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Supplement: the Story Behind Meldonium–From Pharmacology to Performance Enhancement: a Narrative Review

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Supplement: The story behind meldonium–From pharmacology to performance enhancement: A narrative review 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. Meldonium acts as a carrier for the transport of activated long-chain fatty acids from the cytosol into the mitochondria, where - oxidation and ATP synthesis take place. The balance of L-carnitine is maintained through biosynthesis, kidney reabsorption, and nutrition intake, particularly from red meat and milk. [1,2] About 25% of L-carnitine in the human organism is derived by endogenous biosynthesis from the amino acids lysine and methionine in the liver and kidney. More than 99% of the body’s L- carnitine can be found intracellularly, mainly in the liver, heart, and skeletal muscle. Because L- carnitine cannot be degraded or metabolised, it needs to be eliminated, mainly in the urine. In the pathway of carnitine biosynthesis, enzymatic processes performed by mitochondrial trimethyllysine aldolase (TMLD), 3-hydroxy-trimethyllysine aldolase (HTMLA) and trimethylaminobutyrate dehydrogenase (TMABA) by the formation of -butyrobetaine (GBB) play a central role. In the final step, GBB is hydroxylated by GBB hydroxylase (BBOX) in order to form L-carnitine.[3] The transport of L-carnitine through cell membranes is performed via Na+ -dependent organic cation transporters (OCTN), mainly OCTN2 and to a lesser extent OCTN1 (figure to supplement). After the activation of fatty acids with a CoA group, the acyl-CoA units are converted into carnitine esters, catalysed by the carnitine palmytoiltransferase I (CPT I), resulting in long-chain acylcarnitine esters. The CPT I-mediated L-carnitine transport is one of the rate-limiting steps of free fatty-acid oxidation, because low carnitine concentrations can inhibit free fatty-acid transport to mitochondria.[4,5] These esters are transported over the inner mitochondrial membrane by carnitine-acylcarnitine translocase (CACT) and are further transesterified to intramitochondrial CoA on the mitochondrial matrix side by carnitine palmitoyltransferase II (CPT II). Acyl-CoA is formed, and these long-chain CoA complexes enter -oxidation, resulting in the formation of acetyl-CoA needed for the citric acid cycle. Catalysed by carnitine acetyltransferase (CAT), the released L-carnitine forms complexes with acetyl residues, which can then leave the mitochondria via CACT. In addition, L-carnitine is 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 of mitochondrial free CoA and thus better availability for further energy production.[6] L-Carnitine is also involved in the regulation of glucose metabolism via the modulation of the free coenzyme A/acetyl-coenzyme A ratio.[7] The main target of meldonium is the enzyme GBB hydroxylase, which can be inhibited competitively as well non-competitively.[8,9] The following main actions of meldonium have been reported (for a review, see [10-12] and figure to supplement). In humans, meldonium decreased the concentrations of L-carnitine and increased the plasma concentration of GBB.[13] The inhibition of -oxidation induced an increase in fatty-acid levels in the sera of treated rats. Meldonium blocked the transport of carnitine inside the mitochondria by a weak inhibition of CAT [14] and inhibited Na+ -dependent carnitine transport and CPT I activity. In addition, weak competitive inhibition of CACT was reported.[15] Meldonium increased the protein content of hexokinase type 1 and sarcoplasmic reticulum Ca2+-ATPase, activated the reuptake of Ca2+ by the sarcoplasmic reticulum, [16-18] and improved the uptake of Ca2+ ions in the sarcoplasmic reticulum.[19] In addition, it induced an increase in renal L-carnitine excretion [13] and a competitive inhibition of OCNT2 proteins by the renal brush-border membrane.[9] In total, the consequences of meldonium applications are: a) a shift of cell metabolism from highly oxygen- consuming fatty-acid oxidation to increased glucose consumption and increased effectiveness of ATP generation and b) a protection of the mitochondria against free fatty-acid overload by the reduction of long-chain acylcarnitines, the activation of mitochondrial free fatty-acid utilization, and the redirection of fatty-acid metabolism from the mitochondria to the peroxisomes. Legend to Figures: Figure to Supplement: Cellular transport of L-carnitine and fatty acids and mitochondrial energy-metabolism pathways including the sites of meldonium actions (adapted from [4, 19]). Abbreviations: inhibition by meldonium; activation by meldonium; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; OCTN2, organic cation/carnitine transporter 2; CPT, carnitine palmytoil-transferase; CACT, carnitine acyl-carnitine translocase; LC-Acyl-CoA, long-chain acyl-coenzyme A; CoASH, free coenzyme A; glucose-6-P, glucose-6- phosphate; PDC, pyruvate dehydrogenase complex; LC-acylcarnitine, long-chain acylcarnitine; LC-acyl-CoA, long-chain acyl-coenzyme A; CAT, carnitine acetyl-transferase Reference List 1. Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 2004;1033:30-41 2. El-Hattab AW, Scaglia F. Disorders of carnitine biosynthesis and transport. Mol Genet Metab 2015;116(3):107-112 3. Strijbis K, Vaz FM, Distel B. Enzymology of the carnitine biosynthesis pathway. IUBMB Life 2010;62(5):357-362 4. Vaz FM, Wanders RJ. Carnitine biosynthesis in mammals. Biochem J 2002;361(Pt 3):417-429 5. Pochini L, Scalise M, Galluccio M, et al. OCTN cation transporters in health and disease: role as drug targets and assay development. J Biomol Screen 2013;18(8):851-867 6. Wanders RJ, Vreken P, Ferdinandusse S, et al. Peroxisomal fatty acid alpha- and beta- oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochem Soc Trans 2001;29(Pt 2):250-267 7. Stephens FB, Constantin-Teodosiu D, Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 2007;581(Pt 2):431-444 8. Simkhovich BZ, Shutenko ZV, Meirena DV, et al. 3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem Pharmacol 1988;37(2):195-202 9. Spaniol M, Brooks H, Auer L, et al. Development and characterization of an animal model of carnitine deficiency. Eur J Biochem 2001;268(6):1876-1887 10. Sjakste N, Gutcaits A, Kalvinsh I. Mildronate: an antiischemic drug for neurological indications. CNS Drug Rev 2005;11(2):151-168 11. Sjakste N, Kalvinsh I. Mildronate: An antiischemic drug with multiple indications. Pharmacologyonline 2006;1:1-18 12. Dambrova M, Makrecka-Kuka M, Vilskersts R, et al. Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity. Pharmacol Res 2016 13. Liepinsh E, Konrade I, Skapare E, et al. Mildronate treatment alters gamma-butyrobetaine and l-carnitine concentrations in healthy volunteers. J Pharm Pharmacol 2011;63(9):1195-1201 14. Jaudzems K, Kuka J, Gutsaits A, et al. Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism. J Enzyme Inhib Med Chem 2009;24(6):1269-1275 15. Oppedisano F, Fanello D, Calvani M, et al. Interaction of mildronate with the mitochondrial carnitine/acylcarnitine transport protein. J Biochem Mol Toxicol 2008;22(1):8-14 16. Hayashi Y, Ishida H, Hoshiai M, et al. MET-88, a gamma-butyrobetaine hydroxylase inhibitor, improves cardiac SR Ca2+ uptake activity in rats with congestive heart failure following myocardial infarction. Mol Cell Biochem 2000;209(1-2):39-46 17. Heidemanis K, Balcere I, I k. Mildronate-plasma membrane interaction mechanisms. Proc Latv Acad Sci 1990;11:108-115 18. Yonekura K, Eto Y, Yokoyama I, et al. Inhibition of carnitine synthesis modulates protein contents of the cardiac sarcoplasmic reticulum Ca2+-ATPase and hexokinase type I in rat hearts with myocardial infarction. Basic Res Cardiol 2000;95(5):343-348 19. Hayashi Y, Muranaka Y, Kirimoto T, et al. Effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on tissue carnitine and lipid levels in rats. Biol Pharm Bull 2000;23(6):770-773 .
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    ANALYSIS OF CARNITINE AND ACYLCARNITINES IN BIOLOGICAL FLUIDS AND APPLICATION TO A CLINICAL STUDY Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Laurence Vernez aus Villars-Bramard, VD Genf, 2005 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Stephan Krähenbühl Prof. Dr. Gérard Hopfgartner Prof. Dr. Wolfgang Thormann Basel, den 6. April 2004 Prof. Dr. Marcel Tanner Dekan POUR TOI QUI M’ATTENDS ENCORE Un savant dans son laboratoire n’est pas seulement un technicien: c’est aussi un enfant placé en face de phénomènes naturels qui l’impressionnent comme un conte de fées Marie Curie-Sklodowska, 1933 Table of contents TABLE OF CONTENTS Résumé 13 Zusammenfassung 16 Summary 18 List of abbreviations 21 1. Introduction 23 1.1 General aspects 23 1.2 Carnitine functions 25 1.2.1. Mitochondrial long-chain fatty acid oxidation 25 1.2.2. Buffering of the mitochondrial acyl-CoA/CoA ratio 27 1.2.3. Removal of potentially toxic acyl-groups 27 1.2.4. Fatty acids oxidation in peroxisomes 28 1.3 Carnitine biosynthesis 28 1.4 Carnitine homeostasis 31 1.4.1. Absorption 31 1.4.2. Tissue distribution - carnitine transporters 32 i. Regulation of tissue distribution 33 ii. Kinetic of exogenous carnitine 33 1.4.3. Metabolism 34 1.4.4. Elimination - role of kidney 35 1.5 Carnitine deficiency 36 1.5.1. Primary carnitine deficiency 37 i. Systemic carnitine deficiency (SCD) 37 ii. Muscle carnitine deficiency (MCD) 38 1.5.2. Secondary carnitine deficiency 38 i.
  • Harmonization of Anti-Doping Policies Within the International Scenario: an Impossible Challenge?

    Harmonization of Anti-Doping Policies Within the International Scenario: an Impossible Challenge?

    Rivista Internazionale di Diritto ed Etica dello Sport 6,7,8 (2016) Submitted 16/04/2017; Published 03/05/2017 Harmonization of anti-doping policies within the international scenario: an impossible challenge? Michael Geistlinger University of Salzburg, Austria [email protected] 1. Introductory Remarks In 1947 the General Assembly of the United Nations established the International Law Commission (ILC) to undertake the mandate of the Assembly, under article 13 (1) (a) of the Charter of the United Nations to “initiate studies and make recommendations for the purpose of ... encouraging the progressive development of international law and its codification”.1 The first Statute of this Commission, which was attached to the respective General Assembly’s Resolution, provided for fifteen members of this Commission who had to be persons of recognized competence in international law.2 There were topics on the Agenda of the ILC, which could be dealt with in a very short period of time, such as the Fundamental Rights and Duties of States or the Formulation of the Nürnberg Principles, both in 1949 – 1950.3 But, whenever it came to substantial issues of public international law, the ILC needed nearly a decade or even well more than a decade for concluding a report and eventually draft articles as a basis for a later convention. Thus, for example, the codification of the law of international treaties stayed on the Agenda of the ILC from 1950 – 1966, treaties concluded between states and international organizations or between two or more international organizations were dealt with by the ILC from 1971 – 1982.