Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.

Abstract. Thrombopoietin, the endogenous c-Mpl ligand, is a novel lineage-specific hematopoietic factor that plays a pivotal role in the regulation of megakaryocytopoiesis and thrombopoiesis. In this study, we examined the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated molecule of recombinant human c-mpl ligand derivatized with polyethylene glycol, on myelosuppressive chemotherapy-induced thrombocytopenia in mice. We developed a new murine model of thrombocytopenia induced by I.V. injections of mitomycin C (MMC) for two consecutive days. In control mice, platelet counts began to decrease on day 6, reached a nadir of less than 5% of basal level on day 14, and could not recover to basal level by day 26. Administration of PEG-rHuMGDF greatly enhanced recovery of the number of megakaryocyte progenitor cells and the megakaryocytes in bone marrow, and markedly reduced the severity of thrombocytopenia; it also accelerated platelet recovery in a dose-dependent manner in myelosuppressed mice. Mice receiving consecutive administration of higher doses of PEG-rHuMGDF showed no thrombocytopenia but rather had platelet counts being increased over basal level. Although absolute neutrophil counts and red cell counts also were decreased following MMC treatment, administration of PEG-rHuMGDF also improved neutropenia and anemia. Administration of PEGrHuMGDF on alternate days or once a week after chemotherapy was almost as effective as consecutive administration in improving thrombocytopenia. Combined administration of PEGrHuMGDF and rHuG-CSF had an addictive effect on improvement of thrombocytopenia and neutropenia. These results suggest that PEGrHuMGDF is a therapeutically effective agent in the treatment of thrombocytopenia associated with chemotherapy.

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Thrombopoietin (TPO) is the recently isolated lineage-dominant hematopoietic factor that plays a pivotal role in the regulation of megakaryocytopoiesis and thrombopoiesis. In vivo studies have shown that daily multiple injections of pegylated human megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated molecule related to human TPO, modified with polyethylene glycol, greatly improve thrombocytopenia and in most cases anemia and neutropenia in myelosuppressed animal models. In this study, we further examined various administration protocols of PEG-rHuMGDF on thrombocytopenia in mice treated with a combination of irradiation and carboplatin. After the myelosuppressive treatment on Day 0, mice received the same amount of PEG-rHuMGDF beginning on Day 1 by a single, 3 times (on alternate days), or 7 day daily administration. A single injection of PEG-rHuMGDF significantly reduced the severity and duration of thrombocytopenia and anemia with a concomitant accelerated recovery of megakaryocytic and erythroid progenitors in the bone marrow, similar to the 2 other administration protocols. As the start of a single injection of PEG-rHuMGDF was delayed, its therapeutic effects were attenuated. These results indicate that an administration of PEG-rHuMGDF at an earlier time after the myelosuppressive treatment is necessary to improve thrombocytopenia and anemia.

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