Leaders in Pharmaceutical Business Intelligence (LPBI) Group

What drug interfered with the performance of Sharapova?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Gayle Nicholas Scott, PharmD

When tennis player Maria Sharapova recently revealed that she had tested positive for the banned drug meldonium, the reaction of most healthcare providers was, “What is it?”

Meldonium is manufactured and sold as Mildronate by the pharmaceutical company Grindeks in the Baltic nation of Latvia. Meldonium is not available in the United States or elsewhere in the European Union (it was grandfathered in Latvia) other than via purchase on the Internet.

The World Anti-Doping Agency classifies meldonium as a “metabolic modulator” and moved the drug from its watch list to its list of banned substances in January 2016.

Other “metabolic modulators” are insulin and trimetazidine, an anti-ischemic metabolic agent that increases myocardial glucose utilization through inhibition of fatty acid metabolism.^[1,2] Trimetazidine is approved in the European Union for the treatment of angina, but it is not approved in the United States.

The chemical name for meldonium is trimethylhydrazinium propionate. Meldonium works by decreasing the availability of levocarnitine (L-carnitine). L-carnitine is found naturally in milk and meats, and also can be synthesized by the body from lysine and methionine with the help of gamma-butyrobetaine hydroxylase. L-carnitine helps move long-chain fatty acids into the mitochondria for oxidation and energy production in the muscles.

Ironically, L-carnitine, which meldonium inhibits, is taken as a dietary supplement alone and as an ingredient in energy drinks to increase athletic performance. (L-carnitine is available in the United States as the prescription drug Carnitor®, which is indicated for carnitine deficiency owing to inborn errors of metabolism and for end-stage renal disease requiring dialysis.) After two decades of research, no consistent evidence has emerged indicating that carnitine supplements can improve exercise or physical performance. Carnitine supplements do not appear to increase the body’s use of oxygen or improve metabolic status when exercising, and may not increase the amount of carnitine in muscle.^[3,4]Carnitine is not on the list of banned substances.^[1]

As a modulator of L-carnitine metabolism, meldonium inhibits gamma-butyrobetaine hydroxylase and L-carnitine transmembrane transport of long-chain fatty acids, thus decreasing L-carnitine levels in tissue and plasma. Reducing the amount of bioavailable L-carnitine shifts the source of metabolic energy production from fatty acid oxidation to glucose metabolism. Aerobic glucose oxidation consumes less oxygen than fatty acid oxidation and increases the effectiveness of adenosine triphosphate (ATP) generation. Additionally, meldonium appears to increase glucose uptake. In ischemic conditions (hypoxia), meldonium appears to restore the balance between cellular oxygen supply and demand, and prevents ATP transport impairment.^[3,5]

All published clinical efficacy studies on meldonium, except one,^[6] are in Russian. Abstracts of randomized controlled trials have reported the efficacy of meldonium in reducing angina, arrhythmias, and anxiety and other early sequelae of myocardial infarction^[7-10]; as an “adaptogen” in patients with cardiovascular disease^[11,12]; and in treating angina and reducing myocardial ischemia after percutaneous coronary intervention,^[6,13,14] heart failure,^[15] and diabetic peripheral neuropathy.^[16] Doses, when included in the abstracts, ranged from 750 to 1000 mg per day. Only one abstract mentioned adverse effects, stating that none occurred.^[7]

A pharmacokinetic study of meldonium showed that the drug has a dose-dependent half-life and volume of distribution with accumulation on multiple-dose administration. In eight healthy volunteers who received meldonium for 13 days, almost all reported insomnia, half reported burping, and one quarter reported “dreaminess.” No serious adverse effects were reported.^[17]

A study in healthy, nonvegetarian volunteers receiving 1000 mg meldonium per day for 4 weeks showed that plasma concentrations of L-carnitine decreased by 18%. Urine samples showed an increase in L-carnitine excretion. Adverse effects were not mentioned.^[18] Meldonium is excreted in the urine largely unchanged, making urine testing a valid monitor presence of meldonium.^[19]

No long-term studies on the safety and efficacy of meldonium have been published. No studies on the effect of meldonium on athletic performance in humans have been published. One study on the reliability of urine testing in professional sports^[19]mentions an article and an abstract, but neither of those appears in PubMed. The abstract purports to be a review of “recent studies on mildronate especially in fields associated with physical work capabilities and sport” but cites only the study mentioned in the urine testing review.^[20] Most articles about meldonium cited on PubMed are by Latvian authors.

Animal research suggests the potential usefulness of meldonium in Alzheimer disease,^[21-23] Parkinson disease,^[24,25] and diabetes.^[26-29] Meldonium increased sexual activity in boars^[30] but not in male rats.^[31] Research in rodents found that meldonium can cause carnitine deficiency in offspring, so the drug should not be taken in pregnancy.^[32]

Because meldonium is excreted renally, serum levels may be higher in patients with reduced kidney function, and the drug may accumulate with repeated dosing.^[19] L-carnitine appears to antagonize the effects of meldonium^[33]; otherwise, drug interactions are not known.

To recap, meldonium is an interesting drug developed by Latvian researchers. Published research suggests that it may be an effective treatment for cardiovascular diseases, such as angina. Little information about its adverse effects has been published, however, and the long-term safety of meldonium is not known. And although reliable research on meldonium’s use for athletic performance is not available, the World Anti-Doping Agency has declared it a banned substance.