Hypoxic Ischemic Encephalopathy Clinical Trial
Official title:
Human Recombinant Erythropoietin (HrEPO) in Asphyxia Neonatorum: A Pilot Trial
In this prospective trial the investigators plan to study the efficacy of erythropoietin as a therapeutic agent in neonates who suffer from brain injury following perinatal asphyxia.
During HIE free radicals are generated within mitochondria and also as byproducts in the
synthesis of prostaglandins.These free radicals ignite a secondary phase of subsequent
damage to the brain by attacking membranal fatty acids. Nitric oxide (NO) is involved in the
cascade of metabolic events that contributes to HIE. It mediates, in part, the cytotoxic
activity of macrophages, induces relaxation of blood vessels, and also acts as a
neurotransmitter in the central and peripheral nervous system. Therefore, the therapeutic
value of NO synthase inhibitors, among many other agents used to ameliorate the course of
HIE, is currently under investigation in experimental animals.
Erythropoietin (EPO) is a cytokine originally identified for its role in erythropoiesis and
more recently shown to be produced in the central nervous system.Relative insufficiency of
endogenous EPO during periods of ischemic stress may trigger neuronal apoptosis, whereas the
provision of exogenous EPO has been shown to inhibit this process. The potential immediate
protective effects of EPO include decreased NO production, activation of antioxidant
enzymes, reduction of glutamate toxicity, inhibition of lipid peroxidation, and reduction of
inflammation. Long-term protective effects of EPO include the generation of neuronal
anti-apoptotic mechanisms, stimulation of angiogenesis, and modulation of neurogenesis.
Preliminary data supports a protective role of exogenous EPO to neuronal cells. The presence
of EPO rescues in vitro cultured neurons from NO-induced death. It specifically protects
cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity.
Intercerebroventricular injection of EPO offered significant protection of neuronal tissue
in animals with focal cerebral ischemia. EPO is able to cross the blood brain barrier, and
its concentration in the cerebrospinal fluid in normal rats significantly increases within
30 minutes following intravenous administration. EPO also offered neuronal protection when
it was administered systemically to animals suffering from global and focal cerebral
ischemia. In adult patients with stroke, the administration of EPO ameliorates the course of
the disease. Therefore, EPO has recently received much attention and is speculated to have a
role in the protection of HIE infants. However, despite the biological plausibility and the
encouraging preliminary data from animals and adult humans, surprisingly EPO has never been
tried in newborns with HIE even though it has already been used in neonates for other
indications and is known to be safe.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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