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Friday, 3 June 2016

Mefenamic acid (Ponstan) for some Autism


Caution:-

Ponstan (Mefenamic Acid) contains a warning:-
Caution should be exercised when treating patients suffering from epilepsy.

At lower doses Ponstan is antiepileptic, but at high doses it can have the opposite effect.  This effect depends on the biological origin of the seizures.
In an earlier post I wrote about a paper by Knut Wittkowski who applied statistics to interpret the existing genetic data on autism. 


“Autism treatments proposed by clinical studies and human genetics are complementary” & the NSAID Ponstan as a Novel AutismTherapy




His analysis suggested the early use of Fenamate drugs could potentially reduce the neurological anomalies that develop in autism as the brain develops.  The natural question arose in the comments was to whether it is too late to use Fenamates in later life.

Knut was particularly looking at a handful of commonly affected genes (ANO 2/4/7 & KCNMA1) where defects should partially be remedied by use of fenamates.

I recently received a comment from a South African reader who finds that his children’s autism improves when he gives them Ponstan and he wondered why.  Ponstan (Mefenamic Acid) is a fenamate drug often used in many countries as a pain killer, particularly in young children.

Ponstan is a cheap NSAID-type drug very widely used in some countries and very rarely used in other countries like the US.  It is available without prescription in some English-speaking countries (try a pharmacy in New Zealand, who sell online) and, as Petra has pointed out, it is widely available in Greece.

I did some more digging and was surprised what other potentially very relevant effects Ponstan has.  Ponstan affects GABAA receptors, where it is a positive allosteric modulator (PAM).  This may be very relevant to many people with autism because we have seen that fine-tuning the response of the sub-units that comprise GABAA receptors you can potentially improve cognition and also modulate anxiety. 

Anxiety seems to be a core issue in Asperger’s, whereas in Classic Autism, or Strict Definition Autism (SDA) the core issue is often actually cognitive function rather than “autism” as such.

In this post I will bring together the science showing why Ponstan should indeed be helpful in some types of autism.

Professor Ritvo from UCLA read Knut’s paper and also the bumetanide research and suggested that babies could be treated with Ponstan and then, later on, with  Bumetanide.

Autism treatments proposed by clinical studies and human genetics are complementary



I do not think the professor or Knut are aware of Ponstan’s effect on GABA.

The benefits from Ponstan may very well be greater if given to babies at risk of autism, but there does seem to be potential benefit for older children and adults, depending on their type of autism.

Professor Ritvo points out that that Ponstan is safely used in 6 month old babies, so trialing it in children and adults with autism should not be troubling.

Being an NSAID, long term use at high doses may well cause GI side effects.  An open question is the dosage at which Ponstan modulates the calcium activated ion channels that are implicated in some autism and also what dosage affects GABAA receptors.  It might well be lower than that required for Ponstan’s known ant-inflammatory effects.


Ponstan vs Ibuprofen

Ibuprofen is quite widely used in autism.  Ibuprofen is an NSAID but also a PPAR gamma agonist.  Ponstan is an NSAID but has no effect on PPAR gamma.

Research shows that some types of autism respond to PPAR gamma agonists.

So it is worth trying both Ponstan and Ibuprofen, but for somewhat different reasons.

They are both interesting to deal with autism flare-ups, which seem common.

Other drugs that people use short term, but are used long term in asthma therapy,  are Singulair (Montelukast) and an interesting Japanese drug called Ibudilast.  Singulair is a Western drug for maintenance therapy in asthma.  Ibudilast is widely used in Japan as maintenance therapy in Asthma, but works in a different way.  Ibudilast is being used in clinical trials in the US to treat Multiple Sclerosis.  Singulair is cheap and widely available, Ibudilast is more expensive and available mainly in Japan.


Pre-vaccination Immunomodulation

In spite of there being no publicly acknowledged link between vaccinations and autism secondary to mitochondrial disease (AMD), I read that short term immunomodulation is used prior to vaccination at Johns Hopkins, for some babies.

Singulair is used, as is apparently ibuprofen.  Ponstan and Ibudilast would also likely be protective.   Ponstan might well be the best choice; it lowers fevers better than ibuprofen.

For those open minded people, here is what a former head of the US National Institutes of Health, Bernadine Healy, had to say about the safe vaccination.  Not surprisingly she was another Johns Hopkins trained doctor, as is Hannah Poling’s Neurologist father.

The Vaccines-Autism War: Détente Needed

“Finally, are certain groups of people especially susceptible to side effects from vaccines, and can we identify them? Youngsters like Hannah Poling, for example, who has an underlying mitochondrial disorder and developed a sudden and dramatic case of regressive autism after receiving nine immunizations, later determined to be the precipitating factor. Other children may have a genetic predisposition to autism, a pre-existing neurological condition worsened by vaccines, or an immune system that is sent into overdrive by too many vaccines, and thus they might deserve special care. This approach challenges the notion that every child must be vaccinated for every pathogen on the government's schedule with almost no exception, a policy that means some will be sacrificed so the vast majority benefit.”


So if I was an American running the FDA/CDC I would suggest giving parents the option of paying a couple of dollars for 10 days of Ponstan prior to these megadose vaccinations and a few days afterwards.  No harm or good done in 99.9% of cases, but maybe some good done for the remainder.

The fact the fact that nobody paid any attention to the late Dr Healy on this subject tells you a lot.



Fenamates (ANO 2/4/7 & KCNMA1)

Here Knut is trying to target the ion channels expressed by the genes ANO 2/4/7 & KCNMA1. 

·        ANO 2/4/7 are calcium activated chloride channels. (CACCs)


·        KCNMA1 is a calcium activated potassium channel.  KCNMA1encodes the ion channel KCa1.1, otherwise known as BK (big potassium).  This was the subject of post that I never got round to publishing.
  
Fenamates are an important group of clinically used non-steroidal anti-inflammatory drugs (NSAIDs), but they have other effects beyond being anti-inflammatory.  They act as CaCC inhibitors and also stimulate BKCa channel activity.


But fenamates also have a potent effect on what seems to be the most dysfunctional receptor in classic autism, the GABAA receptor.




The fenamate NSAID, mefenamic acid (MFA) prevents convulsions and protects rats from seizure-induced forebrain damage evoked by pilocarpine (Ikonomidou-Turski et al., 1988) and is anti-epileptogenic against pentylenetetrazol (PTZ)-induced seizure activity, but at high doses induces seizures (Wallenstein, 1991). In humans, MFA overdose can lead to convulsions and coma (Balali-Mood et al, 1981; Young et al., 1979; Smolinske et al., 1990). More recent data by Chen and colleagues (1998) have shown that the fenamates, flufenamic, meclofenamic and mefenamic acid, protect chick embryo retinal neurons against ischaemic and excitotoxic (kainate and NMDA) induced neuronal cell death in vitro (Chen et al., 1998a; 1998b). MFA has also been reported to reduce neuronal damage induced by intraventricular amyloid beta peptide (Aβ1-42) and improve learning in rats treated with Aβ1-42 (Joo et al., 2006). The mechanisms underlying these anti-epileptic and neuroprotective effects are not well understood but together suggest that fenamates may influence neuronal excitability through modulation of ligand and/or voltage-gated ion channels. In the present study, therefore, we have investigated this hypothesis by determining the actions of five representative fenamate NSAIDs at the major excitatory and inhibitory ligand-gated ion channels in cultured hippocampal neurons


This study demonstrates for the first time that mefenamic acid and 4 other representatives of the fenamate NSAIDs are highly effective and potent modulators of native hippocampal neuron GABAA receptors. MFA was the most potent and at concentrations equal to or greater than 10 μM was also able to directly activate the GABAA gated chloride channel. A previous study from this laboratory reported that mefenamic acid potentiated recombinant GABAA receptors expressed in HEK-293 cells and in Xenopus laevis oocytes (Halliwell et al., 1999). Together these studies lead to the conclusion that fenamate NSAIDs should now also be considered a robust class of GABAA receptor modulators.


Also demonstrated for the first time here is the direct activation of neuronal GABAA receptors by mefenamic acid. Other allosteric potentiators, including the neuroactive steroids and the depressant barbiturates share this property, with MFA at least equipotent to neurosteroids and significantly more potent than the barbiturates. The mechanism(s) of the direct gating of GABAA receptor chloride channels by MFA requires further investigation using ultra-fast perfusion techniques but may be distinct from that reported for neurosteroids (see, Hosie et al., 2006). Mefenamic acid induced a leftward shift in the GABA dose-response curve consistent with an increase in receptor affinity for the agonist. This is an action observed with other positive allosteric GABAA receptor modulators, including the benzodiazepine agonist, diazepam, the neuroactive steroid, allopregnanolone, and the intravenous anesthetics, pentobarbitone and propofol (e.g. Johnston, 2005). To our knowledge, a unique property of MFA was that it was significantly (F = 10.35; p≤ 0.001) more effective potentiating GABA currents at hyperpolarized holding potentials (especially greater than −60mV). Further experiments are required however to determine the underlying mechanism(s).

The highly effective modulation of GABAA receptors in cultured hippocampal neurons suggests the fenamates may have central actions. Consistent with this hypothesis, mefenamic acid concentrations are 40–80μM in plasma with therapeutic doses (Cryer & Feldman, 1998); fenamates can also cross the blood brain barrier (Houin et al., 1983; Bannwarth et al., 1989) Coyne et al. Page 5 Neurochem Int. Author manuscript; available in PMC 2008 November 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript and in overdose in humans are associated with coma and convulsions (Smolinske et al., 1990). In animal studies, mefenamic acid is anticonvulsant and neuroprotective against seizureinduced forebrain damage in rodents (Ikonomidou-Turski et al., 1988). The present study would suggest that the anticonvulsant effects of fenamates may be related, in part, to their efficacy to potentiate native GABAA receptors in the brain, although a recent study has suggested that activation of M-type K+ channels may contribute to this action (Peretz et al., 2005) Finally, Joo and co-workers (2006) have recently reported that mefenamic acid provided neuroprotection against β-amyloid (Aβ1-42) induced neurodegeneration and attenuated cognitive impairments in this animal model of Alzheimer’s disease. The authors proposed that neuroprotection may have resulted from inhibition of cytochrome c release from mitochondria and reduced caspase-3 activation by mefenamic acid. Clearly it would also be of interest to evaluate the role of GABA receptor modulation in this in vivo model of Alzheimer’s disease. Moreover, considerable evidence has emerged in the last few years indicating that GABA receptor subtypes are involved in distinct neuronal functions and subtype modulators may provide novel pharmacological therapies (Rudolf & Mohler, 2006). Our present data showing that fenamates are highly effective modulators of native GABAA receptors and that mefenamic acid is highly subtype-selective (Halliwell et al., 1999) suggests that further studies of its cognitive and behavioral effects would be of value.

  

Note in the above paper that NSAIDs other than mefenamic acid also modulate GABAA receptors.

Just a couple of months ago a rather complicated paper was published, again showing that NSAIDs modulate GABAA receptors and showing that this is achieved via the same calcium activated chloride channels (CaCC) referred to by Knut.

NSAIDs modulate GABA-activated currents via Ca2+-activated Cl channels in rat dorsal root ganglion neurons






"Schematic displaying the effects of CaCCs on GABA-activated inward currents and depolarization. GABA activates the GABAA receptor to open the Cl  channel and the Cl efflux induces the depolarization response (inward current) of the membrane of dorsal root ganglion (DRG) neurons. Then, voltage dependent L-type Ca2+ channels are activated by the depolarization, and give rise to an increase in intracellular Ca2+. CaCCs are activated by an increase in intracellular Ca2+ concentration which, in turn, increases the driving force for Cl efflux. Finally, the synergistic action of the chloride ion efflux through GABAA receptors and NFA-sensitive CaCCs causes GABA-activated currents or depolarization response in rat DRG neurons."


Note in the complex explanation above the L-type calcium channels, which are already being targeted by Verapamil, in the PolyPill.



Mefenamic Acid and Potassium Channels

We know that Mefenamic acid also affects Kv7.1 (KvLQT1).

A closely related substance called meclofenamic acid is known to act as novel KCNQ2/Q3 channel openers and is seen as having potential for the treatment of neuronal hyper-excitability including epilepsy, migraine, or neuropathic pain.



The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel  subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC50  25 M) and diclofenac (EC50  2.6 M) resulted in the activation of KCNQ2/Q3 K currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (23 and 15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel  subunits. In contrast, they did not enhance KCNQ1 K currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED50  43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain. Volt




BK channel

KCNMA1encodes the ion channel KCa1.1, otherwise known as BK (big potassium). BK channels are implicated not only by Knut’s statistics, but numerous studies ranging from schizophrenia to Fragile X. 

Usually it is a case of too little BK channel activity.

The BK channel is implicated in some epilepsy.

  

Pharmacology

BK channels are pharmacological targets for the treatment of several medical disorders including stroke and overactive bladder. Although pharmaceutical companies have attempted to develop synthetic molecules targeting BK channels, their efforts have proved largely ineffective. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo. However, BKCa channels are reduced in patients suffering from the Fragile X syndrome and the agonist, BMS-204352, corrects some of the deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome.
BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide and hydrogen sulphide.
BK channels can be readily inhibited by a range of compounds including tetraethylammonium (TEA), paxilline and iberiotoxin.



Achieving a better understanding of BK channel function is important not only for furthering our knowledge of the involvement of these channels in physiological processes, but also for pathophysiological conditions, as has been demonstrated by recent discoveries implicating these channels in neurological disorders. One such disorder is schizophrenia where BK channels are hypothesized to play a role in the etiology of the disease due to the effects of commonly used antipsychotic drugs on enhancing K+ conductance [101]. Furthermore, this same study found that the mRNA expression levels of the BK channel were significantly lower in the prefrontal cortex of the schizophrenic group than in the control group [101]. Similarly, autism and mental retardation have been linked to haploinsufficiency of the Slo1 gene and decreased BK channel expression [102].
Two mutations in BK channel genes have been associated with epilepsy. One mutation has been identified on the accessory β3 subunit, which results in an early truncation of the protein and has been significantly correlated in patients with idiopathic generalized epilepsy [103]. The other mutation is located on the Slo1gene, and was identified through genetic screening of a family with generalized epilepsy and paroxysmal dyskinesia [104]. The biophysical properties of this Slo1 mutation indicates enhanced sensitivity to Ca2+ and an increased average time that the channel remains open [104107]. This increased Ca2+ sensitivity is dependent on the specific type of β subunit associating with the BK channel [106, 107]. In association with the β3 subunit, the mutation does not alter the Ca2+-dependent properties of the channel, but with the β4 subunit the mutation increases the Ca2+ sensitivity [105107]. This is significant considering the relatively high abundance of the β4 subunit compared to the weak distribution of the β3 subunit in the brain [12, 13,15, 106, 107]. It has been proposed that a gain of BK channel function may result in increases in the firing frequency due to rapid repolarization of APs, which allows a quick recovery of Na+ channels from inactivation, thereby facilitating the firing of subsequent APs [104]. Supporting this hypothesis, mice null for the β4 subunit showed enhanced Ca2+ sensitivity of BK channels, resulting in temporal lobe epilepsy, which was likely due to a shortened duration and increased frequency of APs [108]. An interesting relevance to the mechanisms of BK channel activation as discussed above, the Slo1 mutation associated with epilepsy only alters Ca2+ dependent activation originated from the Ca2+ binding site in RCK1, but not from the Ca2+bowl, by altering the coupling mechanism between Ca2+ binding and gate opening [100]. Since Ca2+dependent activation originated from the Ca2+ binding site in RCK1 is enhanced by membrane depolarization, at the peak of an action potential the binding of Ca2+ to the site in RCK1 contributes much more than binding to the Ca2+ bowl to activating the channel [84, 109].
Although these associations between specific mutations in BK channel subunits and various neurological disorders have been demonstrated by numerous studies, it is also important to point out certain caveats with these studies, such as genetic linkage between BK channels and different diseases do not necessary show causation as these studies were performed based on correlation between changes in the protein/genetic marker and overall phenotype. Furthermore, studies performed using a mouse model also can fail to indicate what may happen in higher-order species, and this is especially true for BK channels, where certain β subunits are only primate specific [110].


  

Possible role of potassium channel, big K in etiology of schizophrenia.

Schizophrenia (SZ), a common severe mental disorder, affecting about 1% of the world population. However, the etiology of SZ is still largely unknown. It is believed that molecules that are in an association with the etiology and pathology of SZ are neurotransmitters including dopamine, 5-HT and gamma-aminobutyric acid (GABA). But several lines of evidences indicate that potassium large conductance calcium-activated channel, known as BK channel, is likely to be included. BK channel belongs to a group of ion channels that plays an important role in regulating neuronal excitability and transmitter releasing. Its involvement in SZ emerges as a great interest. For example, commonly used neuroleptics, in clinical therapeutic concentrations, alter calcium-activated potassium conductance in central neurons. Diazoxide, a potassium channel opener/activator, showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms in SZ. Additionally, estrogen, which regulates the activity of BK channel, modulates dopaminergic D2 receptor and has an antipsychotic-like effect. Therefore, we hypothesize that BK channel may play a role in SZ and those agents, which can target either BK channel functions or its expression may contribute to the therapeutic actions of SZ treatment.




Conclusion

It appears that Ponstan and related substances have some interesting effects that are only now emerging in the research.

People with autism, and indeed schizophrenia, may potentially benefit from Ponstan and for a variety of different reasons.

I think it will take many decades for any conclusive research to be published on this subject, because this is an off-patent generic drug.

As with most NSAIDS, it is simple to trial Ponstan.

Thanks to Knut for the idea, Professor Ritvo for his endorsement of the idea and our reader from South Africa for sharing his positive experience with Ponstan. 







19 comments:

  1. Interesting post Peter. To add more fuel to the fire here is an article I read today about another genomics study strongly linking autism to schizophrenia (which you discussed in length in this latest post of yours):

    https://spectrumnews.org/news/brain-tissue-study-bolsters-autism-schizophrenia-link/

    Also, something else I came across which I believe downstream may be one small part in a comprehensive therapy for achieving acceptable outcomes for severely autistic people:

    http://med.stanford.edu/news/all-news/2016/06/stem-cells-shown-safe-beneficial-for-chronic-stroke-patients.html

    What this shows is that stem cell therapy is not only safe, but very beneficial to stroke victims. I have read quite a lot of about stroke and there are some striking similarities to autism in terms of the type of stress and the way the immune system reacts (or overreacts) at the cellular level. While stroke itself is acute (just like concussions from years of football playing) the recovery process and the cleanup/repair process can go awry and do more damage than good and lead to chronic brain encephalitis over time. This is an open debate in autism since having a big database of donated brain tissue from those with autism at all ages of life makes studies on the matter rather underpowered, but there does seem to be a trend in what I have read where children with autism have an overabundance of brain cells and then by the time they are adults, they show the kind of signs of stress you find in other degenerative brain diseases to the point you might look at a 30 year old brain of someone with autism and conclude that it looks like that of a 50 year old.

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  2. Hi Peter, Liquid food processing is different to solid food.
    I'll start with a conclusion which may be incorrect, particularly when it comes to drugs. I'm sure you can check on that.

    Ponstan treatment has really intrigued me since when you released your earlier relevant post.
    I used Ponstan syrup for my son as a baby and during his childhood years, after vaccinations, when fever, inflammation etc., very effectively.
    Going back to Ponstan pills as an adult I had mixed results and this has made me curious.
    Possible reasonable explanations I've come up with is the fact that pills may cause GI side effects or processed differently or the dose is too high. I now see that Ponstan is not well tolerated with the evidence he definitely has GI isues.
    It may be the syrup that works better for some responders. This might also apply to melatonin supplementation; I'll have to check.

    Low dose Baclofen replaced both Ponstan and Ibuprofen when there is a "hidden" inlammation. According to my observations, some food, processed carbs in particular, affect my son. He gets agitated, serotonin drops and when given baclofen it really helps him.
    It also ameliorates cholinergic function.
    There are some papers supporting Baclofen alters gut to brain signaling during inflammation and also GABA B agonists (in rabbits) are dependent on cholinergic neurotransmission. It seems that it's not as harmful for GI as anti-inflamatory drugs should be.

    So, if you find reason for liquid Postan, I could always send you from Greece, where it's widely available.

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  3. This comment has been removed by the author.

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    1. In the UK prescribing is very much limited to what NICE (National Institute for Clinical Excellence) recommend. They made a very detailed review of the autism literature and concluded that nothing works. I trialled Bumetanide, which had been reviewed by NICE, and it certainly did work in our case.

      The three key drugs I use (Bumetanide, Verapamil and Atorvastatin) are all drugs used long term by many people 50+. As a result in countries like Spain these drugs are handed out by pharmacists without the need for a prescription, even though they are prescription drugs. This may sound odd to someone in Northern Europe. If you specifically ask do you need a prescription they would say yes.

      In the US there are doctors who will prescribe off-label, i.e. for uses that are not specifically approved.

      So if you want to treat autism you will have to self treat. This is frowned upon because some people will end up doing stupid things, but you can also do stupid things with supplements freely available on Amazon.

      Many people use offshore internet pharmacies, it is probably cheaper to have a City break in Spain.

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    2. Thank you for your reply Peter. I will certainly do this. I wonder whether France or Ireland are the same...I will look into this also as easier for me to drive to these locations.
      The research you are doing is so valuable, It would be good to see this work acknowledged. Best of luck,
      Kind regards
      Sarah

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    3. Sarah, I know for sure that France, Germany, Austria, Poland all require a prescription. The only flexible countries are the more Latin ones. Greece is flexible, but do not have bumetanide. I think Ireland will be just like the UK. Some things are drugs, eg Ponstan, in the UK but OTC in other countries. Things like NAC are available on Amazon and similar sites. NAC is very helpful in many cases.

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    4. Thank you Peter, I will go to Spain for sure. I did buy NAC from Amazon but like you detailed the sulphur odour happened pretty much as soon as the bag of powder was opened, I think the best way is to open the capsules, but again the dosage is harder to gauge when opening capsules. My son has started refusing to take tablets now (because he never swallows - always bites/chews - when I gave him a couple of other softgels recently he wasn't impressed with the taste so this has put him off) so the only way to get things into him is via liquid versions in juice.
      On another note I wanted to share the link on Dr Mary Newport which links cognition improvements to Coconut Oil (we have been using it over 8 weeks and it seems promising)

      https://www.youtube.com/watch?v=feyydeMFWy4

      kind regards
      Sarah

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    5. Coconut oil and some other changes would take you towards a ketogenic diet, which does help some people, particularly those with epilepsy.

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  4. my son seems to have inflammatory pain reaction to coconut oil, coconut milk, MCT oil. Last check two yrs ago his cholesterol was high. Sticking with just olive oil.

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  5. Hi Peter and all of you contributing with insightful comments!

    You have been a true resource for me during the worst time of my life when I realized my sweet daughter had autism and there was no cure...
    I am now mentally ready to start some medical intervention for her.

    My daughter is almost 2 years old and around 13 kg.
    She seems to have classic autism, with impaired cognition, "slow", nonverbal, apraxic, but social.
    No known allergies (small skin reaction to cinnamon though), no GI, no bad behaviour, no sleeping problems, no sensory overload. Yet.

    I was pondering Bumetadin, but then saw the posts on Ponstan (still looking for information on dosage/length of treatment).
    What else would you recommend as a starting point for medical intervention for someone as small (and still maybe having a window of opportunity)?

    Also, maybe you could recommend any tests that she should do to get a better idea of what phenotype she belongs to? Genetic testing did not show anything special, and some metabolic tests were done as part of national PKU-testing with no result.
    I am trying to get an EEG "just in case".

    Thanks in advance,
    /Ling

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    1. Ling, why not contact Knut Wittkowski, Rockefeller University, and ask him about Ponstan. It is his big idea.

      The suggestion either in this post, or another one from the clinician at UCLA was to start Ponstan and Bumetanide ASAP.

      "Yet" is very relevant. Autism tends to get worse.

      Antioxidants like NAC may be protective and prevent some damage.

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    2. Ling,

      Bumetanide (a very strong diuretic) blocks *in*flux of chloride into neurons. This decreases excitability only in children who fall not asleep with valium.

      Mefenamic acid (an NSAID) blocks the *ef*flux of chlorid from neurons (and activates the efflux of potassium). Both actions should decrease excitability most >1 yr old children.

      Unless your daughter has the above paradoxical response to valium, bumetanide and mefenamic acid may have opposite effects. You should discuss with your physician which drug might work best for your daughter.

      The approved dose in the UK for Ponstan is 25 mg/kg/d in four divided doses, but to prevent mutism one would only need to give 6 mg/kg twice (morning and noon).

      /Knut

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    3. Still confused about ponstan in that is it an alternative to bumetanide use and will have the same function as bumetanide or is it a different thing altogether

      Cheers Paul

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    4. A different thing altogether. Ponstan may help 1-yr olds with developing language, bumetanide has shown mixed results in older children.

      Knut

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  6. Seems that taking the idea of mefenamic acid for autism to the treatment level just took a great step forward:
    http://medcitynews.com/2017/04/q-biomed-early-stage-autism-deal-asdera/?rf=1

    /Ling

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  7. I am not sure if this adds anything to our knowledge regarding mefenamic acid/Ponstan, but I link to it since it seems relevant (I just don't know how yet ;-) ):

    http://www.tandfonline.com/doi/abs/10.3109/10715762.2012.669836?src=recsys&journalCode=ifra20

    "We found that D-serine significantly increased oxidative stress, levels of inflammation- and apoptosis-related molecules in a region specific manner. Mefenamic acid treatment provided significant protection against the elevation of lipid peroxidation, protein oxidation, levels of TNF-α, IL-1β and Bax. "

    /Ling

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  8. Finally, here is my report on 1 month use of mefenamic acid for autism (and pain).
    My daughter is 25 months / 13 kg. She had 80 mg Ponstan from a divided capsule twice a day. No interfering medication, but she was having a new tooth during the first weeks.

    -----------------------------------
    The first few days I noticed that she seemed faster, in everything. She was almost running around our house, when she usually toddles. Maybe it was something about faster reactions or better coordination? She also seemed “stronger”, suddenly using her muscles and squeezing me hard with her hands on a couple of occasions. The painkilling effect was very clear and superior to the usual paracetamol/acetaminophen.
    At day ten I could see a strange pattern: two hours or so after intake she would lean forward and scream joyfully. I have no idea what this was about, but she sure seemed to enjoy it. Some irritability, which might or might not be related.
    Around day 14 or so she started to notice details that she had not “seen” before. The most obvious example would be when she was pointing at the two paintings that have been hanging over her bed since she was born. Or, some knobs in eye-height on her drawer that she passes many times each day but never has been interested in.
    Day 17. At this time I asked myself if her receptive language was better than before (or placebo effect on me). She would of course not understand so many new words after such a short period, but if something was messing with her neurological hearing capabilities before and now was inhibited it would surely look like this. She was also much more active – not hyperactive, but “normal” active for a 2 year old kid. No social gain yet.
    Day 25. I have now seen some spontaneous imitation. This is pretty remarkable since it has always been very hard to make her imitate anything (and believe me I’ve tried!). One example: As I was putting cutlery on the table before dinner she unprompted took some spoons from the drawer (she is even too short to see what’s in it) and brought them to the table. She has learnt to use two new signs (+20% vocabulary) since day 1 and relearned one sign she previously stopped using.

    After 1 month we stopped treatment. First days without medication she was doing strange movements with her hands. Then, slower reactions and not responding as good/fast as before to talking. A lot of staring episodes. Not using signs as much as before. But still happy.

    Eventually adverse effects:
    -
    On day 10 she had a short staring episode when she did not respond to me even when I was yelling her name right beside her. Usually I can see that she is hearing my voice during these events. So I was a little bit shaky thinking immediately at the epilepsy warning on this medication. On the other hand, her staring episodes accelerated without the medicine
    Some loose stools at the end of the month.
    Spots on the cheeks after food intake; typical histamine reaction, but maybe a bit more of this than before.

    /Ling

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    1. Ling, very interesting. It does seem that Ponstan should be most effective in very young children, since it is proposed to stop autism getting worse, rather than reverse it. Do you plan to continue?

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