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