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Monday, 20 October 2014

Sulforaphane (Broccoli) for Cancer, Autism and COPD





One advantage this blog has is that it looks at the comorbidities of autism, so we are aware of useful findings in related areas.  So it then does not come as a big surprise when a therapy effective in related areas also helps with autism.

One of the most useful is asthma.  Chronic obstructive pulmonary disease (COPD) is a related condition, brought on by smoking or pollution.  It kills 3 million people a year; COPD is made much worse by chronic oxidative stress.  We saw in an earlier post that oxidative stress stops the asthma drugs from working.  The current treatment for oxidative stress in COPD is N-acetyl cysteine (NAC).  I recall they are still looking for a better treatment; perhaps the search is over.  (see later).

We also saw that there is already some overlap between “emerging” research findings in cancer and those in autism. These include:-

·        PAK1, mTOR (Rapamycin), Wnt signaling
·        Ivermectin treatment for Leukemia and Autism
·        Quercetin and NAC aiding recovery for specific cancers and helping some in autism

For twenty years researchers have known about the potential cancer fighting benefits of Sulforaphane, which is produced by a chemical reaction when you eat fresh broccoli that was only lightly cooked.

In the intervening years vast amounts of research has been going on to tinker with broccoli to maximize/harness the potential health benefit, and also to develop related synthetic drugs (analogs of Sulforaphane) like Sulforadex.

Twenty years later, and a vast amount of broccoli supplement pills later, not many people have benefitted.  When you look into the matter, it really is rather bizarre.

Fresh raw broccoli was found to contain large amounts of both Glucoraphanin and an enzyme called Myrosinase.  When you eat the raw broccoli the Glucoraphanin and Myrosinase react to produce a potent substance called Sulforaphane, which seems to have numerous positive effects.  A powerful anti-oxidative process is triggered that was shown to have a strong anti-cancer effect.

The problem is that myrosinase from broccoli is not stable; when you cook it, freeze it, or process it, you lose it.  So, soggy cooked broccoli, crisp frozen broccoli and almost all the broccoli pills on the market have no myrosinase and therefore no Sulforaphane will be produced.

There have been numerous studies showing this and also a few clever ideas to get around it have been investigated.

Sulforaphane is itself also unstable and has to be used immediately or kept frozen.


Johns Hopkins and Sulforaphane

Sulforaphane was discovered in 1992 at Johns Hopkins and much related research still comes from there.  They hold the key patents and indeed went as far as to try to stop other people growing/selling broccoli sprouts.  They have developed a way to produce Sulforaphane in the laboratory and then it is freeze dried and kept frozen at -20 Celsius.

Cancer research

The cancers where Sulforaphane has shown promise include:-


COPD

What caught my attention was a paper from 2008 by Peter Barnes, one of only two Englishmen on my Dean’s list and the only one that lives there.



This has been followed up and there is now a Phase 2 clinical trial of Sulforaphane for treatment of COPD.



Barnes is my kind of scientist.  He has noted that the most potent, safe antioxidant to treat COPD is NAC (N-acetyl cysteine) but he wanted more, and has been on the look-out for years for a stronger, but safe, alternative.  He concluded that

“It has been difficult to find new more effective antioxidants that are not toxic. A more attractive approach may be to restore Nrf2 levels to normal through inhibiting the action of Keap1. This has been achieved in vitro and in vivo by isothiocyanate compounds, such as Sulforaphane, which occur naturally in broccoli”


And finally to Autism

So the recent big news that Sulforaphane was remarkable successful in a small trial at Massachusetts General Hospital (MGH) and Johns Hopkins maybe should not be such a surprise.
Sulforaphane treatment of autism spectrum disorder (ASD)
Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medicoeconomic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled,double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 μmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

What surprised me was just how big an impact the Sulforaphane had and the fact that these are very serious researchers, unlike many others.

Since we are talking about a therapy that has a strong anti-oxidant connection I compared the trial results from the Stanford NAC trial, with those from the Sulforaphane trial at MGH.

Monty, aged 11 with ASD, responded almost immediately to NAC and so of course I am interested in any additional, even overlapping, therapy.

For anyone interested, the following table shows the results from the NAC study:-




The data shows a large drop in irritability and hyperactivity and a moderate improvement in stereotypy, compulsions and SIB.  On the Social Responsiveness Scale, the people on NAC dropped by 18 , versus a drop of 6 for the placebo group.
Now we have the results from the Sulforaphane (broccoli) study.

On the Social Responsiveness Scale (SRS) , the people on Sulforaphane dropped by 20, versus a drop of 2 for the placebo group.

Moving on to the Aberrant Behavior Checklist (ABC) we can compare the improvement in four sub-categories:-

NAC               Sulforaphane
Irritability                 -9.7                     -4
Lethargy                  -4.2                     -4.5
Stereotypy              -3.5                      -2.7
Hyperactivity           -11                      -4.8


Now these figures are averages.  In reality you are likely either a responder or non-responder, nobody is likely to be Mr. Average.

I found these results very encouraging, albeit less so than the NAC trial.  The Sulforaphane trial was conducted among young adults whereas NAC was trialed on children.  You might expect children to be more responsive, since their autism tends to be less controlled than it tends to be in adulthood.

Since both trials are drawn from a population with behavioral autism and not any biological specific dysfunction both groups will likely include people with :-

·        Classic early onset autism caused by multiple genetic and epigenetic (environmental) hits

·        Mitochondrial disease triggered regressive autism, with no inherent prior dysfunction

·        Single gene disorders, probably never identified

Any trial with responders > 30% is therefore very interesting.  This trial was much better than that.

Now, both classic autism and Mitochondrial disease triggered regressive autism are associated with oxidative stress.  People with classic autism do seem to respond to NAC, whereas some people with Mitochondrial disease do not.


















In the NAC trial the dose was stepped up every 4 weeks  (0.9g 1.8g 2.7g).  In the Sulforaphane trial the dose remained the same but the effect grew.

So the method of action of both drugs may be similar, but it is not identical.  NAC is a ”primary anti-oxidant”, in that NAC and its end product Glutathione (GSH) are themselves anti-oxidants.   

Sulforaphane appears to be a “secondary anti-oxidant”, it activates Nrf2 which then triggers a set of reactions that promotes an anti-oxidant response.  So it is logical that there is a time delay.

But after week 18, Sulforaphane treatment was stopped and at week 22 all benefit had been lost.


So we can conclude, even though these are two different trials with different groups of people, that if anything NAC looks more potent than Sulforaphane.

The question is whether Sulforaphane plus NAC would be even better than NAC (or Sulforaphane) alone.

  
Mode of Action

I know that NAC is a “direct” anti-oxidant and it is a precursor for glutathione (GSH); its effect is almost immediate, whereas the MGH researchers inform us that Sulforaphane became effective over a matter of weeks.  We know that Sulforaphane activates a transcription factor, Nrf2 in the cell. Once activated, Nrf2 then translocates to the nucleus of the cell, where it aligns itself with the antioxidant response element (ARE) in the promoter region of target genes. The target genes are associated with process which assists in regulating cellular defences. Such cytoprotective genes include that for glutathione (GSH).

So it is clear that both NAC and Sulforaphane will affect the level of the boy’s most important antioxidant glutathione (GSH).

That may possibly be the end of the story.

Science does tell us that Sulforaphane has many other effects that may also be beneficial in autism.  They do seem to have an effect in cancer and some do relate to reversing epigenetic “errors”.  Classic autism is also likely triggered, in part, by epigenetic “markers” on undamaged parts of the DNA.  Any method of selectively removing these markers and turning genes “off” that were “on” in error and vice versa is very interesting.

Sulforaphane’s effect in cancer appears to be more than just an antioxidant.  Research has shown that it is indeed active epigenetically (switching on and off genes).

The logical next step would be to test NAC vs Sulforaphane vs (NAC + Sulforaphane).

Since we live in an imperfect world, rather than wait half a century for a clinical trial, you might have to do a home trial.

In the next post we will see how to make Sulforaphane at home.

As is often the case, it is not as simple as buying some on Amazon.

Sulforaphane survives for 30  minutes outside the freezer and almost all broccoli supplements have been shown to have no active Myrosinase.  Without this enzyme almost no Sulforaphane will be produced, no matter how many broccoli tablets you take.

This reminds me of people buying oxytocin over the internet.  If it is not kept chilled, by the time it arrives at your place, a few days later, it will be totally inactive and so ineffective.  You will have wasted your money and perhaps falsely concluded that oxytocin is ineffective.

This is how the Sulforaphane is made by Johns Hopkins:-

Preparation of Sulforaphane-Rich Broccoli Sprout Extracts.

Sulforaphane rich broccoli sprout extract (SF-BSE) was prepared by the Cullman Chemoprotection Center at The Johns Hopkins University essentially as described in Egner et al. In brief, specially selected broccoli seeds were surface-disinfected and grown (sprouted) for 3 d in a commercial sprouting facility under controlled light and moisture conditions. A boiling water extract was prepared, filtered, cooled, and treated with the enzyme myrosinase (from daikon sprouts) to convert precursor glucosinolates to isothiocyanates, and
then lyophilized at a food processing facility (Oregon Freeze Dry, Albany, OR). The lyophilized powder (216 μmol SF/g powder) was encapsulated into #1 gelcaps by ALFA Specialty Pharmacy (Columbia, MD); each capsule contained 50 μmol SF (232 mg of SFBSE); placebo capsules were filled with microcrystalline cellulose.
The powders (bulk and capsules) were maintained at approximately
20 °C and repeatedly checked for microbial contaminants and SF
titer before conveyance to the study site pharmacy (Massachusetts
General Hospital) to be dispensed to patients.

  
Thanks to all the research done on Sulforaphane/broccoli as chemoprotective agent, all the pieces of the puzzle exist.  My first choice would always be the stable analog of Sulforaphane, but it is not yet available and will no doubt be ultra expensive.  So I will work with second best.

The nice people at Johns Hopkins did reply to my questions, so I think I have figured out what I needed to know.




                                           How to make Sulforaphane at home



22 comments:

  1. How can one make this sulforafane at home??

    ReplyDelete
    Replies
    1. I will write a post shortly. You either eat fresh broccoli sprouts, or combine daikon powder with broccoli powder. Eating fresh broccoli itself would require you to eat a VERY large amount.

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  2. But have you seen http://phys.org/news/2011-01-supplements-team-boost-broccoli-cancer-fighting.html which seems to provide a solution to the myrosinase problem.

    ReplyDelete
    Replies
    1. I wrote a later post all about the clever ways to get the full sulforaphane potentail. My final solution, which does seem to work, is a broccoli sprout powder from Australia which has active myrosinase. I was a sceptic, till I tried it.

      http://epiphanyasd.blogspot.com/2014/11/dr-dolittle-autism-and-broccoli-sprouts.html

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  3. Thank you for this interesting article. I must say I have a little bit of trouble translating these figures into actual behavioural changes, but who wouldnt?

    I have two humble propositions on things I'd love to see you discuss, one is a page where all studies with measurable outcomes are compared (abc, cgi), with a comment on side effects, shortcomings, etc. for instance, this would be nice to include http://www.update-software.com/BCP/WileyPDF/EN/CD009043.pdf

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  4. ... The second would be a page with particularly interesting ongoing and finished clinical trials, with comments on outcomes and other.

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  5. I know myself & I know that I won't make it everyday so I have been ordering and giving my son EnduraCell from Australia for 6 months now. It have given us some big gains that have held. I buy the powder and put it in a kids mouth syringe with a teaspoon of organic apple juice it tastes like mud with black pepper in it but my son just gobbles it down. At first you must go slow because it makes you poop more. The Australian Post cost $12 shipping and takes 2 weeks but we order it way before we are out of it.

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  6. 1. Delineation of root causes are often useful in treatment planning. While articles on Sulforaphane abound a more recent study may provide the linkage that finally (sic) makes coherent sense see http://www.nature.com/nrm/journal/v15/n6/abs/nrm3810.html
    2. Then availability. Testing shows high levels of stable sulforaphane (75 micromoles in 33 ml of juice) in raw broccoli sprout juice that has been treated with High Pressure and lactic acid. Just look for whole raw "broccoli sprout juice" on line or in the shops.

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  7. try to synthesis SFN-NAC analogues in my lab, hope got some interesting results to share with you

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  8. I just received the PharmaNAC yesterday. I decided to give it a try even though I'm not thrilled with the Nutrasweet ingredient. It is 900 mg per tablet. My 11 year old son is 75lbs. I gave it to him in the morning before camp and then I will give it again when he gets home in the afternoon. Can I give a third dose right before bed? I read that it can help with insomnia since it helps with racing thoughts? Thank you! Christine

    ReplyDelete
    Replies
    1. I would not bother giving it before bed, he will be asleep while it has an effect. The half-life is quite short. So if you cannot give it in the middle of the day, I would not bother with the third dose. I doubt it really helps insommnia, perhaps try some melatonin.

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  9. Peter-
    Can you recommend any brands/sources for the Australian broccoli powder. I found this one, which seems to match your description:

    http://nourishinghub.com.au/products/super-sprout-broccoli-sprout-powder

    ReplyDelete
    Replies
    1. The Australian producer's site is

      http://aus.supersprout.co/

      They now have a US website for orders

      http://usa.supersprout.co/

      The web addresses look a bit odd but do work.

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  10. Thank you--I just ordered some!

    Do you know of any good non-RX sources for Bumetanide?

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    Replies
    1. Popular choices are Mexico, either in person or via the internet and Spain in person. It all depends where you live.

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    2. Peter,

      I had enquired from a few Mexican online sites about shipping to India through their customer service. Did not receive any response though they were selling miccil quite cheap.

      Ironically relatives from my in-laws sides are pharmacists in the US and but it seems laws governing drug use and sale are quite stringent there.

      The only option it seems now is to wait for somebody to travel to a country where it's OTC or beg and plead a fellow parent at son's therapy center who happens to be a paediatrician with a severely autistic child with multiple comorbidities, for a prescription. The doctor gives off unfriendly vibes though, and probably it's understandable.

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    3. Kritika, why not take a chance and order some Mexican Miccil. It will probably arrive in a month or two.

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    4. Yes, did think of that. OK, will order and see what happens.

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  11. Thanks, Peter. I live in the US. My 7 y.o. son is undiagnosed and very much a "borderline" case. He comes up subclinical in all of the online assessments. Good verbal communication and play/social skills, no apparent cognitive impairments, no stereotypies. But he has strong OCD tendencies and has had persistent challenges with irritability/aggression. His issues definitely get worse over the summer, which is how I found your blog.

    Do you think he might benefit from Bumetanide? I'm definitely going to start giving him the BioGaia, NAC, and broccoli powder.

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    Replies
    1. Andrew, it is worth trying bumetanide, it does help some people with milder autism, but there is no diagnostic test.

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    2. I think a good protocol may be to trial low dosage clonazepam first. We found that there is a 4 day course on the NHS in the UK for prevention of seizures that can easily be prescribed.

      Otherwise prescription for anxiety, which is pretty much prevalent in ASD, may be a viable route.

      If there is a change (of any type) with LDC then bumetanide is likely to be more effective.

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    3. Hello Emily,

      Actually, this crossed my mind as well..a positive response to LD clonazepam could be indicative of a good response to bumetanide as well. And in the country I belong to, clonazepam might be easier access. And as Peter mentioned somewhere, LDC in itself might have greater effects when used singularly rather than in combination with bumetanide where its effect is synergistic.









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