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Thursday 24 January 2019

Cheap common drugs may help mental illness










Stockholm, Sweden

When most people think of Sweden, they probably think of Volvo cars, now actually Chinese, and Ikea.  Today you will have to add keeping detailed centralized medical records to the list.
Today’s study included 142,691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia (SCZ), or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. 
It is relevant to readers of this blog because it shows that some of the same cheap generic drugs written about in this blog to modify aspects of autistic brain function do indeed show up as beneficial to those Swedes, with BPP, SCZ or NAP, who had by chance been prescribed those drugs for other reasons.
Numerous genetic studies have shown that the genes miss-expressed in autism overlap with those miss-expressed in bipolar (BPD) and schizophrenia (SCZ).
Clearly some people will get upset about autism (AUT) being called a mental illness. Whatever you choose to call SCZ and BPD you really need to apply to AUT, they are clearly just 3 overlapping clusters of gene miss-expression.
The study was summed up nicely in this BBC article.


Cheap and widely used drugs for diabetes and heart health have potential for treating severe mental illness, a study hints.
It showed the number of times patients needed hospital treatment fell by up to a fifth when they took the drugs.
The researchers at University College London say their findings have "enormous potential".
But they, and independent experts, say the results now need to be tested in clinical trials.
The starting point for the researchers was a list of currently prescribed medications that science predicts could also help patients with severe mental health disorders.
The team focused on:
§  anti-cholesterol drugs called statins - which may calm inflammation linked to mental health problems or help the body absorb anti-psychotic medications
§  blood pressure drugs - which may alter the calcium signalling in the brain that has been linked to bipolar disorder and schizophrenia
§  type 2 diabetes drug metformin - which may alter mood
But rather than test them in trials, the scientists went looking for evidence in the real world.
   
The press release from the lead author, who is at University College London



The full paper



Key Points

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?
Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalizaiton compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists.
Meaning  Hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides hold potential as repurposed agents in serious mental illness, and the central nervous system mechanism of action of these drugs requires further investigation.
Abstract 
Importance  Drug repurposing is potentially cost-effective, low risk, and necessary in psychiatric drug development. The availability of large, routine data sets provides the opportunity to evaluate the potential for currently used medication to benefit people with serious mental illness (SMI).
Objective  To determine whether hydroxylmethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA RIs), L-type calcium channel (LTCC) antagonists, and biguanides are associated with reduced psychiatric hospitalization and self-harm in individuals with SMI.
Design, Setting, and Participants  These within-individual cohort studies of patients with SMI compared rates of psychiatric hospitalization and self-harm during periods of exposure and nonexposure to the study drugs, with adjusting for a number of time-varying covariates. Participants included 142 691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia, or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. Data were analyzed from April 1 through August 31, 2018.
Interventions  Treatment with HMG-CoA RIs, LTCC antagonists, or biguanides.
Main Outcomes and Measures  Psychiatric hospitalizations and self-harm admissions.
Results  Among the 142 691 eligible participants, the HMG-CoA RI exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.89; P < .001), schizophrenia (aHR, 0.75; 95% CI, 0.71-0.79; P < .001), and NAP (aHR, 0.80; 95% CI, 0.75-0.85; P < .001) and reduced self-harm rates in BPD (aHR, 0.76; 95% CI, 0.66-0.86; P < .001) and schizophrenia (aHR, 0.58; 95% CI, 0.45-0.74; P < .001). Exposure to LTCC antagonists was associated with reduced rates of psychiatric hospitalization and self-harm in subgroups with BPD (aHRs, 0.92 [95% CI, 0.88-0.96; P < .001] and 0.81 [95% CI, 0.68-0.95; P = .01], respectively), schizophrenia (aHRs, 0.80 [95% CI, 0.74-0.85; P < .001] and 0.30 [95% CI, 0.18-0.48; P < .001], respectively), and NAP (aHRs, 0.89 [95% CI, 0.83-0.96; P = .002] and 0.56 [95% CI, 0.42-0.74; P < .001], respectively). During biguanide exposure, psychiatric hospitalization rates were reduced in subgroups with BPD (aHR, 0.80; 95% CI, 0.77-0.84; P < .001), schizophrenia (aHR, 0.73; 95% CI, 0.69-0.77; P < .001), and NAP (aHR, 0.85; 95% CI, 0.79-0.92; P < .001), and self-harm was reduced in BPD (aHR, 0.73; 95% CI, 0.62-0.84; P < .001) and schizophrenia (aHR, 0.64; 95% CI, 0.48-0.85; P < .001.
Conclusions and Relevance  This study provides additional evidence that exposure to HMG-CoA RIs, LTCC antagonists, and biguanides might lead to improved outcomes for individuals with SMI. Given the well-known adverse event profiles of these agents, they should be further investigated as repurposed agents for psychiatric symptoms.

Conclusion
If you are trying to convince your GP to prescribe some drugs off-label for autism, this study may help you convince him/her.
If your spouse, or other family members, think treating autism is folly, they might also benefit from reading about this study. 

The very old drug Metformin, used to treat type 2 diabetes has been mentioned many times in this blog and in today's study it was suggested to alter mood.  For severe autism mood is often not such a big issue, but for some mild autism mood is the big issue.
This study again shows how Scandinavian medicine collects a great deal of very usable data, in a recent post we saw something similar from Denmark. This is an example of socialized medicine at its best. I suppose the English lead author could not gather equivalent data in his home country.






Tuesday 15 January 2019

More Myelin? Or just Better Myelination - Intelligence, PDE4 and Clemastine again




Myelination in the Central Nervous System (CNS)                  Oligodendrocyte myelinating multiple axons

The previous post on myelin was this one.


In that post we saw that you can activate P2X7 receptors with an antihistamine called Clemastine and you can block P2X7 with another cheap antihistamine called Oxatomide. The P2X7 receptor plays a role in both inflammation and myelination and this receptor appears to be linked to neurological disorders including schizophrenia and even depression.
In that post I also compared experimental MS therapies with experimental autism therapies.




The yellow box means, we know it works, at least for some people, based on trial results.

The widely available PDE4 inhibitor, Roflumilast, has been patented as a cognitive enhancer, but even at that lower dose it can make people vomit.  Ibudilast seems to have fewer side effects and is under investigation in the US to treat MS, but is currently only approved in Japan and as an asthma therapy.
The logical next step is to investigate the two P2X7 modifying antihistamines, which should have opposing effects.
Oxatomide is widely used in Italy. Clemastine is OTC in the US and the UK.
I did some more investigation of Clemastine and came across some encouraging reports of off-label use in psychiatry at modest doses. Off label use to treat MS at high doses was associated with quite negative reports, due to the sedating effect, which is inevitable with antihistamines that can cross the blood brain barrier.
Today’s post goes into more detail about myelination and concludes with the open question of who might actually benefit from a half dose of clemastine, (Dayhist in the US, Tavegil in the UK); clearly some people do already benefit. 
At least one US child psychiatrist is a fan and the research suggests many conditions might benefit, ranging from severe to more trivial.  At 15-20 times higher dosage, clemastine is proposed as a therapy for Multiple Sclerosis (MS), but at that dosage clemastine is highly sedating. High dose clemastine might be a potential immediate response to the onset of regression in autism and CDD (Childhood Disintegrative Disorder).
Clemastine and Ibudilast have different modes of action. Clemastine works by activating P2X7 receptors in oligodendrocytes (in the CNS) and schwann cells (in the PNS) to make more myelin.
PDE4 inhibitors cause enhanced differentiation of OPCs (oligodendrocyte progenitor cells). OPC are precursors to oligodendrocytes.
So Roflumilast and Ibudilast should make more oligodendrocytes, while clemastine just kicks the ones you already have to work harder.  So in any one person the effect of these two types of drug may very well differ. 
Also, note that myelin needs to be constantly repaired in a process naturally called remyelination. So really we are just trying to benefit from improving this already existing repair service.

Some relevant background information:



“Myelination is only prevalent in a few brain regions at birth and continues into adulthood. The entire process is not complete until about 25–30 years of age. Myelination is an important component of intelligence. Neuroscientist Vincent J. Schmithorst proposes that there is a correlation with white matter and intelligence. People with greater white matter had higher IQs. A study done with rats by Janice M. Juraska showed that rats that were raised in an enriched environment had more myelination in their corpus callosum. 
In cerebral palsy, spinal cord injury, stroke and possibly multiple sclerosis, oligodendrocytes are thought to be damaged by excessive release of the neurotransmitter, glutamate. Damage has also been shown to be mediated by N-methyl-D-aspartate receptors. Oligodendrocyte dysfunction may also be implicated in the pathophysiology of schizophrenia and bipolar disorder.”

The role of myelin
Myelin has been compared to the insulation on electrical cables.  If only it was that simple, there would not be so many genes involved in the process.

Nodes of Ranvier do matter
If you look at the above graphic of a neuron you will see gaps in the myelin, that are called Nodes of Ranvier.
The electrical signal does not pass along the axon like a piece of copper wire, rather it jumps from one Node of Ranvier to the next, in a process called saltatory conduction.
Also each subsequent piece of myelin along the length of an axon is connected to a different oligodendrocyte. Otherwise there would be no electrical conduction possible; there has to be a “potential difference” for a current to flow.
Each oligodendrocyte can be connected to 50 different pieces of myelin, many on different axons. Just imagine what that looks like; forget the spaghetti of cables connected to your TV, this is something really jumbled up.
If the electrical signal jumps to an adjacent axon rather than jumping along the same axon, there will be a problem.
If there is too much myelin produced you might squeeze out the node of Ranvier and then the signal cannot pass along to the next neuron.



Myelination Defects in Autism
We have already seen in previous posts that myelination is often found to be abnormal in autism.
A very thorough recent study looked at myelination in a number of single gene autisms. The conclusion was that in these very different types of autism there was a common theme of defective myelination.
This adds further weight to the idea of considering impaired myelination a key feature of much autism.
Loss of myelination has been suggested to be a core feature of regressive autism and I propose a very likely driver of Childhood Disintegrative Disorder (CDD).
“Improving myelination” rather than simply “more myelination” might well be very helpful to many types of severe autism. It seems that even in much milder neurological conditions improving myelination can be therapeutic.
The usual target of experimental myelination therapies is Multiple Sclerosis (MS), it may also be the hardest to treat.
Some researchers and clinicians are repurposing MS therapies for other neurological disorders, either in mouse models or in humans.  This seems like a very good idea to me. 

One Sentence Summary: RNA sequencing of seven syndromic autism mouse models identify myelination genes disrupted in human ASD.

Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Ptenm3m4/m3m4, Mecp2KO). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.

To address these questions, we performed integrative transcriptomic analyses of seven independent mouse models of three syndromic forms of ASD generated across five laboratories, and assessed dysregulated genes and their pathways in human postmortem brain from patients with ASD and unaffected controls. These cross-species analyses converged on shared disruptions in myelination and axon development across both syndromic and idiopathic ASD, highlighting both the face validity of mouse models for these disorders and identifying novel convergent molecular phenotypes amendable to rescue with therapeutics. 

Shared myelination gene regulation between mouse models of syndromic ASD. Venn diagram of DEGs (differentially expressed genes) in each mouse model of ASD




Top GO (Gene ontology) terms of the CAGs (convergent ASD genes) enrich for myelination processes



P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.

The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina. The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death, regulation of receptor trafficking, mast cell degranulation, and inflammation.


Our findings point to P2X7R as a potential therapeutic target in schizophrenia.


The P2X7 purinergic receptor: An emerging therapeutic target in cardiovascular diseases

The P2X7 purinergic receptor, a calcium permeable cationic channel, is activated by extracellular ATP. Most studies show that P2X7 receptor plays an important role in the nervous system diseases, immune response, osteoporosis and cancer. Mounting evidence indicates that P2X7 receptor is also associated with cardiovascular disease. For example, the P2X7 receptor activated by ATP can attenuate myocardial ischemia-reperfusion injury. By contrast, inhibition of P2X7 receptor decreases arrhythmia after myocardial infarction, prolongs cardiac survival after a long term heart transplant, alleviates the dilated cardiomyopathy and the autoimmune myocarditis process. The P2X7 receptor also mitigates vascular diseases including atherosclerosis, hypertension, thrombosis and diabetic retinopathy. This review focuses on the latest research on the role and therapeutic potential of P2X7 receptor in cardiovascular diseases.

Clemastine is an extracellularly binding allosteric P2X7 receptor modulator.
Clemastine can potentiate the sensitivity of P2X7 to lower ATP concentrations. Additionally, clemastine increases the release of IL-1β from macrophages. Thus, clemastine may be a potential P2X7 activator.

Brain ischemia leading to stroke is a major cause of disability in developed countries. Therapeutic strategies have most commonly focused on protecting neurons from ischemic damage. However, ischemic damage to white matter causes oligodendrocyte death, myelin disruption, and axon dysfunction, and it is partially mediated by glutamate excitotoxicity. We have previously demonstrated that oligodendrocytes express ionotropic purinergic receptors. The objective of this study was to investigate the role of purinergic signaling in white matter ischemia. We show that, in addition to glutamate, enhanced ATP signaling during ischemia is also deleterious to oligodendrocytes and myelin, and impairs white matter function. Thus, ischemic oligodendrocytes in culture display an inward current and cytosolic Ca(2+) overload, which is partially mediated by P2X7 receptors. Indeed, oligodendrocytes release ATP after oxygen and glucose deprivation through the opening of pannexin hemichannels. Consistently, ischemia-induced mitochondrial depolarization as well as oxidative stress culminating in cell death are partially reversed by P2X7 receptor antagonists, by the ATP degrading enzyme apyrase and by blockers of pannexin hemichannels. In turn, ischemic damage in isolated optic nerves, which share the properties of brain white matter, is greatly attenuated by all these drugs. Ultrastructural analysis and electrophysiological recordings demonstrated that P2X7 antagonists prevent ischemic damage to oligodendrocytes and myelin, and improved action potential recovery after ischemia. These data indicate that ATP released during ischemia and the subsequent activation of P2X7 receptor is critical to white matter demise during stroke and point to this receptor type as a therapeutic target to limit tissue damage in cerebrovascular diseases.

Clemastine as a practical intervention
I came across a discussion among MS sufferers and a specific comment from a US child psychiatrist that drew my attention.


Daniel Kerlinsky says:   september 1 1, 2018 at 123 AM

Clemastine is a highly effective medication for re-myelination of white matter fiber bundles that connect neurons everywhere in the brain.
High doses aren't needed. One quarter of a 2.68 mg tablet is enough to start recruiting new oligodendrocytes to start making and applying myelin.
It does not have to be taken every day; it can be taken twice a week and still have a positive effect by recruiting the worker cells that repair the brain.
Remember normal myelination starts at the top of the brain and works downward during childhood development. At first the baby can't hold its head up, then it can sit up, then crawl, then stand.
Many MS lesions are located further down inside the brain and spinal cord so it takes time to get there.
The anti-inflammatory Minocycline taken once or twice a week is needed to stop the inflammatory part of the disease.                                                                            
And it takes cranio-sacral therapy to take full advantage of the new myelin which plumps the brain and even lubricates stiff joints like the sphenoid-occipital junction.
Don't give up on clemastine.

Its first and most obvious effect is improved emotional self regulation. Because myelination increases the speed of information processing ten-fold you will notice that thinking better comes next.
I can't tell you how long it will take to notice a difference. But the MS patient who told me about Clemastine got up out of her electric wheel chair and walked down the hall and back without a walker or her canes for the first time in two years.
It works great for kids with tantrums and developmental problems in about a month. It helps people with chronic depression and PTSD in about three months.
Back your dose down to 1.34 mg or 0.67 mg and give it two years. It takes a toddler that long.„



Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior.

SIGNIFICANCE STATEMENT Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under demyelinating conditions, successfully reversed social avoidance behavior in adult socially isolated mice. This was associated with enhanced myelination and oligodendrocyte differentiation in the prefrontal cortex through epigenetic regulation. Thus, enhancing myelination may be a potential means of reversing depressive-like social behavior.



BACKGROUND:

Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis.

METHODS:


We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298.

FINDINGS:


Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.

INTERPRETATION:


To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage.



Drug: Clemastine

12mg (4mg 3x/day) clemastine for 7 days followed by 8mg clemastine (4mg 2x/day) until 3 months. Patients will be off treatment from 3-9 months and will be reevaluated at 9 months.



Conclusion
Hopefully this post takes us one step closer to finding safe, side effect free, inexpensive ways to improve myelination in those with impaired myelination.

In the case of treating Multiple Sclerosis (MS), side effects clearly remain an issue. The suggestion of the psychiatrist in today’s post is to just lower the clemastine dosage and give it some time (2 years).  That sounds like smart advice to me.
Fortunately, it appears that in less severe cases of impaired myelination you may not need to wait 2 years.

Who exactly is going to benefit remains an open question, but for people already using H1 antihistamines to treat allergy, or other mast cell activation, switching to a different OTC antihistamine drug does not look like such a big step to take.
People with schizophrenia and allergy also might want to consider switching their antihistamine.

Undoubtedly some people will have the opposite issue with P2X7 receptors and for them there is another old antihistamine drug called Oxatomide.




Tuesday 8 January 2019

BHB + C8 in Autism, a Work-in-Progress



The potential benefit of the ketone BHB in autism was covered extensively in earlier posts.  It looks like different people may benefit for entirely different reasons and some may not benefit at all. 

Some MCT oils, taken as precursors to BHB, can actually make people worse.


Measuring ketones and glucose in blood


Click for a summary of the previous posts.

I know that some readers of this blog have found that BHB/C8 does indeed provide a benefit in their specific type of autism.  The benefit seems to vary, but given all the biological modes of action of the ketone BHB that is not surprising.  Increased speech is a frequently noted benefit.
My initial combination of Ketoforce plus C8 continues to be effective.
Substituting a cheaper MCT oil containing both C8 and C10 (Bulletproof XCT oil), was less effective and after a matter of weeks produced a negative effect. It appears that C10, after a while, can produce mild anxiety and agitation in some people. In our case this goes away when stopping the C8+C10 MCT oil and then reappears restarting it.
When it comes to C8, it appears that not all food grade 98% C8 products are actually what they claim to be. This is a recurring theme with all supplements, they lack the quality control you get with pharmaceuticals.
Our reader Yi did at one point raise the issue of BHB causing diuresis. We also experienced this and much more so with the “mixed” C8+C10 MCT oil, rather than the “pure” C8.
The combination of increased diuresis and all the sodium, magnesium, potassium in the BHB salts may very well create an issue with electrolyte levels. Potassium does seem to be the most critical one to monitor.
Different BHB products contain very different amounts of sodium, magnesium, potassium and so it is unwise to simply substitute one for another.
Our reader Agnieszka did experiment with different BHB products and found that, based on urine testing, Ketoforce was the most effective. I also think this is likely the best choice.  Ideally you would measure BHB in blood and devices are available (see above photo).
For people living in Europe, BHB products have fallen foul of EU legislation that requires new supplements to be approved before they can be sold in the European Union. As BHB is a recently introduced supplement, it cannot legally be sold in the EU until someone pays for it to be approved. This means that in EU countries that strictly apply the rules, like the UK, you cannot buy BHB, but in other EU countries you still can.
The same legal status regarding BHB in the EU also applies to Agmatine.
Another oddity is that Melatonin is banned as a supplement in the UK, but not other EU countries; it is a very popular supplement in North America.




Tuesday 1 January 2019

Apple Cider Vinegar (ACV), Phloretin, Phloridzin, Chlorogenic Acid, OAT3, Autism and Colon Cancer



Today’s post is only marginally related to autism, but does again show how some common food products have potential medical benefits.




Where I currently live people have been using apple cider vinegar (ACV) as a home remedy for generations. It is the apple part, rather than the vinegar part that is most interesting. I think they should continue with this home remedy, just be careful not to dissolve the enamel on their teeth. 
Rather surprisingly we can link ACV to improving Bumetanide effectiveness in autism and the chemoprotective effect of statins.
I have read so much research about statins, I do take Atorvastatin myself. The only downside is that research shows it does increase fasting glucose levels by about 0.4 mmol/L, exactly why nobody is quite sure.
If you want to further boost the chemoprotective power of statins it seems you may need a little help from something called Phloretin. Phloretin is a phenol that occurs in apples and the leaves of apple trees.  Apple cider vinegar (ACV) is rich in Phloretin.




Viability of HCT 116 colon cancer cells 48 hours after treatment with:-

PT = Phloretin
ATST = Atorvastatin
PT+ATST =  Phloretin + Atorvastatin

The closer to zero the better the result.  

If you want to improve insulin sensitivity and reduce fasting glucose levels it looks like it is the Phloridzin, a close relative of Phloretin, in apple cider vinegar that is useful.
If you want to improve the pharmacokinetics (how a drug is absorbed, distributed, metabolized, and excreted) of bumetanide you may also be able to use apple cider vinegar (ACV).  ACV also contains Chlorogenic acid which we we saw in an earlier post inhibits excretion of bumetanide through OAT3 (Organic acid transporter 3). Chlorogenic acid is also found in coffee.
In theory ACV will cause the level of bumetanide in blood to be higher, which might increase the amount that crosses the blood brain barrier and so make bumetanide a more potent autism drug. 
One odd proposed benefit of ACV is on GERD/reflux. You might have thought taking an acid would be the last thing that would help.
You would have thought that strong alcohol (also low pH, so very acidic) would also upset people with GERD/esophagitis, but some people I know swear that it is very beneficial.
In the case of GERD/esophagitis rather bizarrely I think it is the acetic acid (low pH) that is the reason why ACV seems to help some people.  I think it may help via feedback loops to trick the body into reducing its own acid production.

The drawbacks of Apple Cider Vinegar (ACV)
The acetic acid in apple cider vinegar can damage your teeth and your esophagus.  People avoid these problems by diluting ACV in a glass of water and rinsing their mouth with clean water afterwards.

ACV can lower potassium levels and it will lower blood glucose levels, which is good thing for most people, but diabetics would need to take care. Low potassium seems to worsen behaviour and increase sound sensitivity.
The Phloridzin in ACV is likely to reduce appetite, which for most people is a good thing, but for those few who struggle to gain weight it might be an issue.
ACV should lower triglycerides significantly, which might be bad for somebody. 



The results of the present study demonstrated that the antitumor efficacy of ATST could be enhanced at a relatively low dosage through the synergistic action with PT, which suggested the potential interaction of statins with other compounds in the food matrix. This interaction affects the efficacy of statins, and may explain the controversial results obtained in prior studies regarding the associations between statin use and the risk of colon cancer-associated mortality (27,28). As the dietary composition is different for each individual, this can result in varying statin efficacy. Conversely, different statins have different antitumor effects. In six colorectal cancer cell lines, including DLD1, HT29, SW620, HCT116, LoVo and colo320, simvastatin and fluvastatin showed strong growth suppressive effects. Atorvastatin demonstrated a relatively weak growth suppressive effect, whereas no growth suppressive effect was observed with pravastatin (29). This may be another reason for the paradoxical results regarding the antitumor effects of statins.
Therefore, the p21 gene may be the potential regulatory target underlying the G2/M phase arrest following the synergistic action of ATST and PT; more in depth future investigations are warranted.
In summary, the present study demonstrated that PT and ATST produce a powerful synergistic interaction in suppressing colon cancer cell growth. This process was accomplished via the synergistic induction of apoptosis and the arrest of the cell cycle at the G2/M checkpoint, which resulted from downregulated cdc2 activation following combined treatment.



Vinegars contain several bioactive compounds that are characterized according to the type of the raw material, such as grape vinegars and apple vinegars. Liquid chromatography coupled to diode array detection and electrospray ionization tandem mass spectrometry was used for identification and quantification of phenolic compounds. Antioxidant properties of vinegars were determined by 2,2diphenyl1picrylhydrazyl and 2,2′azinobis3ethylbenzthiazoline6sulphonic acid assays. Antimicrobial activities of vinegars were examined with an agar disc diffusion method with Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Gallic acid and chlorogenic acid were found to be the major phenolic acids accounting for the largest proportion of the total phenolic acid contents in grape vinegars and apple vinegars. Within the flavonols, quercetin3Ogalactoside and quercetin were detected as the major compounds in grape vinegars. Apple vinegars were characterized by phloridzin, phloretin and high chlorogenic acid content. Antimicrobial activity results indicated that grape vinegars exhibited higher antimicrobial activity against tested bacterial strains correlated with their higher antioxidant capacity.

In conclusion, gallic acid, tyrosol, protocatechuic acid, caftaric acid, catechin, epicatechin and syringic acid constituted the highest proportion of the total phenolic contents in GV. Chlorogenic acid, phloridzin and phloretin were found to be the major phenolic compounds in AV. With respect to antimicrobial and antioxidant activity results, GV showed higher antimicrobial and antioxidant activity than AV. With regard to phenolic composition of vinegars with their antioxidant capacities, two separate groups were obtained and characterized the vinegars with PCA based on the type of raw material. The results we obtained in this study extend our knowledge about the composition of vinegars obtained from different raw materials consumed in Turkey and allow the consumer to compare vinegar brands with the highest contents of beneficial compounds.


Coffee = chlorogenic acids  = 1,3- and 1,5-dicaffeoylquinic acid
Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions

3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids

Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus  pmol mg 10  , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.


Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats.

Abstract


Phloridzin is the specific and competitive inhibition of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products. The effect of phloridzin orally doses 5, 10, 20 and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic, urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.  

Harvard Medical School vs the BBC?
You might expect when it comes to investigating health claims about apple cider vinegar (ACV) that Harvard would give you the science and the BBC would be just superficial.
While neither actually bother to use google to find what the active constituents of ACV might be, the BBC do actually make a trial in humans and measure the results in a lab.                                                                                             


It looks like if you have high triglycerides, or indeed high blood glucose, ACV is a potentially interesting non-drug therapy.
The guys at Harvard should watch the BBC and try a little harder next time.


Conclusion
Apple cider vinegar (ACV) is one home remedy that now has some science to support it. It is cheap and easy to access.
It is perhaps not relevant to many people with autism, but does show how medicine turns a blind eye to some old treatments that were stumbled upon as being effective hundreds of years ago.
When it comes to chemoprevention, the majority of cancers in males (prostate, colon, esophagus, bladder etc) have been shown in the research to be inhibited by statins. Some people know they have a familial risk of one or more of these cancers, would it not make sense that they be informed about chemoprevention?  It is much better to avoid cancer than to have to try to treat it.  In colon cancer it appears that phloretin from ACV might even be helpful.
We also saw that people with type 2 diabetes often find the beta cells in their pancreas die and so they stop making insulin, and yet a cheap calcium channel blocker can protect those insulin-producing cells and put off the day that insulin injections are required.
I did actually borrow my “polypill” name for my son’s autism therapy from another polypill that was designed to extend the healthy life expectancy of older people. Their pill has not been a huge success.

What is needed is a personalized polypill, whether it is for people with autism or typical adults from the age of 50.
I imagine, in 50 years time, when your family doctor has your genome on file, you probably will have a personalized little pill to help you minimize the risk of developing preventable disease.