oxypurinol and Asphyxia-Neonatorum

At present no standard pharmacological intervention strategy is available to reduce these adverse effects of birth asphyxia. In the present study we aimed to evaluate placental transfer of allopurinol, an inhibitor of XOR. For this purpose, fetal catheterization of the jugular vein was conducted in five late pregnant sows (one fetus per sow). At 24-48 h after surgery, sows received allopurinol (15 mg/kg body weight; i.v.) and pharmacokinetics of allopurinol and its active metabolite oxypurinol were measured in both late pregnant sows and fetuses. Maternal and fetal blood samples were collected during and after allopurinol administration. Maternal C(max) values averaged 41.90 microg/mL (allopurinol) and 3.68 microg/mL (oxypurinol). Allopurinol crossed the placental barrier as shown by the average fetal C(max) values of 5.05 microg/mL at 1.47 h after allopurinol administration to the sow. In only one fetus low plasma oxypurinol concentrations were found. Incubations of subcellular hepatic fractions of sows and 24-h-old piglets confirmed that allopurinol could be metabolized into oxypurinol. In conclusion, we demonstrated that allopurinol can cross the placental barrier, a prerequisite for further studies evaluating the use of allopurinol as a neuroprotective agent to reduce the adverse effects following birth asphyxia in neonatal piglets.

Topics: Allopurinol; Animals; Area Under Curve; Asphyxia Neonatorum; Blood Gas Analysis; Disease Models, Animal; Enzyme Inhibitors; Female; Half-Life; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Metabolic Clearance Rate; Oxypurinol; Pregnancy; Swine; Xanthine Dehydrogenase

We have previously shown that generation of superoxide anion occurs in cerebral cortex during asphyxia/reventilation in newborn pigs and that a high dose of indomethacin (5 mg/kg i.v.) abolishes superoxide anion production. The purposes of this study were 1) to determine whether the generation of superoxide anion occurs primarily during asphyxia or whether reventilation must take place, 2) to investigate the effects of indomethacin pretreatment at a therapeutic dose of 0.2 mg/kg i.v. on superoxide anion generation, and 3) to investigate the effects of oxypurinol, an oxygen free radical scavenger, on superoxide anion production during asphyxia/reventilation. Superoxide anion production on cerebral cortex was determined by superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction using closed cranial windows. Superoxide anion generation during asphyxia without reventilation was 4 +/- 2 pmol NBT/mm2 per 20 min, which was significantly lower than during asphyxia/reventilation (16 +/- 4 pmol NBT/mm2 per 20 min) but comparable to the control group (3 +/- 1 pmol NBT/mm2 per 20 min). Indomethacin given at therapeutic dosage before asphyxia/reventilation decreased superoxide anion production to 3 +/- 1 pmol NBT/mm2 per 20 min, values not significantly different from the control group and from piglets pretreated with oxypurinol at a dose of 50 mg/kg i.v. (4 +/- 2 pmol NBT/mm2 per 20 min). We conclude that in newborn pigs 1) superoxide anions are generated largely during reventilation rather than during asphyxia; 2) the therapeutic dose of indomethacin (0.2 mg/kg) is effective in inhibiting the superoxide anion generation during asphyxia/reventilation; and 3) oxypurinol reduces the superoxide anion accumulation on cerebral cortex during asphyxia/reventilation.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Blood Pressure; Cerebral Cortex; Disease Models, Animal; Humans; Indomethacin; Infant, Newborn; Oxygen; Oxypurinol; Reactive Oxygen Species; Respiration, Artificial; Superoxides; Swine