Kim Annink

149 Allopurinol: old drug, new indication in neonates? Allopurinol: from gout therapy to neuroprotective agent Allopurinol is a xanthine-oxidase inhibitor that inhibits the production of uric acid. The enzyme xanthine-oxidase converts hypoxanthine into uric acid (1). Allopurinol is almost completely metabolized into oxypurinol by aldehyde oxidase in the liver and is eliminated by the kidneys (1). Oxypurinol is the active metabolite of allopurinol and predominantly inhibits xanthine-oxidase because allopurinol is almost completely metabolized into oxypurinol and oxypurinol has a longer half-life than allopurinol (2). Historically, allopurinol is a well-known therapy for gout in adults by reducing the concentrations of uric acid and thereby the formation of uric acid crystals (1). Furthermore, allopurinol is widely used as therapy for tumor lysis syndrome and kidney stones. Allopurinol also inhibits the production of free radicals. Therefore, new indications have been investigated for this ‘old drug’. Currently, research is focusing on possible cardioprotective and neuroprotective effects of allopurinol by inhibiting the formation of the free radical superoxide production in neonates and adults. Free radicals lead to cell damage by causing oxidative stress i.e. the peroxidation of proteins, lipids and DNA, which in turn causes mitochondrial damage and induce apoptotic pathways (3,4). These free radicals are formed in the presence of oxygen: hypoxanthine and oxygen are converted into uric acid and superoxide by xanthine-oxidase (5). Allopurinol and oxypurinol can both inhibit xanthine-oxidase and thereby the production of superoxide. An additional working mechanism of allopurinol and oxypurinol is free radical scavenging; in neonates as well non- protein-bound iron (NPBI) and the hydroxyl radical seemed to be directly scavenged by allopurinol and oxypurinol (6,7). From the 1970’s onwards, allopurinol was investigated in animal studies because of its possible cardioprotective effect by inhibiting the formation of oxygen radicals (8-13). Following animal studies, it was shown that allopurinol pre-treatment in adult patients undergoing coronary bypass surgery led to a better recovery (14). Also, the hospital mortality, cardiac performance and postoperative recovery, defined as less inotropic and mechanical support, improved after cardiac bypass surgery in allopurinol treated patients (15). On the contrary, other studies did not find an improvement in cardiac function after surgery in these patients (10). Allopurinol was also investigated as a therapy for chronic heart failure and angina pectoris. The hypothesis was that inhibition of the formation of uric acid and the free radical superoxide might prevent endothelial damage and myocardial oxidative stress (16). 7