Erythropoietins: A common mechanism of action

Elliott, Steve; Pham, Elizabeth; Macdougall, Iain C.

doi:10.1016/j.exphem.2008.08.003

Cited by 217 publications

(194 citation statements)

References 95 publications

(156 reference statements)

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“…As with darbepoetin alfa, other ESAs, such as pegylated forms of rHuEPO, biosimilars, or EPO mimetic peptides (Hematide), have the same mechanism of action as rHuEpo: binding and activation of EPOR [60]. However, they can be differentiated from each other according to differences in manufacturing methods, affinity to the EPO receptor, and Fig.…”

Section: Other Esasmentioning

confidence: 99%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

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Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesisstimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivospecific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains.

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Section: Other Esasmentioning

confidence: 99%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

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“…Epoetin beta pegol is a continuous erythropoietin receptor activator with a long half-life. Structurally, a pegylated glycoprotein consisting of a linear methoxy polyethylene glycol (PEG) molecule is attached to an amino acid residue of epoetin beta [13]. Pegylation is the process of covalent attachment of PEG polymer chains to another molecule, usually a drug or therapeutic protein.…”

Section: Discussionmentioning

confidence: 99%

Successful treatment of a hemodialyzed patient with pure red cell aplasia associated with epoetin beta pegol therapy with cyclosporine

et al. 2015

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A 42-year-old man with end-stage renal failure had been receiving hemodialysis therapy since April 2009. Initially, darbepoetin alfa was administered to treat his renal anemia. After treatment was switched to epoetin beta pegol, the patient's hemoglobin levels rapidly decreased. He was diagnosed with pure red cell aplasia (PRCA) based on the results of a bone marrow examination. Epoetin beta pegol was strongly suspected to be the cause of the PRCA, and although he tested negative for anti-epoetin beta pegol antibodies, epoetin beta pegol was discontinued and cyclosporine therapy was initiated. Thereafter, his hemoglobin levels increased, and his anemia dramatically improved after 3 months.

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“…Thrombotic toxicities reported in a subset of preclinical toxicology studies conducted with all different classes of ESAs (Elliott, Pham, and Macdougall 2008) were related to ESA dose level, dose frequency, and study duration despite a similarly high HCT across all dosed groups . We confirmed this observation by eliciting thrombotic toxicities in the highest dose groups of Sprague-Dawley rats dosed 3 times weekly for 1 month with a novel, hyperglycosylated analog of recombinant human erythropoietin (rHu-EPO), AMG 114, but not in the lowest dosed groups or when the higher dose levels were administered once weekly despite a similarly high HCT across all dose groups and experimental conditions .…”

Section: Introductionmentioning

confidence: 99%

Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

Andrews

Hamadeh

et al. 2013

Toxicol Pathol

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We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 highdose group, but not in lower dose groups with a similar high HCT.

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Erythropoietins: A common mechanism of action

Cited by 217 publications

References 95 publications

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Successful treatment of a hemodialyzed patient with pure red cell aplasia associated with epoetin beta pegol therapy with cyclosporine

Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

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