Multiple Epo doses with hypothermia offers neonate neuroprotection

Multiple doses of erythropoietin (Epo) in combination with hypothermia could be neuroprotective in neonates with hypoxic‑ischemic encephalopathy (HIE), say researchers.

A multicenter phase I study showed that when 24 newborns undergoing hypothermia for HIE were treated with Epo 1000 U/kg per dose intravenously, it was well-tolerated and produced plasma concentrations that are neuroprotective.

"A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcomes in infants undergoing hypothermia for HIE," say Yvonne Wu (University of California, San Francisco, USA) and colleagues in Pediatrics.

Area under the curve (AUC) analysis of plasma Epo concentration versus time (in hours) showed that as Epo dose increased, disproportionately large increases in the AUC occurred. The mean AUC ratios were 2.7 for the 500 U/kg versus 250 U/kg doses; 7.1 for the 1000 U/kg versus 250 U/kg doses; and 17.8 for the 2500 U/kg versus 250 U/kg doses.

This pattern of change in AUC was due to a progressive 49% decrease in clearance with dose escalation from 250 U/kg to 2500 U/kg, mean residence time increase of 164% from the lowest to the highest dose, and an increase in half-life of 146% over the dosage range, explain the authors.

They note that at doses of 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours, respectively, and its maximum concentration was 7046, 13,780, and 33,316 U/L, respectively. In addition, total Epo exposure, according to AUC, was 50,306, 131,054, and 328,002 U*h/L, at Epo doses of 500, 1000, and 2500 U/kg.

Wu and team add that drug clearance at a given dose was lower than reported in noncooled preterm infants, and that no deaths or serious adverse events were reported.

They explain that when Epo binds to its receptor, several intracellular signaling pathways are triggered. Activation of one of these pathways, the Janus kinase/Stat5 pathway, along with nuclear factor kappa B (KFκB) and Akt phosphorylation, appears to be responsible for reduced apoptotic cell death after Epo.

"Epo also stimulates growth factors and enhances neurogenesis, angiogenesis, and long-term repair and plasticity, thus providing neuroprotective and trophic effects that last well beyond the acute period of injury," Wu et al write.

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