Long-term follow-up of premature infants treated with prophylactic, intratracheal recombinant human CuZn superoxide dismutase.

OBJECTIVE: To examine the long-term effects of treatment with recombinant human CuZn superoxide dismutase (rhSOD) in infants enrolled previously in two placebo-controlled trials. STUDY DESIGN: Records for 46 (88%) infants were examined, with 19 infants having received either single or multiple intratracheal (i.t.) doses of placebo, 12 having received a single i.t. dose of rhSOD, and 15 having received multiple i.t. doses of rhSOD. Mean age at follow-up was 28 months corrected age. Records were examined for neurologic dysfunction, developmental delay, and any significant medical disorders. RESULTS: Four placebo infants (21%) had evidence of neurodevelopmental abnormalities and four infants developed asthma. Four single-dose rhSOD infants (33%) had neurodevelopmental abnormalities and two infants developed asthma. One multiple-dose rhSOD infant had evidence of neurodevelopmental abnormalities and one developed asthma. No other differences were found between the placebo and rhSOD groups. CONCLUSION: Preliminary data suggest that rhSOD is safe and not associated with any long-term adverse effects. Further results will depend on the results of multicenter trials of rhSOD in preterm infants.

Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVES: To examine the safety and pharmacokinetics of multiple intratracheal (IT) doses of recombinant human CuZn superoxide dismutase (rhSOD) in premature infants with respiratory distress syndrome who are at risk for developing bronchopulmonary dysplasia (BPD). Methods. Thirty-three infants (700 to 1300 g) were randomized and blindly received saline, 2.5 mg/kg or 5 mg/kg rhSOD IT within 2 hours of surfactant administration. Infants were treated every 48 hours (as long as endotracheal intubation was required) up to 7 doses. Serial blood and urine studies, chest radiographs, neurosonograms, SOD concentration and activity measurements, and tracheal aspirate (TA) inflammatory markers were assessed throughout the 28-day study. RESULTS: SOD concentrations in serum (0.1 [0.05/0.15] microg/mL-geometric mean with lower/upper confidence intervals), tracheal aspirates (TA) (0.2 [0.1/0.3] microg/mL) and urine (0.3 [0.2/0.4] microg/mL) were similar at baseline in all 3 groups and did not change significantly in the placebo group. In the rhSOD treatment groups, SOD concentrations were increased on day 3 and did not change significantly thereafter over the 14-day dosing period (also measured on days 5, 7, and 13). SOD concentrations averaged 0.4 [0.3/0.5] microg/mL in serum, 0.8 [0.6/1.2] microg/mL in TA and 1.1 [1.0/1.3] microg/mL in urine for the low-dose group and 0.6 [0.5/0.7] microg/mL in serum, 1.1 [0.9/1.5] microg/mL in TA, and 2.2 [1.6/2.9] microg/mL in urine for the high-dose group over the 14-day dosing period. Enzyme activity directly correlated with SOD concentration and rhSOD was active even when excreted in urine. TA markers of acute lung injury (neutrophil chemotactic activity, albumin concentration) were lower in the rhSOD agroups compared with placebo. No significant differences in any clinical outcome variable were noted between groups. CONCLUSIONS: These data indicate that multiple IT doses of rhSOD increase the concentration and activity of the enzyme in serum, TA and urine, reduce TA lung injury markers and are well-tolerated. Further clinical trials examining the efficacy of rhSOD in the prevention of BPD are warranted.

Pharmacologic interactions of exogenous lung surfactant and recombinant human Cu/Zn superoxide dismutase.

The effect of exogenous surfactant on the pharmacokinetics of intratracheally administered recombinant human superoxide dismutase (rhSOD) was studied. Five groups of rats received the following intratracheally: 1 mL/kg of saline; 5 or 25 mg/kg of rhSOD; or 4 mL/kg of exogenous surfactant followed in 30 min by 5 or 25 mg/kg of rhSOD. Animals were killed at 24, 48, and 72 h, and serum, bronchoalveolar lavage, and lung tissue were analyzed for rhSOD. rhSOD was not detected in the lungs of saline-treated animals or in serum from any animals. At 24 h, lung-tissue rhSOD was higher in rats treated with surfactant and rhSOD versus rhSOD alone (5 mg/kg: 6.8 +/- 2.5 versus 0 microgram/whole lung, p < 0.05; 25 mg/kg: 29.9 +/- 9.6 versus 0.1 +/- 0.1 microgram/whole lung, p < 0.05). Bronchoalveolar lavage fluid levels correlated well with lung tissue concentrations. By 48 h, lung tissue rhSOD concentrations were insignificant in all groups. rhSOD was still present in lavage fluid from rats treated with surfactant and rhSOD. No rhSOD was detected at 72 h. In separate in vitro experiments, physical and biological drug-drug interaction studies were performed. When radiolabeled rhSOD was combined with exogenous surfactant and centrifuged at 10,000 x g for 30 min, 81.3 +/- 2.5% of rhSOD was found in the supernatant versus 18.7 +/- 2.5% in the surfactant pellet. Serial washing of the surfactant pellet removed virtually all remaining rhSOD. This finding suggests that the rhSOD and surfactant were only weakly associated. Combining rhSOD and exogenous surfactant did not alter the activity of either agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Prophylactic effects of recombinant human superoxide dismutase in neonatal lung injury.

To determine if recombinant human Cu-Zn superoxide dismutase (rhSOD) would prevent acute lung injury caused by hyperoxia and barotrauma, 26 newborn piglets were studied. Ten piglets were hyperventilated (arterial PCO2 15-20 Torr) with 100% O2 for 48 h. A second group received identical treatment for 4 h (n = 2) or 48 h (n = 8) but was given 5 mg/kg of rhSOD intratracheally at time 0. Six piglets were normally ventilated (arterial PCO2 40-45 Torr) for 48 h with 21% O2. Pulmonary function and tracheal aspirates were examined at time 0 and at 24 and 48 h, and bronchoalveolar lavage was performed at 48 h. In piglets treated with hyperoxia and hyperventilation, lung compliance decreased 42%, and tracheal aspirates showed an increase in neutrophil chemotactic activity (32%), total cell counts (135%), elastase activity (93%), and albumin concentration (339%) over 48 h (P < 0.05). All variables were significantly lower in rhSOD-treated piglets and comparable to normoxic control values. Surfactant remained active in all groups. Immunohistochemistry demonstrated that at 48 h significant rhSOD was distributed homogeneously in terminal airways. Adding rhSOD to tracheal aspirates of hyperoxic hyperventilated piglets did not alter neutrophil chemotaxis, suggesting that rhSOD protected the lung by reducing the production of chemotactic mediators. Results indicate that acute lung injury caused by 48 h of hyperoxia and hyperventilation is significantly ameliorated by prophylactic intratracheal administration of rhSOD.