Erythropoiesis Stimulating Agents Demonstrate Safety and Show Promise as Neuroprotective Agents in Neonates

Ohls, Robin K.; Christensen, Robert D.; Widness, John A.; Juul, Sandra E.

doi:10.1016/j.jpeds.2015.03.054

Cited by 15 publications

(4 citation statements)

References 20 publications

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“…There is robust data from preclinical animal work showing that Epo, when used at optimal doses (1000–5000 U/kg), shows short and long term improvement in brain injury that approximates 50–80 %, and no safety issues have been discovered. Even the risk of retinopathy of prematurity (ROP) has not been substantiated in randomized controlled trials [ 70 , 71 ]. Safety data for high dose Epo (3000 U/kg x 3 doses) have recently been published [ 65 ].…”

Section: Translational Trials Of Neonatal Epo Neuroprotection For Prementioning

confidence: 99%

Neuroprotective potential of erythropoietin in neonates; design of a randomized trial

Juul

Mayock

Comstock

et al. 2015

matern health, neonatol and perinatol

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BackgroundIn 2013, nearly four million babies were born in the U.S., among whom 447,875 were born preterm. Approximately 30,000 of these infants were born before 28 weeks of gestation. These infants, termed Extremely Low Gestational Age Neonates (ELGANs), experience high morbidity and mortality despite modern therapies: approximately 20 % of ELGANs admitted to an NICU die before discharge, 20 % of survivors have severe, and 20 % moderate neurodevelopmental impairment (NDI). New approaches are needed to improve neonatal outcomes. Recombinant erythropoietin (Epo) is a promising neuroprotective agent that is widely available, affordable, and has been used safely in neonates to stimulate erythropoiesis. There are extensive preclinical data to support its use as a neuroprotective intervention: Epo promotes normal brain maturation by increasing neurogenesis, angiogenesis, and by protecting oligodendrocytes. Epo also decreases acute brain injury following hypoxia ischemia by decreasing inflammation, oxidative and excitotoxic injury, resulting in decreased apoptosis. Despite the availability of both preclinical and safety data there has not been a definitive clinical evaluation of the benefit of Epo, and a large phase III trial is necessary to provide evidence to support potential changes in practice guidelines.FindingsWe first review the preclinical data motivating further clinical trials, and then describe in detail the design of the PENUT study (Preterm Epo Neuroprotection). PENUT is a phase III study evaluating the effect of neonatal Epo treatment on the combined outcome of death or severe NDI among ELGANS. 940 subjects will be randomized to determine: 1) whether Epo decreases the combined outcome of death or NDI at 22–26 months corrected age; 2) the safety of high dose Epo administration to ELGANs; 3) whether Epo treatment decreases serial measures of circulating inflammatory mediators, and improves biomarkers of brain injury; and 4) whether Epo treatment improves brain structure at 36 weeks postmenstrual age as measured by MRI.ConclusionsEpo neuroprotection is an exciting new approach to preterm neuroprotection, and if efficacious, will provide a much-needed therapy for this group of vulnerable infants.

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Section: Translational Trials Of Neonatal Epo Neuroprotection For Prementioning

confidence: 99%

Neuroprotective potential of erythropoietin in neonates; design of a randomized trial

Juul

Mayock

Comstock

et al. 2015

matern health, neonatol and perinatol

Self Cite

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“…7, 13 -15 Debate continues over whether premature infants at high risk of neurodevelopmental impairment may benefit from prophylactic rhEPO. 16 Most clinical follow-up studies on preterm infants primarily treated with rhEPO (or its higherglycosylated derivate darbepoetin) for anemia of prematurity indicated improved neurodevelopmental outcomes, 17 -21 whereas only a few studies have shown no effect. 22,23 In 2005, the first phase I and II trials were initiated to establish the safety of early high-dose rhEPO for neuroprotection.…”

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confidence: 99%

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis

et al. 2017

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“…Erythropoietin (EPO) is a hematopoietic hormone with multiple functions involved in neurogenesis, angiogenesis, and immune response, which also acts as a cytokine with anti-apoptotic activity (12). Its synthetic form, approved by the US Food and Drug Administration (FDA), is a commercially available and easy to administer agent with minimal side effects (13) and has been proven to have remarkable neuroprotective and neuro-regenerative effects in ischemic brain injuries (14)(15)(16). It has also been suggested as an effective adjunctive therapy to be used along with TTM in neonates with HIE (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Effect of Erythropoietin on Short-term Prognosis of Newborns with Hypoxic-Ischemic Encephalopathy: A Clinical Trial

et al. 2022

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Background: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of mortality and morbidity in neonates. Head cooling is considered the standard treatment that reduces mortality and morbidity by decreasing the adverse effects of the disease. Some medicines having neuroprotective properties may be beneficial in treating HIE. Objectives: We aimed to evaluate the effect of erythropoietin (EPO) on short-time outcomes in newborns with HIE. Methods: This study was conducted on 62 newborns with moderate to severe HIE hospitalized in Fatemieh Hospital, affiliated with Hamadan University of Medical Sciences, Hamadan, Iran, from 2019 to 2020. Eighteen patients who received head cooling plus 1000 IU/kg/d EPO were considered the intervention group and compared with 44 neonates who received only head cooling alone. Short-term outcomes, including length of stay (LOS), thrombocytopenia, seizure, need for mechanical ventilation, multiple anticonvulsant drugs, and in-hospital mortality, were compared between the groups using SPSS version 22. Results: The mean LOS was 21.2 ± 9.6 and 21.5 ± 12.3 days (P = 0.927), thrombocytopenia occurred in 27.8% and 34.1% (P = 0.629), and 84.1% - 88.9% of newborns required mechanical ventilation (P = 1.0). The seizure was observed in 93.2 -94.4% of newborns (P = 0.29), and multiple anti-seizure drugs were required in 35.3% and 48.9% of EPO and control groups retrospectively (P = 0.66). The mortality rate was significantly different between the EPO and control groups (11.1% vs 44%; P = 0.02). Conclusions: High-dose EPO can reduce the mortality rate of neonates with HIE when used in addition to head cooling compared to head cooling alone.

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Erythropoiesis Stimulating Agents Demonstrate Safety and Show Promise as Neuroprotective Agents in Neonates

Cited by 15 publications

References 20 publications

Neuroprotective potential of erythropoietin in neonates; design of a randomized trial

Neuroprotective potential of erythropoietin in neonates; design of a randomized trial

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis

Effect of Erythropoietin on Short-term Prognosis of Newborns with Hypoxic-Ischemic Encephalopathy: A Clinical Trial

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