Xiaoyu Yan1, Sihem Ait-Oudhia, Wojciech Krzyzanski. 1. Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 370 Kapoor Hall, Buffalo, New York 14214, USA.
Abstract
PURPOSE: The purpose of this study is to demonstrate that the erythroid precursor depletion in bone marrow induced by recombinant human erythropoietin (rHuEPO) treatment may be another contributing factor to erythropoietin hyporesponsiveness. METHODS: Healthy Wistar rats were given single dose (SD) or multiple doses (MD) of rHuEPO (100 IU/kg). In MD study, animals were challenged with thrice-weekly over two weeks. Blood, bone marrow and spleen (for SD only) were collected. The erythropoietic responses in bone marrow and spleen were quantified using a flow cytometric immunophenotyping technique. A mathematical approach involving measuring reticulocyte age distribution was developed to evaluate the reticulocyte loss due to neocytolysis. RESULTS: A reduced level of erythropoietic responses below the baseline was observed for both MD and SD studies. In SD study, the reticulocyte decreased below the baseline after day 6. A depletion of the bone marrow erythroid precursor cells was observed. However, neocytolysis of reticulocyte only occurs from day 3-5 after rHuEPO injection. CONCLUSIONS: The findings demonstrate that EPO-induced erythroid precursor depletion in bone marrow is responsible for reduced reticulocyte response and may contribute to erythropoietin hyporesponsiveness. Therefore, this study provides further justification for reducing the doses of erythropoietin-stimulating agents in anemic patients demonstrating hyporesponsiveness.
PURPOSE: The purpose of this study is to demonstrate that the erythroid precursor depletion in bone marrow induced by recombinant humanerythropoietin (rHuEPO) treatment may be another contributing factor to erythropoietinhyporesponsiveness. METHODS: Healthy Wistar rats were given single dose (SD) or multiple doses (MD) of rHuEPO (100 IU/kg). In MD study, animals were challenged with thrice-weekly over two weeks. Blood, bone marrow and spleen (for SD only) were collected. The erythropoietic responses in bone marrow and spleen were quantified using a flow cytometric immunophenotyping technique. A mathematical approach involving measuring reticulocyte age distribution was developed to evaluate the reticulocyte loss due to neocytolysis. RESULTS: A reduced level of erythropoietic responses below the baseline was observed for both MD and SD studies. In SD study, the reticulocyte decreased below the baseline after day 6. A depletion of the bone marrow erythroid precursor cells was observed. However, neocytolysis of reticulocyte only occurs from day 3-5 after rHuEPO injection. CONCLUSIONS: The findings demonstrate that EPO-induced erythroid precursor depletion in bone marrow is responsible for reduced reticulocyte response and may contribute to erythropoietinhyporesponsiveness. Therefore, this study provides further justification for reducing the doses of erythropoietin-stimulating agents in anemicpatients demonstrating hyporesponsiveness.
Authors: L Rice; W Ruiz; T Driscoll; C E Whitley; R Tapia; D L Hachey; G F Gonzales; C P Alfrey Journal: Ann Intern Med Date: 2001-04-17 Impact factor: 25.391