81732
document
Results of a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in very low birthweight neonates : significant induction of circulatory neutrophils , monocytes , platelets , and bone marrow neutrophils . Neonates , especially those of very low birthweight ( VLBW ) , have an increased risk of nosocomial infections secondary to deficiencies in development . We previously demonstrated that granulocyte-macrophage colony-stimulating factor ( GM-CSF ) production and mRNA expression from stimulated neonatal mononuclear cells are significantly less than that from adult cells . Recombinant murine GM-CSF administration to neonatal rats has resulted in neutrophilia , increased neutrophil production , and increased survival of pups during experimental Staphylococcus aureus sepsis . In the present study , we sought to determine the safety and biologic response of recombinant human ( rhu ) GM-CSF in VLBW neonates . Twenty VLBW neonates ( 500 to 1,500 g ) , aged < 72 hours , were randomized to receive either placebo ( n = 5 ) or rhuGM-CSF at 5.0 micrograms/kg once per day ( n = 5 ) , 5.0 micrograms/kg twice per day ( n = 5 ) , or 10 micrograms/kg once per day ( n = 5 ) given via 2-hour intravenous infusion for 7 days . Complete blood counts , differential , and platelet counts were obtained , and tibial bone marrow aspirate was performed on day 8 . Neutrophil C3bi receptor expression was measured at 0 and 24 hours . GM-CSF levels were measured by a sandwich enzyme-linked immunosorbent assay at 2 , 4 , 6 , 12 , and 24 hours after the first dose of rhuGM-CSF . At all doses , rhuGM-CSF was well tolerated , and there was no evidence of grade III or IV toxicity . Within 48 hours of administration , there was a significant increase in the circulating absolute neutrophil count ( ANC ) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day , which continued for at least 24 hours after discontinuation of rhuGM-CSF . When the ANC was normalized for each patient 's first ANC , there was a significant increase in the ANC on days 6 and 7 at each dose level . By day 7 , all tested doses of rhuGM-CSF resulted in an increase in the absolute monocyte count ( AMC ) compared with placebo-treated neonates . In those receiving rhuGM-CSF 5.0 micrograms/kg twice per day , there was additionally a significant increase in the day 7 and 8 platelet count . Tibial bone marrow aspirates demonstrated a significant increase in the bone marrow neutrophil storage pool ( BM NSP ) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day . Neutrophil C3bi receptor expression was significantly increased 24 hours after the first dose of rhuGM-CSF at 5.0 micrograms/kg once per day . The elimination half-life ( T1/2 ) of rhuGM-CSF was 1.4 +/- 0.8 to 3.9 +/- 2.8 hours . ( ABSTRACT TRUNCATED AT 400 WORDS )
81733
Intervention_Pharmacological
recombinant human granulocyte-macrophage colony-stimulating factor
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Intervention_Physical
Recombinant murine GM-CSF administration
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Intervention_Pharmacological
recombinant human ( rhu ) GM-CSF
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Intervention_Control
placebo
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Intervention_Pharmacological
rhuGM-CSF
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Intervention_Pharmacological
rhuGM-CSF
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Intervention_Pharmacological
rhuGM-CSF
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Intervention_Pharmacological
rhuGM-CSF .
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Intervention_Pharmacological
rhuGM-CSF
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Intervention_Pharmacological
rhuGM-CSF
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Intervention_Pharmacological
rhuGM-CSF
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Outcome_Physical
GM-CSF levels
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Outcome_Physical
grade III or IV toxicity
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Outcome_Physical
circulating absolute neutrophil count ( ANC )
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Outcome_Physical
ANC
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Outcome_Physical
absolute monocyte count ( AMC )
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Outcome_Physical
day 7 and 8 platelet count
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Outcome_Physical
bone marrow neutrophil storage pool ( BM NSP )
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Outcome_Physical
Neutrophil C3bi receptor expression