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Meldonium

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Posted: 1/16/2017 10:24:06 AM
Edited: 1/17/2017 10:29:22 AM (1)
 
OK, there's got to be a downside here. Skip the first part. I've highlighted the good stuff.

 

Story Behind Meldonium

From Pharmacology to Performance Enhancement: A Narrative Review

Wolfgang Schobersberger; Tobias Dünnwald; Günther Gmeiner; Cornelia Blank

Br J Sports Med. 2017;51(1):22-25. 

Abstract and Introduction

Abstract

Recent reports from the World Anti-Doping Agency (WADA) indicate an alarming prevalence in the use of meldonium among elite athletes. Therefore, in January 2016, meldonium was added to WADA's prohibited list after being monitored since 2015. Meldonium has been shown to have beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective properties, which are ascribed mainly to its inhibition of ß-oxidation and its activation of glycolysis. Despite its widespread use, there are only a few clinical studies or clinical trials available. Meldonium is registered in most Baltic countries and is easily accessible through the internet with no serious adverse effects reported by the manufacturer so far. Among athletes, meldonium is used with the purpose of increasing recovery rate or exercise performance. The benefit of taking meldonium in view of performance enhancement in athletes is quite speculative and is discussed without sound scientific evidence. This narrative review provides a detailed overview of the drug meldonium, focusing on the main topics pharmacology and biochemical actions, clinical applications, pharmacokinetics, methods of detection and potential for performance enhancement in athletes.

Introduction

Since the inception of organised sports, doping, as defined by the World Anti-Doping Agency (WADA),[1] has been prevalent. Most prominent doping is the 'presence of a prohibited substance or its metabolites or markers in an athlete's sample'.[1] The substances and methods to be considered prohibited are defined by WADA's prohibited list, which is updated annually based on specified criteria.[1]

Although prohibited substances and methods are clearly defined, their detection has limitations, and athletes who use a sophisticated approach can use drugs without detection throughout their career.[2] This is problematic, especially in view of the apparent existence of new medications with performance-enhancing properties and the potential to be misused for doping purposes.[3] One such example currently in the media worldwide is meldonium (Mildronate). Meldonium is an anti-ischaemic drug,[4] originally developed by the Latvian Institute of Organic Synthesis in the 1970s as a growth-promoting agent for animals.[5] 'Mildronate is the leading agent of the cardiovascular group, anti-ischemic agent of a metabolic action (that) acts as anti-ischemic cell protector in patients with angina pectoris, chronic heart failure, brain circulation disorders (and) improves physical capacity and mental function in the case of ischaemia and in healthy people'.[6] Furthermore, the manufacturer reports no serious adverse side effects. Behind Latvia, the drug is currently registered for human therapeutic use only in Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Ukraine, Uzbekistan and Russia. Even though meldonium is not a new drug per se, it was added to WADA's prohibited list only in January 2016 after having been included in WADA's Monitoring Programme in January 2015. There were anecdotal reports of increased use of meldonium during the London 2012 Olympics and Paralympics which are supported by a very recent study that provides estimates of meldonium use during the Baku 2015 European Games.[7] Results showed that meldonium use was detected across 15 of the 21 sports across 46 of the 50 countries participating. Interestingly, Meldonium use should have been declared by the athletes as part of the doping control but was under-reported. Of 662 tested athletes, only 3% (n=23), of whom 13 won medals, self-reported having used the substance, although 8.7% (n=66) were identified by laboratories. In addition, even though meldonium is only registered for medical use in 10 European countries, the results of the study suggest prevalence in countries where the drug is not registered.

On the basis of this research and other monitoring procedures indicating noticeable meldonium use among athletes, WADA has reacted by placing it on its prohibited list, effective as of January 2016. Citing WADA, 'Meldonium was added (to the prohibited list) because of evidence of its use by athletes with the intentions of enhancing performance'.[8] Stuart et al[7] concluded that reasons for meldonium use among healthy athletes could possibly be found in the drug's relatively mild adverse effects combined with the perception of some effect in regard to performance enhancement.

Meldonium's inclusion within WADA's prohibited list affects several stakeholders in sport who need sound, evidence-based information. It affects the medical entourage of elite athletes. There is a need for an independent and unbiased presentation of scientific facts about meldonium in order for sport physicians in countries where meldonium is registered for human therapeutic use to be able to inform athletes. Given the recent meldonium doping cases, sport physicians in countries where meldonium is not registered for human therapeutic use and those who have not yet heard about meldonium also need to be educated. International federations and national antidoping organisations need to be informed about its mode of action, effectivity, pharmacology and half-life values in order to fairly judge athletes and deal with therapeutic use exemptions. The complexity of these decisions has just been demonstrated by a statement issued by WADA on meldonium.[9] Given the actual relevance of the topic, the aim of the current systematic review is to provide the interested readership with a summary and critical discussion of the relevant scientific evidence on meldonium. 'Meldonium' and 'Mildronate' were systematically searched with the main focus on (1) pharmacology and biochemical actions, (2) applications in disease treatment, (3) pharmacokinetics, (4) detection methods and (5) efficacy in exercise performance in athletes.

Pharmacology and Biochemical Actions of L-carnitine and Meldonium

The design of meldonium was aimed at interference with L-carnitine metabolism. L-carnitine, a quaternary amine, is a water-soluble molecule that is especially important in mammalian metabolism for the mitochondrial oxidation of fatty acids. L-carnitine acts as a carrier for the transport of activated long-chain fatty acids from the cytosol into the mitochondria, where β-oxidation and adenosine triphosphate (ATP) synthesis take place.[10,11]

In the pathway of carnitine biosynthesis, four enzymatic processes are involved. The formation of γ-butyrobetaine (GBB) plays a central role which, in the final step, is hydroxylated by GBB hydroxylase (BBOX) in order to form L-carnitine.[12] After cellular uptake via Na+ -dependent organic cation transporters, conversion into carnitine esters and transport through the inner mitochondrial membrane, L-carnitine is restored and long-chain acetyl-coenzyme A (Acetyl-CoA) is formed. These long-chain CoA complexes enter β-oxidation, resulting in the formation of acetyl-CoA needed for the citric acid cycle finally producing ATP.[13,14] L-carnitine is also involved in the recycling of CoA, facilitating the shuttling of short-chain acyl groups from the mitochondria to the cytosol (peroxisomes), which results in an increase in mitochondrial-free CoA and thus better availability for further energy production.[15]

The main target of meldonium is the inhibition of GBB hydroxylase.[16,17] Different biochemical actions of meldonium have been reported (for a review, see[4,18–26]). In total, the final consequences of meldonium applications are: (1) a shift of cell metabolism from highly oxygen-consuming fatty-acid oxidation to increased glucose consumption and increased effectiveness of ATP generation and (2) a protection of the mitochondria against free fatty-acid overload by the reduction of long-chain acylcarnitines, the activation of mitochondrial free fatty-acid utilisation and the redirection of fatty-acid metabolism from the mitochondria to the peroxisomes. For a more detailed presentation of pharmacology and biochemical actions of meldonium, please refer to the online supplement and its figure (Supplement: the story behind meldonium–from pharmacology to performance enhancement: a narrative review), belonging to this review.

Meldonium as a Medication and its Applications

The clinical use of meldonium is widespread mainly in the Baltic countries and is prescribed in neurological, metabolic, cardiovascular, pulmonary and ophthalmological diseases (for a review, see ref.[4]).

Neurological Diseases. L-Carnitine acts as a potent free-radical scavenger and, when used as a supplement, might limit neurological damage derived from oxidative injury.[27] One concept of the neurological actions of meldonium is that due to its structural similarity to L-carnitine, it could act as a carnitine-mimicking substance ('false carnitine'[28]). High concentrations of meldonium should lead to a negative feedback, with the consequence of a compensatory decrease in intracellular L-carnitine. Therefore, meldonium was suggested to fulfil the criteria as a replacement medication for L-carnitine.[28] In different animal models of neurotoxicity and neurodegenerative diseases, meldonium was shown to exhibit beneficial effects in the regulation of neuroinflammation, neuroregeneration and apoptosis, with its main actions on the regulation of mitochondrial processes and the expression of nerve-cell proteins.[28–32] In animal models of ischaemic brain damage, meldonium improved neurological outcomes[33] and tolerance against anoxia-reoxygenation.[34] In addition, memory-enhancing effects[31] and positive effects on stress-induced memory impairment[35] were reported. Despite the fact that clinical trials are at present missing, it is much speculated that in the future meldonium could be applied in neurological disorders (eg, Parkinson's disease), diabetic neuropathies and stroke and also in neurological conditions with cognitive impairment (eg, neurodegenerative diseases and schizophrenia).[28] In summary, the scientific level of evidence that meldonium is of clinical importance in neurological diseases is at present low.

Metabolic Diseases. A few studies focused on the effects of meldonium on metabolic parameters and insulin resistance in type 2 diabetes mellitus. In rat models of type 2 diabetes, meldonium decreased L-carnitine and blood-glucose concentrations, improved glucose tolerance, reduced glycated haemoglobin, normalised GLUT1 gene expression and had cardioprotective effects.[36–38] Individuals with insulin resistance and type 2 diabetes mellitus often exhibit impaired skeletal muscle-oxidative capacity and a disturbance of fatty-acid β-oxidation accompanied by muscle mitochondrial dysfunction and oxidative stress.[39] In a mouse and human myotube model, meldonium was able to reverse acylcarnitine-induced insulin resistance.[40] Although some beneficial effects of meldonium on type 2 diabetes were shown in animal models, high-quality clinical trials in patients with diabetes are missing.

Cardiovascular Diseases. Several studies have shown that the reduction of L-carnitine in cardiac tissues by meldonium might protect the heart against ischaemia-reperfusion in healthy and diabetic rats[20,37,41–43] due to an attenuation of fatty-acid metabolism, resulting in the facilitation of glucose metabolism.[44] In addition, as a so-called 'metabolic modulator,' meldonium stimulates the synthesis of GBB, which exhibits cardioprotective activity by activating NO synthetase[45,46] and attenuating endothelial dysfunction in experimental models of hypertension and atherosclerosis.[45,47,48] Meldonium also preserves cardiac sarcoplasmic-reticulum Ca2+-ATPase and hexokinase type I in myocardial infarction, thus reducing tissue damage.[26]

Meldonium has been approved for clinical use in patients with stable angina in Latvia, Lithuania, Russia, Ukraine and Georgia. In clinical trials, meldonium has been investigated for the treatment of myocardial ischaemia. It was shown to improve left and right ventricular systolic function, inhibit myocardial hypertrophy and dilation, decrease pulmonary artery pressure, increase peripheral blood circulation by reducing peripheral arterial resistance, improve stress tolerance (exercise time) and ultimately improve patients' quality of life.[19,49–56] Although some clinical trials have been published, mostly in the Russian language, reporting positive effects in patients with cardiovascular diseases, the level of evidence for meldonium's therapeutic efficacy in cardiovascular diseases is moderate.

Other Clinical Applications for Meldonium. In countries where meldonium is permitted for clinical use, it is recommended as an immunomodulator and immunoadjuvant,[4] mostly for the treatment of bronchial asthma and obstructive bronchitis. The few existing clinical trials were performed more than 20 years ago, however, and most of the publications are not available in English. Recapitulating all clinical trials on meldonium, there is no convincing evidence for its use as first-line medication.

Pharmacokinetics

In the studies performed at the Latvian Institute of Organic Synthesis,[16] the maximal blood concentration of meldonium in healthy volunteers occurred 2 hours after oral administration, and the plasma excretion half-life was ~18 hours. For the ingestion of meldonium capsules (single oral dose up to 1500 mg or 500 mg three times a day for 13 consecutive days), the respective t1/2 values were 6.58±0.91 hours and 14.60±2.52 hours, indicating the accumulation of meldonium after multidose oral application.[57] After a single intravenous injection of meldonium (1000 mg), the plasma elimination t1/2 was 6.55±1.17 hours.[58] After a multidose administration (500 mg injection for 6 consecutive days), the t1/2 of meldonium was increased to 15.34±3.14 hours, indicating plasma accumulation of meldonium after repeated injections. Similar results were recently reported by Zhao et al.[59] In a randomised, open label, single and multidosage phase I trial, the t1/2 of meldonium after a 750 mg intravenous injection was 3.3±1.13 hours, and it increased to 6.12±1.33 hours after multiple injections (500 mg over 5 days). Since the elimination kinetics of meldonium after multidose application are non-linear, and exact data on the urinary elimination kinetics over a longer observation period are missing, further clarifying studies on meldonium's full elimination time are urgently needed. These investigations are essential for many of the running meldonium doping cases, because most of the athletes claim to have taken the medication in December 2015, before it was put on WADA's list of prohibited substances on 1 January 2016. In their recent 'Notice-Meldonium',[9] WADA put emphasis on this issue by providing the stakeholders with new information on preliminary results obtained from single and multiple drug applications. First light on the discussion on meldonium's elimination brought a recent pilot study by Tretzel et al.[60] Preliminary data could demonstrate that there exists a second, very slow elimination phase of meldonium with urinary concentrations of 80 ng/mL 16 days and between 10 and 200 ng/mL for up to 49 days postadministration after a single dose of 500 mg. Urinary meldonium concentration profiles revealed values between 1 and 9 μg/mL after multiple applications (3×500 mg/day for 6 days) until day 33. Since meldonium was abundantly present in the red blood cell fraction, the authors conclude that meldonium can be incorporated into erythrocytes allowing for sustained liberation during eryptosis which may last over months. These new data are of extraordinary importance and have to be included in the decision process for antidoping hearing panels. Based on these results, presumably a certain percentage of the competitive bans shall be subject to reconsideration. However, these studies are still running in order to obtain a higher number of cases and need to be incorporated in future results managements and adjudication.

Detection

Since the inclusion of meldonium into WADA's monitoring programme in January 2015, the analytical detection of meldonium has been mainly based on urine samples and has been systematically entered into the routine screening methods in WADA-accredited laboratories. The detection, as well as the unequivocal confirmation, of the presence of meldonium in the specimen is mainly based on the study published by Görgens et al.[61]

In brief, an aliquot of the urine sample is diluted with deionised water and spiked with an internal standard (preferably a deuterated analogue of meldonium). The mixture is then analysed using a combination of liquid chromatography and mass spectrometry.

Owing to the very polar structure of Mildronate–the molecule carries a positive charge (see insert in figure 1)–reversed-phase chromatography leads to early compound elution. While initial testing procedures, used to indicate the possible presence of meldonium in the athlete's sample, rely on reversed-phase chromatography, hydrophilic interaction liquid chromatography (HILIC) has proven to be more suitable for confirmation analysis, resulting in a better separation of the target compound from the interfering matrix components.

Figure 1.

 

Comparison of the chromatograms of a blank urine sample (A), a blank urine sample spiked with 1000 ng/mL meldonium (B), and an athlete's sample that tested positive for the presence of meldonium (C). Detection conditions include HILIC and tandem mass spectrometry. For each sample, chromatograms of the three mass traces (top: 147→58, middle: 147→43, bottom: 147→42) are given. The insert shows the chemical structure of meldonium. HILIC, hydrophilic interaction liquid chromatography.

 

 

On the mass spectrometric part, high-resolution mass spectrometry (resolution of more than 15 000 full width half maximum), tandem mass spectrometry or a combination of both is currently used for substance detection. The limits of detection are in the low ng/mL range. For example, figure 1 shows the chromatograms of a blank urine sample, a blank urine sample spiked with 1000 ng/mL meldonium, and an athlete's sample that tested positive for the presence of meldonium.

Meldonium and Exercise Performance

The results of the systematic search indicate that there is no reliable study examining the effects of meldonium on exercise performance, either in healthy volunteers or in highly trained athletes. Kakhabrishvili et al[62] evaluated the effect of meldonium (250 mg four times a day over 20 days) on physical work capacity (PWC 170 and judo-specific mixed aerobic-anaerobic test) in seven Georgian National Team judokas. From their data, the authors conclude 'that meldonium can be used as an agent for increasing the physical capacity in the practice of sports pharmacology for combat sports'. However, that study lacks methodological quality (ie, low number of athletes, unclear validation of exercise tests, no statistical methods reported).[62]

In a recent study, the effects of meldonium alone and in combination with asparcam+metaprote on physical work capacity were examined in an experimental animal model.[63] After the completion of a forced swimming test, the greatest effect on recovery rate and performance change was shown for meldonium (65% and 49.4%, respectively) when the drugs were administered separately. In pretrained rats, meldonium applied over 10 days was reported to increase maximum running speed and endurance.[64]

Generally, during intensive physical exercise, there is a shift from fatty-acid metabolism to carbohydrate oxidation (for a review, see[65,66]). Fatty-acid oxidation in working muscles using long-chain fatty acids as an energy substrate progressively decreases at exercise intensities above ~65% of maximum oxygen uptake (VO2max), while glycolysis becomes more pronounced.[67] The shift of the proportion is dependent on the exercise intensity, duration, fitness level and type of exercise, as well as on the substrate availability.[68] Carbohydrate oxidation is less oxygen demanding per molecule of ATP produced than fatty-acid oxidation,[69] but it is limited to the carbohydrate storage. However, during prolonged exercise, lipids might be the more important source of energy, and a high capability for lipid oxidation delays carbohydrate depletion and increases endurance capacity.[70] L-carnitine is suggested to be the major direct regulator of fatty-acid oxidation in the transition from moderate to higher exercise intensities.[66] Although controversial, nutritional support with L-carnitine was reported to alter skeletal-muscle metabolism and improve exercise performance.[71,72] Whether or not meldonium, with its multiple inhibitory actions on cell metabolism in skeletal muscles, including the metabolism of L-carnitine, improves endurance exercise and postexercise recovery in athletes is still a matter of debate. Since meldonium is a banned substance, conducting new high-quality research studies which could clarify its suggested performance enhancing effect is, from an ethical point of view, unacceptable. In summarising the suggested effects of meldonium as a performance enhancer, there is insufficient scientific evidence to answer that question.

Conclusion

Meldonium has been shown to have some beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective properties, which are ascribed mainly to its inhibition of ß-oxidation and its activation of glycolysis. Despite its widespread use, there are only a few clinical studies or clinical trials of meldonium. Those clinical trials that are published in English or that include a structured summary in English lack a high level of evidence as compared with the clinical studies required for the registration process as a medication in Western countries. Since the prohibition of meldonium by WADA, the number of athletes who test positive for meldonium has dramatically increased, which could be at least for many cases the result of its incorporation in red cells and sustained liberation over months. Focusing on meldonium as a WADA-prohibited substance since January 2016, there is a lack of a systematic, scientific fundament as well as a lack of studies performed with highly trained athletes and published in peer-reviewed journals that prove that meldonium actually improves exercise performance. However, since several compounds acting as BBOX inhibitors with molecular structures similar to that of meldonium were recently described,[73] one can assume that such compounds will enter the pharmaceutical market in the future both for patients and athletes.

Sidebar 1

What are the Findings

  • Review on the application of meldonium in cardiovascular, neurological and metabolic diseases.

  • No scientific evidence of performance enhancing properties of meldonium.

  • Pharmacokinetics of meldonium with some evidence on urinary detection over months.

  • Knowledge should be included in the decision process for antidoping hearing panels.

Sidebar 2

How might it impact on clinical practice in the future?

  • Alarming prevalence in the use of meldonium among elite athletes.

  • Meldonium added on the Prohibited List as of January 2016.

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  55. Tsverava MD. Influence of mildronat on left ventricular systolic, diastolic functional parameters, pulmonary arterial flow and systolic dyssynchrony in patients with congestive heart failure. Georgian Med News 2013;218:34–40 (218).

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Posted: 1/16/2017 11:04:10 AM
 
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Posted: 5/10/2017 10:14:08 AM
 
X - you can get it.
Seems to work in some.
Preliminary evidence is to use it intermittently.
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Posted: 7/9/2019 5:13:14 PM
 
Wow, very interesting. Have there been any updates or new research on mildronate?
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Posted: 7/10/2019 11:07:14 AM
 
Yes Kathy, there are more recent articles. Most of the clinical articles are on beneficial effects in angina, congestive heart failure, ischemic stroke. One on beneficial effects in Huntington’s disease. And yes, one on Parkinsons.


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Posted: 7/11/2019 10:18:25 AM
 
Yes Kathy, I have a number of patients who have tried it. Usually at 500mg twice a day. Some have noticed no effect. But there are certainly those who have benefited. None have reported side effects.


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Posted: 7/17/2019 4:00:15 PM
 
where to buy meldonium ?


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Posted: 7/17/2019 9:45:18 PM
 
Amazon has it!
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Posted: 7/18/2019 8:51:57 AM
 
Yup. Cheapest price right now.


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Posted: 7/19/2019 10:02:48 AM
 
cpatr922

Yes there are studies. Please read the highlighted portion of the article above. Then look at references 51 through 55. If you read Russian, there are more.


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Posted: 7/20/2019 8:05:35 AM
 
Thanks, I read in one of the article that this med is not produced in USA because perhaps no pharma has economic interest to develop it. Another reason to try it out. Many thanks to introduce this.
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Posted: 7/22/2019 12:40:12 PM
 
Do you plan to take it daily ?
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