Erythropoietin , anemia

Erythropoietins Anemia in kidney and cancer patients Procrit, Eprex, Aranesp, Epogen, NeoRecormon... 

Amgen Epogen, Procrit, Eprex (erythropoietin) Anemia 2013 Expired, 2004... 

Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with end-stage renal disease (8). Because oral iron formulations are relatively ineffective and poorly tolerated, intravenous iron dextran has been widely used, despite the risk of adverse effects. 

Erythropoietin Anemias, especially associated with renal failure... 

Differentiation of cells of the erythroid series is controlled by the hormone erythropoietin. Anemia stimulates erythropoietin formation, and this stimulates erythropoiesis. Erythropoietin also increases hemoglobin synthesis by stimulating synthesis of the corresponding messenger RNA (Krantz and Goldwasser, 1965). However, the possible link between erythropoietin and activation of adult hemoglobin (HbA and not HbF) has not yet been studied. 

As of early 1992, the market for ceU culture-derived products approached 1 billion per year. The market is expected to grow substantially throughout the 1990s. CeU culture products include erythropoietin, 1991 sales of approximately 400 million, for the treatment of anemia associated with kidney dialysis, and tissue plasminogen activator, 1991 sales approximately 200 million, for treating heart attack victims with blocked arteries (see Cardiovascularagents). 

There are undifferentiated stem cells of the blood elements in the bone marrow that differentiate and mature into erythrocytes, (red blood cells), thrombocytes (platelets), and white blood cells (leukocytes and lymphocytes). The production of erythrocytes is regulated by a hormone, erythropoietin (see the section on kidney toxicity), that is synthetized and excreted by the kidney. An increase in the number of premature erythrocytes is an indication of stimulation of erythropoiesis, i.e., increased production of erythrocytes in anemia due to continuous bleeding. 

Erythropoietin (Eprex ) is physiologically produced in the kidney and regulates proliferation of committed progenitors of red blood cells. It is used to substitute erythropoietin in severe anemias due to end stage renal disease or treatment of cancer with cytostatic agents. Side effects include hypertension and increased risk of thrombosis. 

Erythropoietin is a growth factor produced by interstitial cells of the kidney in response to hypoxia. Erythropoietin stimulates haematopoiesis in the bone marrow. Recombinant human erythropoietin is used to treat anemias, e.g. anemia caused by chronic renal failure and anemia in AIDS and cancer patients. 

Macdougall IC (2005) CERA (Continuous Erythropoietin Receptor Activator) a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 4 436-440... 

Anemia may occur in patients with chronic renal failure as tlie result of the inability of the kidney to produce erythropoietin. Erythropoietin is a glycoprotein hormone synthesized mainly in the kidneys and used to stimulate and regulate the production of erythrocytes or red blood cells (RBCs). Failure to produce the needed erythrocytes results in anemia Two examples of drug used to treat anemia associated with chronic renal failure are epoetin alfa (Epogen) and darbepoetin alfa (Aranesp). 

Epoetin alfa (erythropoietin EPO) and darbepoetin alfa are usually well tolerated. The most common adverse reactions include hypertension, headache, tachycardia, nausea, vomiting, diarrhea, skin rashes, fever, myalgia, and skin reaction at tlie injection site. See the Summary Drug Table Drug Used in the Treatment of Anemia for more information on these drug. 

Anemia may be present in some patients due to impaired erythropoietin regulation, nutritional factors (vitamin E and iron malabsorption), or chronic inflammation. With chronic pulmonary disease, increased cytokine production can lead to shortened red blood cell survival, reduced erythropoietin response, and impaired mobilization of iron stores. 

About 10% to 25% of patients treated with interferon and ribavirin require dosage reductions when hemoglobin levels decrease or they develop intolerable symptoms such as shortness of breath or severe fatigue. If warranted, erythropoietin may be used as adjunctive therapy for ribavirin-induced hemolytic anemia.45... 

The most common complication of CKD is anemia, which is caused by a decline in erythropoietin production by the kidneys and can lead to cardiovascular disease. 

The progenitor cells of the kidney produce 90% of the hormone erythropoietin (EPO), which stimulates red blood cell (RBC) production. Reduction in nephron mass decreases renal production of EPO, which is the primary cause of anemia in patients with CKD. The development of anemia of CKD results in decreased oxygen delivery and utilization, leading to increased cardiac output and left ventricular hypertrophy (LVH), which increase the cardiovascular risk and mortality in patients with CKD. 

The first-line treatment for anemia of CKD involves replacement of erythropoietin with erythropoiesis-stimulating agents (ESAs). Use of ESAs increases the iron demand for RBC production and iron deficiency is common, requiring iron supplementation to correct and maintain adequate iron stores to promote RBC production. Androgens were used extensively... 

Less blood loss and iron deficiency, resulting in easier management of anemia or reduced requirements for erythropoietin and parenteral iron. 

Patients with CKD suffer from a decrease in erythropoietin production because erythropoietin is produced mainly in the kidneys.4,5 Finally, in patients with anemia of chronic disease, there is a blunted erythropoietin production as well as a diminished response to erythropoietin.9 Anemia of chronic disease also affects iron homeostasis, causing iron sequestration into storage sites and decreasing the amount available to the rest of the body.9... 

Parenteral iron therapy currently is available in three different formulations, which are listed in Table 63-3. Iron dex-tran was the first parenteral iron formulation to be approved, followed by ferric gluconate, and then iron sucrose. Although these newer agents are only approved by the Food and Drug Administration (FDA) to treat anemia associated with CKD in patients receiving erythropoietin products, they are effective in treating iron-deficiency anemia as well. Iron dextran is FDA approved for treating documented iron deficiency in patients who are unable to tolerate the oral formulation. 

Studies have shown that in patients with chemotherapy-related anemia, therapy with erythropoietin products (epoetin-alfa and darbepoetin) can increase hemoglobin, decrease transfusion requirements, and improve quality of life.12 Epoetin is recombinant human erythropoietin, and darbepoetin is structurally similar to endogenous erythropoietin. Both bind to the same receptor to stimulate red blood cell production. Darbepoetin differs from epoetin in that it is a glycosylated form and exhibits a longer half-life in the body. The half-lives of a single subcutaneous injection of epoetin or darbepoetin in patients are roughly 27 and 43 hours, respectively. 

Cancer patients also may have concurrent iron deficiency secondary to erythropoietin use ( functional iron deficiency) or to cancer. Therefore, it is imperative that these patients have iron studies done to assess adequate iron stores needed to drive hematopoiesis. If the patient is determined to have sub-optimal iron stores or is iron deficient, then replacement either orally or intravenously may be necessary, in addition to the use of erythropoietin products. The use of iron in these patients is the same as discussed previously under Iron-Deficiency Anemia. ... 

TABLE 63-4. Erythropoietin Products and Their Usual Doses for Anemia from Cancer/Chemotherapy and CKD... 

Although EPO deficiency is the primary cause of CKD anemia, iron deficiency is often present, and it is essential to assess and monitor the CKD patient s iron status (NKF-K/DOQI guidelines). Iron stores in patients with CKD should be maintained so that transferrin saturation (TSAT) is greater than 20% and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L). If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective, and most CKD patients will require iron supplementation. Oral iron therapy can be used, but it is often ineffective, particularly in CKD patients on dialysis. Therefore, intravenous iron therapy is used extensively in these patients. Details of the pharmacology, pharmacokinetics, adverse effects, interactions, dose, and administration of erythropoietin and iron products have been discussed previously. 

Besides anemia associated with cancer and CKD, anemia of chronic disease can result from inflammatory processes and occurs commonly in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. In treating these types of anemia of chronic disease, the most important principle is treating the underlying disease. These patients also may have iron deficiency and should be treated in the manner already discussed. Erythropoietin therapy such as epoetin-alfa therapy at a dose of 150 units/kg three times a week also may be used in these patients. 

Bone marrow suppression ZDV Onset Few weeks to months Symptoms Fatigue, risk of T bacterial infections due to neutropenia anemia, neutropenia 1. Advanced HIV 2. High dose ZDV 3. Preexisting anemia or neutropenia 4. Concomitant use of bone marrow suppressants Avoid in patients with high risk for bone marrow suppression avoid other suppressing agents monitor CBC with differential at least every 3 months Switch to another NRTI D/C concomitant bone marrow suppressant, if possible for anemia Identify and treat other causes consider erythropoietin treatment or blood transfusion, if indicated for neutropenia Identify and treat other causes consider filgrastim treatment, if indicated... 

Anemia of chronic kidney disease A decline in red blood cell production caused by a decrease in erythropoietin production by the progenitor cells of the kidney. As kidney function declines in chronic kidney disease, erythropoietin production also declines, resulting in decreased red blood cell production. Other contributing factors include iron deficiency and decreased red blood cell lifespan, caused by uremia. 

Erythropoietin A hormone primarily produced by the progenitor cells of the kidney that stimulates red blood cell production in the bone marrow. Lack of this hormone leads to anemia. 

Although the kidneys are not considered endocrine glands per se, they are involved in hormone production. Erythropoietin is a peptide hormone that stimulates red blood cell production in bone marrow. Its primary source is the kidneys. Erythropoietin is secreted in response to renal hypoxia. Chronic renal disease may impair the secretion of erythropoietin, leading to development of anemia. The kidneys also produce enzymes. The enzyme renin is part of the renin-angiotensin-aldosterone system. As will be discussed, these substances play an important role in the regulation of plasma volume and therefore blood pressure. Other renal enzymes are needed for the conversion of vitamin D into its active form, 1,25-d i hyd ro xyv itamin D3, which is involved with calcium balance. 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Buemi, M., Aloisi, C., Cavallaro, E., Corica, F., Floccari, F., Grasso, G., Lasco, A., Pettinato, G, Ruello, A., Sturiale, A., and Frisina, N. 2002. Recombinant human erythropoietin more than just the correction of uremic anemia. Journal of Nephrology 15(2), 97-103. 

Heuser, M. and Ganser, A. 2006. Recombinant human erythropoietin in the treatment of nonrenal anemia. Annals of Hematology 85(2), 69-78. 

Strauss, R. 2006. Controversies in the management of the anemia of prematurity using single-donor red blood cell transfusions and/or recombinant human erythropoietin. Transfusion Medicine Review 20(1), 34-44. 

The primary cause of anemia in patients with CKD or ESRD is erythropoietin deficiency. Other contributing factors include decreased lifespan of red blood cells, blood loss, and iron deficiency. 

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