1 Year since P&G TMA-blocker announcement

A year has passed since Procter and Gamble announced a deal with Cleveland Clinic to market an over-the-counter trimethylamine inhibitor drug.

Who is the tma-inhibitor for ?
The 'drug' is intended for the 'atherosclerosis' market, which is one of the main causes of diseases (e.g. heart disease). This is why we can be sure it will be created. In 2011 Hazen et al at Cleveland Clinic put forward a theory that trimethylamine-n-oxide may be a main factor in causing atherosclerosis. It's not known how currently accepted this theory is among atherosclerosis experts.

What's this to do with systemic body odor ?
Currently trimethylamine (TMA) is the only fairly well documented volatile identified as causing 'systemic/metabolic body odor'. This new pill will inhibit TMA formation in the gut from it's precursors (e.g. choline). If you think TMA is the only source of your SBO then this would be an ideal therapy. But I suspect those with FMO3 weakness may be vulnerable to all FMO3 substrates (mainly certain many sulfides and amines), so I am a bit concerned it may not be ideal, but we will see. It's a lucky break for TMAU people that TMAO has been suggested as a CVD cause, and the best way to block it is at the pre TMA stage. They mention they could have targeted the TMA - TMAO stage but this would have made CVD patients smell of fish. Lucky for us.

When will it be available ?
Studies can often take maybe 5 years. 1 year has gone. They have only done mice-work so far. No word of human trials. But since it is likely a natural product it may not have to go through rigorous safety trials. So it could be anytime really, but it could be 4+ years.

What else we know so far
It won't be 3,3 dimethyl butanol (DMB). In an interview Dr Hazen said this is too weak for a pill. But they likely have stronger alternatives, so that's not a bad thing.
It will be a natural product probably.
Probably still has to go through human trials but not as long as normal for a non-natural drug.
You won't need a prescription and can buy over the counter.

Look out for :
Any research papers or interviews by Hazen and/or Wang, or Cleveland Heartlab.

I am pretty sure once the pill is available the SBO community will quickly know. I'm hopeful it will be on the sooner side but we need to wait I guess. These sort of research products, you hear nothing until they make a press release or publish a paper, or perhaps elaborate in an interview.

Hopefulness rating (for TMAU) : 9/10

Links :
P&G press release : Aug 2015
Cleveland Clinic TMAO paper 2011 

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By sysbodyodor

DMB pill, Hazen TMAO research, TMAO Research, TMAO-CVD, TMAU research

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P&G TMA-blocker will be stronger than DMB

In a magazine article in April about the gut flora, this statement was made

"Hazen says DMB, the olive-oil molecule from his study, is too weak to put into a pill. He’s working on creating stronger inhibitors."

So it looks like something stronger than DMB will be used by the Cleveland Clinic for their 'TMA-blocking supplement' which will be marketed as an over-the-counter product sometime in the future by Proctor & Gamble.

Full article : Statnews April 2016

DMB : 3,3 di-methyl-1-butanol (wikipedia)
DMB is of interest to the TMAU community as it's been shown to block the formation of trimethylamine in the gut (of mice) by gut flora. It's naturally present in olive oil, balsamic vinegar etc.

TMA-oxide and atherosclerosis theory (wikipedia)
In 2011 Dr Hazen et al at the Cleveland Clinic put forward a theory that tma-oxide may be a factor (perhaps main factor) in the development of atherosclerosis. Since then the lab has been researching this and putting many papers forward to enforce this. In 2015 they said that DMB was an inhibitor of TMA in the gut of mice.

Analogs
Quite often an approach in humans to damage is to find an 'inhibitor' which stops a damaging checmical reaction. in the 'TMA precursor (choline etc) -- TMA -- TMA-oxide' cycle of reactions, the aim is to block TMA formation. 'Inhibitors' or often refered to as Analogs, and in this case they found that DMB is an inhibitor of TMA formation (from choline etc).

Better inhibitor than DMB
So it seems they are looking at stronger inhibitors than DMB to put in the P&G 'supplement'. The final product will not be a 'DMB pill'. This is even better news I guess. A heart-disease expert recently reviewed the evidence on the 'TMAO- atherosclerosis' theory and estimated that perhaps 10-20g of DMB (in divided doses) would be needed to block TMA in the gut. But something better than DMB is even better.

Possible 'resistance' like antibiotics ?
One potential 'danger' pointed out is that the article seems to say that the DMB probably alters the gut flora composition, which might mean 'immune' bacteria then become dominant. Very much like antibiotic drug resistance. DMB is not lethal to gut flora like antibiotics, but nevertheless the same resistance may occur due to flora composition change.

Good news for Trimethylamiuria people
Obviously blocking TMA formation in the gut is great news for those with TMAU. First documented in 1970, up until this interest in 'TMAO-atherosclerosis' there has been almost no interest in TMA metabolism in humans. Now suddenly TMA metabolism in humans is of main interest in human health research.

My view (in terms of systemic body odor) :
A 'TMA-blocker' pill sold over-the-counter by Proctor & Gamble will definitely happen. Anyone who thinks trimethylamine is the sole cause of their systemic malodor should regard this as possible a very good therapy for 'TMAU'. But personally I feel TMA may not be the only volatile that causes what I call 'FMO3 smells', so I am a bit worried. But maybe TMA is a main factor (indirectly) and blocking TMA may relieve the pressure on FMO3 (for example). Anyhow, I will definitely be trying it and could be regarded a 'banker' hopeful therapy that will happen while we worry about other hopes.
 

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By sysbodyodor

DMB pill, gut dysbiosis, metabolic malodor, metabolic/systemic malodor research, possible future therapy, systemic body odor, TMAO Research

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How much DMB for TMAU ?

What daily dosage of DMB should a TMAU patient take to block TMA formation in the gut each day ?

Answer (estimate, in theory) : about 10-20g DMB a day (divided into doses) 

About this answer :
This is an estimate by a very respected CVD expert in a recent overview paper of the TMA-oxide - atherosclerosis connection proposed by Hazen et al in 2011.

Answer is based on Mouse studies for atherosclerosis :
The answer is not based on humans taking DMB as trials have not reached that stage. It is an estimate based on extrapolating the dosage given in mice studies. So you could say it is a 'expert estimate based on mouse studies' given the current info.

The estimate is generally from this overview paper : link

Acronyms

DMB :  3, 3 dimethyl-1-butanol
TMAO : trimethylamine-n-oxide
TMA : trimethylamine
CVD : cardiovascular disease
FMO3 : flavin mono-oxygenase enzyme (isoform 3)

About DMB :
DMB in this case refers to 3, 3 dimethyl-1-butanol.

Atherosclerosis and TMA-oxide theory :
Put forward by Hazen et al of Cleveland Clinic in 2011. My impression is that the theory is that TMA-oxide may be the main factor in the development of atherosclerosis.

Connection with TMAU :
Since TMAU is proposed as being a malodor caused by TMA, any research that may block TMA formation in the gut would be a potential therapy. This is an obvious target for the 'atherosclerosis researchers' to aim for. So TMAU patients should be incidental benefactors of this approach.

Where do you humans get TMA from ?
TMA is smelly so is not normally consumed by humans. Nor is it a metabolite from human metabolism. It's only real source in humans is gut flora altering certain compounds in the diet (e.g. choline, carnitine, lecithin, TMA-oxide in fish).

The 'TMA blocker' story so far :
Hazen et al lead research into the TMAO - CVD theory. In Nov 2015 they published a paper showing DMB blocks TMA formation in mice (gut).

How long until a 'TMA blocker' drug is available ?
Cleveland Heartlab have already signed a deal with Proctor & Gamble to market an 'over the counter' TMA-blocker drug. It is not known when this will be available. I am currently presuming it may be DMB based, but perhaps they will find an even better 'TMA-blocker'.  

How can you get DMB now ?
DMB is a natural compound in things like balsamic vinegar, olive oil, red wine etc. I do not know how much you would need to take to get 10-20g daily of DMB. My own view is that these foods are probably bad for people with FMO3 issues, as they will likely contain many other FMO3 substrates that may end up causing smells (probably indirectly after being altered by gut flora).          

My own view :
I am very optimistic about a 'TMA-blocker'. But my own belief is that people with an FMO3 issue probably smell of all FMO3 substrates and not just TMA. So that concerns me but I am still optimistic. Also FMO3/TMAU was a very neglected disorder, but now TMA metabolism in humans is on the center of radars for atherosclerosis researchers. I will certainly buy DMB when available. If I thought TMA was the only malodor problem I would be ecstatic.

It also shows how TMAU/FMO3 has been a neglected disorder, as this therapy is an obvious concept which was never looked at for TMAU. Now that it is proposed to be connected with CVD we can expect lots of research into TMA metabolism.

My feelings on this (in tags) in relation to metabolic/systemic malodor :
optimistic, excited, cautious, research leads could appear from anywhere now, TMA metabolism is on the radar bigtime.

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By sysbodyodor

DMB pill, gut dysbiosis, Hazen TMAO research, metabolic/systemic malodor research, possible future therapy, research, systemic body odor, systemic malodor syndrome, TMAO Research, TMAO-CVD, tmau

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Hazen and Wang : article on DMB blocking TMA

Article from Albany Daily Star (circa spring 2016).
Concise article explaining how DMB 'blocks' trimethylamine production.
Hazen and Wang are the names to look out for re Cleveland lab research.

This article (Daily Albany Star : spring 2016) concisely explains in layperson terms how DMB 'blocks' TMA formation by bacteria in the gut. It includes quotes from Dr Hazen (well known to us) and his collegue Dr Zeneng Wang. Dr Wang seems to be the lead author of most of the research from Cleveland Clinic lab research on ways to block TMA formation in the gut. The Hazen lab was the one who in 2011 put forward the theory that TMA-oxide may be a major factor in atherosclerosis.

Read the TMA - DMB article 

Acronyms
DMB : dimethyl butanol : wikipedia
TMA : trimethylamine
TMAU : trimethylaminuria

Connection with systemic body odor :
As TMAU is the only current 'benign' systemic malodor disorder documented (really), with the cause of the malodor said to be trimethylamine, then any research that might block TMA formation in humans will be of interest to those who feel TMA is solely responsible for their smell (or partly). So we follow the research of the Cleveland lab in particular (e.g. papers with Wang and/or Hazen) and any others researching this theory.

DMB-TMA Cleveland research : What we know so far 
In Late 2015 Wang et al issued a paper saying DMB 'blocked' TMA formation in mice gut.
In Aug 2015 the lab announced a deal with Proctor and Gamble to sell an over-the-counter product to help with 'TMA-oxide management'. It's not known when it will be on sale.

Comments on the article :
The article explains how DMB acts as a 'gobstopper' to the enzyme in the bacteria, blocking it's ability to oxidize TMA. This is because DMB is stuturally similar to choline. Enzyme blockers are often 'analogs' of the substrate that act as a decoy.

It's interesting to note they mention TMA smells. Perhaps this was an influence on Dr Hazen, though it says originally they looked for a TMA-oxide blocker. Anyhow Dr Hazen is aware of TMAU since 2011.

It's a case now of waiting for the DMB supplement to be on sale, though it could take years.

So Wang went after the microbes instead. He identified a substance called DMB that looks a little like choline, and acts as a gobstopper. It gums up the enzymes that the bacteria normally use to digest choline, which prevents them from producing TMA...

...To be clear, the researchers aren’t trying to kill the microbes. Their substance isn’t an antibiotic; it just nudges the microbes’ behavior away from certain actions that negatively affect our health. “It’s a new approach to treating not just the individual Homo sapiens but also the microbes that live with us, and collectively contribute to disease,” says Hazen...

... At first, Hazen’s team tried to prevent the second part of this chain by blocking the animal enzyme. They succeeded, lowering TMAO levels in mice and making them resistant to atherosclerosis. But there was just one problem: Disabling the enzyme leads to a build-up of TMA, which doesn’t harm the heart but does smell of rotting fish....

Read the TMA - DMB article 

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By sysbodyodor

DMB pill, Hazen TMAO research, metabolic/systemic malodor research, TMAO Research, TMAO-CVD

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DMB food products for TMAU : bad ?

Future 'DMB pill' is exciting development for TMAU
But I am not keen on takings foods with DMB in them
Foods rich in DMB probably are high in choline and other FMO3 sulfides/amines

It seems likely that Cleveland Heartlab and Proctor & Gamble have agreed to make and sell a 'DMB pill' as a protective heart disease supplement. It's unknown when this will be available. This is being sold as a 'TMAO management' supplement. It will likely reduce TMA levels in the human gut, which is great news for those who feel TMA is the sole source of their systemic malodor.

DMB is an alcohol naturally present in certain types of foods, such as 'extra virgin olive oil' and 'balsamic vinegar'. I have a feeling these foods will be bad for people with FMO3 issues.

Reasons :
1 : They are probably high in choline ? If you think TMA is the only source of your odor, then I presume taking high choline foods may be contra-indicative.

2 : They are probably full of FMO3 substrates (sulfides and amines) which might also cause malodor or feed malodor causing bacteria.

3 : Other vague reasons such as concern about acidity.

I tend to find I have a natural aversion to these type of foods, which I suspect is due to them being full of FMO3 sulfide/amines and maybe feeding bacteria that produce sulfide/amines. I had a go with the balsamic vinegar but after a week or 2 started getting migraines.

DMB pill :
Presumably the DMB pill will not have choline or the other FMO3 sulfides/amines, so I will certainly be trying that when it arrives.

FMO3 malodor :
As I always say, I do not think those with FMO3 issues have a problem solely with TMA, so I am always sceptical about something that may help only with TMA.

Links :
P&G announce TMAO management deal Aug 2015
Buffalo news : A DMB pill ?         

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By sysbodyodor

DMB pill, fmo3, Hazen TMAO research, possible future therapy, TMAO Research

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