Erythropoietin gene doping: facts and fictions

Jelkmann, Wolfgang

doi:10.1007/s12662-012-0268-2

Cited by 5 publications

(6 citation statements)

References 30 publications

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“…However, the method has made little progress and not stepped beyond the clinical trial phase after many years of study. Taken together, due to technical difficulties, gene doping with EPO is probably not applied in sports so far [24] .…”

Section: Epo Gene Transfermentioning

confidence: 99%

Erythropoietin

Jelkmann¹

2016

Frontiers of Hormone Research

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Total hemoglobin (Hb) mass is an important determinant of aerobic power. The glycoprotein erythropoietin (Epo) promotes the production of red blood cells (RBCs). The present article reviews the regulation of erythropoiesis and ways of its manipulation. The various Epos, e.g. recombinant human (rh)Epo and (epoetin), and their long-acting analogues can be misused by cheating athletes, but the drugs are detectable by chemical tests, because their glycan isoform structures differ from those of endogenous Epo. Still, anti-doping control has become more difficult, since additional erythropoiesis-stimulating agents have become available (Epo mimetics, activin inhibitors, and small-molecule chemical drugs activating EPO expression). A major problem is created by hypoxia-inducible factor (HIF) stabilizers (e.g. α-ketoglutarate competitors and Co2+ salt) which activate HIFs and thus increase EPO expression. Direct EPO transfer is theoretically also possible but medically little advanced. To overcome weaknesses of direct testing of biological fluids, the World Anti-Doping Agency has implemented the Athlete Biological Passport for continuous monitoring of RBC parameters of athletes. Blood doping is assumed when distinct parameters (blood Hb concentration and reticulocytes) change in a nonphysiological way.

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Section: Epo Gene Transfermentioning

confidence: 99%

Erythropoietin

Jelkmann¹

2016

Frontiers of Hormone Research

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“…Soluble cobalt supplements with recommended daily doses up to 1 mg cobalt per day are increasingly being marketed to consumers interested in healthy living practices [18]. Hence, suspicion has been raised that Co 2+ salts could be misused in sports as an alternative to rHuEpo doping [29,37]. Indeed, athletes may take cobalt salt tablets to enhance the production of their own, endogenous, Epo.…”

Section: Potential Misuse Of Co 2+ In Sportsmentioning

confidence: 99%

“…An Internet search (Google; assessed 10/23/2012) for "doping, cobalt, sport" yielded >100,000 hits, including reports of the effects of cobalt on erythropoiesis. However, like in the early days of hematological research [13] the understanding of the mechanisms of the action of cobalt in erythropoiesis is generally poor, as the role of cobalt in cobalamin (vitamin B 12 , contains cobaltcorrin complexes) is not separated from the function of inorganic cobalt ions (Co 2+ ) [29,64]. Cobalamin plays a vital role in DNA synthesis and cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

The Disparate Roles of Cobalt in Erythropoiesis, and Doping Relevance

Jelkmann

2012

Open J. Hematol.

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Some athletes seek to increase their red blood cells, because the aerobic capacity correlates with the mass of hemoglobin. Cobalt as part of dietary supplements is proclaimed to increase erythropoiesis and physical performance. However, the knowledge of the disparate mechanisms of cobalt´s actions in erythropoiesis is generally insufficient. First, there are cobalt-containing corrinoids, termed cobalamin or vitamin B 12. These are naturally present only in animal-derived foods. The active forms in the human body are methylcobalamin and deoxyadenosylcobalamin, which are essential cofactors for the methionine synthase and the L-methylmalonylcoenzyme A mutase. Cobalamin deficiency can result in anemia. However, supplemental cobalamin does not benefit performance unless a nutritional deficit is present. Second, inorganic cobalt ions (Co 2+) stimulate erythropoiesis, even in non-anemic subjects. Co 2+ stabilizes the hypoxia-inducible transcription factors (HIFs) which increase the expression of the erythropoietin gene (EPO). Cobaltous salts are orally active, easy to obtain and inexpensive. Typical side effects associated with chronic Co 2+ exposure include nausea, vomiting, heart failure, hypothyroidism and goiter. The potential misuse of inorganic cobalt deserves attention in anti-doping efforts.

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“…In the present author's mind there could be a revival of the drug. The misuse of EMPs for stimulation of erythropoiesis by athletes is a more realistic threat compared to, for example, public attention‐getting Epo gene doping . Doping with peginesatide can be reliably detected by electrophoresis or mass spectrometry.…”

Section: Discussionmentioning

confidence: 99%

Watch out for a revival of peginesatide in sports

Jelkmann

2016

Drug Testing and Analysis

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The erythropoietin-mimetic peptide (EMP) peginesatide belongs to the group of erythropoiesis-stimulating agents (ESAs) that are prohibited when misused in sports. Peginesatide is a synthetic pegylated homodimer of two cyclic 21-amino acid chains. It was approved for the treatment of anaemic patients with chronic kidney disease in the USA in 2012, but recalled in 2013 due to prevalent cases of acute severe anaphylactoid reactions and associated fatalities (0.02%). The drug was considered obsolete for athletes and part of the anti-doping scene lost sight of it. However, recent research indicates that the adverse events were not caused by the drug substance, but by the drug product formulated in multi-use vials. These vials contained comparably high levels of subvisible particles. Phenol was identified as a critical component of the drug formulation, which caused the release of histamine from mast cells. Tricky athletes might consider peginesatide a pharmacologically safe ESA in an appropriate formulation. In addition, other EMPs may get a second wind for therapy including misuse in sports. Therefore, it is very important to proceed in developing electrophoretic, immunological, and mass spectroscopic methods for detecting peginesatide and other EMPs in human urine and blood samples. Copyright © 2016 John Wiley & Sons, Ltd.

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Erythropoietin gene doping: facts and fictions

Cited by 5 publications

References 30 publications

Erythropoietin

Erythropoietin

The Disparate Roles of Cobalt in Erythropoiesis, and Doping Relevance

Watch out for a revival of peginesatide in sports

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