Trimetazidine (TMZ) – what is it and how does it work?

Trimetazidine (TMZ) is a small molecule drug that is taken orally. It was invented in the 1960s by entrepreneurial French doctor, Jacques Servier, and patented and marketed by the company – Laboratoires Servier –  he founded in the 1950s. TMZ belongs to a class of compounds called piperazines. The initial patents on the class of compounds seem to focus on a possible role in increasing blood flow. However, further studies suggest that its mechanism may be nothing to do with physiology (blood flow increases), but instead have a more biochemical role (inhibiting metabolic pathways). The drug was targeted as a possible treatment for angina.

Why does changing blood flow and oxygen metabolism matter in angina? Well angina is chest pain caused by decreased blood flow to the heart muscles. Accompanying the blood is of course the oxygen that is needed to fuel the heart contractions. Lack of oxygen is obviously a problem for the heart. Angina is common and treatable (hence the historic interest from pharmaceutical companies). 

 

An acute angina attack is treated differently to long term (chronic) symptoms. 

 

In an acute attack the goal is to increase blood flow to the heart. A class of drugs called “nitrates” are used. You are probably familiar with people reaching for their nitrate sprays or tablets when suffering an attack. Interesting the compound most commonly used is glycerol trinitrate. This is more commonly known as TNT – the explosive invented by Alfred Nobel. Intriguingly Nobel suffered from angina and was offered the TNT he invented as a treatment. He refused at the time, but it later became a standard treatment. About a hundred years after Nobel died the biological mechanism of action of TNT was discovered. TNT releases a gas called nitric oxide in the blood stream that relaxes smooth muscles and increases blood flow, easing the pain of an angina attack. For this work, in 1998, three scientists were awarded the prize that Nobel himself founded. 

 

Chronic angina is treated by lowering the oxygen requirement for the heart, making it better able to cope with reduced blood flow. The standard treatments here are beta blocker drugs which lower the heart rate and therefore reduce the hearts demand for oxygen. 

 

[As an aside beta blockers are banned in sports such as archery, shooting golf and ski jumping where lowering your heart rate and/or calming your nerves may be performance enhancing; in certain circumstances athletes with angina can get a Therapeutic Use Exemption (TUE) to enable their use in competition]. 

 

So why is TMZ used as a treatment for angina? Like beta blockers it is taken chronically, not to increase blood flow, but instead - it is claimed – to reduce the oxygen cost of a heart contraction. So what is its mechanism of action? 

 

TMZ is suggested to inhibit a specific metabolic pathway; hence its appearance on the WADA list as a “metabolic modulator”. To understand how it works we need to know that there are different routes for getting useful chemical energy from the food that we eat. Three different pathways exist for fats (fatty acids) carbohydrates (glucose) and proteins (amino acids). Proteins are only a minor source of energy so we can focus on fats and carbohydrates.

 

The amount of chemical energy (ATP) made per molecule of oxygen consumed is measured as a P/O ratio. For a carbohydrate such as glucose this is about 2.3, whereas for a fatty acid such as palmitic acid, the number is 2.1. The difference is subtle and for those who are interested comes about because glucose can generate additional ATP via a pathway called glycolysis that is not available to fatty acids which use a process called beta oxidation instead. 

 

It is hypothesized that TMZ inhibits an enzyme (called 3-ketoacyl coenzyme A thiolase) in the beta oxidation pathway. The heart then adjusts to use more energy via the carbohydrate (glycolytic) route. This results in less oxygen being consumed to produce the same amount of useful chemical energy (ATP). So TMZ could be useful as a treatment for angina, a condition where less oxygen is delivered to the heart muscle. 

 

It is worth mentioning that, whilst TMZ inhibits the enzyme 3-ketoacyl coenzyme A thiolase in the test tube (in vitro), it is not completely proven that this is its major effect in the body (in vivo). TMZ can also have, for example, more direct effects on oxygen consumption in mitochondria and/or activate nitric oxide production. It can also potentially protect the heart by inhibiting cardiac fibrosis, and thus preventing thickening and inflexibility in the heart valves. 

 

Personally, I have some suspicions about a model where TMZ works chronically via significantly altering the balance between fat and carbohydrate metabolism in the heart. These are already under tight hormonal control via insulin, thyroid hormones, growth hormone and cortisol and hormonal changes might counter any chronic effects of TMZ. 

 

In terms of side effects, TMZ is generally well tolerated. The major concern is that in some patients it seems to trigger Parkinson Disease symptoms, such as shaking, slow movement, muscle stiffness and other motor disorders. This concern is serious enough that TMZ is not licensed at all in the USA and is only approved in Europe for treating angina – and then only as add-on to existing treatments in patients who are not adequately controlled by or who are intolerant to other medicines. In fact, when the European Medicines Agency last looked at TMZ, a minority report argued for it being completely withdrawn from use. 

 

Of course, drug prescription is always a cost-benefit analysis. So, the chance of side effects can be tolerated if the efficacy is very high. The further reading below puts both sides of these arguments. 

 

We shall see in the next blog if TMZ really does affect the efficiency of cardiac metabolism and what effect this might have for an athlete.

 

 

FURTHER READING

 

1          A paper that discusses the mechanism of action of TMZ and its possible use in treating angina and other diseases

 

The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent

 

2          A paper that describes the differences in efficiency of fat and carbohydrate oxygen metabolism. 

 

The efficiency and plasticity of mitochondrial energy transduction

 

This is a complex paper for biochemical aficionados only! But as this topic is covered so badly (and usually incorrectly!) in most text books, I felt the need to present the views of a genuine expert on this topic

 

3          A recent clinical trial suggesting TMZ may not be beneficial in some patients with angina 

 

Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial

 

4          The European Medicine Agency report on whether – and how – TMZ should be used clinically

 

Assessment Report for trimetazidine containing medicinal products

 

A new direction for my Drugs in Sport blog

A while ago, I was thinking of a follow up to Run Swim Throw Cheat. One idea was to  write a similar book on supplements. Maybe I could look at different kinds of pills? I could explain the science behind how they might work and look at the evidence whether they did actually work. At the same I would highlight the key research papers if readers wanted to dig deeper into any topic. The idea never got beyond a web site url as my EPSRC Senior Media Fellowship ended and my more “normal” academic life intervened filled with its usual grant writing, research papers and university teaching and administration. However, the idea never quite went away. In fact I think now it would be interesting to apply the same strategy to explore the biochemistry, physiology and performance benefits of all the prohibited drugs and methods listed on the WADA prohibited list. 

 

I will write three blogs per compound attempting to answer the following questions :

 

1.     What is the biochemistry and/or physiology of the drug that might enhance performance?

2.     What is the best evidence that the drug does indeed enhance performance?

3.     Are there good examples of the drug being used by elite athletes?

 

 

So where to start? Well it so happens that one of the hottest current topics – the trimetazidine that Kamila Valieva tested positive for – is in one of the most interesting class of molecules for us biochemists, namely metabolic modulators. These sit in Section S4.4 of the WADA list, are prohibited at all times (in- and out-of-competition) and are “non specified” substances. A specified substance is one that is more likely to have been consumed or used by an Athlete for a purpose other than the enhancement of sport performance. This means that it can incur a lower punishment. In contrast a non specified substance – like all the metabolic modulators -  is likely to have been consumed by an Athlete for the enhancement of sport performance and there is no mitigating defence. 

 

Metabolic Modulators are listed by WADA (S4.4) as 

 

4.1 Activators of the AMP-activated protein kinase (AMPK), e.g. AICAR, SR9009;

and peroxisome proliferator-activated receptor delta (PPARδ) agonists, e.g. 2-(2-methyl-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methylthio)phenoxy) acetic acid (GW1516, GW501516)

4.2 Insulins and insulin-mimetics 

4.3 Meldonium

4.4 Trimetazidine

 

To start topically, I will write first about Trimetazidine. Two final points:

 

1.     I will try and write one blog a week, but don’t hold me to that!

2.     I will try and open the blogs for comments. Last time I did this I was inundated with people trying to plug the sale of peptides and had to shut down all comments. Let’s see if it works any better this time! 

  

Kamila Valieva CAS ruling – what it means

 So the Court of Arbitration for Sport (CAS) has ruled that Kamila Valieva can compete in the individual ice-skating competition [1]. As I suggested in my last blog this seems to be largely based on her “protected person” status given that she is a minor. I don’t find this surprising, especially as a doping offence has not been admitted by the athlete or her team and – apparently – the B sample has not been tested. However, neither the IOC [2] nor WADA [3] are happy about this; indeed WADA feels that CAS did not understand the WADA rules. Also it blames Russia for not requesting that her sample be fast tracked so that the result was known prior to the start of the Olympics. 

 

However, the CAS judgement was ONLY with regards to whether she can compete in the event. Not whether she (or more reasonably those who are responsible for her wellbeing) committed a doping offence. She  - and indeed the whole ROC team – could still lose all their medals. And no medal ceremonies will be held for either the team or individual women’s ice skating at these Olympics. An extra (25^th) athlete is being allowed to skate in the final free skating in the (admittedly unlikely chance) that the 25^th best skater would have been denied a medal if Valieva was later banned. 

 

Meanwhile WADA have said they will investigate the role of Valieva’s support personnel, a process already started by the Russian Anti-Doping Agency. I could comment but as this is more (all?) about the law rather than the science of doping – and laced with bit of politics of course – there is not much more that I can usefully ad as a scientist. 

 

[1] 

https://www.tas-cas.org/fileadmin/user_upload/CAS_Ad_Hoc_Media_Release_Beijing_8.pdf

 

[2] 

https://olympics.com/en/news/ioc-eb-decides-no-medal-ceremonies-following-cas-decision-on-the-case-of-roc-ska

 

[3] 

https://www.wada-ama.org/en/news/wada-statement-following-cas-decision-not-reinstate-skaters-provisional-suspension

Kamila Valieva, trimetazidine and figure skating's elusive quad jumps

Interestingly I was contacted only a few weeks ago by the journalist Sarah Stodola who was writing an article for New York magazine [1] . She asked me whether I thought Russian skaters might be using drugs to enable them to do their quadruple jumps, given how they were so much better than anyone else. I replied that figure skating is not my area of expertise, but I didn’t think there was an obvious drug that would help so specific a goal. Power/weight ratio obviously matters but how that transfers into the number of spins possible (let alone what counts as a full rotation) was outside my expertise. So I didn’t have a view as to what drugs would or wouldn't benefit. And – of course – my view is always to assume an athlete’s innocence until proven otherwise.

 

My not seeing how drugs might improve figure skating performance doesn't mean people wouldn’t try though of course. Well, now we have the story that a Russian skater  - actually not just any old Russian skater but their golden girl, Kamila Valieva -  tested positive for the banned performance enhancing drug trimetazidine. This anti-angina drug inhibits fatty acid oxidation, allowing the heart to make greater proportion of the more efficient glucose as its metabolic fuel. 

 

The Russian anti-doping agency (RUSADA) originally banned her, then allowed her appeal the next day. The IOC are appealing the RUSADA appeal decision; the Court of Arbitration for Sport (CAS) will presumably deliver their verdict in the next couple of days

 

Obviously, this story has hit the news [2]. There’s not a lot I can add to what is being currently discussed until then. Still some points seem relatively uncontentious.

 

Namely:

 

·       The anti-angina drug Trimetazidine has been banned at all times since 2015 [3] as it has the possibility to make the heart use fuel more efficiently. In this it has some features similar to meldonium, a drug that was frequently used by athletes in Eastern Europe until it was banned by WADA in 2016

·       Trimetazidine use within the World Anti-Doping Rules would require a TEU (therapeutic use exemption), presumably given for an athlete suffering from angina. 

·       A TUE seems unlikely for a teenager, but I am not a clinician so cannot really answer to this point

·       It seems unlikely a valid TUE was in place for Valieva or the case would not have got this far. 

·       There are rare circumstances where a positive case can result in a very short ban (or even very unusually no ban). This would require the athlete to provide definitive proof that they were not taking the substance knowingly and that - even then - there was no performance benefit. It is up to the athlete to prove this unequivocally. Ignorance is no defence.

I await the CAS decision with interest.....

[post original blog edit]. In the case of a minor like Valieva,  I have just realised that "strict liability" does not apply as she is a "protected person" under WADA's rules [4].  More flexible sanctioning rules apply to minors (persons under 18) with no requirement to establish how a prohibited substance entered the athlete’s system to benefit from the No Significant Fault or Negligence rule. The Minimum sanction is a reprimand when No Significant Fault is established. So I think this means that even if she does not know how the drug got into her system, she can still get away with just a reprimand. So no suspension for at all. But I’m not a lawyer. I [still] await the CAS decision with interest.....

 

[1] https://www.thecut.com/2022/02/quadruple-jumps-womens-figure-skating-winter-olympics.html

 [2] https://www.theguardian.com/sport/2022/feb/10/kamila-valieva-russian-skater-positive-test-winter-olympics-trimetazidine

 [3] Trimetazidine was originally banned as a “stimulant" in 2014. So only banned ”in competition”. But it was reclassified as a “metabolic modulator” in 2015 and thus banned at all times. This has resulted in some confusion in the press yesterday. Under the 2014 rules Valieva would not have been banned as the test was taken on Christmas Day (out of competition). But under the 2015 rules and beyond, she would have been banned. The 2015 change was well publicised. Again ignorance is no defence. Even in high profile doping cases like Maria Sharapova and meldonium, ignorance (arguing her team didn’t check the updated WADA list) only resulted in a shortening of the length of her ban.

[4] https://www.wada-ama.org/sites/default/files/resources/files/worldconferencebackgrounder_0.pdf

Doping at the Tokyo Paralympic Games

As someone with a chronic, progressive disability, I have mixed views about the Paralympics. For me an inspirational story for someone with a disability is surviving another day in good cheer and not being too much of a burden on others. Interestingly as my disability has got worse my feelings about the Paralympics have, if anything, become more conflicted. I suspect what I am feeling is something akin to what I felt about elite sport when I was young. The realisation of a young boy that I was never good enough to play centre forward for the England football team has now been joined by an ageing man who has been reminded that another opportunity for sporting excellence has passed him by. Probably time to see my therapist again! 

Anyway, this is a roundabout way of saying that I watch the Paralympics solely as an example of elite sport and view it on those terms. Studies show that elite sport or even hosting the Olympic Games has no discernible benefit in improving the health of physical activity of the nation. I strongly suspect that the Paralympics likewise have minimal, if any, effect on the physical activity and/or rights of disabled people. But, actually why should we put this “burden of inspiration” on Paralympians. Let’s just treat them as elite athletes in their own right. No more, no less. Neither positive nor negative role models. Just ordinary people doing extraordinary deeds. The same as the Olympians. 

 

Viewed in that light, as I said about London 2012, we should expect the same issues to arise in Paralympic sport with regards to doping. And they do. In fact, Paralympians with spinal cord injuries even have their own unique way of cheating. “Boosting” by blocking a catheter, squeezing a scrotum or breaking a toe can increase performance by inducing a pain free rise in blood pressure. Even in more “normal” doping methods, Paralympians equal or outshine Olympians. We don’t have the Tokyo numbers yet, but in Rio 2016, roughly the same number of doping tests per competitor were carried out at the Olympics and the Paralympics. The Paralympians “won” by having 0.71% positive tests compared to the Olympians 0.59%. 

 

So let’s raise a “tainted” toast to Marcin Polak, the Polish visually impaired tandem cyclist. Polak ‘won’ a bronze medal on August 25, but then was informed two days later that he had tested positive for the blood booster EPO in an earlier out of competition test on August 2 and so had to cut short his Paralympic “journey” [1]. Polak reminds us that Paralympians are the same as Olympians in all ways, good bad and ugly. And that’s why – on reflection – I think I’ll carry on watching the Paralympics after all. Next stop Paris......

 

[1] For those wondering why Polack was allowed to compete on August 25,when his positive test sample was collected on August 2, this is a most likely due to the peculiarity of EPO testing. The interpretation of the test gel is somewhat subjective, so requires independent verification by a second anti-doping laboratory. So the Warsaw positive result had to be re-analysed, and confirmed  by the Tokyo lab, before the athlete would have been informed.  Hence the reason for the delay.  

Doping at the Tokyo Olympic Games

My first blog in almost two years. Perhaps because nothing much has changed in the period in the field or perhaps because I had other things to do in my life! Still, hopefully I can be a bit more fruitful in the future.

I covered my current views on the Olympics in a podcast I did for the Economist which is openly accessible by the link below. 

 

https://www.economist.com/podcasts/2021/07/20/cloud-of-suspicion-how-doping-is-common-in-elite-sport

 

 

For the podcast, I was asked to comment on drugs like AICAR and other so-called “exercise mimetics”. I might follow up on this with a couple of future blogs. 

 

There was a nice graphic also from the Economist contrasting different countries doping in athletics 

 

https://www.economist.com/graphic-detail/2021/08/05/russia-and-kenya-take-the-podium-in-the-athletics-doping-contest

 

I was also featured in an article in the Daily Telegraph newspaper (unfortunately behind a firewall).

 

https://www.telegraph.co.uk/athletics/2021/08/15/catching-suspected-dopers-remains-game-whack-a-mole-tokyo/

 

If you don’t have time to follow these links, my take home messages about the Tokyo Olympics are:

 

·      It is unclear how much the pandemic has impacted on the effectiveness of out-of-competition anti-doping tests in the run up to the Olympics. Presumably it has been slightly easier to avoid being caught although it also might have been difficult to procure and effectively use doping methods.  

·      The IAAF’s Athlete Integrity Unit (AIU) are having an impact. I was surprised there was not more media outcry over the significant number of athletes not allowed to compete in the game because they were not tested enough, apparently through no fault of their own. I guess the list of athletes and the countries they represented did not appear high enough profile for the Western media I follow, although I suspect there was more outcry in the countries themselves, such as Nigeria. https://www.independent.co.uk/sport/olympics/olympics-tokyo-athletes-drug-testing-b1892437.html

·      We saw one highly significant event; the readmission of essentially the whole Russian team; this despite the Russian anti-doping agency still not being WADA compliant and no admission from Russia that there was any state involvement in cheating. This seems to have put this issue to bed, perhaps in a not altogether satisfactory manner. We await to see how IOC, WADA and CAS deal with the next state player that is involved in doping. It seems the precedent has been set for a mild rebuke for the county concerned. An individual who is selected by that country will still be able to compete with zero penalties unless doping evidence exists against that specific individual. Countries themselves will never suffer the ultimate sanction of their athletes not being allowed to compete in the Olympics. Time will tell if this works as any kind of deterrent. 

·      The issue of potentially non-performance enhancing drugs being on the banned list arose (at least in the US media) because of the positive test for cannabis of Sha'Carri Richardson in the US Olympic trials. This case just seems to show that even the high-profile athletes in a country with a well-funded and assertive anti-doping agency, still don’t seem to treat the WADA list with enough seriousness. Richardson should have known she would likely be drug tested if she finished in the top three at the US trials and  – so whatever her mental state at the time – her elite athlete warning bells should have sounded off that she was breaking a rule that would likely result in a ban. Given how well she ran at the trials, she was obviously superbly prepared in every other way to perform.

·      At the games themselves there were the usual spattering of positive tests. The cynical comment is that you only catch the “dopy” dopers at the Games themselves, as those in the know will be well aware of how long a drug lasts in their system and will arrive “clean”. It is true that sometimes a better detection method can catch dopers unawares. However, this happens rarely at the Games themselves, but instead when samples are retested over the next 10 years. Over 130 athletes were retrospectively stripped of their results from the Rio 2016 and London 2012 Games. Athletes who have doped at the 2021 Olympics can really only breathe a sigh of relief that they have got away with cheating when the samples they have given are destroyed in 2031.  

·      In light of the above it was unusual that a positive test for one of the more high-profile track and field athletes - Blessing Okagbare – was reported at the Games.  Okagbare tested positive for human growth hormone. However, although reported at the Games, the test was taken out-of-competition on 19 July. Despite already having received any performance benefit, she would probably have tested ‘clean’ when competing at the Games, again stressing the importance of out of competition testing (it should be noted that Okagbare  has so far not admitted to any offence) https://www.athleticsintegrity.org/downloads/pdfs/disciplinary-process/en/AIU-PRESS-RELEASE-BLESSING-OKAGBARE-OF-NIGERIA-PROVISIONALLY-SUSPENDED.pdf

·      Of course, for my own country the big issue was the sprinter CJ Ujah, who was one of the athletes in the 4 x 100m silver medal winning team. He tested positive for S23 and ostsarine – two Selective Androgen Receptor Modulators. These are on the banned list for two reasons. First they are aimed at improving muscle mass (like anabolic steroids) but without the adverse sex hormone side effects; and secondly they are both investigational drugs that are not approved for human use anywhere in the world. This doesn’t stop unscrupulous supplement companies adding them to their formulations. Of course, as they are not approved for human use, they won’t be listed on the label. It looks like this ‘mislabelling’ might be the defence CJ Ujah’s laywers will use. https://www.dailymail.co.uk/sport/olympics/article-9896225/CJ-Ujah-set-blame-labelling-error-positive-test-strip-GB-4x100m-relay-silver.html. 
If Ujah still has the bottle in question, can get it retested and show it contains S23 and ostarine, this might just reduce the length of his penalty. But, I predict that the silver medal will still be lost, as he won’t be able to prove that he did not get a performance benefit from the drug in his system.

·      I am continually surprised why elite athletes insist on using supplements that have minimal performance benefit (unless they contain anbabolic steroids or SARMS of course). Taking ANY supplement seems a very high risk:reward ratio. It suggests athletes  (or their coaches) have not carefully read or digested the comprehensive IAAF Consenus statement on nutrition. The only evidence-based supplements are caffeine, bicarbonate, beta-alanine, nitrate, and creatine (none of which are on the banned list) https://journals.humankinetics.com/view/journals/ijsnem/29/2/article-p73.xml.   
It follows that if an athlete sees performance benefits using any other supplement than these five, it is likely a placebo effect or due to a “contaminant” in the bottle.  A contaminant that could get you a ban. Caveat emptor. 

Nobel Prize for working out how EPO works!

It’s nice to blog about the science of EPO (erythropoietin) without immediately talking about doping for a change. Today three great scientists were awarded the Nobel Prize in Physiology or Medicine for working out how mammalian cells sense and adapt to oxygen availability. The science underpinning the award to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza is described here. 

Most sports scientists and athletes know that EPO is a protein that increases the number of red blood cells. Altitude training increase levels of EPO and hence increases the number of red blood cells, increasing the amount of oxygen in the blood and potentially increasing performance. The discoveries of Semenza, Ratcliffe and Kaelin revealed that a protein called HIF-1 alpha binds to DNA and increases the production of several proteins including EPO. EPO then binds to other proteins that increase the synthesis of red blood cells. However, in the presence of oxygen HIF-1 alpha is degraded inside the cell in a structure called the proteasome. Thus, when oxygen is abundant there is not enough HIF-1 alpha to bind to DNA, EPO levels fall to normal and red blood cell production decreases. 

Of course, directly injecting EPO or receiving a blood transfusion bypasses the clever biological pathways that safely regulate the number of red blood cells in the body that match oxygen supply and demand. Hence the reason for blood doping being banned in sport. In fact, if you look at current research following on from the work of Kaelin, Ratcliffe and Semenza, you can see other proteins that could be targeted to increase or decrease red blood cell production. This is relevant for developing new drugs to treat anaemia and cancer. Of course it could also be relevant to sports doping; the HIF-1 alpha/ EPO pathway is perhaps the most obvious “known unknown” when it comes to new drugs in sport. By this I mean, we know modifying this pathway could improve sports performance, but it is unknown if anyone is currently exploiting it. Or at least no one has been caught doing it, which amounts to the same thing. But it would not surprise me if people were trying.

In a personal level this is the second time my research career has intersected with research that led to a Nobel Prize. The other time was the role of the gas nitric oxide that controls blood flow in the body. It is one of the privileges of a scientific career to be close to seeing such clever people in action, even if that closeness sometimes just involves admiring their research at conferences and in publications.