topiramate and Asphyxia-Neonatorum

Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate.. Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots.. Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time-concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital.. Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

Topics: Asphyxia Neonatorum; Combined Modality Therapy; Drug Therapy, Combination; Female; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Neuroprotective Agents; Phenobarbital; Topiramate; Treatment Outcome

Perinatal hypoxia-ischemia (HI) is associated with delayed cerebral damage, which involves receptor-mediated excitotoxicity. Until now, successful interventions to reduce excitotoxicity early after HI in experimental settings failed to transform into clinical applications owing to negative side effects. A promising new approach using the anticonvulsant Topiramate (TPM) has shown to be effective to reduce brain damage after early HI in a rodent model of combined TPM-hypothermia. Here, we used TPM solely administered 1 h after HI in a neonatal piglet model in order to verify possible neuroprotection.. Newborn piglets were subjected to HI by transient occlusion of carotid arteries and hypotension (62-65% of baseline). Fifteen minutes later, an additional reduction of the inspired oxygen fraction to 0.06 was performed for 13 min. One cohort (VEHICLE, n = 8) received saline solution i.v. 1 h after HI and then twice a day. Two further cohorts were treated at same times with TPM (HI-TPM10, n = 8, loading dose 20 mg/kg; maintenance dose 10 mg/kg/day; HI-TPM20, n = 8, loading dose 50 mg/kg; maintenance dose 20 mg/kg/day). Untreated animals (CONTROL, n = 8) received all experimental procedures except HI. Animals were monitored 3 days after HI concerning occurrence of seizures as well as neurological and behavioral functions. After 72 h, the brains were perfused and processed to assess neuronal loss and DNA-fragments (TUNEL staining).. There was a significant reduction of neuronal cell loss in HI-TPM20 animals. However, apoptosis was increased in the frontal white matter of HI-TPM20 animals.. Exclusive TPM treatment shows neuroprotection in newborn piglets after HI.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Brain; Brain Infarction; Disease Models, Animal; DNA Fragmentation; Fructose; Humans; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Infant, Newborn; Nerve Degeneration; Neuroprotective Agents; Sus scrofa; Topiramate; Treatment Outcome