Short-term dose-response characteristics of 2-iminobiotin immediately postinsult in the neonatal piglet after hypoxia-ischemia.
OBJECTIVE
To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia.


METHODS
Newborn piglets were subjected to a 30-minute hypoxia-ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia-ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration.


RESULTS
A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB-treated animals, indicating decreased cellular damage. Neurobehavior, caspase-3 activity in thalamus, and histology scores were not significantly different.


CONCLUSIONS
Based on survival with a normal aEEG, 0.2 mg/kg 2-IB is likely to be the most appropriate dose for use in future clinical trials in neonates with perinatal hypoxia-ischemia.
The University of Queensland, Royal Brisbane and Women's Hospital, Brisbane , Australia. t.bjorkman@uq.edu.au
S Tracey
ST
Bjorkman
Zoe
Z
Ireland
Xiyong
X
Fan
Willem M
WM
van der Wal
Kit C B
KC
Roes
Paul B
PB
Colditz
Cacha M P C D
CM
Peeters-Scholte
D000818:Animals; D001237:Asphyxia / Q000188:drug therapy* / Q000209:etiology*; D001710:Biotin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D013552:Swine; D013997:Time Factors; D016896:Treatment Outcome
D001710:Biotin; D019001:Nitric Oxide Synthase; D053148:Caspase 3; C028072:2-iminobiotin