Erythropoietin

Erythropoietin ( Hormone that is a Cytokine for Erythrocyte ( Red Blood Cell ) precursors in the Bone Marrow . It is produced by the kidney, and is the hormone regulating red blood cell production. Synthetic erythropoietin is available as a therapeutic agent produced by Recombinant DNA Technology . It is used in treating Anemia resulting from Chronic Renal Failure or from Cancer Chemotherapy . Its use is also believed to be common as a Blood Doping agent in endurance Sports such as Bicycle Racing , Triathlons and Marathon running.

DISCOVERY AND BIOLOGICAL ROLE

The existence of a Humoral factor regulating Red Blood Cell production was first postulated in 1906 based on transfusion experiments in rabbits. In 1950 , the still unidentified Erythropoietic Factor was found to be stimulated in rats breathing a low-oxygen atmosphere, thus establishing the elements of its biological regulation. In the 1960s its source was identified as the Kidneys . Human EPO was first purified from human urine by T. Miyake, C. K. Kung and E. Goldwasser at the University of Chicago in 1977 . Limited quantitites of the native human protein were used experimentally to treat patients with Anemia .

EPO has now been identified as a Glycoprotein with a Molecular Mass of about 30,000 Daltons . It has a 165 Amino Acid chain with four Oligosaccharide side chains and circulates in the Blood Plasma at a very low concentration (about 5 Pmol / L ).

In adult humans, EPO is produced primarily by peritubular cells in the Kidney s, where its production is stimulated by low Oxygen levels in the Blood . Some EPO is also produced by the Liver , which is the primary source in the Fetus .

EPO acts by binding to a specific erythropoietin Receptor (EpoR) on the surface of red cell precursors in the Bone Marrow , stimulating them to transform into mature Red Blood Cell s. As a result the Oxygen level in blood reaching the kidney rises and the amount of EPO produced decreases.

Because the kidneys are the primary source of erythropoietin, Chronic Kidney Disease often results in a systemic deficiency of EPO and consequent Anemia . Anemia can also occur in cancer patients, sometimes as a direct result of the malignancy but usually as an adverse effect of Chemotherapy .

Also, in patients who may require a Blood Transfusion or undergo surgery where blood loss is expected, EPO is given in advance as a precaution. The Bone Marrow produces more red blood cells, and if blood is lost during the operation, there is still enough to sustain the patient.

EPO AS A THERAPEUTIC AGENT

Therapeutic human erythropoietin was initially isolated and purified from urine in 1977. In 1983 , the Gene coding for erythropoietin was identified by a team headed by Fu-Kuen Lin at U.S. Biotechnology company Amgen . Researchers at The Genetics Insitute (now part of Wyeth ) independently discovered the gene at approximately the same time. The resulting patent dispute led to Amgen gaining exclusive marketing rights for erythropoietin in the U.S. Recombinant DNA Technology was used to Express the Protein in Chinese Hamster Ovary Cells , which allowed a synthetic form of EPO (rEPO) to be produced in commercial quantities for the first time.

Recombinant EPO was launched as a pharmaceutical product by Amgen for treatment of anemia resulting from Chronic Renal Failure in 1989 under the brand name Epogen. In 1991 it was also approved for treating anemia resulting from cancer chemotherapy. Johnson & Johnson (J&J), an American pharmaceutical company, markets EPO under license from Amgen for cancer chemotherapy under the brand name Procrit. Amgen’s patents have so far prevented other companies from entering the U.S. market. Even though the patents are all based on work done in the early 1980s, the last of them will not expire until 2015, thirty-two years after the date of the original application.

A longer-acting erythropoietin analogue, Darbepoetin (dEPO), also known as novel erythropoiesis-stimulating protein (NESP), was launched by Amgen under the brand name Aranesp in 2001. Relative to rEPO, dEPO has a slightly different Amino Acid sequence and a greater number of Oligosaccharide residues.

Outside the U.S. Amgen’s patents did not prevail and two other brands of EPO are available: Eprex (J&J) and NeoRecorman. (Roche). Two new long-acting forms may be launched in Europe in 2006: CERA (Roche) and Dynepo ( Shire )

EPO is generally injected Subcutaneously (under the skin) by the patient, although it may also be given Intravenously . Several injections weekly are required for the original forms, but the long-acting forms may require injections only once every two weeks. EPO cannot be used by patients with Leukemia and should be used cautiously by patients with uncontrolled High Blood Pressure . An extremely rare but severe adverse effect of EPO is acquired Pure Red Cell Aplasia (PRCA), an Auto-immune condition in which the bone marrow loses its ability to produce red blood cells, leaving the patient dependent on Blood Transfusion s. Certain lots of the J&J Eprex product were associated with a higher incidence of this problem. Studies at J&J showed that the PRCA was caused by interaction of EPO protein with a rubber compound in the pre-filled syringe used to distribute the product. Substitution of a teflon-coated syringe plunger eliminated the problem.

All forms of recombinant erythropoeitin are expensive. A dialysis patient, who can expect to require lifelong EPO treatment, will pay up to $10,000 per year for the drug in the U.S. Cancer chemotherapy patients, who require EPO for shorter periods, pay about $1,000 per month in the U.S. Worldwide revenues for sales of EPO were over USD$10 billion in 2004.

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Erythropoietin

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