Kim Annink

195 Pharmacokinetics of allopurinol in the ALBINO trial INTRODUCTION Hypoxic-ischemic encephalopathy (HIE) following perinatal asphyxia has an incidence of 1-4 per 1000 neonates, and remains one of the main causes of morbidity and mortality in term neonates worldwide (1). Therapeutic moderate hypothermia (HT) is the only currently proven effective therapy to reduce reperfusion injury in infants with HIE with a number needed to treat for an additional beneficial outcome of 7 (2,3). However, despite therapeutic hypothermia, still 45-50% of the infants with moderate to severe HIE die or develop long-term neurological problems such as motor or cognitive impairments, learning and memory difficulties, epilepsy or behavioral problems (4). Therefore, the search for additional (pharmacological) neuroprotective therapies is essential to further improve their outcome. Brain injury in asphyxiated infants who develop HIE evolves in two stages: first, the acute (fetal) hypoxia leads to primary energy failure and immediate cell injury, secondly reperfusion and reoxygenation can cause additional brain injury. During the acute (fetal) hypoxia, several compounds and enzymes are formed such as hypoxanthine, pro-radicals and nitric oxide synthase that are subsequently metabolized during reperfusion because of renewed oxygenation (5,6). This leads to the formation of superoxide, free radicals and other compounds that are toxic for the immature brain (5,6). In particular the availability of superoxide plays a central role in the induction of several destructive molecular pathways, resulting in additional brain injury (5,6). A potentially neuroprotective drug is allopurinol. Allopurinol is a xanthine-oxidase inhibitor and can thereby reduce the production of superoxide substantially (7) (Figure 1). Additionally, allopurinol, especially in high doses, is a direct scavenger for the most toxic free radical ‘hydroxyl’ and chelates non-protein-bound iron (8,9). Given the proposed positive effects of allopurinol and its metabolite oxypurinol on superoxide and free radical reduction and consequently its preventing action on reperfusion-induced inflammation, the neuroprotective effect of allopurinol in HIE has been investigated and confirmed in several experimental studies (10–17). Based on these mechanisms, postnatal and antenatal clinical studies have been performed (18–23). Postnatal allopurinol administration showed a modest neuroprotective effect in infants with moderate HIE at follow-up (22,24,25). However, the “therapeutic 9