Pharmacological effects of meldonium : Biochemical mechanisms andbiomarkers of cardiometabolic activity / Maija Dambrovaa, Marina Makrecka-Kukaa, Reinis Vilskersts, Elina Makarovaa, Janis Kukaa, Edgars Liepinshaa. - (Pharmacological Research 15 (2016, 2 February) p. 1-10) doi:10.1016/j.phrs.2016.01.019
PMID: 26850121

Abstract

Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis. Since l-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Here, we briefly reviewed the pharmacological effects and mechanisms of meldonium in treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.

Mildronate (Meldonium) in professional sports : monitoring doping control urine samples using hydrophilic interaction liquid chromatography - high resolution/high accuracy mass spectrometry / Christian Görgens, Sven Guddat, Josef Dib, Hans Geyer, Wilhelm Schänzer, Mario Thevis. - (Drug Testing and Analysis 7 (2015) 11-12 (November-December) p. 973-979)

• DOI: 10.1002/dta.1788

Content:

- Introduction
- Experimental
• Chemicals and reagents
• Synthesis of labelled IS
• Sample preparation
• LC-MS/MS
* Initial testing
* Confirmatory analysis
• Method validation
• Routine doping control samples
- Results and discussion
• Mass spectrometry
• Liquid chromatography
• Method validation
• Routine doping control samples
- Conclusion

Abstract:

To date, substances such as Mildronate (Meldonium) are not on the radar of anti-doping laboratories as the compound is not explicitly classified as prohibited. However, the anti-ischemic drug Mildronate demonstrates an increase in endurance performance of athletes, improved rehabilitation after exercise, protection against stress, and enhanced activations of central nervous system (CNS) functions.
In the present study, the existing evidence of Mildronate’s usage in sport,which is arguably not exclusively) based onmedicinal reasons, is corroborated by unequivocal analytical data allowing the estimation of the prevalence and extent of misuse in professional sports. Such data are vital to support decision-making processes, particularly regarding the ban on drugs in sport. Due to the growing body of evidence (black market products and athlete statements) concerning its misuse in sport, adequate test methods for the reliable identification of Mildronate are required, especially since the substance has been added to the 2015 World Anti-Doping Agency (WADA) monitoring program.
In the present study, two approaches were established using an in-house synthesized labelled internal standard (Mildronate-D3). One aimed at the implementation of the analyte into routine doping control screening methods to enable its monitoring at the lowest possible additional workload for the laboratory, and another that is appropriate for the peculiar specifics of the analyte, allowing the unequivocal confirmation of findings using hydrophilic interaction liquid chromatography-high resolution/high accuracy mass spectrometry (HILIC-HRMS). Here, according to applicable regulations in sports drug testing, a full qualitative validation was conducted. The assay demonstrated good specificity, robustness (rRT=0.3%), precision (intra-day: 7.0–8.4%; inter-day: 9.9–12.9%), excellent linearity (R>0.99) and an adequate lower limit of detection (<10 ng/mL).

Meldonium, or mildronate / Timo Seppälä. - Helsinki : Finnish Antidoping Agency (FINADA), 2016. - 2 p., lit.

Meldonium [3-(2,2,2-trimethylhydraziniumyl)propionate; mildronate] was added to the World Anti-Doping Agency (WADA) list of prohibited substances effective 1 January 2016.
In WADA’s list of prohibited substances and methods, meldonium is listed under S4.5 ’Metabolic modulators’. These substances are prohibited at all times. They are not ’specified substances’, and their use normally carries a sanction of ineligibility of four (4) years.

Annual banned-substance review: analytical approaches in human sports drug testing / Mario Thevis, Tiia Kuuranne, Katja Walpurgis, Hans Geyer, Wilhelm Schänzer. - (Drug Testing and Analysis 8 (2016) 1 (January); p. 7-29)

• PMID: 26767774
• DOI: 10.1002/dta.1928

Abstract

The aim of improving anti-doping efforts is predicated on several different pillars, including, amongst others, optimized analytical methods. These commonly result from exploiting most recent developments in analytical instrumentation as well as research data on elite athletes' physiology in general, and pharmacology, metabolism, elimination, and downstream effects of prohibited substances and methods of doping, in particular. The need for frequent and adequate adaptations of sports drug testing procedures has been incessant, largely due to the uninterrupted emergence of new chemical entities but also due to the apparent use of established or even obsolete drugs for reasons other than therapeutic means, such as assumed beneficial effects on endurance, strength, and regeneration capacities. Continuing the series of annual banned-substance reviews, literature concerning human sports drug testing published between October 2014 and September 2015 is summarized and reviewed in reference to the content of the 2015 Prohibited List as issued by the World Anti-Doping Agency (WADA), with particular emphasis on analytical approaches and their contribution to enhanced doping controls.

Prohibited List January 2016 : The World Anti-Doping Code International Standard / World Anti-Doping Agency (WADA). - Montreal : WADA, 2015.

- The official text of the Prohibited List shall be maintained by WADA and shall be published in English and French. In the event of any conflict between the English and French versions, the English version shall prevail.
- This List shall come into effect on 1 January 2016