A microscale HPLC‐UV method for the determination of latamoxef in plasma: An adapted method for therapeutic drug monitoring in neonates

Latamoxef, a broad‐spectrum anti‐bacterial agent of the β‐lactam antibiotics, is used off‐label in treatment of neonatal sepsis. Large inter‐individual variability and uncertainty of treatment make therapeutic drug monitoring (TDM) useful to optimize antimicrobial therapy. The objective of this study was to develop and validate a simple, selective and reliable HPLC method for the determination of latamoxef in small volumes of plasma, which could be used in neonatal TDM. After a simple protein precipitation, analytes were separated with liquid chromatography and quantified by UV detection, with tinidazole as the internal standard. The calibration range was linear from 3.0 to 60.0 μg/mL. Intra‐ and inter‐day precisions were < 7.2%. The acceptance criteria of accuracy (between 85 and 115%, 120% for lower limit of quantification) were met in all cases. A plasma volume of 50 μL was required to achieve the limit of quantification of 3.0 μg/mL. The TDM results showed a large variability in trough concentrations. A large number of patients were underdosed, highlighting the unmet need for TDM to optimize latamoxef therapy in neonates.     

15Nmethacetin test to control liver function of infants with formerly very low birth weight

Abstract

Hepatic detoxification capacities of three groups of infants aged about two were estimated using the [¹⁵N]methacetin elimination test, as well as standard serum parameters:

1. Formerly hypotrophically born infants still too small for their age (n = 23)

2. Patients suffering from severe liver diseases (n = 15)

3. Patients without liver diseases (n = 14).

17 of the infants of group 1 showed ¹⁵N elimination rates as low as the rates of the liver-diseased patients of group 2. Compared to the infants of group 3, who had normal values, the findings reflect diminished hepatic monooxygenases activities in groups 1 and 2. On the other hand, the serum parameters of the infants of group 1 did not deviate from normal values estimated in group 3. Here only group 2 showed pathological values. Consequently, the [¹⁵N]methacetin test seems to be more sensitive in controlling hepatic parameters of growth retardations than the usual serum parameters used here. Further investigations have to answer the question to which proportion intrauterine malnutrition and postnatal effects, such as environmental living conditions, contribute to the retardation of liver function development in combination with growth retardation.     

Der [15N]Methacetin-Leberfunktionstest zum Nachweis von Arzneimittelnebenwirkungen. Antibiotika-Therapie mit Amplicillin und mit Gefotaxime bei Neugeborenen

Abstract

The effect of soil temperature and moisture on plant growth and mineralisation of organic residues was investigated using ¹⁵N-labelled soybean residues and temperature-controlled tanks in the glasshouse. Treatments were arranged in a factorial design with: three soil temperatures (20, 26 and 30°C), two soil moisture regimes (8% (–800 Kpa) or 12% (–100 Kpa)), soybean residues added (enriched at 1.82 atom % ¹⁵N excess) or no residues; and either sown with ryegrass or not sown. Pots were sampled six weeks after planting and ¹⁵N-enrichment and δ¹³C of the plant and soil fractions were determined. Soil inorganic N was also periodically measured.

Available inorganic N increased significantly with addition of residues and generally decreased with increasing temperature. Plant dry matter decreased significantly with increase in soil temperature and increased with increasing moisture. Root-to-shoot ratio declined with increased temperature and moisture. Percentage nitrogen derived from residues (%Ndfr) increased linearly with increased temperature and moisture. Δ¹³C decreased linearly with increasing temperature and decreasing moisture status. There was a significant correlation between transpiration and dry matter production, but there was no correlation between water use efficiency and Δ¹³C.

The results suggest that C: N ratio of the root material effects the root turnover and in turn the water supply capacity of the root system.     

Simultaneous assay of sildenafil and desmethylsildenafil in neonatal plasma by ultra‐performance liquid chromatography–tandem mass spectrometry

Sildenafil is used to treat pulmonary hypertension in neonatal and pediatric patients. Pharmacokinetic studies in these patients are complicated by the limited sample volume. We present the validation results of an assay method to quantitate sildenafil and desmethylsildenafil simultaneously in 50 µL of plasma. Deuterated sildenafil was used as an internal standard. After liquid–liquid extraction, analytes were separated on an ultra‐performance liquid chromatography (UPLC)‐column and quantified via tandem mass spectrometry. The calibration range was linear, with acceptable accuracy and a precision of <15% for both compounds. The lower limits of quantification were 1 ng/mL. Matrix effects were present, but inter‐plasma batch variability was under 12%. The method was successfully applied to samples from a pharmacokinetic study into sildenafil pharmacokinetics in neonates, making maximum use of the limited number and amount of plasma samples available. Copyright © 2009 John Wiley & Sons, Ltd.     

Determination of ciprofloxacin in plasma by micro‐liquid chromatography–mass spectrometry: An adapted method for neonates

There are many limitations to conducting pharmacokinetic studies in neonates, both ethical and technical. Regarding technical aspects, the number and volume of samples are limited, and the analytical method to measure drug concentration should be both specific and highly sensitive. In the present report, an analytical method adapted to neonates was developed for the determination of ciprofloxacin plasma concentration. After a simple protein precipitation, analytes were separated on a micro‐liquid chromatography and quantified by mass spectrometry, with D8‐ciprofloxacin as internal standard. The calibration range was linear from 25 to 3000 ng/mL. Intra‐ and inter‐day precision was less than 2.4 and 4.1%, respectively. The acceptance criteria of accuracy (between 85 and 115%) were met in all cases. A plasma volume of 150 µL was required to achieve the limit of quantification of 25 ng/mL. The method was successfully applied to routine monitoring of ciprofloxacin in pediatric patients and also used in preclinical studies. It will be used to determine the population pharmacokinetic parameters of ciprofloxacin in neonates. Copyright © 2010 John Wiley & Sons, Ltd.     

The Stool Volatile Metabolome of Pre-Term Babies

The fecal metabolome in early life has seldom been studied. We investigated its evolution in pre-term babies during their first weeks of life. Multiple (n = 152) stool samples were studied from 51 babies, all <32 weeks gestation. Volatile organic compounds (VOCs) were analyzed by headspace solid phase microextraction gas chromatography mass spectrometry. Data were interpreted using Automated Mass Spectral Deconvolution System (AMDIS) with the National Institute of Standards and Technology (NIST) reference library. Statistical analysis was based on linear mixed modelling, the number of VOCs increased over time; a rise was mainly observed between day 5 and day 10. The shift at day 5 was associated with products of branched-chain fatty acids. Prior to this, the metabolome was dominated by aldehydes and acetic acid. Caesarean delivery showed a modest association with molecules of fungal origin. This study shows how the metabolome changes in early life in pre-term babies. The shift in the metabolome 5 days after delivery coincides with the establishment of enteral feeding and the transition from meconium to feces. Great diversity of metabolites was associated with being fed greater volumes of milk.