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Meldonium

Meldonium, marketed under the brand name Mildronate, is a synthetic anti-ischemic drug developed in 1970 in Latvia as a cardioprotective agent and produced by the pharmaceutical company Grindeks.^[1] It functions as a partial inhibitor of fatty acid oxidation by competitively binding to and inhibiting the enzyme gamma-butyrobetaine hydroxylase, which reduces the synthesis of L-carnitine and shifts myocardial energy metabolism toward more efficient glucose utilization under hypoxic conditions.^[2]^[3] Primarily prescribed in Eastern Europe and parts of Asia for treating cardiovascular conditions such as stable angina, chronic heart failure, and post-myocardial infarction recovery, meldonium has also shown applications in neurological indications like brain circulation disorders by improving cerebral blood flow and patient activity levels.^[4]^[5] Its inclusion on the World Anti-Doping Agency's prohibited substances list effective January 1, 2016, under the category of metabolic modulators stemmed from analytical evidence of its prevalent non-therapeutic use among athletes to potentially enhance endurance and recovery, despite limited Western clinical validation of performance benefits.^[6]^[7] This ban triggered numerous positive tests among elite competitors, particularly from Russia and Eastern Europe, highlighting debates over its ergogenic effects versus established medical utility in ischemia management.^[8]

History and Development

Discovery and Early Research

Meldonium, chemically known as 3-(2,2,2-trimethylhydrazinium)propionate, was first synthesized in 1975 at the Latvian Institute of Organic Synthesis (LIOS) in Riga, Latvia, during the Soviet era, by chemist Ivars Kalviņš as part of efforts to develop metabolic modulators for ischemic conditions.^[9] The LIOS, established under the Latvian SSR Academy of Sciences, prioritized pharmaceutical research aligned with Soviet biomedical priorities, including cardioprotective agents to address tissue oxygen deficits.^[10] Kalviņš's work drew from observations of carnitine's role in fatty acid transport, aiming to create a compound that could shift cellular energy production toward more efficient glucose oxidation under hypoxic stress.^[11] Initial preclinical investigations targeted veterinary applications, where meldonium was tested for its potential to enhance animal growth and resilience by improving metabolic efficiency in low-oxygen environments, such as during stress or disease.^[10] In early animal models, including rats and dogs, the compound demonstrated anti-ischemic effects, reducing myocardial damage in ischemia-reperfusion scenarios through inhibition of gamma-butyrobetaine hydroxylase, which lowered endogenous carnitine levels and curtailed fatty acid beta-oxidation.^[12] These Latvian-conducted studies, completed within months of synthesis, reported improved survival rates and tissue preservation in hypoxic models, with no acute toxicity observed at doses exceeding 5000 mg/kg in rodents and canines.^[13] Subsequent early research expanded to cardioprotective mechanisms, revealing meldonium's capacity to stabilize cellular energy homeostasis in preclinical ischemia simulations, paving the way for its repurposing beyond veterinary use.^[11] By 1976, Soviet inventor's certification affirmed its novelty, based on empirical data from LIOS animal trials emphasizing causal links between metabolic reprogramming and reduced ischemic injury, rather than unsubstantiated performance claims.^[14] These foundational experiments underscored meldonium's role in modulating biochemical pathways affected by oxygen scarcity, with findings disseminated primarily within Soviet scientific networks due to classified aspects of the research.^[15]

Initial Synthesis and Patenting

Meldonium, chemically known as 3-(2,2,2-trimethylhydrazinium)propionate, was first synthesized in the early 1970s by Latvian chemist Ivars Kalviņš at the Institute of Organic Synthesis in Riga, which was then part of the Latvian Soviet Socialist Republic.^[1] This synthesis aimed to create a structural analog of γ-butyrobetaine, the endogenous precursor to L-carnitine, by replacing a methylene group with a trimethylhydrazinium moiety to modulate metabolic pathways.^[16] The compound received an inventor's certificate in the USSR in 1976, recognizing Kalviņš' innovation, followed by a patent issuance in 1984 that secured intellectual property rights for its production and use.^[14] These protections were held under the auspices of Soviet-era pharmaceutical development, primarily through the Latvian firm Grindeks, which refined the synthesis for pharmaceutical-grade production.^[17] Following the dissolution of the Soviet Union in 1991, Grindeks transitioned meldonium from laboratory-scale to commercial manufacturing in independent Latvia, branding it as Mildronate and establishing its availability primarily in Eastern European markets where Soviet-influenced medical practices persisted.^[18] This shift enabled scaled-up synthesis methods, including efficient routes from key intermediates like 3-chloropropionic acid and 1,1-dimethylhydrazine, while retaining the original patented framework.^[19]

Chemical Properties

Molecular Structure and Physical Characteristics

Meldonium, systematically named 3-(2,2,2-trimethylhydrazinium)propanoate, possesses the molecular formula C₆H₁₄N₂O₂ for its anhydrous form, with a molecular weight of 146.19 g/mol; it is commonly utilized as the dihydrate (C₆H₁₈N₂O₄, molecular weight 182.22 g/mol).^[20] This compound is classified as an ammonium betaine, characterized by a zwitterionic structure with a trimethylhydrazinium cation and a propanoate anion, akin to endogenous betaines involved in metabolic processes.^[20] In its physical form, meldonium dihydrate manifests as a white to off-white crystalline powder, exhibiting a melting point range of 85–87 °C. It demonstrates high solubility in water, exceeding 40 mg/mL, which facilitates its formulation in aqueous solutions, while maintaining stability under standard physiological conditions such as neutral pH and moderate temperatures. Structurally, meldonium serves as an analog of γ-butyrobetaine, a key precursor in the endogenous biosynthesis pathway of L-carnitine, sharing a similar trimethylammonium-substituted carboxylate framework.^[13]

Synthesis Methods

The primary industrial synthesis of meldonium, chemically 3-(2,2,2-trimethylhydrazin-1-ium-1-yl)propanoate dihydrate, proceeds via Michael addition of 1,1,1-trimethylhydrazine to methyl acrylate, affording the intermediate methyl 3-(2,2,2-trimethylhydrazinio)propanoate chloride salt.^[21] This salt undergoes alkaline hydrolysis, typically with sodium hydroxide in aqueous solution at controlled temperatures (40–50°C), to cleave the ester group and form the free propionate, followed by acidification and purification.^[22] ^[23] Key intermediates, such as the trimethylhydrazinium ester salts, are handled under inert conditions to prevent side reactions, with the quaternized hydrazinium moiety providing stability during processing. Hydrolysis yields crude meldonium, which is purified via recrystallization from aqueous ethanol or similar solvents to achieve pharmaceutical-grade purity exceeding 99%, minimizing impurities like unreacted hydrazine derivatives.^[19] The final dihydrate form is crystallized by adjusting water content and cooling, ensuring consistent hydration for stability and bioavailability in clinical formulations.^[24] Grindeks, the primary manufacturer, has adapted this route for scalable production, incorporating quality controls like HPLC monitoring to meet GMP standards, with yields typically above 80% from the addition step onward. Alternative routes using acrylonitrile instead of the acrylate ester involve harsher nitrile hydrolysis but are less favored industrially due to byproduct formation and purification challenges.^[25] These methods prioritize efficiency and cost-effectiveness while avoiding toxic catalysts, aligning with large-scale pharmaceutical demands.^[2]

Pharmacology

Mechanism of Action

Meldonium exerts its primary biochemical effect through competitive inhibition of γ-butyrobetaine hydroxylase (BBOX), a 2-oxoglutarate-dependent dioxygenase enzyme that catalyzes the hydroxylation of γ-butyrobetaine to form L-carnitine, the final step in endogenous carnitine biosynthesis.^[26] ^[2] This inhibition leads to elevated levels of γ-butyrobetaine and a dose-dependent reduction in L-carnitine concentrations within cells, particularly in tissues with high metabolic demand such as myocardium and skeletal muscle.^[27] ^[13] The resultant decrease in L-carnitine impairs the carnitine acylcarnitine translocase system, which shuttles long-chain acyl-CoA esters across the mitochondrial inner membrane for β-oxidation of fatty acids.^[28] This disruption shifts cellular energy metabolism from oxygen-intensive fatty acid β-oxidation—yielding approximately 2.83 molecules of ATP per atom of oxygen consumed—to more efficient glucose oxidation via glycolysis and the tricarboxylic acid cycle, which produces about 3.17 ATP per oxygen atom under aerobic conditions.^[4] ^[29] In ischemic or hypoxic states, this substrate preference reduces oxygen demand and mitigates ATP depletion by prioritizing pathways that generate energy with less reliance on mitochondrial fatty acid uptake.^[30] These mitochondrial adaptations confer anti-hypoxic cytoprotection by preserving bioenergetic homeostasis; meldonium enhances mitochondrial respiratory capacity under low-oxygen conditions, as evidenced by increased oxygen consumption rates and attenuated dysfunction in hypoxia-exposed models.^[31] ^[32] The mechanism does not directly target electron transport chain components but indirectly optimizes flux through pyruvate dehydrogenase, favoring carbohydrate-derived substrates over acyl-carnitines.^[33]

Pharmacokinetics and Metabolism

Meldonium is rapidly absorbed following oral administration, with a bioavailability of approximately 78%.^[26] ^[34] Peak plasma concentrations are achieved within 1 to 2 hours post-ingestion, though food intake may delay this time to peak without significantly altering maximum concentration or area under the curve.^[26] ^[34] The drug distributes widely, accumulating preferentially in tissues expressing the organic cation transporter 2 (OCTN2), including the heart, skeletal muscle, kidney, and brain.^[13] This accumulation facilitates its targeted effects in metabolically active organs, with meldonium forming ion pairs with plasma lipids to enable crossing of barriers such as the blood-brain barrier.^[13] Metabolism occurs primarily in the liver via gamma-butyrobetaine hydroxylase, yielding metabolites such as dimethylamine, 2-hydroxymethyl-2-(hydroxymethylamino)-propane-1,3-diol, 3-amino-4-(hydroxymethyl-methyl-amino)-butyric acid, and 3-hydroxypropionic acid (which converts to succinic acid).^[13] Excretion is predominantly renal, with 34% to 60% of the administered dose recovered unchanged in urine.^[13] The elimination half-life following single oral doses typically ranges from 3 to 7 hours, though it exhibits dose- and regimen-dependent nonlinearity, extending up to 15 hours with capsules or multiple doses; a three-compartment pharmacokinetic model describes this process, featuring initial (alpha) half-life of about 1.5 hours, intermediate (beta) of 9 hours, and terminal (gamma) exceeding 600 hours in some cases.^[2] ^[13]

Biochemical Pathways Affected

Meldonium acts as a competitive inhibitor of γ-butyrobetaine dioxygenase (BBOX), the enzyme responsible for the hydroxylation of γ-butyrobetaine to L-carnitine in the final step of endogenous carnitine biosynthesis.^[35] This inhibition reduces hepatic and systemic L-carnitine levels, as confirmed in preclinical models where meldonium administration led to dose-dependent decreases in plasma and tissue carnitine concentrations.^[36] Consequently, the availability of carnitine for conjugation with long-chain fatty acyl-CoA esters is limited, impairing the carnitine shuttle mechanism mediated by carnitine palmitoyltransferases I and II (CPT1 and CPT2).^[37] The diminished carnitine-dependent transport restricts entry of fatty acyl-CoA into the mitochondrial matrix, thereby suppressing β-oxidation of fatty acids.^[38] This metabolic perturbation shifts cellular energy production from oxygen-intensive fatty acid oxidation to more oxygen-efficient glycolysis and glucose oxidation.^[39] In conditions of limited oxygen supply, such as ischemia, this adaptation sustains ATP generation by prioritizing carbohydrate substrates that yield more ATP per mole of oxygen consumed compared to fatty acids.^[30] Furthermore, the reduction in β-oxidation mitigates the accumulation of potentially toxic long-chain acylcarnitines, which can disrupt mitochondrial function.^[40] By optimizing substrate utilization, meldonium may decrease lactate production under stress, as evidenced by lowered lactate levels in exercise and hypoxic models, contributing to potential neuroprotective outcomes through preserved energy homeostasis and reduced acidosis.^[4]^[31]

Medical Uses

Approved Indications

Meldonium, sold under the brand name Mildronate by manufacturer Grindeks, is approved in Latvia, Russia, and certain other post-Soviet states for cardioprotective indications, specifically as an adjuvant therapy in mild to moderate chronic heart failure (NYHA classes I–III) and chronic ischemic heart disease, including stable angina pectoris.^[41]^[42] These approvals stem from its anti-ischemic properties, aimed at improving myocardial oxygen utilization and reducing symptoms such as fatigue and reduced exercise tolerance in affected patients.^[43] In neurological contexts, it is indicated for disorders of cerebral circulation, particularly chronic ischemic conditions, to support recovery from brain ischemia and enhance metabolic adaptation in hypoperfused tissues.^[13]^[44] Adjunctive use extends to post-myocardial infarction rehabilitation, where it is prescribed to mitigate ischemic damage and aid functional recovery, typically in combination with standard therapies.^[45] These indications are limited to regions with national regulatory approval, such as Latvia (where it has been registered since the 1980s) and Russia, and do not include broader Western approvals like those from the FDA or EMA.^[46]^[47]

Clinical Forms and Dosage

Meldonium, marketed as Mildronate by Grindeks, is formulated in multiple pharmaceutical forms for clinical administration, including hard capsules containing 250 mg or 500 mg of meldonium dihydrate, a 10% solution for injection (500 mg/5 mL), and an oral syrup at 50 mg/mL concentration.^[34]^[48]^[41] For adult patients, the recommended oral dosage is 500 to 1000 mg daily, typically administered as one or two 500 mg capsules, with the total daily dose dividable into two administrations.^[34]^[41] The maximum daily dose is 1000 mg, and treatment duration for short courses is 10 to 14 days, potentially repeatable after a 2- to 3-week interval.^[41]^[49] In acute ischemic conditions, such as recent myocardial infarction, initial intravenous injection of 500 mg (5 mL) once daily for 10 days is followed by transition to oral capsules at 500 to 1000 mg daily for a total course of 4 to 6 weeks.^[13]^[50] For chronic conditions like stable angina pectoris or heart failure, oral administration of 500 mg twice daily for 4 to 6 weeks is standard.^[13] Dosage and duration are adjusted based on the severity of the condition and patient response, with intramuscular or intravenous routes used when oral intake is not feasible.^[51] Pediatric use is not recommended due to insufficient safety and efficacy data in individuals under 18 years.^[52] In countries of origin such as Latvia and Russia, veterinary formulations exist for animal cardiac support, though human clinical guidelines prioritize adult applications.^[53]

Evidence of Efficacy and Safety

Meldonium has demonstrated cardioprotective effects in clinical trials focused on ischemic heart disease, particularly in models of myocardial ischemia where it improves energy metabolism and reduces tissue damage. A randomized controlled trial of 120 patients with stable effort angina pectoris reported that adjunctive meldonium therapy increased overall treatment efficacy four-fold compared to standard antianginal regimens alone, with improvements in exercise tolerance and symptom relief observed after 10 days of intravenous administration followed by oral dosing. Similarly, in patients with chronic heart failure, meldonium enhanced peripheral circulation and reduced markers of metabolic stress, as evidenced by a clinical study measuring hemodynamic parameters and quality-of-life scores. These outcomes align with meldonium's role in modulating fatty acid oxidation to preserve ATP levels during oxygen deprivation, supported by preclinical ischemia-reperfusion models showing preserved mitochondrial function. Despite these findings, primarily from Eastern European cohorts, the evidence base lacks robust validation through large-scale, double-blind, placebo-controlled randomized controlled trials (RCTs) conducted in Western settings. Meta-analyses of metabolic modulators, including meldonium analogs like trimetazidine, indicate heterogeneous results for arrhythmia reduction and heart failure endpoints, with meldonium-specific data limited to smaller studies prone to publication bias in regions where the drug is commercially produced. For instance, while some trials report decreased ventricular arrhythmias in ischemic genesis via optimized myocardial energetics, placebo-controlled evidence remains mixed, with no consistent demonstration of superiority over standard beta-blockers or anti-ischemics in diverse populations. This gap underscores reliance on observational or open-label designs, potentially inflating efficacy estimates due to unblinded assessments and regional patient selection. Meldonium's safety profile is generally favorable, with adverse events occurring in fewer than 15% of participants across clinical studies, predominantly mild and self-limiting. Common side effects include gastrointestinal upset (e.g., dyspepsia), headache, agitation, and allergic skin reactions, while cardiovascular effects such as tachycardia or hypotension are infrequent and dose-dependent. No serious or life-threatening toxicities have been consistently reported in human trials, including those involving ischemic stroke or post-infarction heart failure patients, though long-term data beyond 6-12 months are absent. Rare instances of bradycardia or arrhythmias have been noted, but these are not statistically elevated over placebo in available cohorts, supporting its tolerability in comorbid populations.^[54]^[29]

Regulatory Status

Approvals and Restrictions by Country

Meldonium is approved for medical use in Latvia, where it was developed and first registered by the pharmaceutical company Grindeks in the 1980s for treating conditions such as ischemia and chronic heart failure, based on local clinical evaluations of its metabolic modulating effects.^[55] Similar approvals exist in Russia, Ukraine, Kazakhstan, and other former Soviet states including Azerbaijan, Belarus, Georgia, Kyrgyzstan, Moldova, and Uzbekistan, where it remains prescribed for cardioprotective purposes, reflecting reliance on regional studies rather than international standards requiring large-scale randomized trials.^[56] In these countries, empirical data from post-Soviet pharmacovigilance supports ongoing availability, often over-the-counter in Latvia, despite limited export to Western markets.^[26] In contrast, Meldonium lacks approval from the United States Food and Drug Administration (FDA), which has not authorized it due to inadequate evidence from rigorous, placebo-controlled trials demonstrating efficacy and safety for proposed indications.^[57] The European Medicines Agency (EMA) has similarly withheld centralized authorization across the European Union, citing insufficient pharmacokinetic and clinical data to meet evidentiary thresholds, though individual member states outside the approval pathway, such as Latvia and Lithuania, maintain national registrations.^[2] It is also unapproved in Australia by the Therapeutic Goods Administration, aligning with Western regulatory emphasis on high-quality, independent verification over anecdotal or regionally derived outcomes.^[58] As of 2025, no substantive regulatory shifts have occurred post-2020; medical use persists in approving jurisdictions without expanded Western endorsements, underscoring divergent standards where Eastern approvals prioritize practical clinical observations amid resource constraints, while agencies like the FDA and EMA demand comprehensive datasets to mitigate unverified risks.^[26]^[59]

Side Effects and Toxicology

Meldonium exhibits a favorable safety profile in clinical use, with adverse effects occurring in fewer than 15% of patients across studies. Commonly reported mild side effects include dyspepsia, headache, and agitation, often resolving without intervention.^[54] Less frequent effects encompass tachycardia, allergic skin reactions, and gastrointestinal upset, while psychomotor agitation appears rare and typically transient.^[29] No serious adverse events have been consistently documented in therapeutic dosing up to 2000 mg daily.^[13] Toxicological data underscore meldonium's low acute toxicity, with no reported cases of acute or chronic human intoxication despite widespread use in certain regions. Animal studies confirm a high therapeutic index, supporting reversibility in potential overdose scenarios, though specific human overdose outcomes remain undocumented due to rarity. Non-clinical evaluations reveal no evidence of genotoxicity, carcinogenicity, or reproductive toxicity, aligning with regulatory assessments deeming it safe under standard posology.^[13]^[34] Drug interactions are minimal, with no significant pharmacokinetic conflicts identified in available data; however, caution is advised when co-administered with carnitine supplements, as meldonium inhibits endogenous carnitine biosynthesis, potentially diminishing the intended metabolic modulation. Limited reports suggest possible enhancement of vasodilatory effects with nitrates like glyceryl trinitrate, but clinical relevance remains unestablished.^[60] Overall, these findings reflect meldonium's design as a metabolic agent with negligible systemic risks at approved doses.^[54]

Sports Usage and Doping

Claims of Performance Enhancement

Athletes and coaches in Eastern European sports have reported anecdotal benefits of meldonium for enhancing endurance, accelerating recovery from high-intensity training, and reducing fatigue, attributing these effects to its metabolic modulation under stress conditions akin to ischemia.^[4] Such perceptions contributed to its widespread pre-ban adoption, with 66 out of 762 urine samples (8.7%) testing positive at the 2015 European Games in Baku, predominantly among competitors from countries like Russia, Ukraine, and Belarus where the drug was readily available over-the-counter.^[61] This usage pattern, observed prior to its January 1, 2016, inclusion on the WADA prohibited list, reflects a belief in its ergogenic potential despite its original development for cardioprotection in ischemic conditions rather than athletic optimization in healthy individuals.^[2] Preliminary animal studies have supported claims of improved exercise tolerance under hypoxic or anoxic stress, with meldonium pretreatment enhancing survival and recovery in models of anoxia-reoxygenation by promoting uncoupling preconditioning and shifting energy metabolism toward glucose oxidation over fatty acids.^[62] In rats, administration depleted muscle L-carnitine levels, reduced β-oxidation of fatty acids, and increased carbohydrate utilization, potentially mimicking benefits in hypoxic training environments by optimizing fuel efficiency during oxygen-limited efforts.^[4] Human data, primarily from clinical populations rather than elite athletes, indicate dose-dependent gains in exercise capacity, such as extended treadmill time in stable angina patients, alongside reductions in lactate accumulation during and post-exercise, which could theoretically delay fatigue in anaerobic bursts.^[4] These claims hinge on meldonium's inhibition of carnitine synthesis and transport, purportedly fostering aerobic endurance via better glycogen preservation and central nervous system activation, though direct evidence in healthy athletes remains extrapolated from ischemia-focused research.^[57] Pre-ban prevalence in endurance and power sports from Eastern regions underscores the perceived edge, even as mechanistic benefits appear more pronounced in compromised physiological states than in normoxic, high-performance scenarios.^[2]

WADA Prohibition and Scientific Rationale

Meldonium was incorporated into the World Anti-Doping Agency (WADA) Prohibited List effective January 1, 2016, categorized as a non-specified substance under section S4 (Hormone and Metabolic Modulators), rendering it banned at all times both in- and out-of-competition.^[63] ^[55] This classification stemmed from its mechanism as a metabolic modulator that inhibits the biosynthesis of L-carnitine, potentially altering fatty acid oxidation and favoring glucose utilization for energy production in cells.^[55] Prior to the ban, meldonium had been placed on WADA's 2015 Monitoring Program, a surveillance mechanism designed to evaluate the prevalence and patterns of substance use among athletes without immediate prohibition.^[64] ^[65] Data from the monitoring program indicated widespread detection of meldonium in athlete samples, with elevated prevalence suggesting systematic non-therapeutic application, particularly among certain national cohorts and sports disciplines.^[63] ^[66] Analysis of Athlete Biological Passport (ABP) profiles further revealed anomalies consistent with exogenous administration for purposes beyond approved medical indications, such as optimizing endurance under stress rather than treating ischemia or cardiac conditions.^[55] These indirect indicators—high usage rates decoupled from documented disease prevalence—formed the primary evidentiary basis for prohibition, prioritizing detection of misuse patterns over isolated therapeutic contexts.^[63] WADA's articulated rationale emphasized meldonium's capacity to enhance aerobic performance in healthy individuals by modulating myocardial and skeletal muscle energy substrates, potentially conferring advantages in prolonged or high-intensity efforts despite the drug's primary development for cardioprotection.^[55] However, this rested on mechanistic plausibility and observational data from the monitoring phase rather than comprehensive, placebo-controlled trials demonstrating statistically significant ergogenic effects in non-pathological athletes.^[8] ^[58] The precautionary framework thus hinged on the substance's theoretical optimization of metabolic efficiency under athletic demands, informed by its biochemical interference with carnitine-dependent processes, even as direct causal links to superior outcomes remained empirically sparse at the time of listing.^[55]

Notable Athlete Cases

Maria Sharapova, a Russian professional tennis player, tested positive for meldonium in an out-of-competition sample collected on January 26, 2016, during the Australian Open.^[67] The International Tennis Federation imposed a two-year suspension on June 8, 2016, which the Court of Arbitration for Sport reduced to 15 months on September 30, 2016, allowing her return in April 2017.^[68] In 2016, following meldonium's addition to the World Anti-Doping Agency prohibited list effective January 1, more than 100 athletes across multiple sports tested positive, including in tennis, cycling, biathlon, and athletics.^[69] Russian athletes accounted for a significant portion, with reports of 102 positives in that country alone, affecting disciplines such as speed skating, swimming, and boxing.^[70] Notable cases included boxer Alexander Povetkin, who tested positive in May 2016 ahead of a scheduled fight. These detections contributed to broader sanctions, with numerous Russian competitors excluded from the 2016 Rio Olympics due to anti-doping violations involving meldonium and other substances.^[71] Post-2016 cases became sporadic, with WADA reporting a decline to 79 adverse analytical findings in 2017.^[72] Isolated positives continued into later years, though fewer reached high-profile status.^[4]

Controversies and Debates

Evidence Gaps in Performance Benefits

A narrative review of meldonium's pharmacology and purported athletic applications has characterized performance enhancement claims as speculative, lacking sound scientific evidence to support benefits in healthy athletes.^[8] Anti-doping expert Don Catlin, founder of the Banned Substances Control Group, has asserted that robust data showing ergogenic effects in non-diseased individuals is absent, emphasizing zero percent evidence for athletic gains under normal physiological conditions.^[73] This assessment aligns with broader critiques of the World Anti-Doping Agency's prohibited list, where a 2025 analysis of post-ban randomized controlled trials (RCTs) for meldonium reported performance improvements below 1%, falling short of thresholds typically deemed meaningful for elite competition.^[74] Human studies on meldonium's effects in athletes remain limited and inconsistent, with early reports of endurance gains often confined to small cohorts or suboptimal designs that fail to isolate causal mechanisms in normoxic settings.^[54] While some investigations suggest minor reductions in lactate accumulation during submaximal exercise, these findings have not been consistently replicated in high-level athletes, where placebo effects, training status, and individual variability confound results.^[75] Positive outcomes in ischemic or hypoxic models—such as improved myocardial oxygen utilization—do not reliably translate to enhanced aerobic capacity in healthy subjects, as evidenced by the absence of dose-response data linking meldonium's gamma-butyrobetaine inhibition to measurable ergogenic shifts outside pathological states.^[54] Preclinical animal data, which underpin many enhancement hypotheses, further highlights translational gaps: rodent and canine models demonstrate cardioprotective effects under stress or ischemia, yet these do not causally extend to human performance metrics like VO2 max or time-to-exhaustion in eucapnic, normoxic environments.^[54] For instance, meldonium's modulation of carnitine biosynthesis yields anti-hypoxic benefits in oxygen-deprived tissues, but lacks empirical support for fatty acid metabolism shifts that would confer advantages in sustained, high-intensity efforts typical of elite sports.^[26] Overall, the evidentiary base prioritizes therapeutic contexts over athletic utility, with methodological limitations in existing trials—such as short durations, low statistical power, and absence of blinded, placebo-controlled protocols in competitive populations—precluding firm conclusions on efficacy.^[74]

Detection Challenges and Retroactive Enforcement

Meldonium exhibits a prolonged urinary detection window, often extending several months after cessation of use, due to its multi-phase elimination pharmacokinetics. Studies have reported detection periods ranging from 64 to 117 days in urine following chronic administration, attributed to a terminal half-life of 22 to 36 days in a three-compartment model, where slow release from deep tissue compartments sustains low-level excretion.^[76]^[77] This atypical profile for a hydrophilic compound arises from accumulation in tissues during repeated dosing, complicating differentiation between recent intentional use and residual traces from prior therapeutic administration.^[78] Individual variability in metabolism further exacerbates detection challenges, as excretion rates differ based on factors such as dosage history, renal function, and genetic influences on carnitine pathway interactions, leading to detection windows from weeks to over five months in some cases.^[13]^[79] Proving intent becomes problematic, as low concentrations (e.g., below 100 ng/mL) may reflect non-doping residual levels rather than deliberate post-ban ingestion, prompting debates over threshold-based interpretations despite WADA's zero-tolerance stance for prohibited substances.^[63] Following its addition to the WADA Prohibited List on January 1, 2016, enforcement involved retroactive application to samples collected post-ban, even if use predated the prohibition, resulting in over 170 adverse analytical findings by April 2016.^[63] Tribunals occasionally reduced sanctions—such as shortening suspensions from two years to 15 months in select appeals—when pharmacokinetic modeling and self-reported cessation timelines (e.g., stopping in late 2015) demonstrated no specified or intentional violation under the WADA Code, highlighting tensions between strict liability and evidentiary burdens.^[80] Advancements in hair analysis have enabled historical detection beyond urine windows, with meldonium incorporating into hair segments at concentrations of 0.7 to 17 pg/mg, reflecting chronic use over months to years via segmental analysis.^[81] A 2025 study validated this method for doping verification, detecting the drug in proximal hair of known users despite challenges from its ionized, amino acid-like properties, potentially aiding retroactive investigations but raising concerns over interpreting low-level incorporations without corroborative urine data.^[82]

Broader Implications for Anti-Doping Policy

The inclusion of meldonium on the World Anti-Doping Agency (WADA) Prohibited List exemplifies the precautionary principle in anti-doping, where substances are banned based on patterns of widespread use and suspected mechanisms of action rather than definitive causal evidence from randomized controlled trials (RCTs) in elite athletes.^[83]^[84] WADA monitored meldonium in 2015, detecting positives in 8.7% of samples at the Baku European Games, which—combined with animal and indirect human data suggesting metabolic modulation—prompted its prohibition effective January 1, 2016, despite no peer-reviewed RCTs demonstrating performance enhancement in trained individuals prior to the ban.^[83]^[85] This approach prioritizes deterrence against potential advantages and undefined health risks over rigorous proof, raising concerns of policy overreach that could extend to other metabolic agents lacking empirical validation.^[84]^[85] Proponents of the ban argue it upholds fair play by addressing non-therapeutic usage patterns indicative of doping intent and mitigates possible long-term health risks from unproven ergogenic aids, aligning with WADA's dual criteria of performance enhancement or spirit-of-sport violation.^[83] Critics counter that such precautionary measures impose undue harm on athletes, particularly those with legitimate therapeutic needs, under strict liability rules that presume guilt without establishing actual enhancement or violation, potentially eroding trust in the system through insufficient evidence thresholds.^[85]^[86] Post-ban analyses have yielded only low-quality studies failing to confirm benefits, underscoring how reliance on suspicion over causal data risks arbitrary enforcement and polarization between regulators and stakeholders.^[84] The meldonium case highlights equity issues in anti-doping enforcement, with disproportionate sanctions affecting Eastern European athletes—such as over 100 positives from Russia and Latvia—due to the drug's established therapeutic role in regional medicine, contrasting with rarer use elsewhere and prompting debates on cultural biases in global standards.^[87]^[88] This regional skew questions whether WADA's harmonized policies inadvertently penalize divergent medical practices without accounting for context, advocating for refined criteria that balance universality with evidence-based flexibility to prevent perceived inequities.^[86]^[85]

Recent Research Developments

Emerging Therapeutic Applications

Recent preclinical studies have explored meldonium's neuroprotective potential in neurodegenerative conditions, including Parkinson's disease and cerebral ischemia models. In a 2024 study, meldonium promoted neuronal survival by protecting mitochondria and reducing apoptosis in cerebral ischemia-reperfusion injury, with applications suggested for stroke and traumatic brain injury.^[39] A 2025 investigation demonstrated region-specific neuroprotective effects via pretreatment in animal models of neurodegeneration, attenuating pathological damage and mitochondrial dysfunction.^[89] These findings build on earlier evidence of meldonium enhancing learning and memory while altering hippocampal gene expression, positioning it as a candidate cognitive enhancer for neurodegenerative disorders.^[90] Emerging research has also examined meldonium in alcohol use disorder, with a 2024 review synthesizing investigations into its role in mitigating alcohol-related neurotoxicity through metabolic modulation, though clinical evidence remains preliminary.^[26] In high-altitude contexts, a 2023 pharmacokinetic study reported meldonium's protective effects against hypoxia-induced pulmonary injury, altering drug dynamics to reduce oxidative stress and tissue damage in acute exposure models.^[32] Experimental applications include glioblastoma treatment, where 2025 case reports on three end-stage recurrent patients documented good tolerability of meldonium-containing therapy, with one case showing long-term tumor growth arrest and clinical stability, suggesting potential outcome improvements pending controlled trials.^[91] Additionally, meldonium exhibits anti-inflammatory properties in pulmonary injury models; a study demonstrated its amelioration of hypoxia-induced lung damage by regulating platelet-type phosphofructokinase-mediated glycolysis and curbing oxidative stress.^[31] These post-2016 explorations indicate broadening therapeutic interest beyond ischemia, emphasizing metabolic reprogramming for neuroprotection and inflammation control.^[26]

Ongoing Studies and Findings

Recent investigations into meldonium's role as a metabolic modulator have focused on its potential in managing chronic conditions beyond traditional ischemic applications, such as cancer-related fatigue and heart failure with preserved ejection fraction. A phase 1/2 clinical trial initiated on October 18, 2024, evaluates the safety and preliminary efficacy of meldonium in patients with metastatic renal cell carcinoma experiencing treatment-associated fatigue, aiming to assess improvements in energy metabolism and symptom relief.^[92] Similarly, a September 8, 2025, trial examines meldonium combined with personalized physical activity in heart failure patients, targeting metabolic optimization without evidence of expanded regulatory approvals for these indications.^[93] Neuroprotective applications remain a key area of exploration, with 2024-2025 studies demonstrating meldonium's ability to preserve mitochondrial function and reduce apoptosis in cerebral ischemia-reperfusion injury models, as shown in preclinical work published August 15, 2024. Case reports from April 28, 2025, suggest tolerability and potential outcome improvements in end-stage recurrent glioblastoma patients treated experimentally with meldonium, though these are limited to small cohorts without randomized controls. Region-specific neuroprotection via pretreatment was reported in an April 30, 2025, study using invasive models, highlighting modulation of cellular energy pathways but underscoring the need for human validation.^[39]^[94]^[89] The World Anti-Doping Agency confirmed meldonium's retention on the 2025 Prohibited List under S4 hormone and metabolic modulators, effective January 1, 2025, with no revisions to its status despite ongoing therapeutic scrutiny. Advancements in detection include a August 17, 2025, method for quantifying meldonium in human hair, enabling retrospective assessment of long-term exposure for doping compliance, which addresses challenges in urine-based testing windows.^[59]^[82] Persistent gaps include the scarcity of large-scale randomized controlled trials (RCTs) establishing non-ischemic benefits, with most evidence derived from preclinical or small observational studies rather than robust athlete or patient RCTs demonstrating causal efficacy in metabolic modulation for chronic non-cardiac conditions. This evidentiary shortfall limits broader therapeutic adoption and fuels debates on its mechanistic claims, as preclinical neuroprotective effects have not yet translated to definitive clinical outcomes in diverse populations.^[26]^[74]

References

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Meldonium - American Chemical Society
Jul 11, 2016 · Meldonium is a zwitterionic compound that was developed in Latvia in 1970 as an anti-ischemia drug. AS Grindeks, a Latvian pharmaceutical company, markets ...
[2]
Meldonium (Mildronate): A Performance‐Enhancing Drug?
Apr 29, 2016 · Meldonium is classified as a partial inhibitor of fatty acid oxidation; it binds to and competitively inhibits gamma-butyrobetaine hydroxylase.
[3]
Meldonium - an overview | ScienceDirect Topics
Meldonium is primarily known as a cardioprotective drug whose mechanism of action is based on decreasing the l-carnitine concentration, regulating energy ...
[4]
Meldonium Supplementation in Professional Athletes
Jul 1, 2024 · Meldonium is used as an anti-anginal medication in countries outside the European Union because it prevents post-infarction ischemia and the ...
[5]
Mildronate: an antiischemic drug for neurological indications - PubMed
The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become more active.
[6]
WADA Statement regarding Maria Sharapova Case
Meldonium was added [to the Prohibited List] because of evidence of its use by athletes with the intention of enhancing performance. '
[7]
Story behind meldonium–from pharmacology to performance ...
Meldonium has been shown to have beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective ...
[8]
Story behind meldonium-from pharmacology to performance ...
Meldonium has been shown to have beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective ...
[9]
Ivars Kalvins named finalist for 2015 European Inventor Award
Apr 21, 2015 · Thanks to his successful approach, after just six months of trials in 1976, the ardent saxophonist discovered that the compound meldonium could ...Missing: Kalviņš | Show results with:Kalviņš
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Meldonium determination in milk and meat through UHPLC-HRMS
Meldonium, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, was first synthesized at the Institute of Organic Synthesis in Latvia in 1970 for veterinary ...Missing: early | Show results with:early
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The story behind meldonium–From pharmacology to performance ...
Meldonium is a well-established drug in Eastern Europe (Mildronate® from Grindeks) for treatment of central nervous and cardiac ischemic diseases [13] .<|control11|><|separator|>
[12]
Pharmacological effects of meldonium: Biochemical mechanisms ...
Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based ...Missing: discovery Ivars Kalviņš early
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Meldonium: Pharmacological, toxicological, and analytical aspects
Mar 27, 2020 · The goal of this review is to relate the use of meldonium as a doping agent, considering its pharmacological, toxicological, and analytical aspects.
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Mildronat: Doping Test Successfully Passed in the Court
Jul 7, 2017 · In 1976 the drug received the inventor's certificate in the USSR and in 1984 a patent was received in the USA. In 1992 due to collapse of the ...
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Maria Sharapova's drug: The secret Cold War origins of meldonium
Mar 21, 2016 · The man who invented meldonium says the drug is medicinal, not performance-enhancing, but says the research is classified.Missing: properties | Show results with:properties<|separator|>
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Mildronate, an Inhibitor of Carnitine Biosynthesis, Induces an ...
Aug 5, 2025 · ... Mildronate (3-(2,2,2-trimethylhydrazinium) propionate) is a structural analog of the precursor to L-carnitine synthesis (γ-butyrobetaine).
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Patents Assigned to Joint Stock Company “Grindeks”
Patent number: 7223797 · Abstract: New salts of Meldonium, the method of their preparation, and pharmaceutical formulation on their basis have been described.
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Formulation of mildronate injection and preparation method - Eureka
The Latvian JSC Grindeks company pushed Meldonium to the former Soviet Union market in the late 1980s. ... invention technology for a patent. Patent full ...
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Preparation method for mildronate and key intermediate of mildronate
Meldonium (also known as THP, MET-88 and mildronate) is a kind of novel heart protecting medicine.It is to be had by LV Latvia Machine synthesis is developed, ...
[20]
Meldonium | C6H14N2O2 | CID 123868 - PubChem - NIH
Molecular Formula. C6H14N2O ; Synonyms. Mildronate; Meldonium; 76144-81-5; Kvaterin; 3-(2,2,2-trimethylhydrazine)propionate ; Molecular Weight. 146.19 g/mol.Missing: solubility | Show results with:solubility
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Mildronate synthesis - chemicalbook
The general procedure for the synthesis of Mildronate from 3-(2,2,2-trimethylhydrazine)-propionic acid methyl ester chloride is as follows: 1.
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CN103483219A - Mildronate dihydrate preparation method
The invention provides a mildronate dihydrate preparation method. According to the method, carbomethoxy groups are removed by performing hydrolysis through ...
[23]
Method for producing 3-(2,2,2-trimethyl-hydrazinium) propionate ...
A method for producing 3-(2,2,2-trimethylhydrazinium)propionate dihydrate by saponification of salts of 3-(2,2,2-trimethylhydrazinium)propionate esters with ...
[24]
EP1667960B1 - Meldonium salts, method of their preparation and ...
Method of salt preparation from meldonium dihydrate. Meldonium and the corresponding acid are dissolved in a small quantity of water at 40-50 C under stirring.
[25]
CN101973909A - Preparation method of mildronate - Google Patents
The invention discloses a preparation method of Meldonium, which belongs to the technical field of chemical synthesis. It is characterized in that it ...
[26]
Unlocking the Potential of Meldonium: From Performance ... - MDPI
May 6, 2024 · This review manuscript delves into the multifaceted roles of meldonium, examining its pharmacological mechanisms, therapeutic applications, and controversial ...
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Mildronate, an inhibitor of carnitine biosynthesis, induces ... - PubMed
By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the ...Missing: meldonium | Show results with:meldonium
[28]
Pharmacological effects of meldonium: Biochemical mechanisms ...
Meldonium is primarily known as a cardioprotective drug whose mechanism of action is based on decreasing the l-carnitine concentration, regulating energy ...
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Meldonium - Cordiner - 2016 - Practical Diabetes - Wiley Online ...
Dec 13, 2016 · So far, Latvian trials in animal models have supported this hypothesis; however, there are no high quality clinical trials in humans.Missing: Early | Show results with:Early
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The effects of meldonium on the acute ischemia/reperfusion liver ...
Jan 14, 2021 · Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis.
[31]
Meldonium Ameliorates Hypoxia-Induced Lung Injury and Oxidative ...
Apr 5, 2022 · ... mitochondrial function was severely affected by hypoxia. The OCR evidently decreased after hypoxia exposure, while meldonium increased OCR ...
[32]
Insights into the pharmacodynamics and pharmacokinetics of ...
Feb 21, 2023 · The study showed that meldonium (50 mg/kg) could significantly reverse heart rate and blood pressure changes, increase cerebral blood flow, ...
[33]
Hyperpolarized magnetic resonance shows that the anti‐ischemic ...
Meldonium treatment induced very few effects in the healthy control animals but it increased PDH flux by 20%, likely indicating increased glucose oxidation. The ...
[34]
[PDF] Summary of Product Characteristics - HPRA
May 22, 2024 · The bioavailability of the medicine at oral application accounted for 78 %. The food intake delayed the Tmax but did not affect the Cmax and AUC ...
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Inhibition of L-carnitine biosynthesis and transport by methyl-γ ...
Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction.
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Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ ...
Nov 3, 2014 · In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) ...
[37]
Meldonium-induced steatosis is associated with increased delta 6 ...
The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines.
[38]
The Effects of a Meldonium Pre-Treatment on the Course of ... - MDPI
The present results suggested that meldonium decreases lipolysis and fatty acids β oxidation, and stimulates aerobic oxidation of glucose as an oxygen-sparing ...
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Meldonium, as a potential neuroprotective agent, promotes neuronal ...
Aug 15, 2024 · Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial ...
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[PDF] Meldonium (Mildronate)
More recently, meldonium has been used in the treatment of acute ischemic stroke. One animal study concluded that meldonium may facilitate vascular reactivity.<|separator|>
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About Mildronate® – Developed by Grindeks for Heart Care
Mildronate (Meldonium) is a cardioprotective drug for the adjuvant treatment of patients with mild chronic cardiac insufficiency.
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(PDF) Mildronate: An Antiischemic drug with multiple indications
Aug 10, 2025 · Mildronate is an officially recommended drug for treatment of chronic heart ischemic disease. and stable angina pectoris, cardiomyopathy in ...Missing: Grindeks | Show results with:Grindeks
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Mildronate: An Antiischemic Drug for Neurological Indications - PMC
It is hypothesized that mildronate may increase the formation of the γ‐butyrobetaine esters. The latter are potent cholinomimetics and may activate eNOS via ...
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Mildronate: An Antiischemic Drug for Neurological Indications
Aug 6, 2025 · The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become ...
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Experts opinion – use of Mildronate® injections is safe - Grindeks
Mar 25, 2009 · It is possible to use Mildronate for the treatment of atherosclerosis, heart failures, heart attacks, stenocardia, thrombus etc. The medication is very ...
[46]
What Is Meldonium? Drug Sharapova Admitted to Taking Improves ...
Mar 8, 2016 · Meldonium can have a protective effect on patients with "angina pectoris [chest pain], chronic heart failure, brain circulation disorders," ...
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Meldonium: The drug behind Maria Sharapova's positive test
Mar 7, 2016 · Meldonium was first developed and marketed by the Latvia-based pharmaceutical company Grindeks and was one of the country's largest exports.
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A kind of prescription and preparation method of Meldonium injection
The marketed dosage forms include injection (500mg/5ml), capsule (250mg, 500mg) and syrup (250ml, 50mg/ml). The main indications of Meldonium listed in these ...
[49]
Mildronate leaflet – Poland | Oladoctor
The recommended dose is 500-1000 mg of meldonium per day. The daily dose can be divided into two single doses. The maximum daily dose is 1000 mg.
[50]
Injections Mildronate: instructions for use, for which they are ...
Dosage for various pathologies · in acute conditions: iv injection of 5 ml of 1 r. / day. - 10 days, then capsules of 0.5-1 g; general course 4-6 weeks; · in ...
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[PDF] Meldonium instructions - Russian Meds Online Pharmacy
The route of administration, doses and duration of the course of treatment are set individually, depending on the indications, the severity of the condition. 1.
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[PDF] Mildronāts-Grindeks 250 mg hard - WordPress.com
This medicine should not be used in children and adolescents under 18 years of age due to lack of data on meldonium safety and efficacy in these age groups.
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Final Dosage Forms - Grindeks
Grindeks' FDFs range from solid form products, solution for injections to ointments and syrups. *This section is intended for healthcare professionals only.Missing: prescribing | Show results with:prescribing
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Misuse of the metabolic modulator meldonium in sports - PMC
Meldonium (commercial name Mildronate) was originally synthesized in the mid-1970s at the Institute of Organic Synthesis of the Latvian Soviet Socialist ...Missing: first | Show results with:first
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Meldonium and the Prohibited List - PMC - NIH
Meldonium was added to the WADA Prohibited List on 1 January 2016 because of evidence of its use by athletes with the intention of enhancing performance.Missing: Western | Show results with:Western<|control11|><|separator|>
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[PDF] Meldonium
Pharmacology. Meldonium (trimethylhydrazinium propionate) regulates energy metabo- lism through reduction of levocarnitine. (L-carnitine); (Figure 1). L- ...
[57]
Substance Profile: Meldonium | U.S. Anti-Doping Agency - Usada
Meldonium (Mildronate) is an anti-ischemic drug that was added to the World Anti-Doping Agency's (WADA) Prohibited List, effective January 1, 2016.
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Meldonium and the WADA Prohibited List - Australian Prescriber
It is predominantly used in Latvia, Russia and Eastern Europe. The drug is not approved for use in Australia. Meldonium is reported to have cardioprotective ...Missing: indications | Show results with:indications
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[PDF] international standard - prohibited list - WADA
Below are some terms used in this List of Prohibited Substances and Prohibited ... Meldonium, 11. MENT, 6. Mephedrone, 15. Mephentermine, 14. Mesocarb, 14.
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(PDF) Unlocking the Potential of Meldonium: From Performance ...
May 6, 2024 · Available studies suggest that meldonium is eliminated mainly by the kidneys. Single dose administration showed … Read more. Article. Urinary ...Missing: percentage | Show results with:percentage
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Meldonium use by athletes at the Baku 2015 European Games ...
Mar 8, 2016 · Meldonium is reported to be registered for medical use in 7 Eastern European countries who competed at the Baku 2015 Games, including Latvia, ...
[62]
Mildronate, the inhibitor of l-carnitine transport, induces brain ...
Jan 15, 2014 · The preservation of mitochondrial function is essential for normal brain function after ischaemia-reperfusion injury. l-carnitine is a ...
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[PDF] NOTICE - MELDONIUM - WADA
Apr 11, 2016 · Athletes must ensure that no prohibited substance is present in their samples. Therefore, if athletes take a substance that is soon to be banned ...
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[PDF] the 2015 monitoring program - WADA
The following substances are placed on the 2015 Monitoring Program: 1. Stimulants: In-Competition only ... in order to detect patterns of misuse in sport.”Missing: detections | Show results with:detections
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Mildronate (Meldonium) in professional sports – monitoring doping ...
Apr 5, 2015 · For in-house synthesis of Mildronate-D3 (3-(2,2,2-trimethylhydrazinium)propionate-D3) as IS, 37.9 g (0.63 mol) of 1,1-dimethylhydrazine was ...
[66]
Meldonium use by athletes at the Baku 2015 European Games
Meldonium is reported to be used by athletes to potentially enhance personal performance and shorten the recovery period after physical activity.
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Maria Sharapova suspended 2 years over positive doping test - ESPN
Jun 8, 2016 · Maria Sharapova was suspended for two years by the International Tennis Federation on Wednesday, for testing positive for the banned substance meldonium.Missing: notable | Show results with:notable
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[PDF] Maria Sharapova v. ITF - TAS xxx - Court of Arbitration for Sport
Sep 30, 2016 · “(1) An anti-doping rule violation contrary to article 2.1 of the TADP was committed by Maria Sharapova as a result of the presence of Meldonium ...
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More than 100 athletes have tested positive for meldonium already ...
Mar 21, 2016 · Since it was banned on January 1, 2016, more than 100 athletes around the world have tested positive for meldonium.
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Russian Athletes Gave 40 Positive Meldonium Tests in 2016
Mar 21, 2016 · A total of 102 Russian athletes have tested positive for meldonium, the TASS news agency reported. Names of 15 athletes have already been ...
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Meldonium - Wikipedia
Meldonium is a pharmaceutical developed in 1970 by Ivars Kalviņš at the USSR Latvia Institute of Organic Synthesis. It is now manufactured by the Latvian ...
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Meldonium Ban Hits Russian Athletes Hard - The New York Times
Mar 9, 2016 · In the two days since Maria Sharapova's announcement, seven Russian athletes have confirmed testing positive for meldonium.
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[PDF] WADA - Executive Summary
The lower number of AAFs is primarily related to the reported cases of meldonium (515 cases in 2016 to 79 cases in 2017) – a substance that was first included ...<|control11|><|separator|>
[74]
Experts say there's little evidence meldonium enhances performance
Apr 5, 2016 · “There's really no evidence that there's any performance enhancement from meldonium. Zero,” said Don Catlin, a long-time anti-doping expert.
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Evidence Gaps in the World Anti-Doping Agency's Prohibited List
Aug 9, 2025 · Objective: To evaluate gaps in the scientific evidence and policy implementation of WADA's Prohibited List using official WADA data and peer- ...Missing: Western | Show results with:Western
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Meldonium Supplementation in Professional Athletes - PubMed
Jul 1, 2024 · Since 2016, meldonium has been included by the World Anti-doping Agency (WADA) on the S4 list of metabolic modulators. In performance ...<|control11|><|separator|>
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The atypical excretion profile of meldonium: Comparison of urinary ...
Despite of the polar and hydrophilic nature of meldonium, a urinary detection window expanding over 64 and 117 days was observed.Missing: bioavailability | Show results with:bioavailability
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Urinary excretion studies of meldonium after multidose parenteral ...
Nov 30, 2018 · A three-compartment model was found to best describe the pharmacokinetics of meldonium with average alpha, beta, and gamma half-lives of 1.4 h, ...Missing: mildronate bioavailability renal
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Meldonium long‐term excretion period and pharmacokinetics in ...
Oct 17, 2018 · The study found meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after ...
[80]
reassessing meldonium detection and doping verdicts in a case study
This study systematically analyzes data from an athlete (Subject 1) who tested positive for meldonium and compares it with data from a healthy volunteer ( ...Missing: variable | Show results with:variable
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Five Lessons Learned from the Sharapova ITF Tribunal Decision
Jun 10, 2016 · The stakes were high, since a finding of intentional doping would have led to a four-year Ineligibility period. As Meldonium is not a Specified ...
[82]
Testing for Meldonium, a Doping Agent, in Human Hair - Kintz
Aug 17, 2025 · Meldonium has been developed in the 70s in Latvia and is currently used in a limited number of countries for heart-related diseases, such as ...Missing: studies | Show results with:studies
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Testing for Meldonium, a Doping Agent, in Human Hair - PubMed
Aug 17, 2025 · Such hair application can be complicated to develop, as meldonium has a chemical formula close to an amino acid and presents an ionized fraction ...Missing: variable | Show results with:variable<|control11|><|separator|>
[84]
Why Meldonium Got Banned In Sports : Shots - Health News - NPR
Jun 14, 2016 · Meldonium was just one of over a dozen drugs in WADA's monitoring program, a sort of watch list for substances the agency may ban in the future.Missing: rationale | Show results with:rationale
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[PDF] The Inclusion in WADA Prohibited List Is Not Always Supported by ...
Feb 25, 2021 · Conclusions: There is insufficient evidence that the previously mentioned substances have any performance enhancing potential. If left on the ...
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Review of WADA Prohibited Substances: Limited Evidence for ...
Nov 8, 2018 · In summary, high-dose AAS appears to increase strength but not endurance performance. The evidence on strength effects is based on three studies ...
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Failure of WADA Communications & the power of condemnation
May 3, 2016 · The issues created by how the anti-doping community has handled meldonium's addition to the Prohibited List has polarised opinion.Missing: precautionary principle
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More Than 60 Athletes Have Tested Positive for Meldonium
Mar 10, 2016 · It was placed on the World Anti-Doping Agency's banned list this year after being monitored by the agency in 2015. ... She said she was unaware ...
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Meldonium in Anti-Doping: Cases, Uses & Classification
Jul 20, 2023 · Antidoping Norway · British Journal of Sports Medicine. Statistics: Russia - 76 doping cases; Kazakhstan - 36 doping cases; Latvia - 16 doping ...Missing: implications | Show results with:implications
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Region-specific neuroprotective effects of meldonium pretreatment ...
Apr 30, 2025 · Meldonium is a drug approved for ischemic heart disease but has also gained attention for its neuroprotective effects. In animal models of ...
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Mildronate enhances learning/memory and changes hippocampal ...
The data from our study suggest that mildronate may be useful as a possible cognitive enhancer for the treatment of patients with neurodegenerative diseases ...
[92]
Case report of three patients with end-stage recurrent glioblastoma ...
Apr 28, 2025 · Here, we report three cases of experimental meldonium-containing therapy in end-stage recurrent glioblastoma patients.
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Safety and Preliminary Efficacy of Meldonium in Patients with ...
Oct 18, 2024 · Meldonium is a fatty acid oxidation inhibitor, and it is now principally used for heart conditions, such as angina, heart attack, heart failure ...
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Study on Meldonium and Physical Activity for Patients with Heart ...
Sep 8, 2025 · This clinical trial is focused on studying the effects of a medication called Meldonium and personalized physical activities in patients ...Missing: ongoing | Show results with:ongoing
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Case report of three patients with end-stage recurrent glioblastoma ...
Apr 28, 2025 · The case reports presented here suggest good tolerability and the potential for meldonium to improve outcome in glioblastoma patients.