Kim Annink

261 General discussion / Conclusions & clinical implications / Future directions dose is given to patients treated with therapeutic hypothermia. The protocol of the ALBINO trial is outlined in chapter eight. This trial is still ongoing in over 60 hospitals in 13 different countries in Europe. So, we have to wait for the results to conclude whether allopurinol is an effective add-on neuroprotective agent in HIE or not. Following previous trials on postnatal allopurinol and antenatal allopurinol administration to mothers during imminent hypoxia, its pharmacokinetics are well known (50–52). However, in these studies neonates with HIE were not treated with hypothermia. Pharmacokinetics might be different due to therapeutic hypothermia (53), e.g. morphine clearance is lower during hypothermia compared to normothermia (54). Also multi-organ failure caused by the hypoxic-ischemia can lead to differences in pharmacokinetics (55,56). In chapter nine we report the pharmacokinetics of allopurinol in the first 15 patients that received allopurinol in the ALBINO trial. The pre-specified target area under the curve concentration (AUC) for allopurinol was met in 100% of the patients undergoing therapeutic hypothermia and 100% of the non-cooled infants. For allopurinol’s active metabolite oxypurinol, which is also important for the neuroprotective effect, 66.7% of the patients undergoing therapeutic hypothermia met the target AUC and 100% in the non-cooled group. Based on these results the dosing regimen in the ALBINO trial is adequate for both cooled and non-cooled infants with HIE. The effect of therapeutic hypothermia and of the severity of perinatal asphyxia (multi-organ failure) could not be investigated in this small cohort and will be investigated in the near future by pooling the data of earlier postnatal studies (50) and the current cohort. Combining the chapters of Part II , we can conclude that allopurinol is a promising add-on neuroprotective agent and timing of administration is essential for its effect. There are several additional advantages of allopurinol as neuroprotective agent. First, a study in sheep revealed that hippocampal injury of fetal sheep was reduced by antenatal allopurinol administration to the mother (57). Additional protection of the hippocampus would be valuable considering the results of chapter five and six. Another benefit of allopurinol as a possible add-on agent, is that it is a cheap medicine and easy to store and administer, which makes it a feasible treatment strategy in low income countries. Thereby it fulfills the criteria of the world health organization to improve neonatal survival worldwide (58). The results of the ALBINO trial need to be awaited to draw definite conclusion on the neuroprotective effect of allopurinol in term infants with HIE. 12