

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    2. It does seem that for many people with ASD extra potassium is beneficial, but within reasonable limits. Most supplements are potassium chloride and or potassium citrate. We use 250mg twice a day using the citrate. Many potassium supplements also contain magnesium, our one does include magnesium. There is an opposing relationship between sodium and potassium in the body. High sodium intake may likely undo the good of the extra potassium. You can buy low sodium table salt. But if your son has a really high salt intake, the best route would be to cut back on savoury items, albeit a challenge to do so. Some kids like spicy food and you might be able to shift from salty to spicy. I don't think sugary foods do any good.

      Eating food high in potassium, like bananas, shows no effect.

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    3. Hi Peter,

      Thanks again for your reply.

      All I could get was 250mg of Potassium Aspartate which is equivalent to 52.5mg Potassium.

      Is this adequate to try or do I really need the citrate or chloride forms?

      Any help with these dosages will be welcomed Peter. Thanks for the tip on the bananas because they had no effect.

      Regards,
      D&G


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    4. Hi D&G

      It is the amount of Potassium itself that matters. In the US this is limited to less than 100 mg per tablet. I do not know what rules apply in Australia.

      The pills I use are French and each one has 500mg. I split them in half and use twice a day.

      It probably makes no difference which type of tablet you use.

      Very large amounts of potassium are dangerous, but the RDA is 3,500g, so 52.5mg will not have much impact.

      It would be good to know what your son's level of potassium and sodium are. It seems that many people with autism do better when they maintain potassium at the high end of normal. If your son's salt intake is too high this would show up in elevated sodium levels.

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    5. Potassium has profound effect on my son, but I saw it only when I gave him 470mg K+ effervescent tablet to drink at once. This stopped his “auditory aura” which used to lead to prolonged episodes with headache and other symptoms. Drinking K+ all over day in small amounts has no effect.

      There is a very practical paper by one doctor who has HPP himself: http://www.translational-medicine.com/content/6/1/18
      He states that significant carbohydrate load in bananas causes a spike of endogenous insulin release, resulting in a potassium shift from outside to inside the cells. The same "triggers inappropriate activity of mutated voltage-gated ion channels after high carbohydrate meal". I remember that this ion shift has been long used in cardiology for other reasons as GIK (glucose+insulin+potassium) infusion.

      This doctor advises K+ prophylaxis before carbohydrate meal or exercise.

      I thought that hyperactivity after meals in my son is related to GI mast cell activation as it got better with oral cromoglicate treatment. How this all can be related?

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    6. Agnieszka, are you giving the effervescent potassium tablet daily?

      I think there are different processes going on at the same time. In many children it seems their autism is worst after waking up but before breakfast. This used to be our case, but is no longer. Dr Kelley suggests that in people with mitochondrial disease, this is a standard symptom.

      I think in some people perhaps variations in blood sugar before/after eating are affecting behavior. Just as it does when type 1 diabetics go hyper and hypo. This would be easy to test.

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    7. I've been giving them daily for a few months to prevent hypokalemia with the use of Bumetanide. Syrup available here is awful. But I was giving small amounts of liquid all over the day, while it's the "potassium shot" what matters. I am not sure what is best for long term use. Do you use tablets?

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    8. We use one 500mg effervescent potassium tablet daily, half in the morning and half in the evening, at the same time as his bumetanide. In some countries they put KCl in the same tablet as the bumetanide.

      We have been doing this since December 2012; just at the beginning it was 1 mg bumetanide + 250 mg potassium, once a day, and since last summer it has been twice a day.

      At one point, for a few months, my son refused to enter the very noisy lift/elevator at his grandparents flat. This "noisy lift phobia" was cured by a single extra dose of K+ and has never returned.

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  3. furosemide would appear to be available online in the UK without prescription.........

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  4. Peter, I have been reading about furosemide and it seems that its diuretic effect is reduced by the antiepileptic therapy, so it wouldnt make sense taking it with valproate.
    Diamox is better,? i think, but do you know if it has a dangerous interaction with any other vitamin or medication? Valentina

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    1. If it was me, I would first try one and then try the other.

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    2. do you mean , try furosemide or diamox without valproat? the process of taking out valproat woul take a lot of months

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  5. Hello Peter,
    Sumer time is near and I wonder if chloride of swimming pool afects to intracelular chloride levels..... Children drink a lot of water while swimming....
    Olga

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    Replies
    1. I thought that dietary chloride intake might have an effect (eating chips/crisps etc), but within reasonable limits I have seen no effect in my son. Also, it is probably the difference in chloride level intra/extra cellular that matters rather than the absolute value within the cell. So eating chips/crisps, or swimming pool water, may not upset things.

      Having a bit extra potassium (K+) should help lower chloride levels and this Professor Ben-Ari did confirm to me. So a but less sodium and bit more potassium is a good idea.

      Delete
  6. Last week my son was scheduled for routine genetic testing after a long wait list. They do things like FraX or CGH microarray if the kid has ID and the parents insist enough. Without much hope we also visited one neurologist there. To my surprise this doctor had all important papers about ASD and calcium channnels with him and was convinced that it’s a kind of channelopathy related migraine-like syndrome responsible for headaches in my son and referred him for genetic calcium channel testing. So instead of FraX we are awaiting CACNA1A sequencing, which is good news. The bad news is that they have a financial capacity for one test per year only, so no FraX until 2016. I am not sure if the gene is the best choice, anyway I think this a good direction in how the diagnostics should like like in ASD.

    The periodicity of the episodes in my son and his response to verapamil were important to this neurologist.
    So it is the use of verapamil which prompted more serious further diagnostics in my son. Now I think that your verapamil invention is even more important than I realized and there should be a kind of diagnostic protocol for ASD affected people: short course of verapamil and a trial with potassium may well indicate the need for further search into channelopathies in responders. What do you think? Potassium is OTC, so it’s easy to do even now.

    My recent trials with potassium made me think more about HPP and Diamox. As Diamox induces metabolic acidosis I looked for some old labs of my son and saw what possibly suggests compensated metabolic acidosis: pH-7,42, HCO3-19 (low), pCO2-31 (low), BE--3,7 (low). Done in hospital and not considered important then. What do you think about Diamox in someone with such result? What confused me more is that I reviewed some labs of other boy with their parents recently and also found the same pattern.

    Also I wonder what do you think about using Diamox together with low dose Clonazepam? I have recently started it, trying to find a good dose.

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    Replies
    1. I was amazed that with the similarity between hypokalemic sensory overload (and hypPP) and what occurs in autism, that nobody had noticed this before. I think some readers of this blog with Asperger's from South Africa are in touch with Prof JJ Gargus at UC Irvine about some similar ideas.

      I think that a large sub-group (if not >50%) of more serious autism will respond to Verapamil.

      Diamox looks to be very safe and I would try it. It is not an approved drug where I live. I thought 60mg twice a day was a conservative dose, but it might even be effective at a lower dose. I found bumetanide ineffective at a low dose, but if already using bumetanide, a smaller dose of Diamox "should" have an effect.

      Since Clonazepam has the same effect as Bumetanide, you might notice the effect more if you temporarily reduce the bumetanide; ie bring back some of the "old autism" so that it is easier to notice clonazepam's effect. I was giving bumetanide only once daily, when I introduced clonazepam, and it was only in the afternoon that the effect was very noticeable, because the bumetanide effect was wearing off.

      I think a short trial of all the safe drugs, shown to have an effect in some types of autism, is the only realistic way to investigate an individual's autism. This is not an approach 99% of doctors and 90% of parents would accept.

      I keep finding new avenues to investigate, the latest interesting drug is Candesartan, which looks like it might be good for people with Self injury/Aggression/flare-ups caused by microglial activation and then some kind of additional stimulus.

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    2. Thanks for these comments. How do you calculate Diamox dose? 125 mg per day seems the lowest used for adults in hypoKPP, for epilepsy in children it is higher. Do you consider using both Bumetanide and Diamox together? I would be afraid of diuretic effect of such combination in my son. It's enough with Bumetanide...

      The trial and error way is something I don’t like also, but once the effect is seen it’s easier to accept (doing nothing is unacceptable then). So maybe more of those 99/90% would get convinced after some kids drink a glass of potassium when sensory overload is expected.

      Candesartan is interesting and I’ve just read that also used in migraines after one neurologist in Norway accidentally found it helpful for his headaches.

      I once tried to figure how microglial activation can be targeted and found this paper about benfotiamine studied in Serbia: http://www.ncbi.nlm.nih.gov/pubmed/25695433
      Vitamin B1 does not seem to be something harmful, even if the effect in vivo would not be the same.

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    3. People do seem to find benfotiamine helps greatly neuropathy. It is cheap and available.

      I think Diamox + Bumetanide is not a bad idea. Our second daily dose of bumetanide does not produce the same diuretic effect as the first. When I looked at the pharmacodynamics of common diuretics, it was clear that there is a plateau above which there is no further diuresis. So 60 mg of Diamox + 1 mg of bumetanide may not produce (much) more diuresis than 1 mg bumetanide. You could look at the effect of potassium sparing diuretics (like spironolactone) used with bumetanide - this must be documented somewhere.

      60mg looked like a fair dose to try based on the current usage, but twice a day.

      Where we live we now have hot summer weather with lots of pollen. Our summertime flare ups began to re-appear a month ago, but have now entirely disappeared. Last year with mast cell therapies we had 80% reduction, now it is 100% . I will wait till September before making final conclusions, but it appears to be the PPAR gamma agonist (Sytrinol) and, perhaps, also the butyric acid producing bacteria Miyairi 588. The Sytrinol has an immediate effect, but the Miyairi 588 has no immediate effect. However it is logical that some things do take time. The Miyairi 588 is very cheap and its only side effect seems to be crowding out harmful bacteria.

      I am just glad that the first thing I experimented with, bumetanide, had such an impact, otherwise I would never have embarked on this investigation. The second and third also had an impact, so it is hard not to continue.

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    4. Agnieszka Wroczyńska,
      Is diamox effective? If so what is the dosage? And with low dose Clonazepam? I want to know because Bumetanide is not available in my country but Diamox is.Thank you.

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    5. Bumetanide made my son start to learn new things again after more than a year of slow regression and also decreased sensory issues. I gave Diamox looking for a drug that would control his extremely severe migraine-like episodes. Diamox 2x60 mg daily further increased his awareness and cognition at the beginning, but it was given in addition to Bumetanide. I did not use Diamox alone longer than for a few days.

      I think it is better to try Bumetanide first. Both have some similar mechanisms of action, but Bumetanide has been studied better in children with autism. Neither Bumetanide nor Diamox are curative meds so safe use is important and it is known more about Bumetanide in term of long term safety. Diamox may affect Clonazepam metabolism, so if you want to use both you may find it difficult to establish the proper dose of the latter, which is in my opinion important when using low dose Clonazepam. This happened to my son.

      What country are you from? Maybe it’s possible to find a solution for this. Bumetanide is also not available where I live.

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    6. Agnieszka,
      We live in India. Here both diamox and lasix (furosemide) are available. But not bumetanide.

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    7. I am from India as well and looking for bumetanide but can't find it in the pharmacies here

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  7. Open question: does anyone know of any doctor that falls into that 1% that do consider low level off-label interventions?

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    1. In the US there are a large number of "alternative" doctors, DAN doctors etc, plus they have a tradition of off-label prescribing. But they may not be prescribing the "right" drugs.

      If you live in the UK, your NHS doctor is just going to follow the NICE guidelines, at best. Apparently some UK paediatricians are showing interest in what the charity Treating Autism is doing, http://treatingautism.co.uk/what-we-do/ so maybe they can suggest someone in the UK.

      I found that if you can show the science behind what you want (i.e. copy of clinical trial etc) there are interested doctors. If you say, can you treat my kid with autism?, you will get one answer, if you say I want to try this drug, for these reasons and here is the latest clinical trial, you may get a different answer. Most doctors are held back by the thought of getting into trouble. In some countries this is a big worry and in others only a minor worry. The UK paediatrician who told us about the successful use of Baclofen in Aspergers did point out that you can always buy from an on-line pharmacy.

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  8. Thanks Peter,

    I am a member of that charity but it currently focuses on biomeds in the main, for similar reasons. I'm focussing on accessing doctors/paediatrician's in the wider EU (or anywhere really!) right now.

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  9. Hi Peter,

    This is another great post on an important topic. I wonder how sulfate fits into the picture of ion channels in autism. As you likely are aware plasma sulfate is almost always low in autism and sulfate loss in the urine is high. See: http://www.ncbi.nlm.nih.gov/pubmed/21651783 and http://informahealthcare.com/doi/abs/10.1080/13590840050000861. In other words a big issue in most cases of autism is excessive sulfate loss via the kidneys.

    There is a family of transporters of sodium sulfate and citrate called SLC13. Perhaps this family of transporters is too porous in autism and if one ingests potassium the kidneys adjust by temporarily shutting down the loss of sodium sulfate resulting in improved behavioral symptoms at least temporarily. In other words, this might help explain why potassium is helpful in many cases of autism.

    Why should the SLC13 transporters be dysfunctionally open in autism? I would guess it is related to auto-immunity or in some cases infection. I think it would be great if some ambitious scientists researched the effects of different compounds on sulfate loss via urine in autism. Those that restrict sulfate loss while allowing nitrogen waste through are likely to be efficacious in autism.

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    1. Hi Seth

      It does look like SLC transporters play a key role in some disease.


      "Members of the SLC13 transporter family play a key role in the regulation of fat storage, insulin resistance, and other processes. Some SLC13 transporters mediate the transport of Krebs cycle intermediates--compounds essential for the body's metabolic activity--across the cell membrane. Previous studies have shown that loss of one member of this family protects mice against obesity and insulin resistance, and loss of another results in reduced fat storage and extended lifespan in fruit flies. These findings hint at the therapeutic potential of targeting these transporters to combat metabolic disease, obesity, diabetes, and other conditions."

      I think that in the future medical science will need to get more sophisticated to better treat people.

      It is indeed odd that sulfur containing compounds are beneficial in autism. Both MSM (Methylsulfonylmethane) and NAC work in the same way to increase glutathione (GSH). Sulfurophane does not seem to affect GSH.

      I expect there are other sulfur containing compounds that also will increase GSH.

      Insulin resistance does seem to several connections to autism and maybe SLC13 is part of the puzzle. Also in a couple of areas even obesity connects with autism.

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  11. Oh Another thing I'd love to know... can you recommend an online pharmacy that you trust? I 'm nervous to order from them...but getting stuff from drs can be quite a hassle if not impossible!

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    Replies
    1. I have only ever ordered one thing from an online pharmacy. The one I used was:-

      http://mymexicandrugstore.org/

      Online pharmacies can be extremely expensive, many of the drugs effective in autism are cheap generic drugs, which cost 30 to 50 X more online.

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  12. This is fascinating. My husband has hypokalemic periodic paralysis and possibly mast cell activation disease (currently being investigated), and our daughter has Asperger's. I'm now wondering whether there's a connection, but I don't know how to go about investigating it. Any suggestions?

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    Replies
    1. There clearly is a connection due to your daughter having similar genes to her father. HypoPP is rare and so you might find an academic who finds it an interesting case, but more likely you will have to do it yourself. Your daughter will likely benefit from potassium supplements and your husband might benefit from verapamil and/or bumetanide.

      Does your daughter have epilepsy?

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  13. Hi Peter,
    My son finally got the go ahead to try Bumetanide. His doctor asked that prior to writing the Rx that we get a basic metabolic blood panel done. Is there anything we should be aware of related to the drug while taking it? Did your son have any bed wetting issues when starting it?
    Also, would you like for me to report on this blog as to how it goes? I know that there haven't been a lot of kids who have tried it. Just as a bit of background, my son is 12 years old (in three weeks)and weighs approx. 75lbs. He is currently taking BioGaia Gastrus (1/day), NAC (2x/day) and long acting Clonidine 0.1mg (1/day). Melatonin at night.
    Thanks,
    Christine

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    Replies
    1. Christine, I am sure people will be interested to read your feedback. Bumetanide should be entirely trouble free for a 12 year old. Measure his potassium level now and then after a week or two on bumetanide. You should assume some potassium loss so add a banana a day and a potassium supplement. In about 20% of people using bumetanide they lose a lot of potassium, but most do not. Potassium does lots of good things so it is good to have dietary potassium and a moderate supplement. If you give 1mg at breakfast and 1mg at 4-6 PM you will not have bed wetting problems, but he will need access to a bathroom. In my son the diuresis is all within 90 minutes. He pays one ot two extra visits to the bathroom. It is no big deal.

      You are unlikely to see big effects in less than 10 days and in some people it takes a month, or even two. If no effect after all that time, you should assume he is not a responder.

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