Development and in vitro evaluation of an infant friendly self-nanoemulsifying drug delivery system (SNEDDS) loaded with an amphotericin B-monoacyl phosphatidylcholine complex for oral delivery.

Until relatively recently, the pediatric population has largely been ignored during the development of new drug products, which has led to a high level of "off-label" use of drugs in this particular population. In this study, an infant friendly self-nanoemulsifying drug delivery system (SNEDDS) was developed for oral delivery of a commonly used "off-label" drug - amphotericin B (AmB). AmB was complexed with monoacyl-phosphatidylcholine (MAPC) by lyophilization, transforming crystalline AmB into its amorphous state in the AmB-MAPC complex (APC). The APC-loaded SNEDDS (APC-SNEDDS) showed excellent self-emulsifying properties; after dispersion of the APC-SNEDDS in purified water, nanoscale emulsion droplets were formed within 1 min with a z-average size of 179 ± 1 nm. In vitro pediatric gastrointestinal (GI) digestion and dissolution results showed that the APC-SNEDDS significantly increased the amount of AmB solubilized in aqueous phase and that the precipitated AmB from the APC-SNEDDS re-dissolved faster, compared with crystalline AmB in SNEDDS (AmB-SNEDDS), the complex without the SNEDDS (APC), the physical mixture of AmB and MAPC (AmB/MAPC PM), and crystalline AmB alone (AmB). Overall, the present in vitro results suggest that integrating the APC into an infant friendly SNEDDS is a promising approach for oral delivery of AmB to young pediatric patients.

Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants.

OBJECTIVES: There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has recently been brought back into use for treatment of infections in newborns; however, it is still used off-label in neonatal clinical practice due to the lack of an evidence-based dosing regimen. This study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants, and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD). METHODS: Opportunistic blood samples from newborns treated with latamoxef were collected to determine the latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range 28.4-46.1 weeks) were available for analysis. RESULTS: A two-compartment model with first-order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicated that the current dosing regimen (30 mg/kg q12h) is adequate with an MIC of 1 mg/L. For an MIC of 4 mg/L, 30 mg/kg q8h was required to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval. CONCLUSIONS: Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen.

Risk factors for prolonged mechanical ventilation in neonates and young infants after cardiac surgery for complicated congenital heart disease / 临床麻醉学杂志

Objective To investigate the risk factors for postoperative prolonged mechanical ventilation in neonates and young infants with complicated congenital heart disease. Methods A retrospective analysis of 150 children (80 males and 70 females, aged ≤ 6 months, RACHS-1 grade ≥ 3) with complex congenital heart disease who were admitted to Children's Heart Surgery Department of Anzhen Hospital from January 2016 to December 2017 was conducted. These data were collected: the demographic data, history of cardicvascular-related diseases, type of surgery, preoperative complications, CPB, CPB time, deep hypothermia, blood gas index, delayed chest closure (DCC), pacemaker; minimum oxygenation index in the first 24 h after operation, maximum vasoactive-inotropic score (VIS), failed extubation and postoperative complications. Logistic regression model was used to analyze the risk factors of prolonged mechanical ventilation within neonates and young infants after complicated congenital heart surgery. Results Forty-two patients (28％) required PMV with mechanical ventilation ≥ 72 h. Univariate analysis showed age, weight, RACHS-1 grade, previous history of cyanosis, history of pneumonia, emergency surgery, preoperative mechanical ventilation, preoperative EF, deep hypothermia, CPB time＞ 132 min, intraoperative minmum pH value, intraoperative maximum blood glucose and lactic acid concentrations, DCC, application of pacemakers, maximum VIS within 24 h after surgery, minimal OI and postoperative complications may be the risk factors of prolonged postoperative mechanical ventilation in neonates and young infants with complicated congenital heart disease (P ＜ 0.05). Multivariate Logistic regression analysis showed that the CPB time＞132 min (OR = 11.04, 95％ CI 2.07-58.96, P = 0.005), intraoperative maximum lactate (OR = 1.53, 95％ CI 1.07-2.20, P = 0.021) and failed extubation (OR = 17.28, 95％ CI 2.46-121.20, P = 0.004) were independent risk factors for prolonged postoperative mechanical ventilation in neonates and young infauts with complicated congenital heart disease. Conclusion CPB time＞132 min, intraoperative maximum lactic acid concentration and failure of extubation can be used as predictors of prolonged postoperative mechanical ventilation in neonates and young infants with complicated congenital heart disease.

Studying furosemide solubilization using an in vitro model simulating gastrointestinal digestion and drug solubilization in neonates and young infants.

OBJECTIVE: The aim of the present study was to study the oral performance of furosemide in neonates and young infants using a newly developed in vitro model simulating digestion and drug solubilization in the gastrointestinal (GI) tract of the human neonate and young infant population (age 0-2months). METHODS: The utilized in vitro model was designed to mimic the digestion and drug solubilization processes occurring in the stomach, and the small intestine of the neonate and young infant population, using physiologically relevant media, volumes and digestive enzymes. Overall the experimental model setup was based on the dynamic in vitro lipolysis model previously described by Fernandez et al. (2009). The amount of furosemide solubilized in the aqueous phase during a digestion study was used as an estimate for the amount of drug available for absorption in vivo. By varying different factors in the model setup, e.g. presence of food (food-effect), effect of digestion (tested with and without addition of digestive enzymes), and properties of the dosage form, it was possible to estimate the importance of these factors in vivo. KEY FINDINGS AND CONCLUSIONS: The present in vitro data suggest that the oral performance of furosemide in neonates and young infants will be increased by the presence of food (frequent feedings) due to increased drug solubilization, however, not influenced by the GI digestion of this food. The properties of the dosage form (immediate release tablets) did not affect the drug solubilization as compared to administration of the pure drug powder.