UA-45667900-1

Monday, 20 January 2020

Sulfarlem / Anethole trithione (AOL) for Autism secondary to Mitochondrial Dysfunction (AMD)? Not to mention Metastasis





Sulfarlem has been used to treat dry mouths for half a century
By www.scientificanimations.com - http://www.scientificanimations.com/wiki-images/, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=77499374


Sulfarlem is a drug containing a chemical called Anethole trithione. Anethole is an organic compound used as a flavouring, it contributes a large component of the odour and flavour of anise and fennel.

Anise seed, or aniseed, contains a large amount of Anethole. The popular Greek drink Ouzo turns cloudy when diluted with water because of the Anethole. For the French it is called Pastis.   


                                                                      
Ouzo has been used to treat dry Greek mouths for seven centuries, particularly after a good meal.


For Anethole without the alcohol, a good source would include aniseed or fennel.


Aniseed



Today's post was prompted by a comment made before Christmas by our reader Claudia; she highlighted some recent French research that repurposes a drug developed by Solvay half a century ago.  The drug is Sulfarlem / Anethole trithione and it is used to treat people with a dry mouth, mainly in French speaking countries (including Canada) and in China, particularly Taiwan.


Sulfarlem appears to have secondary effects that include inhibiting oxidative stress in mitochondria which might benefit a long list of diseases, though they do not mention autism secondary to mitochondrial disease.

The other effect is a reduction in metastasis in people with cancer. This effect was written about in 2002 in the mass media.



Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity. 

Conclusion / Significance This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer’s diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.


Here is the associated patent:-


  
SUMMARY 

The present invention relates to an inhibitor of production of reactive oxygen species (ROS) for treating or for use in the treatment of free oxygen-radicals related diseases. In one embodiment, said inhibitor is anethole trithione (AOL). In one embodiment, said inhibitor inhibits mitochondrial production of ROS. In a preferred embodiment, said inhibitor inhibits mitochondrial production of ROS at site IQ of complex I of mitochondria

In one embodiment, said free oxygen-radicals related diseases are selected from the group comprising: age-related macular degeneration, Parkinson's disease, Alzheimer's disease, ischemic and reperfusion injury, pulmonary arterial hypertension, scleroderma, atherosclerosis, heart failure, myocardial infarction, arthritis, pulmonary toxicity, cardiopulmonary diseases, inflammatory diseases, cancer, metastasis, cardiac toxicity of anthracyclines, heart failure regardless of origin, ischemia, heart attack, stroke, thrombosis and embolism, asthma, allergic/inflammatory conditions, bronchial asthma, rheumatoid arthritis, Inflammatory Bowel Disease, Huntington's disease, cognitive disorders, Progeria, progeroid syndromes, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia, HIV-1-associated dementia, post-stroke dementia, Down's syndrome, motor neuron disease, amyloidosis, amyloid associated with type 11 diabetes, Creutzfelt-Jakob disease, necrotic cell death, Gerstmann-Straussler syndrome, kuru and animal scrapie, amyloid associated with longterm hemodialysis, senile cardiac amyloid and Familial Amyloidotic Polyneuropathy, cerebropathy, neurospanchnic disorders, memory loss, aluminum intoxication, reducing the level of iron in the cells of living subjects, reducing free transition metal ion levels in mammals, patients having toxic amounts of metal in the body or in certain body compartments, multiple sclerosis, amyotrophic lateral sclerosis, cataract, diabetes, cancer, liver diseases, skin ageing, transplantation, ototoxic secondary effects of aminoglycosides, neoplasms and toxicity of anti-neoplastic or immunosuppressive agents and chemicals, innate immune responses, and, Friedreich's Ataxia.

In one embodiment, said inhibitor is for preventing or for use in the prevention of metastasis.

                                                                                                   
From way back in 2002: -

Dry-Mouth Drug Joins Cancer Fight

Stephen Lam, director of the lung cancer prevention program at the British Columbia Cancer Research Center in Vancouver, British Columbia, found that one of Solvay's drugs, marketed as Sialor or Sulfarlem, also significantly reduces the spread of lung-cancer tumors.

Lam's study completed the second phase of trials necessary for the FDA's consideration. Over six months, 101 smokers and former smokers took the dry-mouth drug. It reduced the progression of their lung cancer tumors by an average of 22 percent.
To participate in the study, the smokers had to have smoked at least a pack a day for 30 years, or two packs a day for 15 years.
Those who took a placebo had 53 percent more new lesions or lesions that got worse than those who took the drug.
The billion-dollar question is, who will pay for more clinical trials? Lam's study was paid for with grants from the National Cancer Institute, and the money has run out. The final stage of clinical trials can cost hundreds of millions of dollars.


The French have recently followed up :-

Mitochondria ROS blocker OP2-113 downregulates the insulin receptor substrate-2 (IRS-2) and inhibits lung tumor growth


They go further in their patent and propose Sulfarlem as a blocker of metastasis.

A recent Chinese paper sets out the mechanism of action.

CXCR4 and PTEN are involved in the anti-metastatic regulation of anethole in DU145 prostate cancer cells

Taken together, anethole demonstrated to act as the CXCR4 antagonist and as the PTEN activator which resulted to PI3K/AKT-mediated inhibition of the metastatic prostate cancer progressions.


Regular readers will know that PTEN is both a cancer gene and an autism gene.

PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat.

Activating PTEN should also help some types of autism.

A recent Japanese study has a different take on the anti-metastatic mode of action.



Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-kB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-kB signal transducers.


Metastasis

There is quite a lot in this blog about cancer, due to the overlapping signalling pathways with autism, so follows a little digression about metastasis.

Metastasis is a pathogenic agent's spread from an initial/primary site to a different/secondary site within the host's body.

Often it is the metastasis that ultimately kills people; indeed this just happened to the mother of one of Monty's friends with autism.

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension.



Source: Mikael Häggström 

If a cheap substance could reduce metastasis that would be a big deal.  Cancer is currently the second most common cause of death.  If you can take cheap/safe chemoprotective agents to reduce cancer’s occurrence and a cheap substance to reduce its spread/metastasis you would be pretty smart.


Cheap Cancer Drugs

Numerous cheap drugs have known anti-cancer properties (Metformin, Aspirin, Statins, plus many more) but absolutely no serious interest is shown to apply any of them.  Instead, some hugely expensive drugs have been developed that often extend life by a matter of months.

Sulfarlem certainly is cheap, costing 3 euros (USD 3.3) a pack in France, where it seems to be sold OTC.

It looks like the world of cancer research is as dysfunctional as the world of autism research, when it comes to translating existing knowledge into beneficial therapies.  Nobody wants a cheap cancer drug and I think nobody wants a cheap autism drug.  

Most people still believe autism cannot be treated and some even think it should not be treated. 


Conclusion

Sulfarlem has been around for 50 years and so there is plenty of safety data regarding its use.

It does look like a significant number of people with autism have a problem with Complex 1 in their mitochondria.  This subject has been covered extensively in this blog in regard to regressive autism and what Dr Kelley, from Johns Hopkins, termed autism secondary to mitochondrial disease (AMD).  Unfortunately for us, he has retired.


Dr Kelley’s mito-cocktail of antioxidants is used by many, but even he makes clear that it is far from perfect and it is not so cheap. 

Sulfarlem looks like an interesting potential add-on, or even a potential replacement.

The fact that Sulfarlem also activates PTEN means that an entirely different group with autism might see a benefit.

Who might carry out a trial of Sulfarlem in autism?  I think the one likely group are those irrepressible autism researchers in Iran, who have trialed so many off-label drugs.  Since Sulfarlem is already licensed in Canada, one of those more enlightened researchers in Toronto might like to investigate.

If you live in France you can skip your early morning expresso and go down to the pharmacy with your three euros and then make your own trial.

Sulfarlem, or just plain anethole, seems a cheap/safe way to potentially reduce metastasis once cancer has been identified. Probably not worth waiting another 20 years for any possible further clinical trials.








15 comments:

  1. Great post Peter! Having read your blog for almost 3 years now I shouldn't be surprised of how many repurposable drugs are sitting on the shelf, but I am.
    /Ling

    ReplyDelete
  2. "Regressive autism" is a controversial entity
    https://www.spectrumnews.org/features/deep-dive/rethinking-regression-autism/?fbclid=IwAR1u-p4rDZ6ulLGi3U9oLhkDzMWVfMKnJ8QKrHJrbxU2reCNBQioi8-QzbM
    However I think my daughter has regressive autism and regressed after 24 months and i do not believe to those who say " there were subtle signs before 24 months and you did not notice then"...Complex 1 is diagnosed only with muscle biopsy? are there less invasive ways? carla marta

    ReplyDelete
    Replies
    1. Carla Marta, Dr Kelley at Johns Hopkins used a blood sample to look at various biomarkers.

      One researcher developed a test that used a sample from inside your cheek (buccal swab).

      A muscle biopsy is the standard test.

      The question is whether you can have a brain-specific mitochondrial disease, in which case the muscle biopsy would give a false negative result.

      People with mitochondrial disease would be expected to have poor exercise endurance.

      Dr Kelley reported that some people respond very quickly to the L carnitine in his "cocktail". But some people with a severe case do not respond much and success is seen as a lack of further deterioration.

      In Spectrum News everything is seen as controversial:- PANDAS, bumetanide, regressive autism ... etc. This is their new journalistic approach.

      Delete
    2. my daughter has couch potato style and refuses to exercise...I tried carnitine with her and saw no improvement but the trial was short because when she is on carnitine her urine smells terribly..i do not know if it is normal, i tried carnitine on myself and found no smell at all

      Delete
    3. I think you have answered your own question.

      Delete
  3. Dear Peter,

    Thank you very much for delving into the subject and for giving us your expert opinion.

    Throughout these years, your blog has been a very important source of possible causes to consider as well as treatments to look into. We have consulted so many doctors desperately looking for help to our son, and the aspects that you are documenting have never been exposed by them to us.

    We are trying to get sulfarlem and once we have used it, we will be reporting our results with it. Hopefully it can be helpful as well as all the proposals in your Polypill.

    On behalf of our entire family, we send you a giant hug with much affection and gratitude,

    Claudia

    ReplyDelete
  4. Claudia, I come from a family full of doctors and I assumed medicine was a science and that doctors were applying what current science tells us. I thought that innovation and indeed some experimentation were part of medicine. I was wrong.

    Modern doctors have to follow rigid rules and conventions, the independent thinking encouraged in many professions is actively discouraged in medicine.

    This cookie cutter method works well for common diseases, but not for complex neurological disorders, where each patient is potentially unique.

    Good luck with your Sulfarlem trial.

    ReplyDelete
  5. Hey Peter--
    Thanks for this article. I've long suspected mitochondrial dysfunction in myself. I've never been able to exercise regularly without feeling chronically exhausted. These days I still exercise, but breatk it up into small sessions throughout the day.
    I also take a handful of supplements daily to help with my energy --including L-Carnitine Fumarate.
    I recently started taking a Fennel extract (by Herb Pharm) to help with my gut health. It's interesting to know it might have other helpful properties.

    ReplyDelete
  6. very intriguing in our case as I was just reading about mito issues behind some hyponatremia episodes. Then there is afib and stroke in family history and my son's ganglioneuroblastoma tumor. Hopefully we get conclusive answers next week if the seizure is a signal of a chronic issue. Thanks for the helpful nuggets of info
    ~Tanya

    ReplyDelete
  7. Peter, I want to somehow divide a 250 mg capsule of Ponstan into 10-12 even parts. It looks challenging. I know you did the solution trick with Clonazepam, but how do I know if it can be done with this drug? I'm not a pharmacist so I have no idea if the drug will decay in water. There is a liquid variant sold in some countries, but probably not accessible for me.

    /Ling

    ReplyDelete
    Replies
    1. Ling, buy some cheap micro-scales from Amazon.

      My Ponstan capsules weigh 420mg. The empty capsule weighs 80mg and the powder weighs 340mg.

      Using the 10 euro microscales you can split the powder into tiny doses quite easily.

      Delete
  8. Hi Peter, my daughter is in UK,graduate trip, could she find Tavegil in the store, Boots I think, without ordering it? I don't think she can go back to the same place.
    Valentina


    ReplyDelete
    Replies
    1. Valentina, Tavegil is not something UK pharmacies have in stock. They can all order it, to be delivered the next day, this is the only way other than ordering on-line for delivery to a UK address.

      Delete
    2. Ok,thank you,she will be for 40 days,she can order it and give the hotel address while she is in London.
      Valentina

      Delete
  9. Peter, what do you of dirty lab mice? Given the importance of immunological hits on autism it is a bit weird that lab mice are kept totally free from germs/infections/immune hits.
    Maybe it's not a big deal, but gut instinct says it must skew results somehow.
    https://www.nature.com/articles/d41586-018-03916-9

    /Ling

    ReplyDelete

Post a comment