Safety and Pharmacokinetics of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase Administered Intratracheally to Premature Neonates With Respiratory Distress Syndrome

Davis, Jonathan M.; Rosenfeld, Warren; Richter, Susan E.; Parad, Richard B.; Gewolb, Ira H; Spitzer, Alan R.; Carlo, Waldemar A.; Couser, Robert J.; Price, Anita P.; Flaster, Edith; Kassem, Nadim; Edwards, Lionel; Tierney, John; Horowitz, Stuart

doi:10.1542/peds.100.1.24

Cited by 114 publications

(67 citation statements)

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“…doses of rhSOD given to premature infants (700 to 1300 gm) with RDS resulted in significant increases in SOD concentration and activity in serum, tracheal aspirates, and urine. 8,9 A variety of cell and biochemical markers of inflammation in tracheal aspirates that appear to be associated with the development of BPD were significantly reduced in rhSOD-treated infants compared with placebo controls. The drug appeared to be well tolerated in the dosage ranges used (0.5 to 5.0 mg/kg) and not associated with any demonstrable short-term abnormalities.…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Follow-up of Premature Infants Treated With Prophylactic, Intratracheal Recombinant Human CuZn Superoxide Dismutase

et al. 2000

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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. Journal of Perinatology 2000; 4:213-216.Oxygen free radical injury has been implicated in the pathogenesis of a wide variety of conditions that may affect newborns. This is not surprising, because newborns (especially premature infants) are uniquely susceptible to free radical injury. Premature infants are exposed to supraphysiological oxygen concentrations compared with the intrauterine environment and may experience reperfusion injury after periods of hypoxia or ischemia. In addition, newborns may have inadequate defenses against free radical injury. Free radicals can cause damage to both the pulmonary and central nervous systems, resulting in significant long-term sequelae. Bronchopulmonary dysplasia (BPD) can develop in up to 40% of premature neonates with birth weights of Ͻ1500 gm who are treated with oxygen and mechanical ventilation. 1 The development of BPD is associated with increased mortality and morbidity, such as repeated hospitalizations and neurodevelopmental handicaps. 2 Intraventricular hemorrhage (IVH) and/or periventricular leukomalacia can also develop in 20% to 40% of very low birth weight infants, resulting in long-term neurodevelopmental deficits such as cerebral palsy. 3 Treatment directed at preventing free radical injury may decrease the incidence and severity of these conditions and improve long-term outcome.Superoxide dismutases (SODs) are ubiquitous antioxidant enzymes that have been shown to prevent free radical injury due to hyperoxia and reperfusion. Several animal studies have demonstrated that SOD treatment mitigated lung injury from prolonged hyperoxia and mechanical ventilation. 4 -6 SOD administration has also been found to decrease the incidence of IVH and brain injury in animal studies. 7 rhSOD is a human recombinant CuZn SOD that has been given to premature infants with respiratory distress synd...

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Section: Discussionmentioning

confidence: 99%

“…doses of rhSOD. 8,9 These studies have established the short-term safety of rhSOD and have suggested that early inflammatory changes in the lung, which appear to be associated with the development of BPD, can be significantly reduced. The current study prospectively examines the longer-term neurodevelopmental and pulmonary outcomes of infants who received i.t.…”

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Long-Term Follow-up of Premature Infants Treated With Prophylactic, Intratracheal Recombinant Human CuZn Superoxide Dismutase

et al. 2000

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“…In a small study, the intratracheal application of recombinant human SOD (rhSOD) in two different dosages every 48 hours up to seven doses was well tolerated by VLBW infants and led to an increased SOD concentration in tracheal aspirate fluid and serum. 44 Neutrophil chemotactic activity was significantly reduced in tracheal aspirate samples of the two intervention groups but the trial failed to show any beneficial effect of the study drug on BPD at 28 days of life or 36 weeks postmenstrual age. In a recently published larger multicenter trial, 302 infants with birth weights of 600 to 1200 grams who were mechanically ventilated and treated with surfactant for respiratory distress syndrome were randomized to receive either intratracheal rhSOD or placebo every 48 hour up to 1 month.…”

Section: Methylxanthinesmentioning

confidence: 93%

Prevention and treatment of bronchopulmonary dysplasia: current status and future prospects

Thomas

Speer

2007

J Perinatol

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This review summarizes the existing evidence for potential non-ventilatordependent strategies to prevent or ameliorate bronchopulmonary dysplasia (BPD). Oxygen plays an important pathogenetic and therapeutic role for BPD. Targeting infants with lower saturation of peripheral oxygen levels than traditionally used seems justified. Inhaled nitric oxide has not proven effective on pulmonary outcome in extremely low birth weight infants. Diuretics can ameliorate lung function transiently. High intramuscular doses of vitamin A reduce the risk of BPD. Prophylactic application of natural surfactant may also confer benefits. Recently, early administration of caffeine has been shown to decrease risk of BPD. However, assessment of long-term effects is needed before routine use can be recommended. Owing to potential short-and long-term effects, postnatal corticosteroids should be restricted to the most severe manifestations of BPD. Superoxide dismutase and a1-proteinase inhibitor have not shown efficacy in preventing BPD. The potential role of anti-inflammatory therapies like Clara Cell 10 kDa protein has yet to be defined.

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“…Markers of lung injury in the tracheal aspirate were lower in the treated infants [44]. Subsequently, in a multicentre randomised control trial (RCT), 302 infants were treated with either intra-tracheal rhCuZnSOD or placebo every 48 hours while they remained mechanically ventilated until a postnatal age of 28 days.…”

Section: Superoxide Dismutase Replacementmentioning

confidence: 99%

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

Ling

Greenough

2017

Expert Opinion on Orphan Drugs

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Introduction: Bronchopulmonary dysplasia (BPD) is common sequaelae of premature birth.It can be complicated by the development of pulmonary hypertension (PH), which significantly increases mortality. Areas covered: The aim of this review is to evaluate emerging drug therapies for prevention and treatment of BPD and associated PH. These include superoxide dismutase, macrolides, Clara secretary cell protein, -1 protease inhibitors, pentoxifylline, melatonin, inositol, N-acetyl cysteine, allopurinol, cimetidine, pulmonary vasodilators and mesenchymal stem cells (MSC). We have also included discussion on longer standing therapies such as corticosteroids, caffeine and vitamin A.Expert opinion: Corticosteroid administration systemically, but not by inhalation, caffeine and vitamin A reduce BPD. Enhancing endogenous anti-oxidant mechanisms through supplementation with superoxide dismutase or Clara cell secretory protein has yielded encouraging results. Azithromycin, a macrolide used to treat Ureaplasma infection, also has anti-inflammatory properties and has been shown to reduce BPD. Sildenafil reduces the echocardiographic markers of pulmonary hypertension associated with BPD, but has not been shown to prevent BPD. In animal models and a small phase one study MSC administration has resulted in promising results. Appropriately powered studies with long term outcomes are required to assess the efficacy of all these treatments.3

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Safety and Pharmacokinetics of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase Administered Intratracheally to Premature Neonates With Respiratory Distress Syndrome

Abstract: 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.

Cited by 114 publications

References 18 publications

Long-Term Follow-up of Premature Infants Treated With Prophylactic, Intratracheal Recombinant Human CuZn Superoxide Dismutase

Long-Term Follow-up of Premature Infants Treated With Prophylactic, Intratracheal Recombinant Human CuZn Superoxide Dismutase

Prevention and treatment of bronchopulmonary dysplasia: current status and future prospects

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

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