Trimetazidine

Source: Wikipedia, the free encyclopedia.
Trimetazidine
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • UK:
    Controlled Drug
Pharmacokinetic data
Bioavailabilitycompletely absorbed at around 5 hours, steady state is reached by 60th hour
Protein bindinglow (16%)
Metabolismminimal
Elimination half-life7 to 12 hours
Excretionmainly renal (unchanged), exposure is increased in renal impairment – on average by four-fold in subjects with severe renal impairment (CrCl <30 ml/min)
Identifiers
  • 1-(2,3,4-trimethoxybenzyl)piperazine
JSmol)
  • O(c1ccc(c(OC)c1OC)CN2CCNCC2)C
  • InChI=1S/C14H22N2O3/c1-17-12-5-4-11(13(18-2)14(12)19-3)10-16-8-6-15-7-9-16/h4-5,15H,6-10H2,1-3H3 checkY
  • Key:UHWVSEOVJBQKBE-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Trimetazidine (

Olympic games
.

Medical uses

Trimetazidine is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for

first-line antianginal therapies.[2]

Controlled studies in angina patients have shown that trimetazidine increases coronary flow reserve (thereby delaying the onset of ischemia associated with exercise), limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.[citation needed]

However, a 2020

coronary angiography.[3]
This study therefore calls into question the clinical utility of trimetazidine in the treatment of angina.

It improves

coronary heart disease.[citation needed] Recently, it has been shown to be effective in patients with heart failure of different etiologies.[4][5]

As of 2023, it is in clinical trials to determine if it is effective in treating

bipolar depression.[6]

Use as a performance-enhancing drug

Although trimetazidine was already developed for medical use in the 1970s, it only became listed in the World Anti-Doping Agency (WADA) prohibited substances list under the category of "hormone and metabolic modulators" in 2014,[7][8] and its use is prohibited at all times "in- and out-of-competition."[9]

In 2014, Chinese Olympic champion swimmer Sun Yang tested positive for trimetazidine, which had been newly banned four months earlier and classified as a prohibited stimulant by WADA; Sun Yang and his doctor claim that they were not made aware of the changes to the use of the drug of which he was prescribed, and was consequently banned by the Chinese Swimming Association for three months.[10]

In January 2015, WADA reclassified and downgraded trimetazidine from a "stimulant" to a "modulator of cardiac metabolism."[11][12]

In 2018, U.S. swimmer

FINA initially reduced her suspension from four years to two years because of Cox's testimony that she did not knowingly ingest the drug.[13] Upon analysis of both opened and sealed bottles of Cooper Complete Elite Athletic multivitamins, the Court of Arbitration for Sport (CAS) determined that the multivitamins were the source, and reduced Cox's suspension to six months. The suspension expired on September 3, 2018.[14]

In February 2022, the medal ceremony for the figure skating team event at the Olympics originally scheduled for Tuesday, 8 February, was delayed over what

RUSADA) on February 9, a day after positive results of a test held in December 2021 were released. The IOC, WADA, and ISU appealed RUSADA's decision.[19] On February 14, the Court of Arbitration for Sport ruled that Valieva would be allowed to compete in the women's single event, deciding that preventing her from competing "would cause her irreparable harm in the circumstances", though her gold medal in the team event was still under consideration. The favorable decision from the court was made in part due to her age, as minor athletes are subject to different rules than adult athletes.[20][21]

The IOC announced that the medal ceremony would not take place until the investigation was over and there was a concrete decision whether to strip Russia of their medals.[22]

ergogenic aid."[23] Doping expert Klaas Faber referred to "grossly inconsistent anti-doping rules" in Sun Yang's case. Faber has pointed out for years the necessity to establish thresholds for trimetazidine detected so as to avoid any inadvertent positive doping cases. Faber has detailed some of these observations published in the journal Science & Justice.[24][12]

On the efficacy of the drug on figure skating and Valieva in particular, heart expert Benjamin J. Levine, a professor of exercise science at the

University of Texas Southwestern Medical School, said "The chance that trimetazidine would improve her performance, in my opinion, is zero. The heart has plenty of blood. And the heart is so good at using different fuels."[23][25]

Aaron Baggish, director of the Cardiovascular Performance Program at Massachusetts General Hospital said "In theory, trimetazidine could aid endurance athletes who have to generate high cardiac output, such as cyclists, rowers and long-distance runners, but would be unlikely to have a direct impact on a figure skater's performance, where there is less demand on the heart."[26]

Besides trimetazidine, Valieva also admitted taking

L-carnitine supplements in her forms, neither of which are banned substances; nevertheless, the combination of these two substances with trimetazidine raised suspicions over a potential deliberate attempt to enhance performance. Some experts believe that the combination of the three substances can reduce fatigue and increased endurance during intense exercises.[27]

Lawrence Cherono, winner of several major marathons, tested positive for trimetazidine and was suspended just one day before slated to run the marathon at the 2022 World Athletics Championships.[28]

Adverse effects

Trimetazidine has been treated as a drug with a high safety and tolerability profile.[29]

Information is scarce about trimetazidine's effect on mortality, cardiovascular events, or quality of life. Long-term, randomized, controlled trials comparing trimetazidine against standard antianginal agents, using clinically important outcomes would be justifiable.[29] Recently, an international multicentre retrospective cohort study has indeed shown that in patients with heart failure of different etiologies, the addition of trimetazidine on conventional optimal therapy can improve mortality and morbidity.[30]

The EMA recommends that doctors should no longer prescribe trimetazidine for the treatment of patients with

restless leg syndrome, and other related movement disorders; most patients recovered within 4 months after treatment discontinuation, so doctors are advised not to prescribe the medicine either to patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome, or other related movement disorders, or to patients with severe renal impairment.[2]

Mechanism of action

The mechanism of action of trimetazidine involves its effect on cellular energy metabolism, specifically the metabolism of fatty acids and glucose.

One of the primary ways that cells generate energy is through the process of oxidation, where molecules such as fatty acids or glucose are broken down to produce ATP (adenosine triphosphate), the main energy currency of cells. In a healthy cell, both fatty acids and glucose can be oxidized to produce ATP.

However, in certain situations such as ischemia (reduced blood flow) or hypoxia (reduced oxygen supply), the cell's ability to generate energy becomes compromised. In these conditions, the cell may experience a shortage of oxygen, which is necessary for the complete oxidation of fatty acids. This can lead to a decrease in ATP production, affecting the cell's ability to maintain its normal functions.

Trimetazidine works by inhibiting a specific enzyme called

beta-oxidation process of fatty acids. By blocking this enzyme, trimetazidine reduces the oxidation of fatty acids and promotes the oxidation of glucose instead. Glucose oxidation requires less oxygen consumption compared to the beta-oxidation of fatty acids.[31]
Therefore, by enhancing glucose oxidation and reducing the reliance on fatty acid metabolism, trimetazidine helps to optimize cellular energy production in conditions where oxygen supply is limited.

By preserving energy metabolism and promoting glucose oxidation, trimetazidine prevents a decrease in intracellular ATP levels. This is important because ATP is essential for various cellular processes, including the functioning of ionic pumps and the maintenance of transmembrane sodium-potassium flow. By ensuring adequate ATP levels, trimetazidine helps to maintain cellular homeostasis, or the balance of different ions and molecules within the cell.[32]

References

  1. ^ "Trimetazidine". Drugs.com.
  2. ^ a b c "European Medicines Agency recommends restricting use of trimetazidine-containing medicines" (PDF). Press release. European Medicines Agency. 2012-06-12. Archived from the original (PDF) on 2013-04-06. Retrieved 2012-06-24.
  3. S2CID 221365071
    .
  4. S2CID 46184701
    .
  5. S2CID 23580702
    .
  6. PMID 37386057
    .
  7. ^ Ritchie H, Ramsay G (10 February 2022). "Trimetazidine: Drug banned by WADA makes 'your heart work more efficiently'". CNN. CNN. Retrieved 10 February 2022.
  8. ^ Howes, Laura (17 February 2022). "What is trimetazidine and why is it banned in Olympic competition?". cen.acs.org. Retrieved 2022-02-19. Trimetazidine (TMZ) is the generic name for the chemical that acts as a vasodilator and was discovered over 50 years ago (1970s). TMZ is commonly prescribed in Europe and Russia where it is taken as a pill or in delayed-release tablets to treat angina as well as vertigo, tinnitus, and certain visual disturbances. Since 2014, WADA has classed TMZ as a prohibited substance.
  9. ^ "World Anti-Doping Code International Standard Prohibited List" (PDF). World Anti-Doping Agency. 1 January 2022.
  10. ^ "Chinese swimmer Sun Yang is being falsely punished". Sports Integrity Initiative. 2020-03-19. Retrieved 2022-02-19.
  11. ^ "Sun Yang, el chico malo de la natación que gana todo pero al que nadie quiere". yahoo.es. 22 July 2019.
  12. ^ a b Selthoffer S (2 December 2014). "The Sun Yang Doping Case: Chapter Two of an Olympic Champion". Swimming World.
  13. ^ "FINA reduces doping ban for world champ Madisyn Cox". CBC. 2018-09-03. Retrieved 2018-09-03.
  14. ^ Gibbs R (2018-08-31). "Madisyn Cox's Suspension Reduced to Six Months after Trimetazidine Detected in Multivitamin". SwimSwam. Retrieved 2018-09-03.
  15. AP News
    . 9 February 2022. Retrieved 9 February 2022.
  16. ^ Tétrault-Farber G, Axon I, Grohmann K (9 February 2022). "Figure skating-Russian media say teen star tested positive for banned drug". Reuters. Retrieved 9 February 2022.
  17. ^ Brennan C (9 February 2022). "Positive drug test by Russian Kamila Valieva has forced a delay of Olympic team medals ceremony". USA Today.
  18. ^ Thompson A (February 11, 2022). "Valieva failed drugs test confirmed". BBC Sport.
  19. ^ Ritchie H, Watson A, Regan H (11 February 2022). "Russian anti-doping agency allowed Kamila Valieva to compete in Olympics despite failed drug test". CNN.
  20. ^ Ellingworth J, Dunbar G (2022-02-14). "Russian skater Kamila Valieva cleared to compete at Olympics". AP NEWS. Retrieved 2022-02-14.
  21. ^ "CAS Ad Hoc Media Release" (PDF).
  22. ^ "IOC EB decides no medal ceremonies following CAS decision on the case of ROC skater". International Olympic Committee.
  23. ^ a b Kiefer P (February 16, 2022). "Kamila Valieva's 'doping' drug probably doesn't give athletes an edge". PopSci.
  24. PMID 22841145
    .
  25. ^ Longman J, Kolata G, Tumin R (11 February 2022). "What Is Trimetazidine, and Would It Have Helped Kamila Valieva of Russia?". The New York Times.
  26. ^ Garcia-Roberts G, Abutaleb Y. "What to know about Trimetazidine, the drug at the center of the Olympic doping case". Washington Post. 0190-8286. Archived from the original on 2022-02-11. Retrieved 2022-02-14.
  27. ^ "Why Would a 15-Year-Old Star Figure Skater Take Heart Medicine?". www.vice.com. 17 February 2022. Retrieved 2022-05-27.
  28. ^ @aiu_athletics (July 16, 2022). "The AIU has provisionally suspended…" (Tweet). Archived from the original on 2022-07-16. Retrieved 2023-05-27 – via Twitter.
  29. ^
    PMID 16235330
    . (Retracted)|This review series was withdrawn because the authors did not opt to continue updating it; the journal has not "withdrawn" it in the usual sense
  30. PMID 23073279
    .
  31. PMID 10720420
    .
  32. S2CID 10407498
    .

Further reading

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