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Sergey Razinkin - One of the best experts on this subject based on the ideXlab platform.
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Meldonium long term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers
Drug Testing and Analysis, 2019Co-Authors: Olivier Rabin, Vladimir Uiba, Yulia Miroshnikova, Maksim Zabelin, Aleksander Samoylov, Vladislav Karkischenko, Sergey Semyonov, T A Astrelina, Sergey RazinkinAbstract:Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of Meldonium. Consequently, the Meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on Meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of Meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on Meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral Meldonium daily for 3 weeks. The study found Meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with Meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.
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Meldonium long‐term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers
Drug testing and analysis, 2018Co-Authors: Olivier Rabin, Vladimir Uiba, Yulia Miroshnikova, Maksim Zabelin, Aleksander Samoylov, Vladislav Karkischenko, Sergey Semyonov, Sergey RazinkinAbstract:Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of Meldonium. Consequently, the Meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on Meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of Meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on Meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral Meldonium daily for 3 weeks. The study found Meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with Meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.
Mario Thevis - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and pharmacodynamics of Meldonium in exercised thoroughbred horses.
Drug testing and analysis, 2017Co-Authors: Heather K Knych, Scott D Stanley, Dan S. Mckemie, Rick Arthur, Ulf Bondesson, Mikael Hedeland, Mario Thevis, Philip H. KassAbstract:Although developed as a therapeutic medication, Meldonium has found widespread use in human sports and was recently added to the World Anti-Doping Agency's list of prohibited substances. Its reported abuse potential in human sports has led to concern by regulatory authorities about the possible misuse of Meldonium in equine athletics. The potential abuse in equine athletes along with the limited data available regarding the pharmacokinetics and pharmacodynamics of Meldonium in horses necessitates further study. Eight exercised adult thoroughbred horses received a single oral dose of 3.5, 7.1, 14.3 or 21.4 mg/kg of Meldonium. Blood and urine samples were collected and analyzed using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using non-compartmental analysis. Maximum serum concentrations ranged from 440.2 to 1147 ng/mL and the elimination half-life from 422 to 647.8 h. Serum concentrations were below the limit of quantitation by days 4, 7, 12 and 12 for doses of 3.5, 7.1, 14.3 and 21.4 mg/kg, respectively. Urine concentrations were below the limit of detection by day 44 following administration of 3.5 mg/kg and day 51 for all other dose groups. No adverse effects were observed following Meldonium administration. While the group numbers were small, changes in heart rate were observed in the 3.5 mg/kg dose group (n = 1). Glucose concentrations changed significantly in all dose groups studied (n = 2 per dose group). Similar to that reported for humans, the detection time of Meldonium in biological samples collected from horses is prolonged, which should allow for satisfactory regulation in performance horses. Copyright © 2017 John Wiley & Sons, Ltd.
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The atypical excretion profile of Meldonium: Comparison of urinary detection windows after single- and multiple-dose application in healthy volunteers.
Journal of pharmaceutical and biomedical analysis, 2017Co-Authors: Christian Görgens, Sven Guddat, Christina Bosse, Hans Geyer, Valentin Pop, Wilhelm Schänzer, Mario ThevisAbstract:Abstract Following a one-year monitoring program providing unequivocal analytical evidence for a high prevalence in international elite sports, Meldonium has been included in the World Anti-Doping Agency’s (WADA) list of prohibited substances that came into effect on 1 January 2016. Despite of the polar and hydrophilic nature of the molecule, an unusual long detection window was observed in pilot elimination studies. Consequently, in the present study, urinary excretion profiles after single-dose (5 volunteers, 1 × 500 mg) and multiple-dose oral application (5 volunteers; 2 × 500 mg/day for 6 days) were determined in order to facilitate the result management concerning Meldonium findings in doping controls. Particularly the option to differentiate between recent use and tapering concentrations was studied. Urinary Meldonium concentrations were determined using an analytical approach based on hydrophilic interaction liquid chromatography and high resolution tandem mass spectrometry. The study corroborates the hypothesis of a non-linear, dose-depended and biphasic excretion profile after oral application of Meldonium and demonstrates that urinary detection windows are of considerable extent with up to 65 and 117 days (concentrations > LOQ of 10 ng/mL) following single- and multiple-dose applications, respectively.
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Analyses of Meldonium (Mildronate) from Blood, Dried Blood Spots (DBS), and Urine Suggest Drug Incorporation into Erythrocytes
International Journal of Sports Medicine, 2016Co-Authors: Laura Tretzel, Christian Görgens, Sven Guddat, Hans Geyer, Valentin Pop, Wilhelm Schänzer, Andreas Thomas, Josef Dib, Mario ThevisAbstract:Initially developed in the late 1970s for veterinary applications due to proposed growth-promoting effects in animals [5], Meldonium has become an approved drug in selected Eastern European countries and is the subject of ongoing clinical trials focusing the compound’s anti-ischemic and cardioprotective properties [2, 3, 12, 15] as well as potential applications regarding diabetes, neurodegenerative disorders, and bronchopulmonary diseases. In the context of athletic performance, beneficial effects on the individuals’ physical working capacity, increased endurance performance, and accelerated recovery after physical activity were discussed [4, 10, 11], mentioning oral doses of Meldonium of up to 2.0 g per day over 2–3 weeks in the course of pre-competition preparation phases [4]. In 2015, the World Anti-Doping Agency (WADA) initiated a one-year monitoring program [22] regarding the prevalence of Meldonium (mildronate) in doping controls. Obtained data demonstrated a considerable extent of Meldonium use by athletes [8, 16], which was further corroborated by a significant number of declarations of use and analytical findings at the Baku 2015 European Games [18]. Subsequently, the WADA Prohibited List that became effective in January 2016 [24] classified Meldonium as banned under S4 (Hormone and Metabolic Modulators). Pharmacokinetic properties of Meldonium were reported for singleand multiple-dose administration studies with healthy volunteers [25], where the drug’s elimination was monitored in plasma over 24 h post-administration and characterized by nonlinear pharmacokinetics. To date, doping controls are based on urine and blood as test matrices, and a variety of alternative matrices including amongst others dried blood spots (DBS) and dried plasma spots (DPS) have been considered lately [20]. Consequently, the knowledge about factors that potentially influence the elimination of target analytes is of particular importance to sports drug testing and, to the best of our knowledge, the role of erythrocytes and their ability to affect detection windows of Meldonium in doping controls (e. g., by incorporation) has not been investigated. Therefore, in the context of a pilot study, DBS, whole blood (Na2EDTA), and urine samples were collected from 2 healthy male volunteers who orally administered Meldonium either as single dose (500 mg) or as multi-dose (3 × 500 mg/day over a period of 6 consecutive days). The study protocol was approved by the local ethics committee of the National Institute for Sports Research (Bucharest, Romania, approval number #162/2016), written consent was obtained from the study participants, and the study was conducted in accordance with ethical standards in sports medicine and exercise science [9]. DBS samples were collected prior to and post-administration up to 16 days using standard DBS collection cards (Whatman DMPK-C, GE Heathcare Europe, Freiburg, Germany), dried at room temperature, and stored at + 4 °C in a plastic bag with desiccant until analysis. Na2-EDTA-stabilized whole blood specimens (3.5 mL) were sampled within the multi-dose study on day 4 and day 28 post-administration, and aliquots (4 × 20 μL) were immediately spotted on DBS cards. Further, following centrifugation of the blood samples at 1 000 × g for 15 min at 10 °C, the plasma was separated from the red blood cell (RBC) fraction, and 200 μL of the RBCs (retained for deposit onto DBS cards) was subsequently washed twice with 600 μL of phosphate-buffered saline (pH 7.4). The obtained plasma and washed erythrocytes were spotted onto DBS cards (four 20 μL aliquots each) and were also stored at + 4 °C in a plastic bag with desiccant until analysis. Online sample preparation of DBS was performed using a DBS card autosampler (DBSA) directly coupled to an automated solid-phase extraction (SPE) cartridge exchange module (SPExos) (Gerstel GmbH, Mulheim a.d.R., Germany). The sample preparation protocol was adapted from a previous application and was optimized to meet the current requirements [21]. In brief, the spots were extracted by means of flow-through desorption technology using 1 200 μL of acetonitrile/water (70:30, v/v), which included the online-addition of stable isotope-labeled Meldonium (triply deuterated, TRC Toronto, Canada) as internal standard. Sample purification was performed by means of online-SPE using hydrophilic interaction liquid chromatography (HILIC) SPE cartridges. The target compounds were eluted onto the analytical column (Hypersil Gold C8, 2.1 mm × 30 mm, 1.9 μm particle size) via the LC mobile phase applying a gradient program with A: 5 mM ammonium acetate buffer (pH 3.5) and B: acetonitrile. LC-HR-MS/MS analysis was performed with a Thermo Dionex Ultimate 3000 liquid chromatograph interfaced to a Q Exactive Plus mass spectrometer (Thermo Scientific, Bremen, Germany). Data were acquired in full scan mode with concomitant targeted higher energy collisional dissociation (HCD) experiments (precursor ion: m/z 147.1126, normalized collision energy: 40). The total sample-to-sample cycle time was 13 min. In addition to blood sampling, post-administration urine specimens were collected over a period of up to 49 days. These samples were subjected to analysis using a hydrophilic interaction liquid chromatography-high resolution high accuracy mass spectrometry approach (HILIC-HR-MS) published previously [8]. The analytical method for DBS measurements was validated for qualitative result evaluation purposes according to current guidelines of the International Standard for Laboratories (ISL) of the World Anti-Doping Code (WADC) [23]. Investigated parameters included specificity, carry-over, LOD (20 ng/mL), robustness, matrix interferences, and linearity (0–2 000 ng/mL), which allowed for estimating Meldonium concentration levels in DBS by means of calibration curves prepared and analyzed with each batch of cards. Based on the method validation results ( ●▶ Table 1), the fitness-for-purpose of the assay was demonstrated. A total of 8 DBS samples collected prior to and up to 16 days post-administration of a single-dose (500 mg) of Meldonium were analyzed using the automated isotope-dilution mass spectrometric approach. Maximum concentration levels were
Olivier Rabin - One of the best experts on this subject based on the ideXlab platform.
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Meldonium long term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers
Drug Testing and Analysis, 2019Co-Authors: Olivier Rabin, Vladimir Uiba, Yulia Miroshnikova, Maksim Zabelin, Aleksander Samoylov, Vladislav Karkischenko, Sergey Semyonov, T A Astrelina, Sergey RazinkinAbstract:Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of Meldonium. Consequently, the Meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on Meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of Meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on Meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral Meldonium daily for 3 weeks. The study found Meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with Meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.
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Meldonium long‐term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers
Drug testing and analysis, 2018Co-Authors: Olivier Rabin, Vladimir Uiba, Yulia Miroshnikova, Maksim Zabelin, Aleksander Samoylov, Vladislav Karkischenko, Sergey Semyonov, Sergey RazinkinAbstract:Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of Meldonium. Consequently, the Meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on Meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of Meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on Meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral Meldonium daily for 3 weeks. The study found Meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with Meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.
Mehmet Gokhan Caglayan - One of the best experts on this subject based on the ideXlab platform.
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Fluorescence chemosensing of Meldonium using a cross-reactive sensor array.
The Analyst, 2020Co-Authors: Ergin Yalçın, Cem Erkmen, Tugba Taskin-tok, Mehmet Gokhan CaglayanAbstract:In this paper, we report a fluorescent sensor array approach for the urinary detection of a prohibited substance in sports, Meldonium. Four chemosensors with ethidium bromide scaffolds were employed in this method. The interaction between Meldonium and chemosensors was investigated by different techniques, such as ultraviolet-visible absorption and fluorescence spectroscopy, nuclear magnetic resonance, and mass spectrometry. Molecular dynamics simulation was also used to elucidate and support the interaction mechanisms between Meldonium and the chemosensors. Differential responses obtained from the sensor array enabled the qualitative and quantitative analyses of Meldonium with low error values. This method was able to detect and quantify Meldonium at the nM level, fulfilling the requirements of minimum performance defined by the World Anti-Doping Agency.
Vladislav Karkischenko - One of the best experts on this subject based on the ideXlab platform.
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Meldonium long term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers
Drug Testing and Analysis, 2019Co-Authors: Olivier Rabin, Vladimir Uiba, Yulia Miroshnikova, Maksim Zabelin, Aleksander Samoylov, Vladislav Karkischenko, Sergey Semyonov, T A Astrelina, Sergey RazinkinAbstract:Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of Meldonium. Consequently, the Meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on Meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of Meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on Meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral Meldonium daily for 3 weeks. The study found Meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with Meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.
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Meldonium long‐term excretion period and pharmacokinetics in blood and urine of healthy athlete volunteers
Drug testing and analysis, 2018Co-Authors: Olivier Rabin, Vladimir Uiba, Yulia Miroshnikova, Maksim Zabelin, Aleksander Samoylov, Vladislav Karkischenko, Sergey Semyonov, Sergey RazinkinAbstract:Meldonium is a metabolic drug whose inclusion in the 2016 List of Prohibited Substances and Methods followed the analysis of data collected under the 2015 World Anti-Doping Agency Monitoring Program. In the early months of 2016, anti-doping laboratories reported an unusually high number of cases in which urine samples contained high concentrations of Meldonium. Consequently, the Meldonium excretion period in healthy athletes and the substance's long-term urine and blood (plasma) pharmacokinetics became central questions for the anti-doping community to address, to ensure appropriate assessment of the scientific and medical situation, and also fair treatment of athletes from a result management and legal standpoint. At the present time, data on Meldonium pharmacokinetics is limited to a few studies, with no known data available on long-term excretion of high oral doses. The primary objective of this open-label study was to determine long-term urine and plasma pharmacokinetic parameters of Meldonium in healthy volunteers. Study design included single and repeated functional load testing and assessment of L-carnitine administration on Meldonium excretion and pharmacokinetics. Thirty-two volunteers were equally divided into two groups receiving either 1.0 g or 2.0 g of oral Meldonium daily for 3 weeks. The study found Meldonium takes several days to attain a steady state in blood and displays an elimination period over several months after cessation of treatment. Moreover, findings demonstrate that the daily dose, periodicity and duration of treatment with Meldonium are the most important factors to consider in calculating the substance's elimination and complete body clearance.