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Meldonium Misconduct: Manufacturers of the controversial drug claim it isn't a PED

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Karim Zidan delves into the ongoing Meldonium scandal with an exclusive interview with the inventors and manufacturers of the scandalous drug.

Last week, renowned Russian heavyweight boxer, Alexander Povetkin, tested positive for Meldonium ahead of his title fight against Deontay Wilder in Moscow. Following much deliberation, it was determined that the fight would be cancelled and Wilder would miss out on his career-high $4 million purse despite his innocence.

Despite the significance behind Povetkin's positive test in the boxing community, it remains the latest in a list of over 200 positive tests for the scandalous substance since the World Anti-Doping Agency (WADA) instated the ban on Jan 1 2016.

Meldonium, an anti-ischemic drug that gained infamy when tennis' highest female earner Maria Sharapova tested positive and was provisionally suspended, was many used for issues concerning blood flow. The drug increases blood flow, which improves exercise capacity by carrying more oxygen to the muscles.

The medication, which is manufactured by a single Latvian company named Grindeks. It helps improve exercise capacity in patients, as well as in healthy individuals and athletes. It has also shown benefits in dealing with diabetes and neurological disorders.

"Its mechanism of actions is based on the regulation of energy metabolism pathways through L-carnitine lowering effect,"Grindeks spokeswoman Ilze Gailite told BloodyElbow. "L-carnitine biosynthesis enzymes gamma-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these 2 targets meldonium optimizes 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 potentially harmful L-carnitine related metabolites, such as long-chain acylcarnitines and trimethyl-N-oxide. This is important in the treatment of pathologies associated with heart ischemia (stenocardia, heart failure, stroke), because in these cases the tissues and cells are not getting enough oxygen and nutrients."

Though meldonium was an acceptable substance to ingest until recently, it was only available in the Russian Federation or the former Soviet Bloc nations such as Moldova, Ukraine, Belarus and Armenia. It is not approved by the United States Food and Drug Administration. However, this is due to the manufacturer's disinterest in undergoing the trials necessary to gain approval, mainly because of the product's success in the former Soviet Bloc.

"Until now, Grindeks has never applied for a licence from the FDA. Mildronate has been marketed since 1984 in the former USSR countries. Ever since, the core market of Mildronate preparations has been Russia with constantly growing turnover. To register medication in the USA through FDA, a marketing authorization applicant has to conduct a full cycle clinical trials in the US prior to submit an application adequate to contemporary requirements, which has not been done for Mildronate® preparations.

"To conduct a full cycle of registration which is a process demanding a long period of time and resources for a product that has lost its patent protection in 2006 would not be expediently for 'Grindeks'."

After monitoring the substance in 2015, WADA classified Meldonium as an S4 substance to do with hormones or metabolic modulation, and officially added it to the prohibited list on Jan. 1 2016. The reason behind this was "because of evidence of its use by athletes with the intention of enhancing performance." However, the Meldonium-specific webpage on the Prohibited List website has no information on why the substance was banned.

Naturally, Grindeks vehemently disagrees with WADA classification of the substance because it does not consider it a performance-enhancer.

"Meldonium is a cytoprotective substance, which is used to prevent death of ischemic cells, and not to increase performance of normal cells. It means that Meldonium cannot improve athletic performance, but it can stop tissue damage in ischemic conditions. That is why it is a therapeutic drug and not a doping substance. By reducing the level of carnitine, Meldonium prevents oxidation of fatty acids. This process does not increase the production of energy and ATP quantity, which is seen using stimulants (doping substances).

"Meldonium should not be considered a performance enhancer in healthy people because of it`s mechanism of action."

However, Grindeks also noted that there are some benefits to healthy individuals, particularly if used because of "reduced working capacity, physical and psycho-emotional overload."

Despite WADA's efforts to finalize a highly contested ban, the anti-doping agency has come under fire for various issues, including their seemingly inefficient method of notifying athletes. Despite their efforts to publicize the information ahead of the ban at the start of the year, nearly 200 tests were flagged for meldonium after Jan 1. The agency also released a statement that meldonium could potentially linger in the athlete's system months after they stop ingesting it.

According to WADA, meldonium has a half-life of approximately 15 hours but can remain in the system in minute doses for weeks, if not months. The agency suggested that amnesty could be provided to athletes "if the concentration is between 1 and 15 µg/mL and the test was taken before 1 March 2016, given that the results of ongoing excretion studies are needed to determine the time of the ingestion."

"In the case of meldonium, there is currently a lack of clear scientific information on excretion times," WADA revealed in an official statement. "For this reason, a hearing panel might justifiably find (unless there is specific evidence to the contrary) that an athlete who has established on the balance of probabilities that he or she ingested meldonium before 1 January 2016 could not reasonably have known or suspected that the meldonium would still be present in his or her body on or after 1 January 2016."

Given that WADA's misconduct and incomplete research offered a lifeline to a significant percentage of the affected athletes, it is little wonder that Povetkin's promoter immediately resorted to a statement on the drug's half life.

While the Meldonium ban has been remarkably mishandled, it remains unclear as to why so many elite athletes relied on heart medication as part of their regular supplementation. According to sources who spoke to BloodyElbow under the condition of anonymity, a significant percentage of Russian MMA fighters and boxers continue to use the substance. This is mainly the result of the drug's easy availability in pharmacies, its legality, and societal acceptance in the region. The alarming trend rekindles the debate about the drug's actual performance enhancing qualities.

Even Grindeks refrained from offering a direct response to the question:

"There is no way we can comment their health condition or reasons they have used the drug. Professional athletes are always supervised and monitored by their physicians. We strongly believe in their professionalism and the best intentions when choosing to prescribe a specific medicine for their patients."

With two conflicting schools of thought on the subject based in two entirely contrasting regions of the world, the future of meldonium remains uncertain.