Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome
Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome
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DOI：
10.1542/peds.100.1.24
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发表时间：
1997-07-01
期刊：
影响因子：
8
通讯作者：
Horowitz, S
中科院分区：
文献类型：
--
作者：
Davis, JM;Rosenfeld, WN;Horowitz, S
目标.目的：研究多剂量重组人铜锌超氧化物歧化酶（rhSOD）静脉注射治疗呼吸窘迫综合征（RDS）早产儿的安全性和药代动力学，这些早产儿有发生支气管肺发育不良（BPD）的风险。33名婴儿（700 - 1300 g）在表面活性剂给药后2小时内随机盲法接受生理盐水、2.5 mg/kg或5 mg/kg rhSOD IT。婴儿每48小时给药一次（只要需要气管插管），最多给药7次。在整个28天的研究中，对一系列血液和尿液研究、胸部X线片、神经超声、SOD浓度和活性测量以及气管抽吸物（TA）炎症标记物进行评估。基线时，所有3组的血清（0.1 [0.05/0.15] μ g/mL-几何平均值和置信区间下限/上限）、气管抽吸物（TA）（0.2 [0.1/0.3] μ g/mL）和尿液（0.3 [0.2/0.4] μ g/mL）中的SOD浓度相似，安慰剂组无显著变化。在rhSOD处理组中，SOD浓度在第3天增加，此后在14天给药期间没有显著变化（也在第5、7和13天测量）。低剂量组血清、TA和尿液中的SOD浓度平均值分别为0.4 [0.3/0.5] μ g/mL、0.8 [0.6/1.2] μ g/mL和1.1 [1.0/1.3] μ g/mL，血清、TA和尿液中的SOD浓度平均值分别为0.6 [0.5/0.7] μ g/mL、1.1 [0.9/1.5] μ g/mL，在14天给药期间，高剂量组的尿液中为2.2 [1.6/2.9] μ g/mL。酶活性与SOD浓度直接相关，rhSOD即使经尿液排泄也具有活性。急性肺损伤的TA标志物（中性粒细胞趋化活性、白蛋白浓度）在rhSOD组中低于安慰剂组。两组间任何临床结果变量均无显著差异。这些数据表明，多次IT剂量的rhSOD增加了血清、TA和尿液中酶的浓度和活性，减少了TA肺损伤标志物，并且耐受性良好。进一步的临床试验检查rhSOD在预防BPD中的疗效是必要的。
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] mu g/mL-geometric mean with lower/upper confidence intervals), tracheal aspirates (TA) (0.2 [0.1/0.3] mu g/mL) and urine (0.3 [0.2/0.4] mu g/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] mu g/mL in serum, 0.8 [0.6/1.2] mu g/mL in TA and 1.1 [1.0/1.3] mu g/mL in urine for the low-dose group and 0.6 [0.5/0.7] mu g/mL in serum, 1.1 [0.9/1.5] mu g/mL in TA, and 2.2 [1.6/2.9] mu g/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.