Chiral pharmacokinetics of ibuprofen enantiomers in Chinese preterm neonates with patent ductus arteriosus using a validated UHPLC-MS/MS method.

Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) - tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 µm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 µg/mL to 50.00 µg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA.

Protective Effects of Lactobacillus reuteri on Intestinal Barrier Function in a Mouse Model of Neonatal Necrotizing Enterocolitis.

OBJECTIVE: The intestinal mucosal and immune barriers play considerable roles in the pathogenesis of necrotizing enterocolitis (NEC). The present research was designed to assess the protective effects of Lactobacillus reuteri (LR) DSM 17938 (LR 17938) on the intestinal barriers and its beneficial effects on inflammation in a neonatal mouse model of NEC. STUDY DESIGN: Overall, 7-day-old 75 C57BL/6 neonatal mice were separated into three groups (n = 25) as follows: (1) control, (2) NEC, and (3) NEC + LR17938 (LR group). NEC mice were administered a hypertonic feeding formula and subjected to asphyxia and hypothermia. Hematoxylin and eosin (HE) staining and pathological scores were used to assess the pathological changes in the intestine. Oxidative stress was evaluated based on the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß levels were detected to assess inflammation. Gut permeability levels, bacterial translocation, and the levels of secretory idioglobulin A (sIgA), ß-defensin, and tight junction (TJ) proteins were detected to evaluate gut mucosal and immune barrier function, and gut microbial diversity was detected to assess the composition of the gut flora. RESULTS: LR 17938 administration decreased the NEC-induced increase in intestinal scores, mortality rate, gut damage, the MDA level, and TNF-α and IL-1ß expressions. Besides, LR 17938 improved the survival rate of NEC mice. Moreover, LR 17938 administration improved gut permeability levels, SOD activity and the bacterial translocation, ameliorated the expression of TJ proteins, and improved the gut microbiota compared with those of NEC mice. CONCLUSION: LR 17938 reduced intestinal inflammation and played a protective role in a neonatal animal model of NEC, possibly by regulating oxidative stress and exerting a protective effect on the gut mucosal and immune barriers. KEY POINTS: · Our research indicated a protective effect of LR 17938 on gut barrier function in NEC mice.. · LR 17938may affect the diversity of gut flora, which are known to target beneficial bacteria.. · LR 17938 protected gut barrier function in the NEC pups by improving gut permeability..