Erythropoietin-stimulating protein

Pharmacology Darbepoetin alfa is an erythropoiesis-stimulating protein produced by recombinant DNA technology. Darbepoetin stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. 

Abbreviations rhuEPO, recombinant human erythropoietin NESP, novel erythropoiesis stimulating protein derived from genetic modification of rhuEPO to create two additional N-linked gylcosylation sites. 

Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function (see Chapter 2). Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the... 

Proteins are also used clinically to treat a variety of diseases. Erythropoietin stimulates erythrocyte production in kidney dialysis and chemotherapy patients. Granulocyte stimulating factor enhances immune systems compromised by cancer treatments. Cytokines such as interferons and interleukins are used for their anti-viral and anti-tumor activities. Other proteins are used to inhibit or stimulate blood clotting. For the most part, the pharmaceutical protein industry relies on cloning native human genes and expressing and purifying their products in recombinant form. 

Recombinant human derived erythropoeisis stimulating protein closely related to erythropoietin... 

Although hemodialysis is very effective in removing toxic waste from the body, it does not solve all the problems brought on by renal failure. For example, until recently, patients suffering from renal failure often became anemic because they lacked a protein hormone called erythropoietin, which is normally secreted by the kidney. (Erythropoietin stimulates red blood cell synthesis.) Because of DNA technology (Chapter 18), erythropoietin is now readily administered to dialysis patients. 

More recently, novel erythropoiesis-stimulating-protein (Nesp) or darbapoetin alfa (Aranesp) has been approved for clinical use in patients with indications similar to those for epoetin alfa. It is a genetically modified form of erythropoietin in which four amino acids have been mutated such that additional carbohydrate side chains are added during its synthesis, prolonging the circulatory survival of the drug to 24 to 26 hours. 

Human erythropoietin is a glycoprotein of 166 amino acids (molecular mass about 34 kDa). Its amount in plasma can be measured by radioimmunoassay. It is the major regulator of human erythropoiesis. Erythropoietin is synthesized mainly by the kidney and is released in response to hypoxia into the bloodstream, in which it travels to the bone marrow. There it interacts with progenitors of red blood cells via a specific receptor. The receptor is a transmembrane protein consisting of two different subunits and a number of domains. It is not a tyrosine kinase, but it stimulates the activities of specific... 

Biomedical research continues to broaden our understanding of the molecular mechanisms underlining both health and disease. Research undertaken since the 1950s has pinpointed a host of proteins produced naturally in the body that have obvious therapeutic applications. Examples include the interferons and interleukins (which regulate the immune response), growth factors, such as erythropoietin (EPO which stimulates red blood cell production), and neurotrophic factors (which regulate the development and maintenance of neural tissue). 

Erythropoietin is a protein produced mainly in the cortex of the kidney. Erythropoietin binds to a receptor on the surface of erythroid precursor cells. It stimulates erythropoiesis and is primarily indicated for the treatment of anemia in patients with chronic renal failure. Other indications are the management of anemia in cancer patients and in HIV positive subjects treated with anti-HIV regimens. 

Studies indieate that the erythrocytosis is mediated by an inereased renal produetion of erythropoietin. Erythropoietin is a protein produced by the kidney, which enhances erythropoiesis by stimulating the formation of proerythrocytes and the release of retieulocytes from the bone marrow. Overall, the results indicate that niekel exposure results in hematological effects in both humans and... 

Mechanism of Action A polypeptide hormone that stimulates cartilaginous growth areas of long bones, increases the number and size of skeletal muscle cells, influences the size of organs, and increases RBC mass by stimulating erythropoietin. Influences the metabolism of carbohydrates (decreases insulin sensitivity), fats (mobilizes fatty acids), minerals (retains phosphorus, sodium, potassium by promotion of cell growth), and proteins (increases protein synthesis). Therapeutic Effect Stimulates growth. 

Currently, most recombinant proteins such as erythropoietin, colony-stimulating factors, and interferons are reviewed by CBER. Under the proposed consolidation plan, these well-characterized and recombinant products are likely to be reviewed by CDER. 

T Erythropoietin is typical of the newer products. This protein hormone (Mr 51,000) stimulates... 

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