Development and characterization of novel erythropoiesis stimulating protein (NESP).

Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor-binding affinity. These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity. Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis. Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP, ARANESP, Amgen Inc, Thousand Oaks, CA), which was engineered to contain 5 N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies. Due to its increased sialic acid-containing carbohydrate content, NESP is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge. Compared with rHuEPO, it has an approximate 3-fold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response. NESP is currently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence.

Treatment of acute postoperative anemia with recombinant human erythropoietin.

Risks inherent in the administration of blood products have increased efforts to avoid homologous transfusion. Although this has increased interest in autologous transfusion and intraoperative salvage, little attention has been focused on efforts to enhance endogenous erythropoiesis as a method of minimizing exposure to homologous blood. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study is to evaluate the effect of rHuEPO, administered postoperatively, on a model of acute blood loss. Eleven adult male baboons were randomized into two groups. All animals underwent a laparotomy and an exchange transfusion, with 6% hetastarch, to a final hematocrit of 15%. Group I (N = 6) received 1,000 units/kg of recombinant human erythropoietin daily for the first 14 postoperative days. Group II (N = 5) received an equivalent volume of placebo. All animals were given supplemental vitamin B12, folate and 200% of shed iron, as iron dextran IV, after exchange transfusion. Response was observed for a period of 35 days. All animals survived the protocol. There were no adverse reactions to rHuEPO or surgical complications. The hematocrits were similar between groups at baseline and after exchange transfusion. The maximal rate of erythropoiesis was significantly faster in the rHuEPO group (2.1 vs. 1.3%/day; p less than 0.01). The time required to return to hematocrits of 30% (9.9 vs. 17.4 days, p less than 0.001) and to baseline hematocrits (11.9 vs. 32.1 days, p less than 0.01) were both significantly shorter in the rHuEPO group. The data show that rHuEPO accelerates the recovery from anemia in the postoperative setting. Acceleration of erythropoiesis represents another alternative to homologous transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human erythropoietin and autologous blood donation.

Risks of transfusion are minimized with autologous blood. However, autologous donation programs require 2 to 5 weeks to yield only 2.2 units per patient. Recombinant human erythropoietin (r-HuEPO) has been shown to increase erythropoiesis. This study evaluated the effects of r-HuEPO on an aggressive autologous donation program. Twelve adult male baboons were randomized into two groups of six. All animals were studied three times per week for 5 weeks. A unit of blood was donated when on any study day the hematocrit was greater than 30%. Animals received intravenously either 750 units/kg of r-HuEPO (n = 6) or placebo (n = 6) on each study day. Iron dextran was given intravenously to replace 150% of shed iron. The r-HuEPO group had an earlier onset of reticulocytosis (2.7 vs 5.5 days, p less than 0.01) and donated 35% more blood (13.5 vs 10.0 units, p = 0.01) than the control group. No adverse reactions to r-HuEPO were observed. The data show that an aggressive autologous donation program can yield 10 units of blood over a 5-week period. Further, r-HuEPO increases that yield by an additional 35%. This aggressive autologous donation program with r-HuEPO may significantly reduce the need for homologous transfusion and its attendant risks.