OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13780, and 33316 U/L, and total Epo exposure (area under the curve) was 50306, 131054, and 328002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.
OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemicencephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS:Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13780, and 33316 U/L, and total Epo exposure (area under the curve) was 50306, 131054, and 328002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS:Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.
Authors: Anargyros Xenocostas; Wing K Cheung; Francis Farrell; Cindy Zakszewski; Marian Kelley; Andrzej Lutynski; Michael Crump; Jeffrey H Lipton; Thomas L Kiss; Catherine Y Lau; Hans A Messner Journal: Eur J Clin Pharmacol Date: 2005-03-18 Impact factor: 2.953
Authors: Seetha Shankaran; Abbot R Laptook; Richard A Ehrenkranz; Jon E Tyson; Scott A McDonald; Edward F Donovan; Avroy A Fanaroff; W Kenneth Poole; Linda L Wright; Rosemary D Higgins; Neil N Finer; Waldemar A Carlo; Shahnaz Duara; William Oh; C Michael Cotten; David K Stevenson; Barbara J Stoll; James A Lemons; Ronnie Guillet; Alan H Jobe Journal: N Engl J Med Date: 2005-10-13 Impact factor: 91.245
Authors: Zhengang Yang; Matthew V Covey; Claudine L Bitel; Li Ni; G Miller Jonakait; Steven W Levison Journal: Ann Neurol Date: 2007-03 Impact factor: 10.422
Authors: Rosemary D Higgins; Tonse Raju; A David Edwards; Denis V Azzopardi; Carl L Bose; Reese H Clark; Donna M Ferriero; Ronnie Guillet; Alistair J Gunn; Henrik Hagberg; Deborah Hirtz; Terrie E Inder; Susan E Jacobs; Dorothea Jenkins; Sandra Juul; Abbot R Laptook; Jerold F Lucey; Mervyn Maze; Charles Palmer; Luann Papile; Robert H Pfister; Nicola J Robertson; Mary Rutherford; Seetha Shankaran; Faye S Silverstein; Roger F Soll; Marianne Thoresen; William F Walsh Journal: J Pediatr Date: 2011-08-27 Impact factor: 4.406
Authors: Sandra E Juul; Bryan A Comstock; Patrick J Heagerty; Dennis E Mayock; Amy M Goodman; Stephanie Hauge; Fernando Gonzalez; Yvonne W Wu Journal: Neonatology Date: 2018-03-07 Impact factor: 4.035
Authors: Christopher P Wayock; Rachel L Meserole; Suchi Saria; Jacky M Jennings; Thierry A G M Huisman; Frances J Northington; Ernest M Graham Journal: Am J Obstet Gynecol Date: 2014-03-18 Impact factor: 8.661
Authors: Robin K Ohls; Daniel C Cannon; John Phillips; Arvind Caprihan; Shrena Patel; Sarah Winter; Michael Steffen; Ronald A Yeo; Richard Campbell; Susan Wiedmeier; Shawna Baker; Sean Gonzales; Jean Lowe Journal: Pediatrics Date: 2016-02-15 Impact factor: 7.124