Preventive potential of N-acetylcysteine in oxidative stress-related complications of prematurity
Year: 2004
Type: dissertation
Abstract: Background: Oxygen therapy and inflammation are key factors in the pathogenesis of bronchopulmonary dysplasia (BPD) and both increase the generation of reactive oxygen species.The synthesis of glutathione, a major intracellular antioxidant, may not be adequate in preterm neonates because of the low levels of cysteine available.N-acetylcysteine (NAC), a free radical scavenger and a precursor for cysteine, has been suggested to increase glutathione synthesis.Aims: To determine whether NAC treatment improves the outcome of preterm infants by preventing oxidative stress-related complications of prematurity, to identify a suitable risk indicator of oxidative damage in extremely low birth weight infants (ELBWI) and to evaluate thiol metabolism in preterm infants during the first week of life.Design: We investigated the pharmacokinetics of NAC in preterm newborn infants and applied the results in the NAC treatment protocol of a randomized, placebo-controlled, double-blind multicentre trial.The primary outcome measures were death and prevalence of BPD at the gestational age of 36 weeks.To identify a suitable risk indicator of oxidative damage and to evaluate the effect of NAC infusion on this marker and on the risk of BPD or death, we measured plasma 8-isoprostane and ascorbyl radical concentrations on days 3 and 7 in a subpopulation of infants participating in the multicentre trial.To further clarify the thiol metabolism during the first week of life, we studied plasma and erythrocyte cysteine and glutathione in very low birth weight infants (VLBWI) and ELBWI, as well as erythrocyte glutathione cycle enzymes in VLBWI.Results: NAC is eliminated slowly in preterm infants, with a mean half-life of 11 hours, which is clearly longer than that described for adults.The clearance of NAC correlates well with weight and gestational age.In most infants, a steady-state concentration was reached within 2-3 days at a constant infusion rate of NAC.The randomized controlled trial, including 391 ELBWI, showed that intravenous NAC, at the dosage used, did not prevent BPD or death in ELBWI.No adverse effects that could be ascribed to NAC treatment were observed.Abstract 10 Plasma 8-isoprostane concentrations during the first week of life were higher in the infants who later developed BPD or died, and increased significantly more in infants who later developed PVL.This marker of oxidative stress may be valuable for defining the risk group for adverse outcome.NAC had no significant effect on plasma 8-isoprostane concentration.The ascorbyl radical concentration on day 3 was significantly higher in those infants who subsequently developed PVL.Plasma glutathione concentrations initially increased and plasma cysteine concentrations initially decreased in VLBWI and ELBWI studied during the first week of life.Infants who developed RDS already had lower glutathione concentrations during the first hours of life.Furthermore, a correlation between intracellular cysteine and glutathione concentrations in erythrocytes was present. Conclusions:The pharmacokinetics of N-acetylcysteine in preterm infants is related to weight and gestational age.The elimination of N-acetylcysteine is much slower in preterm newborns than in adults.At 36 gestational weeks no beneficial effects of a 6-day course of intravenous NAC, at the dosage used, were demonstrated on BPD.NAC treatment did not have any impact on plasma free 8-isoprostane or ascorbyl radical.An association between elevated plasma free 8-isoprostane, BPD and PVL, as well as between plasma ascorbyl radical signal and PVL, was found.VLBWI and ELBWI have an initial increase in plasma glutathione and an initial decrease in plasma cysteine concentration, in addition to a positive correlation between erythrocyte cysteine and glutathione concentrations during the first week of life.
Source: Työväentutkimus Vuosikirja
Author: Terhi Ahola
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W658732113