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Monday 27 April 2015

RAS signaling, Autism, Cancer and Gingerols



Sytrinol (Tangeretin), sacrificial Gummy Bear and Gingerol


Today’s post follows on from an earlier one that introduced the term RASopathy.  A RASopathy is a disease characterized by over-activation of the RAS protein.

RASopathies are of interest because if you have one, you are highly likely to also have autism.

RAS dysfunction is also present in many types of cancer and there are existing drugs to inhibit RAS signaling.  It has been claimed that:-

"If RAS proves to be a key player in autism …  it might suggest new treatments for autism, as many cancer drugs inhibit RAS signaling."


Regular readers of the Simons Foundation autism blog may have read the following:



  


If RAS proves to be a key player in autism, she says, it might suggest new treatments for autism, as many cancer drugs inhibit RAS signaling.



RAS-based interventions

My Polypill already has one RAS-based component, the statin.  This (the statin) is now being patented by the University of California.



Innovation
Professor Alcino Silva and colleagues at the UCLA department of Neurobiology have repurposed HMG-CoA reductase inhibitors (or statins) to reverse the cognitive dysfunction associated with RASopathies. By blocking HMG-CoA reductase, the drug prevents overactivation of the Ras protein, which leads to deficits in long term potentiation, a mechanism of learning and memory. Using in vivo models of NF1 and Noonan Syndrome, the researchers have shown that lovastatin is able to restore both LTP deficits and cognitive function to wild-type levels.
Applications
• Treatment of cognitive dysfunction associated with NF1
• Treatment of cognitive dysfunction associated with Noonan syndrome
• Treatment of other disorders driven by hyperactivation of the Ras-MAPK pathway
Advantages
• Statins would represent the first and only drug available to treat the cognitive defects observed in NF1, Noonan and other RASopathies
• Statins have already been approved by the FDA as a cholesterol-lowering drug, demonstrating an amenable safety profile in humans
• Effectiveness in restoring cognitive function has been demonstrated in vivo

  

The studies using Lovastatin were positive:-





However in the following trial in the Netherlands, Simvastatin was shown not to be effective in NF-1.




The UCLA team seem to think Lovastatin has potential, even though Simvastatin appears not to.

There is a comprehensive presentation from Silvalab at UCLA below,













It seems that in Rett Syndrome (not a RASopathy) statins may also help.





So choose your statin with care. 

We use Atorvastatin.  It works; but it has various possible modes of action, one of which is RAS.  Another is upregulating PTEN.

Upregulating PTEN is good, but if used to excess it may lead to reduced insulin sensitivity and type 2 diabetes.

However, anti-oxidants, sulfurophane and PPAR gamma agonists (Gingerols, tangeretin) all increase insulin sensitivity so this tiny risk can be mitigated.  Verapamil protects beta cells (that produce insulin) from damage.


Statin MAX

I was interested in further increasing the RAS inhibition to see if there would be further cognitive or other improvement.  This is not possible via increasing the dose of statin, but it is possible by using Farnesyltransferase inhibitors, these are mainly anti-cancer research compounds, but one is the flavonoid Gingerol.

Ginger is another of those substances that has been used for centuries in traditional medicine. Gingerols are found in uncooked ginger.


Gingerols in “Medicine”

Fortunately ginger has many claimed medical benefits, ranging from arthritis to cancer prevention and treatment.  As a result standardized concentrated versions are widely available.

When it comes to my experiments, one problem has been the taste of the substance and the loss in bioavailability by having to open up/crush the various substances.


Swallowing Pills

Swallowing pills is not an option for some people, but in some cases you lose the effect of a drug if you remove the outer coating.  This is true with the drugs that lower the acidity of your stomach (Proton Pump Inhibitors).  They are designed to dissolve in the acidity of your intestines and not before.

Sytrinol ,the tangeretin flavonoid that is an attractive PPAR gamma inhibitor, is packed in a thick capsule, because the research shows this increases its bioavailability.  So me squeezing it out on a piece of toast will dilute its potency.  

Having obtained my high gingerol content potion, the first thing I did was to open the capsule and taste it.  Not nice at all.

Monty, aged 11 with ASD, has an elder brother who makes an enormous fuss on the very rare occasion he has to swallow a tablet.

Having overcome the usual autism problems of visiting a dentist and a hairdresser, the time had come for Monty to learn how to swallow pills.

In the end it was a non-event.

Having agreed that a gummy bear would be the reward and with the usual glass of water sitting beside it, the lesson began.  I put a NAC pill on my tongue and he put a Tangeretin capsule on his.

Before I could even suggest he drank some water, he had swallow the Tangeretin and bitten the head off the gummy bear.

This was swiftly followed by the rather odd smelling gingerol capsule.

So, rather unexpectedly, I can proceed with my gingerol investigation.

Gingerol may or may not be effective in our type of autism, but the research is highly promising in several other areas, some comorbid* with autism.

·        Asthma*
·        Ulcerative Colitis*
·        Arthritis *
·        Alzheimer’s Disease
·        Cancer*

No data suggests people with ASD are prone to Alzheimer’s, although some Alzheimer’s drugs do help some people with ASD.  It may just be that people with ASD do not make it to their eighties. 


Safety

Ginger is very widely used and I do not see any safety issues, just taste issues.



Asthma




Clinical Relevance

Natural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonistinduced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.




Arthritis



“In conclusion, these data document a very significant joint-protective effect of these ginger samples, and suggest that non-gingerol components are bioactive and can enhance the antiarthritic effects of the more widely studied gingerols.”


Arthritis. Some research shows that taking ginger can modestly reduce pain in some people with a form of arthritis called “osteoarthritis.” One study shows that taking a specific ginger extract (Zintona EC) 250 mg four times daily reduced arthritis pain in the knee after 3 months of treatment. Another study shows that using a different ginger extract (Eurovita Extract 77; EV ext-77), which combines a ginger with alpinia also reduces pain upon standing, pain after walking, and stiffness. Some research has compared ginger to medications such as ibuprofen. In one study, a specific ginger extract (Eurovita Extract 33; EV ext-33) did not work as well as taking ibuprofen 400 mg three times daily for reducing arthritis pain. But in another study, taking ginger extract 500 mg twice daily worked about as well as ibuprofen 400 mg three times daily for hip and knee pain related to arthritis. In another study, a specific ginger extract combined with glucosamine (Zinaxin glucosamine, EV ext-35) worked as well as the anti-inflamatory medication diclofenac slow release 100 mg daily plus glucosamine sulfate 1 gram daily. Research also suggests that massage therapy using an oil containing ginger and orange seems to reduce short-term stiffness and pain in people with knee pain.


Ulcerative Colitis



Gingerols are phenolic compounds in ginger (Zingiber officinale), which have been reported to exhibit anti-inflammatory, antioxidant, and anticancer properties. The present study aimed at evaluating the possible pharmacologic activity of 6-gingerol in a mouse model of dextran sulphate sodium (DSS)-induced ulcerative colitis. Adult male mice were exposed to DSS in drinking water alone or co-treated with 6-gingerol orally at 50, 100, and 200 mg/kg for 7 days. Disease activity index, inflammatory mediators, oxidative stress indices, and histopathological examination of the colons were evaluated to monitor treatment-related effects of 6-gingerol in DSS-treated mice. Administration of 6-gingerol significantly reversed the DSS-mediated reduction in body weight, diarrhea, rectal bleeding, and colon shrinkage to near normal. Moreover, 6-gingerol significantly suppressed the circulating concentrations of interleukin-1β and tumor necrosis factor alpha and restored the colonic nitric oxide concentration and myeloperoxidase activity to normal in DSS-treated mice. 6-Gingerol efficiently prevented colonic oxidative damage by increasing the activities of antioxidant enzymes and glutathione content, decreasing the hydrogen peroxide and malondialdehyde levels, and ameliorated the colonic atrophy in DSS-treated mice. 6-Gingerol suppressed the induction of ulcerative colitis in mice via antioxidant and anti-inflammatory activities, and may thus represent a potential anticolitis drug candidate.


PPARγ

6-gingerol inhibits rosiglitazone-induced adipogenesis in 3T3-L1 adipocytes.


Abstract

We investigated the effects of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone) on the inhibition of rosiglitazone (RGZ)-induced adipogenesis in 3T3-L1 cells. The morphological changes were photographed based on staining lipid accumulation by Oil-Red O in RGZ (1 µmol/l)-treated 3T3-L1 cells without or with various concentrations of 6-gingerol on differentiation day 8. Quantitation of triglycerides content was performed in cells on day 8 after differentiation induction. Differentiated cells were lysed to detect mRNA and protein levels of adipocyte-specific transcription factors by real-time reverse transcription-polymerase chain reaction and Western blot analysis, respectively. 6-gingerol (50 µmol/l) effectively suppressed oil droplet accumulation and reduced the sizes of the droplets in RGZ-induced adipocyte differentiation in 3T3-L1 cells. The triglyceride accumulation induced by RGZ in differentiated 3T3-L1 cells was also reduced by 6-gingerol (50 µmol/l). Treatment of differentiated 3T3-L1 cells with 6-gingerol (50 µmol/l) antagonized RGZ-induced gene expression of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein α. Additionally, the increased levels of mRNA and protein in adipocyte-specific fatty acid binding protein 4 and fatty acid synthase induced by RGZ in 3T3-L1 cells were decreased upon treatment with 6-gingerol. Our data suggests that 6-gingerol may be beneficial in obesity, by reducing adipogenesis partly through the down-regulating PPARγ activity.





ABSTRACT In this study, we demonstrated that the two ginger-derived components have a potent and unique pharmacological function in 3T3-L1 adipocytes via different mechanisms. Both pretreatment of 6-shogaol (6S) and 6-gingerol (6G) significantly inhibited the tumor necrosis factor-alpha (TNF-alpha) mediated downregulation of the adiponectin expression in 3T3-L1 adipocytes. Our study demonstrate that (1) 6S functions as a PPARgamma agonist with its inhibitory mechanism due to the PPARgamma transactivation, and (2) 6G is not a PPARgamma agonist, but it is an effective inhibitor of TNF-alpha induced c-Jun-NH(2)-terminal kinase signaling activation and thus, its inhibitory mechanism is due to this inhibitory effect.


Microglial Activation



Abstract: Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation.
Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed.
Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.


8. Gingerol from Zingiber officinale
Ginger, the rhizome of the plant Zingiber officinale, has a long history of medicinal use. In traditional oriental medicine, ginger has been used to treat a wide range of ailments including stomach aches, diarrhea, nausea, asthma, respiratory disorders, toothache, gingivitis, and arthritis [98-100]. Several studies have shown that ginger inhibits pro-inflammatory cytokines, including IL-1β, IL-2 , TNF-α, and interferon (IFN)-gamma [101]. Ginger also has been shown to decrease synthesis of pro-inflammatory prostaglandins and leukotrienes via inhibition of COX-2 and 5-lipoxygenase (5- LOX) enzymes, which are the targets for numerous anti-inflammatory pharmaceuticals.
Grzanna et al. tested the effects of a ginger extract on THP-1 monocytic cells to determine whether it can block the induction of pro-inflammatory cytokines in these cells stimulated with LPS. The results of this study suggest that the anti-inflammatory properties of the ginger extract may provide beneficial effects similar to those of currently used COX inhibitors [102].
Recently, Jung et al. reported that the hexane fraction of Zingiberis Rhizoma Crudus extract inhibits the production of nitric oxide and pro-inflammatory cytokines in LPS-stimulated BV-2 microglial cells via the NF-κB pathway [103]. The authors indicated that ginger hexane extract significantly inhibited the excessive production of NO, PGE2, TNF-α, and IL-1β in LPS-stimulated BV-2 cells. Ginger extract also attenuated the mRNA expressions and protein levels of iNOS, COX-2, and proinflammatory cytokines. The molecular mechanisms that underlie ginger hexane extract-mediated attenuation of neuroinflammation were related to the inhibition of the phosphorylation of three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK), and the activation of NF-κB [103].
6-Gingerol (Figure 2B), one of the active ingredients of ginger, has been reported to impart ginger with its anti-inflammatory properties. The 6-gingerol inhibited the production of pro-inflammatory cytokines from LPS-stimulated macrophages, and inhibited COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester-stimulated mouse skin [104-105]. Data indicate that several doses of 6-gingerol selectively inhibit production of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-12 by murine peritoneal macrophages in the presence of LPS stimulation.
The authors also revealed that 6-gingerol does not affect antigen presenting cell (APC) function or cell surface expression of MHC II and co-stimulatory molecules [105]. These remarkable beneficial properties of ginger and 6-gingerol and the lack of gastrointestinal and renal side effects distinguish it from other NSAIDS. Considering the broad spectrum of ginger’s anti-inflammatory actions and its safety record in clinical trials, it is likely to be a valuable dietary supplement in the treatment of neurodegenerative and neuroinflammatory diseases. However, the ability of gingerol to cross bloodbrain barrier has not yet been explicitly demonstrated and needs further investigation.

.

Alzheimer’s Disease

At least in rats, we know that Gingerol does cross the blood brain barrier.

Protective effects of ginger root extract on Alzheimer disease-induced behavioral dysfunction in rats.


Abstract

The aim of this study was to assess the ability of a traditional Chinese medicinal ginger root extract (GRE) to prevent behavioral dysfunction in the Alzheimer disease (AD) rat model. Rat AD models were established by an operation (OP) in which rats were treated with a one-time intra-cerebroventricuIar injection of amyloid β-protein (Aβ) and continuous gavage of aluminum chloride every day for 4 weeks. GRE was administered intra-gastrically to rats. After 35 days, learning and memory were assessed in all of the rats. Brain sections were processed for immunohistochemistry and Hematoxylin & Eosin (H&E) and Nissl staining. The latency to show significant memory deficits was shorter in the group that received OP with a high dose of GRE (HG)(OP+HG) than in the groups that received OP with a low or moderate dose of GRE (LG, MG)(OP+LG, OP+MG) (p<0.05). The expression of superoxide dismutase (SOD) and catalase (CAT) in the OP+MG and OP+LG groups was up-regulated compared to the OP+HG groups (p<0.05). The rats in the OP+HG groups had lower levels of nuclear factor-κB (NF-κB), interleukin-1β (IL-1β), and malondialdehyde (MDA) expression than the rats in the OP+MG and OP+LG groups (p<0.05). This experiment demonstrates that the administration of GRE reverses behavioral dysfunction and prevents AD-like symptoms in our rat model.




 Abstract

β-Amyloid (Aβ) is involved in the formation of senile plaques, the typical neuropathological marker for Alzheimer’s disease (AD) and has been reported to cause apoptosis in neurons via oxidative and/or nitrosative stress. In this study, we have investigated the neuroprotective effect and molecular mechanism of [6]-gingerol, a pungent ingredient of ginger against Αβ25–35-induced oxidative and/or nitrosative cell death in SH-SY5Y cells. [6]-Gingerol pretreatment protected against Aβ25–35-induced cytotoxicity and apoptotic cell death such as DNA fragmentation, disruption of mitochondrial membrane potential, elevated Bax/Bcl-2 ratio, and activation of caspase-3. To elucidate the neuroprotective mechanism of [6]-gingerol, we have examined Aβ25–35-induced oxidative and/or nitrosative stress and cellular antioxidant defense system against them. [6]-Gingerol effectively suppressed Aβ25–35-induced intracellular accumulation of reactive oxygen and/or nitrogen species and restored Aβ25–35-depleted endogenous antioxidant glutathione levels. Furthermore, [6]-gingerol treatment up-regulated the mRNA and protein expression of antioxidant enzymes such as γ-glutamylcysteine ligase (GCL) and heme oxygenase-1 (HO-1), the rate limiting enzymes in the glutathione biosynthesis and the degradation of heme, respectively. The expression of aforementioned antioxidant enzymes seemed to be mediated by activation of NF-E2-related factor 2 (Nrf2). These results suggest that [6]-gingerol exhibits preventive and/or therapeutic potential for the management of AD via augmentation of antioxidant capacity.


Cancer


NAC interferes with some anti-cancer actions, be careful if self treating




Abstract

Ginger, the rhizome of Zingiber officinale, is a traditional medicine with anti-inflammatory and anticarcinogenic properties. This study examined the growth inhibitory effects of the structurally related compounds 6-gingerol and 6-shogaol on human cancer cells. 6-Shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] inhibits the growth of human cancer cells and induces apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 6-shogaol-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. Up-regulation of Bax, Fas, and FasL, as well as down-regulation of Bcl-2 and Bcl-XL were observed in 6-shogaol-treated COLO 205 cells. N-acetylcysteine (NAC), but not by other antioxidants, suppress 6-shogaol-induced apoptosis. The growth arrest and DNA damage (GADD)-inducible transcription factor 153 (GADD153) mRNA and protein is markedly induced in a time- and concentration-dependent manner in response to 6-shogaol.



Results
In the antioxidant activity assay, [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol exhibited substantial scavenging activities with IC50 values of 26.3, 19.47, 10.47 and 8.05 μM against DPPH radical, IC50 values of 4.05, 2.5, 1.68 and 0.85 μM against superoxide radical and IC50 values of 4.62, 1.97, 1.35 and 0.72 μM against hydroxyl radical, respectively. The free radical scavenging activity of these compounds also enhanced with increasing concentration (P < 0.05). On the other hand, all the compounds at a concentration of 6 μM have significantly inhibited (P < 0.05) f-MLP-stimulated oxidative burst in PMN. In addition, production of inflammatory mediators (NO and PGE2) has been inhibited significantly (P < 0.05) and dose-dependently.
Conclusions
6-Shogaol has exhibited the most potent antioxidant and anti-inflammatory properties which can be attributed to the presence of α,β-unsaturated ketone moiety. The carbon chain length has also played a significant role in making 10-gingerol as the most potent among all the gingerols. This study justifies the use of dry ginger in traditional systems of medicine.



Conclusion: The study reports the antiproliferative and apoptosis-mediated cytotoxic effects of green tea and ginger polyphenolic extracts on human H460 cell line, indicating their promising chemopreventive effect against lung cancer.





Conclusion

Ginger certainly does look to be good for you, but it has to be uncooked, otherwise you lose those gingerols.

I expect in ten years’ time we will know whether RAS signaling does underlie the autism of a wider group of people than those with currently identified RASopathies.

If you are impatient to know the answer you have a few choices:-

·        Statins

·        Gingerols

·        Other farnesyltransferase inhibitors (FTIs), a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in cancer.











Thursday 23 April 2015

Buy Arbaclofen for Autism? Perhaps try Pantogam Aktiv?


             
An Enantiomer is like a mirror image,
so there are two versions of the “same” molecule one called R- and one called  S-


Some people are still looking to obtain Arbaclofen to treat autism and Fragile-X, they regularly stumble upon this blog.

A couple of years ago there was a lot of interest in Arbaclofen (R-baclofen), a GABAB drug, which is, in effect, a special version of a cheap existing drug called Baclofen.  Baclofen is generally used to treat spasticity, but also alcoholism and even hiccups.

As we saw in earlier posts, the drug Baclofen is a mixture of R-Baclofen and S-Baclofen. The research showed that their action is different and that S-Baclofen reduced the effect of R-baclofen.  So in some modes of action, pure R-Baclofen would have much greater effect than the regular Baclofen mixture.

If you use the "index by subject" on this blog, which is a tab at the top, you can find the posts that relate to Arbaclofen.

Arbaclofen

Arbaclofen Research in Autism/Fragile X

This very expensive episode was triggered by one child with autism being prescribed regular Baclofen, for an unrelated issue.  That child’s autism had dramatically improved, this then led to the interest of Seaside Therapeutics, who already had another prospective autism drug.

After tens of millions of dollars spent, everything stopped a couple of years ago.  The developer, Seaside Therapeutics, appears to have been shut down, although in its clinical trial a substantial minority found the drug was effective.  The way the trial had been structured, the drug did not achieve is “primary endpoint” and so Roche, the potential follow-on investor, deemed the trial a failure.

This led to many unhappy parents seeking alternative sources of R-Baclofen, which they believed had been effective.


Baclofen for Asperger’s?

At least one regular reader of this blog finds that Baclofen is very helpful for himself.

Yesterday before completing this post I had some exchanges with a UK pediatrician (spelled paediatrician in the UK) who is prescribing Baclofen to eight children with Asperger’s to treat anxiety. The results are very positive.  I do wonder is this a 100% response rate,  or are the eight a subset of all the children that have tried the drug?

One of our Australian readers of this blog is very interested in minimizing anxiety in his child with high functioning autism.  He did forward me some research, a while back,  that links GABAB to Somatostatin, also called Growth Hormone Inhibiting Hormone (GHIH) .  The research from Carnegie Mellon shows that GHIH changes the way the brain functions. 
This does get very complicated the more you dig and, until today, I did not start to write up my findings.  This is just some initial thoughts/links for scientists.
“Furthermore, by silencing certain parts of the neuronal network, the activity of the somatostatin neurons also can change the way the brain functions, heightening some perceptual pathways and silencing others.” 

“If the levels of human growth hormone in circulation in the brain and the blood get too high, then special cells called somatostatin neurons detect this. These neurons then trigger the creation of more GHIH in the brain. This then in turn slows down the secretion of human growth hormone.”

 “Mature interneurons from this brain region mainly express either parvalbumin or somatostatin, which serve as markers of these subtypes. Parvalbumin neurons tend to fire quickly in response to signals, whereas the somatostatin ones respond more slowly.
In control mice, the ratio of these two subtypes is about 50:50. By contrast, the mutant mice show a dramatic decrease in the number of interneurons expressing somatostatin. This results in an excess of abnormally large cells expressing parvalbumin.
Despite an overall loss of interneurons, the mice have more inhibitory signals than controls do, skewing the signaling balance to excitation.” 

We do know that the various growth factors in people with autism can be disturbed, but in different types of autism that disturbance varies, just to complicate things.

Various therapies based on this are under development (one uses IGF-1 and NNZ-256 is another).  We also know that many people with classic autism have accelerated growth (both body and head) in the first two years.  We also know that brain growth is also accelerated.

We know from the genetic research that many of the anomalies relate to GABA.

We know that targeting the GABAA receptor can be hugely beneficial in classic autism (bumetanide and micro-dose clonazepam).  We can also fine tune the structure of the GABAA receptor and potentiate it using allosteric modulators (like Pregnenolone or progesterone).  This also gets very complicated.



Baclofen for Classic Autism?

Baclofen is a spasticity drug:

Spasticity (from Greek spasmos-, meaning "drawing, pulling") is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles.

People with (classic) autism as opposed to Asperger’s can have all sorts of fine and gross motor issues, particularly as young children.

They can “toe walk”, walk with their feet pointing in different directions, they can have “claw hand”.  They can struggle to control a pencil and even when they learn, their handwriting can be very sloppy.

Are these spasticity issues?  I think they probably are.

When people’s autism flares up, an early sign is worsening handwriting.

When my son’s Polypill begins to wear off in spring/summer at school at around 11 am, the claw hand returns.

I did indeed try Baclofen about a year ago.  There is an effect - no claw hand.

The problem with Baclofen is tolerance, the more you use it the higher the effective dose becomes, just like benzodiazepines.

So I noted that there was an effect, but chose to move on.


Meanwhile over in Russia

For many years in Russia they have had their own GABAB drug, similar to Baclofen, it is called Pantogam.  Pantogam has been used for years as a therapy for neurological conditions including autism.

Just as Baclofen is “racemic mixture” of left-baclofen and right-baclofen, so is Pantogam.  There is S-Pantogam and R-Pantogam.


Enantiomers

There is nothing strange about these left and right versions of a drug


Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is sometimes a marked difference in the effects of two enantiomers on living beings. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for adverse effects.
Owing to this discovery, drugs composed of only one enantiomer ("enantiopure") can be developed to enhance the pharmacological efficacy and sometimes do away with some side effects. An example of this kind of drug is eszopiclone (Lunesta), which is enantiopure and therefore is given in doses that are exactly 1/2 of the older, racemic mixture called zopiclone. In the case of eszopiclone, the S enantiomer is responsible for all the desired effects, though the other enantiomer seems to be inactive; while an individual must take 2 mg of zopiclone to get the same therapeutic benefit as they would receive from 1 mg of eszopiclone, that appears to be the only difference between the two drugs.

Another good example is a common antihistamine:-
Levocetirizine (Xyzal) and cetirizine (Zyrtec)
Cetirizine, an effective H1-receptor antagonist, is a racemate mixture of two enantiomers: levocetirizine (R enantiomer) and dextrocetirizine (S enantiomer).  Chemically, levocetirizine is the active enantiomer of cetirizine. It is the L-enantiomer of the cetirizine racemate.
Cetirizine is sold as Zyrtec and Levocetirizine is sold as Xyzal.

If you prefer Claritin:
Claritin is loratadine.  The active half of this mixture is desloratadine.
So they have separated this out and produced a single-enantiomer drug made exclusively of desloratadine.  You can buy this as Clarinex/Aerius, depending on where you live.

In many cases the single-enantiomer drug works no better, it just costs more and may allow for a patent to be extended, which may mean billions of extra dollars.

Single-enantiomer drugs: elegant science, disappointing effects.
Abstract
Most new drugs are marketed as single enantiomers but many older agents are still available in racemic form. As these drugs reach the end of their patent life manufacturers become interested in marketing single enantiomer equivalents. This is called 'chiral switching' and it has been claimed that it will bring clinical benefits in terms of improved efficacy, more predictable pharmacokinetics or reduced toxicity. We reviewed the clinical evidence and prices for three recently marketed single enantiomer versions of widely used racemic drugs: escitalopram, esomeprazole and levosalbutamol. Claims of increased efficacy were based on comparisons of non-equivalent doses and any advantages seemed small and clinically unimportant. Prices of esomeprazole and levosalbutamol were higher than their racemic alternatives and we predict that these prices will remain high despite the market presence of generic versions of the racemates. Patent protection and a perception of superiority based on promotion rather than evidence will maintain price premiums for single enantiomer drugs that are not justified on the basis of clinical performance


Back to Russia

In Russia they have now marketed the single enantiomer drug of Pantogam, which is called Pantogam Aktiv.
Does Pantogam Aktiv work “better” than Pantogam, or does it just cost more?
Is Pantogam Aktiv equivalent to R-baclofen (arbaclofen)?

How would those eight kids with Asperger's in the UK fare on Pantogam Aktiv, as opposed to Baclofen?  Is tolerance an issue with Pantogam Aktiv? 

“Failed” Arbaclofen Trial
Rather than spend tens of millions of dollars on Arbaclofen, why did not someone just think of first trying Pantogam and Pantogam Aktiv on that very first child who responded to Baclofen?
When they closed the trial (and the company) why did they not suggest to those unhappy parents to try Pantogam and Pantogam Aktiv?

Pantogam Research
Most research is in Russian, but there is some in English.  Interestingly this drug affects both GABAA and GABAB.
While its main effect is on GABAB. like Baclofen, it also has the effect of modulating the GABAA response.  This effect means that when combined with benzodiazepines, where normally people build up a tolerance, and so the dose needs to be increased, no tolerance develops.  We saw this very effect on GABAA with tiny doses of other drugs in earlier posts.

 A total of 32 children aged 6–12 years with attention deficit hyperactivity disorder (ADHD) were monitored during prolonged (6–8 months) treatment with Pantogam (homopantothenic acid) at daily doses of 500–1000 mg. Treatment results were assessed using the DSM-IV core ADHD symptom scales and the WFIRS-P (parental) scale every two months. Decreases in core symptoms on the DSM-IV core ADHD symptom scale were seen at two months of treatment. Significant changes on the WFIRS-P scale took longer: improvements in self-concept, socialization, and social activity were seen at four months and in behavior and schoolwork, basic life skills, along with decreases in risk-associated behavior, at six months. Thus, in contrast to regression of core ADHD symptoms, overcoming impairments in social-psychological adaptation required longer treatment periods.




Conclusion
Arbaclofen (R-Baclofen) failed its clinical trial, so it is no wonder drug for Fragile X and classic autism, but is was effective in a minority of people. 
It is possible that it would have been much more effective on people at the other end of the spectrum, those with Asperger’s – like the reader of this blog and the UK pediatrician using cheap Baclofen.
The people behind the Arbaclofen trial were super-brainy types from MIT, dig a bit deeper and I recall family links to Fragile-X.  So objectivity went out of the window, along with all those millions of dollars.
I do not suppose Pantogam and Pantogam Aktiv are autism wonder drugs, but they must help in some cases, otherwise the Russians would not be prescribing them. 
For those who found Arbaclofen really did help, why not try Pantogam and Pantogam Aktiv?  Just use Google:- “Buy Pantogam” in place of “Buy Arbaclofen”.
You would have thought someone smart at the US NIMH would have thought of this.  There are some very clever Russians and they do have autism over there too.





Monday 20 April 2015

Butyric Acid and Autism

Following on the previous posts about Tregs (regulatory T cells) and Short Chained Fatty Acids (SCFAs), today we get to the final steps and some more scientific data.
Butyric acid seems to be the best choice of an SCFA, as a possible anti-inflammatory autism therapy.
We have a research study that measured Butyric acid and compared the levels in people with and without autism.  It also splits out those with and without any GI issues.
We have another study showing that Butyric acid “attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism.” This is as relevant as you want to believe.
Since Butyric acid is widely used worldwide for animals and in Asia for humans, we have a great deal of data available.
The research shows that moderately increasing the level of Butyric acid does do good, but go too far and you lose the benefit. (Farmers do not over feed your chickens)

In both humans and animals two different methods are used:-
1.     Supplement with sodium/calcium/magnesium butyrate
2.     Supplement with Clostridium butyricum, bacteria/probiotic to stimulate the natural fermentation process in the colon.
A problem with the first method is the taste and smell. Butyric acid can be used to make a stink bomb.  Also some people find magnesium acts as a laxative and some people do not want to use sodium.  Sodium acts counter to potassium in the body, and we have seen earlier that, possibly due to potassium channel dysfunction, we generally want more potassium and less sodium.
Taking this into account, I prefer the second option, which follows a well-trodden path.  In Japan alone, over 200,000 packages of the Miyairi 588 probiotic have been sold since commercial production began in 1940.  The product has been used in various forms, ethical and OTC drugs, veterinary drugs, feed and food supplements.

The research on Sodium Butyrate
This compound is used in both human and animal research.  It is sold in tiny quantities as an OTC supplement and in large commercial quantities as an animal feed additive.
It is sold to improve gut integrity and reduce inflammatory disease.  In animals the key selling point is faster weight gain.  In humans I do not expect weight gain, in fact quite the reverse.
A very easy to read presentation is for the animal version:-

The supplement sold to humans just says:- 
Butyrate is a short chain fatty acid that is a potent detoxifier of ammonia and neurotoxins. It encourages the formation of friendly bacteria in the gut.

 The Research on Miyairi 588
Miyairi 588, a form of Clostridium butyricum, is produced by a Japanese pharmaceutical company.  They have recently gained approval for its use in Europe for chickens, pigs and turkey.  Now they have applied to sell the human version.  So there is plenty of information available in English.

Probiotics are microorganisms and in or to know the potency you need to know the number of organisms in your pill.  The more potent tablet, Miyarisan Strong says it has at least 0.45 million.
  








Here is one example of the animal research which shows exactly what I expect, based on the research by Wendy Garrett at Harvard.  She found that raising SCFAs, raised Tregs which then lowered the pro-inflammatory cytokine IL-6.
Wendy’s research was on mice, the following Chinese research was on chickens and my interest is humans.

Abstract
1. The experiment was conducted to investigate the effects of dietary sodium butyrate on the growth performance and immune response of broiler chickens. In experiment 1, 240 1-d-old chickens were allocated into 4 dietary groups (0, 0·25, 0·50 or 1·00 g sodium butyrate/kg) with 6 replicates each. In experiment 2, 120 1-d-old chickens were fed a control diet (without sodium butyrate) or 1·00 g sodium butyrate/kg diet. Half of the chickens fed on each diet were injected intra-peritoneally with 0·5 g/kg body weight of Escherichia coli lipopolysaccharide (LPS) at 16, 18 and 20 d of age. 2. There was no effect of dietary sodium butyrate on growth performance. On d 21, serum interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) were decreased in chickens given 1·00 g sodium butyrate/kg, serum superoxide dismutase (SOD) and catalase activities were significantly increased, and malondialdehyde (MDA) was decreased by dietary sodium butyrate at 0·50 or 1·00 g/kg. On d 42, serum IL-6 was markedly decreased by dietary sodium butyrate, while 1·00 g sodium butyrate/kg greatly reduced MDA and increased catalase. 3. LPS challenge significantly reduced the growth performance of chickens. Serum IL-1β, IL-6, TNF-α, corticosterone, alpha-1 acid glycoprotein (AGP) and prostaglandin E(2) (PGE(2)) were increased in LPS-challenged chickens. Dietary sodium butyrate supplementation maintained the body weight gain and feed intake. Sodium butyrate supplementation inhibited the increase in IL-6 and AGP in serum at 16 d of age and TNF-α, corticosterone, AGP and PGE(2) at 20 d of age. Similar inhibitory effects of sodium butyrate in serum glucose and total protein concentrations were also found at 20 d of age. 4. The results indicated that dietary sodium butyrate supplementation can improve the growth performance in chickens under stress and that this may be used to moderate the immune response and reduce tissue damage.
  
Butyric Acid levels in Humans 
We all have Butyric Acid in our colons; it is produced there via fermentation of fibres in our diet.  Depending on what bacteria you have in your colon and what food you eat, you will have a different amount.










In spite of the title of the above paper, when you look at the above chart, if you rule out 10% that are outliers, you can see that nothing correlates with anything (GI disturbance, gluten free diet, autism or not).


So who does currently benefit from extra Butyric Acid?

·        Humans with Ulcerative Colitis in clinical trials and the early adopters who read about the trials

·        Japanese people with GI disturbance

·        Farmers who feed it to their chickens, turkeys and pigs


Too much may not be good
There is some research showing that large amounts of Butyric acid may not be good and this likely holds true for animal and humans.  Note the very large variation in humans in the chart above.

The recent EU approval of animal version of Clostridium butyricum  called Miya-Gold® for use with turkeys notes that:

“…  a meta-analysis pooling data from these trials showed significant improvement in daily weight gain and feed to gain ratio when Miya-Gold® was supplemented at the minimum recommended dose of 1.25 108 CFU/kg feed.”
  
So a good starting point for humans is likely at the lower end of the suggested human dose. The suggested dose is 3 to 18 human tablets a day.
The good news is that these tablets are inexpensive.  630 tablets cost $17 including shipping from Japan.  If they do nothing for autism, they probably will do some good for the family pet, assuming you have no chickens.