Trimetazidine

Last updated

Trimetazidine
Trimetazidine.svg
Clinical data
Trade names Angintriz
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability completely absorbed at around 5 hours, steady state is reached by 60th hour
Protein binding low (16%)
Metabolism minimal
Elimination half-life 7 to 12 hours
Excretion mainly 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
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.023.355 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H22N2O3
Molar mass 266.341 g·mol−1
3D model (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 Yes check.svgY
  • Key:UHWVSEOVJBQKBE-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Trimetazidine (IUPAC: 1-(2,3,4-trimethoxybenzyl)piperazine) is a drug used in the treatment of angina pectoris, a condition characterized by chest pain due to reduced blood flow to the heart. [1] Developed and first marketed by Laboratoires Servier (France), it is described as the first cytoprotective anti-ischemic agent. Trimetazidine is an antianginal metabolic drug of the fatty acid oxidation inhibitor class; it shifts cardiac energy metabolism from fatty acid utilization toward glucose oxidation, thereby improving the efficiency of energy production in ischemic conditions.

Contents

The drug has also become controversial as a performance-enhancing drug, with multiple doping scandals linked to its use at successive Olympic Games.

Medical uses

Trimetazidine is prescribed primarily as a long-term treatment for angina pectoris. In some countries, including France, it has also been used for tinnitus and dizziness. The drug is typically administered twice daily. In 2012, the European Medicines Agency (EMA) completed a review of its benefits and risks and recommended restricting trimetazidine-containing medicines to use only as an add-on therapy for angina pectoris when first-line antianginal agents are insufficient or not tolerated. [2]

Controlled studies in patients with angina have shown that trimetazidine increases coronary flow reserve, delays the onset of exercise-induced ischemia, stabilizes blood pressure without significantly affecting heart rate, reduces the frequency of angina attacks, and decreases the need for symptomatic nitrate use. [3]

Trimetazidine has also been reported to improve left ventricular function in patients with coronary heart disease and diabetes. [4]

As of 2023, it is under investigation for the treatment of bipolar depression. [5]

Use as a performance-enhancing drug

Although developed for medical use in the 1970s, trimetazidine was only added to the World Anti-Doping Agency (WADA) list of prohibited substances in 2014 under the category of "hormone and metabolic modulators." [6] [7] Its use is prohibited at all times, both in and out of competition. [8]

In 2014, Chinese Olympic swimmer Sun Yang tested positive for trimetazidine, four months after it had been added to the banned list. He was suspended for three months by the Chinese Swimming Association. [9] Later that year, WADA reclassified trimetazidine from a "stimulant" to a "modulator of cardiac metabolism." [10] [ permanent dead link ] [11]

In 2018, U.S. swimmer Madisyn Cox tested positive for trimetazidine and was initially suspended for two years. Testing later confirmed contamination of her multivitamins, and the Court of Arbitration for Sport reduced her suspension to six months, which expired in September 2018. [12] [13]

In 2021, 23 Chinese swimmers tested positive for trimetazidine in cases reported to WADA by the China Anti-Doping Agency. Following review in June and July 2021, WADA concluded that the threshold to open an investigation had not been met. The United States Anti-Doping Agency (USADA) had raised concerns in 2020 and again in 2023 about possible cover-ups, but these allegations were deemed unsubstantiated. [14]

In February 2022, the medal ceremony for the Olympic figure skating team event, scheduled for 8 February, was delayed after what International Olympic Committee (IOC) spokesperson Mark Adams described as a matter requiring "legal consultation" with the International Skating Union (ISU). [15] Media reports later revealed the issue concerned a positive December 2021 test for trimetazidine by Russian skater Kamila Valieva, [16] [17] which was publicly disclosed on 11 February. [18] Valieva was cleared by the Russian Anti-Doping Agency (RUSADA) on 9 February, but the IOC, WADA, and ISU appealed the decision. [19] On 14 February, the Court of Arbitration for Sport ruled that Valieva could compete in the women’s singles, citing her age and the potential for “irreparable harm,” though her team-event gold medal remained under review. [20] [21] The IOC confirmed that the medal ceremony would not take place until the investigation concluded. [22] Besides trimetazidine, Valieva declared using hypoxen and L-carnitine, neither of which is banned. However, experts noted that the combination with trimetazidine could indicate an attempt to enhance endurance and reduce fatigue. [23]

Lawrence Cherono, winner of several major marathons, tested positive for trimetazidine and was suspended one day before the 2022 World Athletics Championships. [24]

In September 2024, Iga Swiatek, then the world’s top-ranked women’s tennis player, tested positive for trimetazidine and received a one-month provisional suspension after accepting a ruling of "No Significant Fault or Negligence," linked to a contaminated melatonin supplement. [25] WADA later announced it would not pursue the case further, describing the explanation as "plausible". [26]

Scientific criticism

Popular Science published an overview of scientific research about the potential for the use of trimetazidine as a performance enhancing drug for athletes. The author of the article concluded in its headline that "there's no hard proof that it would improve a figure skater's performance". Scott Powers, a physiologist at the University of Florida who studies the effects of exercise on the heart explained how trimetazidine was included in WADA list. "I've been involved in roundtables with the International Olympic Committee, and I think their policy is: When in doubt, ban the drug," says Scott Powers. "I guess they're just trying to err on the possibility that this drug may be an ergogenic aid." [27] 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 . [28] [11]

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." [27] [29]

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." [30]

Adverse effects

Trimetazidine has been treated as a drug with a high safety and tolerability profile. [31]

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. [31] A 2013 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. [32]

The EMA recommends that doctors no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo, or disturbances in vision. [2] The recent EMA evaluation also revealed rare cases (3.6/1,000,000 patient years) of parkinsonian (or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, 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] Parkinson’s-like symptoms may increase the risk for falls, as it was observed in a case-control study.

Mechanism of action

Trimetazidine acts by modulating cellular energy metabolism, particularly the balance between fatty acid and glucose oxidation.

Under normal conditions, cells generate ATP (adenosine triphosphate), the primary energy currency, by oxidizing both fatty acids and glucose. However, during ischemia (reduced blood flow) or hypoxia (reduced oxygen supply), oxygen availability is limited, and fatty acid oxidation becomes inefficient, leading to reduced ATP production and impaired cellular function.

Trimetazidine selectively inhibits the mitochondrial enzyme long-chain 3-ketoacyl-CoA thiolase, a key catalyst in the beta-oxidation of fatty acids. Inhibition of this enzyme decreases fatty acid oxidation and shifts substrate utilization toward glucose oxidation. [33] Because glucose oxidation consumes less oxygen per molecule of ATP produced than fatty acid oxidation, this metabolic shift improves the efficiency of ATP generation under oxygen-limited conditions.

By preserving intracellular ATP levels, trimetazidine supports energy-dependent processes such as ionic pump activity and the maintenance of transmembrane sodium–potassium gradients. This stabilization of cellular homeostasis helps protect cardiac cells during ischemic stress. [34]

References

Notes

  1. ↑ "Trimetazidine". Drugs.com.
  2. 1 2 3 "European Medicines Agency recommends restricting use of trimetazidine-containing medicines" (PDF). Press release. European Medicines Agency. 12 June 2012. Archived from the original (PDF) on 6 April 2013. Retrieved 24 June 2012.
  3. ↑ Gupta R, Sawhney JP, Narain VS (2005). "Treatment of stable angina pectoris with trimetazidine modified release in Indian primary-care practice". American Journal of Cardiovascular Drugs. 5 (5): 325–329. doi:10.2165/00129784-200505050-00005. PMID   16156688.
  4. ↑ Marzilli M, Vinereanu D, Lopaschuk G, Chen Y, Dalal JJ, Danchin N, et al. (2019). "Trimetazidine in cardiovascular medicine". International Journal of Cardiology. 293: 39–44. doi:10.1016/j.ijcard.2019.05.063. PMID   31178223.
  5. ↑ Khanra S, Reddy P, Giménez-Palomo A, Park CH, Panizzutti B, McCallum M, et al. (August 2023). "Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine". Molecular Psychiatry. 28 (8): 3231–3242. doi: 10.1038/s41380-023-02134-8 . PMC   10618096 . PMID   37386057.
  6. ↑ Ritchie H, Ramsay G (10 February 2022). "Trimetazidine: Drug banned by WADA makes 'your heart work more efficiently'". CNN. CNN. Retrieved 10 February 2022.
  7. ↑ Howes L (17 February 2022). "What is trimetazidine and why is it banned in Olympic competition?". cen.acs.org. Retrieved 19 February 2022.
  8. ↑ "The 2022 Prohibited List: World Anti-Doping Code" (PDF). World Anti-Doping Agency. 1 January 2022.
  9. ↑ Sterling R (19 March 2020). "Chinese swimmer Sun Yang is being falsely punished". Sports Integrity Initiative. Retrieved 19 February 2022.
  10. ↑ "Sun Yang, el chico malo de la natación que gana todo pero al que nadie quiere". yahoo.es (in Spanish). 22 July 2019.
  11. 1 2 Selthoffer S (2 December 2014). "The Sun Yang Doping Case: Chapter Two of an Olympic Champion". Swimming World.
  12. ↑ "FINA reduces doping ban for world champ Madisyn Cox". CBC. Associated Press. 3 September 2018. Retrieved 3 September 2018.
  13. ↑ Gibbs R (31 August 2018). "Madisyn Cox's Suspension Reduced to Six Months after Trimetazidine Detected in Multivitamin". SwimSwam. Retrieved 3 September 2018.
  14. ↑ "WADA statement on case of 23 swimmers from China". World Anti Doping Agency. 20 April 2024. Retrieved 1 August 2024.
  15. ↑ "Olympic medals in team figure skating delayed by legal issue". 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 (11 February 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 (14 February 2022). "Russian skater Kamila Valieva cleared to compete at Olympics". AP News. Retrieved 14 February 2022.
  21. ↑ "The CAS Ad Hoc Division Declines To Impose a Provisional Suspension on the Russian Figure Skater Kamila Valieva" (PDF) (Press release). Beijing: Court of Arbitration for Sport. 14 February 2022.
  22. ↑ "IOC EB decides no medal ceremonies following CAS decision on the case of ROC skater". International Olympic Committee.
  23. ↑ "Why Would a 15-Year-Old Star Figure Skater Take Heart Medicine?". Vice.com. 17 February 2022. Retrieved 27 May 2022.
  24. ↑ @aiu_athletics (16 July 2022). "The AIU has provisionally suspended Kenyan marathon runner, Lawrence Cherono and 400m runner, Randolph Ross of the USA; both athletes are out of @WCHoregon22. ..." (Tweet). Archived from the original on 16 July 2022. Retrieved 27 May 2023– via Twitter.
  25. ↑ "Polish tennis player Iga Świątek accepts one-month suspension under Tennis Anti-Doping Programme". 28 November 2024. Archived from the original on 28 November 2024. Retrieved 1 January 2025.
  26. ↑ "World Anti-Doping Agency will not appeal Iga Swiatek's "plausible" drug-case ruling". Tennis Magazine . Associated Press. 20 January 2025.
  27. 1 2 Kiefer P (16 February 2022). "Kamila Valieva's 'doping' drug probably doesn't give athletes an edge". PopSci.
  28. ↑ Burke MG, Faber K (September 2012). "A plea for thresholds, i.e., maximal allowed levels for prohibited substances, to prevent questionable doping convictions". Science & Justice. 52 (3): 199–201. doi:10.1016/j.scijus.2012.02.002. PMID   22841145.
  29. ↑ 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.
  30. ↑ 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 11 February 2022. Retrieved 14 February 2022.
  31. 1 2 Ciapponi A, Pizarro R, Harrison J (October 2005). Ciapponi A (ed.). "Trimetazidine for stable angina". Cochrane Database Syst Rev. 2017 (4): CD003614. doi:10.1002/14651858.CD003614.pub3. PMC   6464521 . PMID   16235330.{{cite journal}}: CS1 maint: article number as page number (link) (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
  32. ↑ Fragasso G, Rosano G, Baek SH, Sisakian H, Di Napoli P, Alberti L, et al. (March 2013). "Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study". International Journal of Cardiology. 163 (3): 320–325. doi:10.1016/j.ijcard.2012.09.123. PMID   23073279.
  33. ↑ Kantor PF, Lucien A, Kozak R, Lopaschuk GD (March 2000). "The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase". Circ. Res. 86 (5): 580–588. doi: 10.1161/01.RES.86.5.580 . PMID   10720420.
  34. ↑ Stanley WC, Marzilli M (April 2003). "Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine". Fundam Clin Pharmacol. 17 (2): 133–145. doi:10.1046/j.1472-8206.2003.00154.x. PMID   12667223. S2CID   10407498.

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