Fenamates (Diclofenac, Ponstan etc): certainly for Alzheimer’s, maybe some Epilepsy, but Autism? I’m Impressed!

 

Some readers of this blog are interested in the potential of mefenamic acid (MFA), sold as Ponstan, to treat autism. There is a lack of evidence currently. 

On the other hand, the evidence looks pretty overwhelming in the case of this class of drug to treat Alzheimer’s, hence today’s post. If you have a case of epilepsy at home, you can follow up on that loose end I left.

I also introduce MFA as a therapy for sound sensitivity and Misophonia. It was pretty impressive in the case of Monty, aged 18 with ASD.

 

The highlights are:

 

·        Fenamate NSAIDs reduce the incidence of Alzheimer’s

·        Fenamate NSAIDs delay the progression of those already with Alzheimer’s

·        Acetaminophen/Paracetamol worsens the progression of Alzheimer’s

·        Low dose aspirin is chemoprotective, as well as reducing blood clots that cause heart attack and stroke, but offers no Alzheimer’s benefit

·        MFA/Ponstan is very effective in reducing Monty’s sound sensitivity

 

The caveats 

As is always the case, there are caveats.

It is well known that low dose aspirin can cause dangerous bleeding events in specific sub-populations.

A study of 6 million people in Denmark showed that older people taking the Fenamate Diclofenac has a slightly higher risk of heart problems than other NSAIDs. The risk is actually very low and symptoms in those affected generally appear within a month (and disappear on cessation).

 

Incidence of Alzheimer’s

 

 

 Source:  https://www.intechopen.com/chapters/43129

 

The longer you live, the chance of developing Alzheimer’s rapidly increases. 

The signs are actual visible in a CT scan decades before the symptoms are evident.

Almost two-thirds of Americans with Alzheimer's are women.

Older Black Americans are about twice as likely to have Alzheimer's or other dementias as older Whites.

Of those with I/DD (Intellectual or Developmental Disability), it is people with Down Syndrome who are at major risk of early onset Alzheimer’s.  More than 50% will develop Alzheimer's. 

 

Non drug methods to protect against Alzheimer’s and other dementia 

In this blog we have encountered numerous dietary methods associated with reduced risk of all types of dementia and Alzheimer’s specifically.

·        Dietary nitrates (beetroot, spinach etc)

·        Betanin (the pigment in beetroot)

·        Ergothioneine (from mushrooms)

·        Spermidine (from wheatgerm and mushrooms)

·        Anthocyanin pigments from superfoods (bilberry, blueberry, purple sweet potato etc)

 

Maintaining normal blood pressure, blood glucose levels and cholesterol levels are big advantages. Normal body mass and regular exercise are also important.

Fenamates are a class of NSAID pain medication that many people have at home. In the US there are 10 million prescriptions a year of Diclofenac / Voltaren.

Another common Fenamate is Mefenamic Acid (MFA), commonly sold as Ponstan.  Ponstan is only expensive in North America. 

Most people’s reaction would be “Ah, yes those are pain medications, how could they help Alzheimer’s or other neurological conditions. Aren’t they the ones with those GI side effects?” 

NSAIDS deaden pain by blocking an enzyme called cyclooxygenase-2 (COX-2). Unfortunately, they also block to some extent a very similar enzyme called  cyclooxygenase-1 (COX-1). COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion.  Blocking COX-1 will cause GI side effects. Most people want to take an NSAID that is selective for COX-2.

 

Low dose Aspirin – the good COX-1 effect

There is a good effect from blocking COX-1, as from low dose aspirin (LDA), because it stops blood platelets sticking together and blocking blood flow.  LDA is also substantially chemoprotective and nobody has figured out why and it likely has nothing to do with COX1 or COX2. 

“Ishikawa et al. analyzed 51 randomized controlled trials (RCTs) and the cumulative evidence strongly supports the hypothesis that daily use of aspirin results in the prevention of cardiovascular disease (CVD), as well as a reduction in cancer-associated mortality [3].”

 

Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate? 

Epidemiological evidence suggests non-steroidal anti-inflammatory drugs reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of non-steroidal anti-inflammatory drug efficacy. This incongruence may be due to the wrong non-steroidal anti-inflammatory drugs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalized linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease Neuroimaging dataset for each commonly used non-steroidal anti-inflammatory drug and paracetamol. Use of most non-steroidal anti-inflammatories was associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these non-steroidal anti-inflammatory drugs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease.

 

  

Diclofenac Use Slows Cognitive Decline in Alzheimer Disease 

CHICAGO — While most common non-steroidal anti-inflammatory drugs (NSAIDs) do not significantly affect cognitive decline in patients with Alzheimer disease or mild cognitive impairment, research presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018, in Chicago, Illinois suggests that diclofenac actually reduces cognitive deterioration, while paracetamol accelerates decline. 

The study investigated cognitive decline associated with NSAID use in 1619 patients from the Alzheimer’s Disease Neuroimaging Initiative dataset. The Mini-Mental State Examination and the Alzheimer disease assessment scale were used to evaluate cognitive functioning. Additional variables that potentially explain cognitive decline were identified for the cohort including gender, apolipoprotein E genotype, level of education, vascular disorders, diabetes, and medication use. 

 

Study results showed that most common NSAIDs, including aspirin, ibuprofen, naproxen, and celecoxib did not alter cognitive degeneration in patients with mild cognitive impairment or Alzheimer disease. Diclofenac was the only NSAID that demonstrated a correlation with a slower rate of cognitive decline (ADAS χ2=4.0, P =.0455, MMSE χ2=4.8, P =.029). Conversely, paracetamol was correlated with accelerated cognitive deterioration (ADAS χ2=6.6, P =.010, MMSE χ2=8.4, P =.004), as well as apolipoprotein E ε4 genotype (ADAS χ2=316.0, P <.0001, MMSE χ2=191.0, P <.0001). 

Diclofenac’s correlation with slowed cognitive deterioration provides “exciting evidence for a potential disease modifying therapeutic,” the study authors wrote. If paracetamol’s deleterious effects are confirmed to be causative, it “would have massive ramifications for the recommended use of this prolific drug.”

 

One reason why paracetamol use might harm Alzheimer’s brains is the same reason it harms autistic brains; it depletes the level of the key antioxidant glutathione (GSH).  GSH will be in big demand in a damaged brain. 

As we will see later in this post, Fenamate class NSAIDs affect numerous ion channels, specifically Kv7.1, as a result some people with heart conditions will get side effects linked to arrhythmia and should therefore discontinue use.

 

Common painkiller linked to increased risk of major heart problems: Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers -- ScienceDaily

Common painkiller linked to increased risk of major heart problems

Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers 

The commonly used painkiller diclofenac is associated with an increased risk of major cardiovascular events, such as heart attack and stroke, compared with no use, paracetamol use, and use of other traditional painkillers, a new study finds.

 

The risk is actual quite low and is going to appear straight away, in terms of arrhythmia. If any drug or supplement makes you feel unwell, stop taking it and tell your doctor.

 

Which Fenamate for Alzheimer’s?

To decide which Fenamate is best for Alzheimer’s and indeed which might be helpful in some autism, it helps to ponder the various modes of action unrelated to COX-1 and COX-2. 

We have the NLRP3 inflammasome, which is suggested as the mechanism in Alzheimer’s.

Here we want to block inflammatory messenger like IL-1beta. In the chart below we see that Ibuprofen is useless, Diclofenac has an effect, Mefenamic acid is better, but Meclofenamic acid is the star.

 

  

Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics.

 

Fenamates and Ion Channels

https://scholarworks.wm.edu/cgi/viewcontent.cgi?article=2671&context=aspubs

 

A very broad range of ion channels are affected by Fenamates.

Researcher Knut Wittkowski focuses on the effect on potassium channels in his theory that Fenamates can treat autism and prevent non-verbal autism if given to toddlers.

• PATENT SUMMARY - Treatment and prevention of autism and autism spectrum disorders

Fenamates actually affect numerous ion channels.

·        Chloride channels

·        Non-selective cation channels

·        Potassium channels (Kv 7.1 , KCa 4.2, K2p 2.1, K2p 4.1, K2p 10.1)

·        Opens large conductance calcium-activated K⁺ channels (BK_Ca channels) 

https://www.researchgate.net/publication/348973521_Pharmacological_inhibition_of_BKCa_channels_induces_a_specific_social_deficit_in_adult_C57BL6J_mice

“Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability… These findings support the relationship between BKCa channel impairment and social behavior. This demonstrates a need for future studies which further examine the contribution of BKCa channels to social behavior, particularly during critical periods of development.

 

·        Sodium channels

·        Blockage of acid-sensing ion channels (ASICs), which are implicated in numerous disorders and had their own post.

https://epiphanyasd.blogspot.com/2017/08/acid-sensing-ion-channels-asics-and.html

 

Fig. 2. Ion channels targeted by flufenamic acid. Flufenamic acid produces inhibition or activation of ion channels. Colored bars near ionic channel name correspond to the estimated EC50 for flufenamic effect. References are provided within the text.

 Having noted the above graphic, which actually applies to the closely related flufenamic acid, a logical question is to ask about the effect of Flufenamic acid on seizures. 

Flufenamic acid shows promise as an epilepsy drug

I am not looking for a seizure therapy, so I leave that loose end for someone who is.

 

Conclusion

The best initial defence against dementia is good diet and exercise. Sometimes that will not be enough, because the healthier you are, the longer you will live and so the threat from dementia increases. Some people have genes that predispose them to dementia.

Since most of us struggle to follow diets like those of ultra healthy people in Okinawa, or on a Greek island, it might be worthwhile adding beneficial functional foods (neutraceuticals) to your existing diet.

I drink a small amount of beetroot juice daily, which is not such a hard step to take. In addition to benefits to your heart and brain, another benefit has just been discovered; now it improves the oral microbiome :-

 

Research suggests changes in mouth bacteria after drinking beetroot juice may promote healthy ageing 

“Our findings suggest that adding nitrate-rich foods to the diet – in this case via beetroot juice – for just ten days can substantially alter the oral microbiome (mix of bacteria) for the better.”

 

Many older people take NSAIDs to treat painful conditions like arthritis, switching to a Fenamate NSAID would not be a difficult option and would give some protection from Alzheimer’s.

People already diagnosed with Alzheimer’s currently do not have any effective therapies. Drugs like memantine exist, but are not so effective.  If I was in that position, I would want to take a low dose of Mefenamic Acid, if that was unavailable, I would settle for Diclofenac.

Diclofenac (25mg to 100mg) is prescribed in much lower doses than Mefenamic Acid (250 to 500mg tablets). We see that the effect on the NLRP3 inflammasome is actually far greater from Mefenamic Acid than Diclofenac. If the Alzheimer’s effect is via inhibiting the NLRP3 inflammasome, then you might expect that only a fraction of a standard capsule of Mefenamic would be needed.  That would then really reduce any GI side effects via the unwanted effect on COX-1 or any chance of arrhythmia. 

The ketone BHB, like fenamate NSAIDs, inhibits the NLRP3 inflammasome.  Since in Alzheimer’s the brain loses the ability to transport enough glucose across the blood brain barrier, ketones can also be used as a supplementary fuel for the brain. In one of my old posts on BHB I remember the doctor treating her husband with early onset Alzheimer’s with large doses of ketones – with some success.

 

And Autism?

Is Knut right that the potassium channel modulation from Mefenamic Acid will benefit autism, or at least a sub-set of severe autism? We do not know.

Mefenamic Acid (MFA) has so many biologic effects, I very much doubt Alzheimer’s is the only neurological condition where it could be beneficial. 

I should add that MFA undoubtedly will have negative effects in some people, this is inevitable.

Stop the noise !!

We did have a problem recently with extreme sound sensitivity. Monty, aged 18 with ASD, has had increasing sound sensitivity (Misophonia) for a year, but the only real issue was with sounds at mealtimes.  Over a recent weekend the sensitivity increased so much he could not sleep and also drank unusually large amounts of water (this also connects to K⁺). 

The next day at school he had a geography exam and he was completely dysfunctional. Monty’s assistant had prewarned the teacher and she agreed that he can sit the exam again next week.   

Fortunately, in the meantime the problem has been now been fixed (see below).

I was suggested to take to Monty to a Neurologist, but since there is no Dr Chez where we live, I did ignore that idea. In mainstream neurology sound sensitivity is just something you have got to learn to live with, perhaps with some Cognitive Behavioral Therapy (CBT) or just a pair of ear defenders, or those noise-cancelling headphones.

I did experiment years ago on the effect of an oral potassium supplement on reducing sound sensitivity, so I have long considered potassium ion channels a prime target.

Both hearing and the processing of the inputs is highly dependent on potassium channels, so I did return to MFA.  It has also been a topic in some recent email exchanges and I have long had some unopened packs of MFA at home.  The answer would be found in the kitchen cabinet and not in the neurology department

In bumetanide responders the Na-K-2Cl cotransporter (NKCC1) is over-expressed; it mediates the “coupled electroneutral movement of 1Na⁺, 1K⁺, and 2Cl^– ions across the plasma membrane of neurons”. This means that with each two chloride ions entering the neuron, come one sodium ion and one potassium ion.

 

Source: https://www.frontiersin.org/articles/10.3389/fncel.2019.00048/full

 

In summary, bumetanide responders have too much chloride in their neurons, the bubble on the left, above.

 

Knut’s theory was put to me recently as “MFA works on reducing neuron excitation by opening K+ channels, emptying the cell, which in return fills up with Cl- “.

If this is the case, MFA would do the opposite of Bumetanide.

I actually think MFA’s effect is much more complex.

The original idea of Knut was to prevent severe non-verbal autism developing in toddlers, by blocking the progression of the disease. MFA was essentially a medium-term treatment for toddlers, until the critical periods in brain development were past.  It was not a treatment for teenagers, by then the damage would have been done.

I think changing the baseline level of K+ inside neurons is going to have many effects.  Changing the baseline level of Cl- has a profound impact on cognition.

Unfortunately, everything is interrelated and so nothing is simple.

I did try MFA to eradicate the extreme sound sensitivity. I was concerned it might reduce cognition, by raising intracellular chloride and undo the bumetanide effect.

The extreme sound sensitivity did disappear following a day or two of starting 250mg a day of MFA, but that may just have been a coincidence.  The more mild sound sensitivity, that we had all learned to live with for months, also vanished; I do not see how that could be a coincidence.  Mood also became very good, perhaps a bit uncontrollably happy.

The next question is what happens to sound sensitivity when I stop giving MFA.  Time will tell, but so far the benefits have been maintained.

Sound sensitivity/Misophonia is a classic feature of autism;  TV depictions often portray a lonely looking boy wearing ear defenders. For many with Asperger’s misophonia is their main troubling issue. None of these people are taking bumetanide.  Monty has taken Bumetanide for nearly 10 years and never needed ear defenders.

You, like Prof Ben-Ari, might wonder if bumetanide use might cause a problem with potassium and hence hearing.  There is indeed a known risk of ototoxicity, which is actually a rare but possible side effect of loop-diuretic use, particularly furosemide.

Fluid in the inner ear is dependent upon a rich supply of potassium, especially in that part of the ear that translates the noises we hear into electrical impulses the brain interprets as sound.

 

Source: http://www.cochlea.eu/en/cochlea/cochlear-fluids

 

“Endolymph (in green) is limited to the scala media (= cochlear duct; 3), is very rich in potassium, secreted by the stria vascularis, and has a positive potential (+80mV) compared to perilymph.

Note that only the surface of the organ of Corti is bathed in endolymph (notably the stereocilia of the hair cells), whilst the main body of hair cells and support cells are bathed in perilymph.”

 

It is important to maintain a high level of potassium (K+) in the endolymph.

How the potassium gets there is a little bit complicated but it relies on:

·        The NKCC1 transporter

·        Potassium channel Kir4.1

·        Potassium channel KCNQ1 (Kv7.1) and in particular subunit KCNE1

 

Bumetanide blocks NKCC1 and so can potentially reduce potassium in the endolymph. Very high dose bumetanide would indeed risk ototoxicity.

We saw earlier in this post that Fenamates affect Kv7.1.

It is very poorly documented in the research, but Fenamates also affect Kir4.1.

 

The cochlea functions like a microphone. The auditory nerve then runs from the cochlea, hopefully bathed in potassium, to a station in the brainstem. From that station, neural impulses travel to the brain – specifically the temporal lobe, containing the primary auditory complex, where sound is attached meaning and we “hear”.

 

The auditory cortex is highlighted in pink and interacts with the other areas highlighted above

 

   Angular Gyrus   Supramarginal Gyrus   Broca's Area   Wernicke's Area 

 

By James.mcd.nz - self-made - reproduction of combined images Surfacegyri.JPG by Reid Offringa and Ventral-dorsal streams.svg by Selket, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=3226132

 

The peripheral auditory system links the microphone/cochlea to the brain. The Primary Auditory Neurons begin in the cochlea and terminate in the Brainstem (in the Cochlear Nuclei). In these neurons potassium channels play a key role.  These channels include K_Na1.1 and K_Na1.2, which are regulated by intracellular Na⁺ and Cl⁻, are found in a variety of neurons.

We assume that intracellular Cl⁻ is disturbed in bumetanide responsive autism.

Everything has to function to ensure normal hearing and with normal perception attached to that hearing.  Problems can arise in the cochlea (microphone) or in any of the above areas in the brain involved in transmitting or processing those signals.

 

Fenamates for some Aspie’s with Misophonia?

Misophonia has been covered in previous posts and we saw that therapies do exist in the research.  I think that there are multiple causes of sound sensitivity and likely also for those with Misophonia.

Low dose roflumilast was one interesting therapy, that works for some people but not others.  It does nothing for Monty regarding misophonia/sensory gating.

I wonder if some sound-troubled Aspies will respond to low dose MFA?

 

The top shelf

In our case, the answer to good health is usually found in the kitchen, but sometimes tucked away out of reach, up high at the back of a shelf, gathering dust, next to my stockpile of NAC.

There will be a dedicated post on sound issues in autism, which will draw everything together to include information from earlier posts.

and, not to forget, 

Danke vielmals Knut !

(Thanks to Knut!)