Wolfgang Jelkmann

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.

Recombinant human erythropoietin (rhEpo, epoetin) has proved beneficial in preventing transfusion-dependent anaemia in patients with chronic kidney disease. Apart from copied epoetins distributed in less regulated markets, ‘biosimilar’ epoetins have gained currency in many regions, where they compete with the originals and with rhEpo analogues with prolonged survival in circulation (‘biobetter’). Recombinant erythropoiesis stimulating agents are potent and well tolerated. However, their production is costly, and they must be administered by the parenteral route. Hence, other anti-anaemia treatments are being evaluated. Clinical trials are being performed with stabilizers of the hypoxia-inducible transcription factors (HIFs), which increase endogenous Epo production. HIF stabilizers are chemical drugs and they are active on oral administration. However, there is fear that they may promote tumour growth. Epo mimetic peptides have also raised expectations. Yet the prototype peginesatide was recalled after just 1 year of its widespread use in the USA because of serious side-effects including cases of death. Most recently, clinical trials have been initiated with sotatercept, a recombinant soluble activin receptor type 2A IgG-Fc fusion protein. Sotatercept binds distinct members of the transforming growth factor-β family, thereby preventing the inhibitory action of these factors in erythropoiesis. Taken together, rhEpo and its long-acting recombinant analogues will likely remain mainstay of anti-anaemia therapies in the near future.

Unfair athletes seek ways to stimulate erythropoiesis, because the mass of haemoglobin is a critical factor in aerobic sports. Here, the potential misuse of cobalt deserves special attention. Cobalt ions (Co²⁺) stabilize the hypoxia‐inducible transcription factors (HIFs) that increase the expression of the erythropoietin (Epo) gene. Co²⁺ is orally active, easy to obtain, and inexpensive. However, its intake can bear risks to health. To elaborate this issue, a review of the pertinent literature was retrieved by a search with the keywords ‘anaemia’, ‘cobalt’, ‘cobalt chloride’, ‘erythropoiesis’, ‘erythropoietin’, ‘Epo’, ‘side‐effects’ and ‘treatment’, amongst others. In earlier years, cobalt chloride was administered at daily doses of 25 to 300 mg for use as an anti‐anaemic agent. Co²⁺ therapy proved effective in stimulating erythropoiesis in both non‐renal and renal anaemia, yet there were also serious medical adverse effects. The intake of inorganic cobalt can cause severe organ damage, concerning primarily the gastrointestinal tract, the thyroid, the heart and the sensory systems. These insights should keep athletes off taking Co²⁺ to stimulate erythropoiesis. Copyright © 2013 John Wiley & Sons, Ltd.

Anemia is common in intensive care unit (ICU) patients. Red blood cell (RBC) transfusions are mainstays of their treatment and can be life-saving. Allogeneic blood components inherently bear risks of infection and immune reactions. Although these risks are rare in developed countries, recombinant human erythropoietin (rhEpo) and other erythropoiesis-stimulating agents (ESAs) have been considered alternative anti-anemia treatment options. As summarized herein, however, most of the clinical studies suggest that ESAs are not usually advisable in ICU patients unless approved indications exist (e.g., renal disease). First, ESAs act in a delayed way, inducing an increase in reticulocytes only after a lag of 3-4 days. Second, many critically ill patients present with ESA resistance as inflammatory mediators impair erythropoietic cell proliferation and iron availability. Third, the ESA doses used for treatment of ICU patients are very high. Fourth, ESAs are not legally approved for general use in ICU patients. Solely in distinct cases, such as Jehovah's Witnesses who refuse allogeneic blood transfusions due to religious beliefs, ESAs may be considered an exceptional therapy.

Human erythropoietin (Epo) is a 30.4 kDa glycoprotein hormone composed of a single 165 amino acid residues chain to which four glycans are attached. The kidneys are the primary sources of Epo, its synthesis is controlled by hypoxia-inducible transcription factors (HIFs). Epo is an essential factor for the viability and proliferation of erythrocytic progenitors. Whether Epo exerts cytoprotection outside the bone marrow still needs to be clarified. Epo deficiency is the primary cause of the anemia in chronic kidney disease (CKD). Treatment with recombinant human Epo (rhEpo, epoetin) can be beneficial not only in CKD but also for other indications, primarily anemia in cancer patients receiving chemotherapy. Considering unwanted events, the administration of rhEpo or its analogs may increase the incidence of thromboembolism. The expiry of the patents for the original epoetins has initiated the production of similar biological medicinal products (‘biosimilars'). Furthermore, analogs (darbepoetin alfa, methoxy PEG-epoetin beta) with prolonged survival in circulation have been developed (‘biobetter'). New erythropoiesis-stimulating agents are in clinical trials. These include compounds that augment erythropoiesis directly (e.g. Epo mimetic peptides or activin A binding protein) and chemicals that act indirectly by stimulating endogenous Epo synthesis (HIF stabilizers).

The Disparate Roles of Cobalt in Erythropoiesis, and Doping Relevance