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Abstract: Objective: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. Methods: Fluorouracil–epirubicin–cyclophosphamide (FEC) and doxorubicin–bleomycin–vinblastine–dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography–mass spectrometry (LC–MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. Results: In nine baboons, at a median gestational age of 139days (range, 93–169), FEC 100% (n =2), FEC 200% (n =1), ABVD 100% (n =5), and ABVD 200% (n =1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5±3.2% (n =6) and 4.0±1.6% (n =8) of maternal concentrations, respectively. Fetal tissues contained 6.3±7.9% and 8.7±8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5±15.5% (n =9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1±6.3% (n =3) and 63.0% (n =1) of the maternal concentrations, respectively. Conclusion: This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide. [Copyright &y& Elsevier]

Abstract: A simple, accurate and fast method was developed for determination of the commonly used HIV protease inhibitors (PIs) amprenavir, indinavir, atazanavir, ritonavir, lopinavir, nelfinavir, M8-nelfinavir metabolite and saquinavir in human plasma. Liquid–liquid extraction was used with hexane/ethylacetate from buffered plasma samples with a borate buffer pH 9.0. Isocratic chromatographic separation of all components was performed on an Allsphere hexyl HPLC column with combined UV and fluorescence detection. Calibration curves were constructed in the range of 0.025–10mg/l. Accuracy and precision of the standards were all below 15% and the lowest limit of quantitation was 0.025mg/l. Stability of quality control samples at different temperature conditions was found to be below 20% of nominal values. The advantages of this method are: (1) inclusion and determination of the newly approved atazanavir, (2) simultaneous isocratic HPLC separation of all compounds and (3) increased specificity and sensitivity for amprenavir by using fluorescence detection. This method can be used for therapeutic drug monitoring of all PIs currently commercialised and is now part of current clinical practice. [Copyright &y& Elsevier]

Presents a letter to the editor, about cerebrospinal fluid pharmacokinetics of paracetamol after intravenous injection of propacetamol in a preterm infant, published in the February 2004 issue of "British Journal of Clinical Pharmacology."

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration ( R = 0.39) had a slope significantly different from zero ( p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) ( p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs. [ABSTRACT FROM AUTHOR]

Background: To document covariates which contribute to inter-individual variability in propofol pharmacokinetics in preterm and term neonates.Methods: Population pharmacokinetics were estimated (non-linear mixed effect modelling) based on the arterial blood samples collected in (pre)term neonates after i.v. bolus administration of propofol (3 mg kg(-1), 10 s). Covariate analysis included postmenstrual age (PMA), postnatal age (PNA), gestational age, weight, and serum creatinine.Results: Two hundred and thirty-five arterial concentration-time points were collected in 25 neonates. Median weight was 2930 (range 680-4030) g, PMA 38 (27-43) weeks, and PNA 8 (1-25) days. In a three-compartment model, PMA was the most predictive covariate for clearance (P<0.001) when parameterized as [CL(std).(PMA/38)(11.5)]. Standardized propofol clearance (CL(std)) at 38 weeks PMA was 0.029 litre min(-1). The addition of a fixed value in neonates with a PNA of >/=10 days further improved the model (P<0.001) and resulted in the equation [CL(std).(PMA/38)(11.5) +0.03] for neonates >/=10 days. Values for central volume (1.32 litre), peripheral volume 1 (15.4 litre), and peripheral volume 2 (1.29 litre) were not significantly influenced by any of the covariates (P>0.001).Conclusions: PMA and PNA contribute to the inter-individual variability of propofol clearance with very fast maturation of clearance in neonatal life. This implicates that preterm neonates and neonates in the first week of postnatal life are at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol. [ABSTRACT FROM AUTHOR]

Objective: Assess in vivo O-demethylation activity in the first months of life. Methods: Time-concentration profiles of tramadol (M) and O-demethyl tramadol (M1) in plasma and urine were simultaneously collected in the first 24 h of continuous intravenous tramadol administration in neonates and young infants. M and M1 were determined by high performance liquid chromatography. Correlations between perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] and the contribution of metabolites (M, M1) to overall tramadol elimination and to the plasma and urine log M/M1 were calculated. Results: Plasma samples were available in 20/29 and complete complete 24-h urine collections were available in 25/29 neonates (25–53 weeks PMA). Mean plasma log M/M1 value (»4 h, n=86) was 0.8 (SD 0.4). A significant correlation between plasma log M/M1 and PMA (r=-0.73, P«0.0001) and PNA (r=-0.58, P«0.005) was observed. In a multiple regression model, only PMA remained an independent variable. Mean urine log M/M1 was 0.94 (SD 0.7). Significant correlations of the urine log M/M1 ratio with PMA (r=-0.73, P«0.0001) and PNA (r=-0.56, P=0.0035) were observed. In a multiple regression model with the urine log M/M1ratio as dependent variable, only PMA remained an independent variable. The maturational half-life of the log M/M1 ratio in early neonatal life in the age range evaluated is about 12–16 weeks without plateau. Conclusions: O-demethylation activity was already observed in early neonatal life. A significant correlation with PMA was documented, but PMA can only partially explain the observed variability in O-demethylation activity. Polymorphism therefore likely already contributes to the interindividual variability observed in neonates. [ABSTRACT FROM AUTHOR]

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood-brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults. [ABSTRACT FROM AUTHOR]

Aim: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. Methods: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m2) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. Results: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m2, at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). Conclusion: Estradiol and weight in part explain the variation in paracetamol clearance in young women. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease. One of the proposed disease mechanisms is excitotoxicity, in which excessive cytosolic calcium causes neuronal death. Although most calcium may originate from the extracellular space through activation of calcium-permeable AMPA receptors, we investigated in this study the contribution of endoplasmic reticulum calcium release by blocking the ryanodine receptor (RyR) using dantrolene. In vitro, dantrolene provides a significant protection to motor neurons exposed to a brief excitotoxic insult. However, daily administration of dantrolene to mice overexpressing superoxide dismutase 1 glycine to alanine at position 93 (SOD1G93A) does affect neither survival nor the number of motor neurons and ubiquitin aggregates indicating that calcium release through RyRs does not contribute to the selective motor neuron death in this animal model for ALS. [Copyright &y& Elsevier]

The article presents a study which measures voriconazole plasma levels in children. The study conducted voriconazole plasma concentration monitoring, C-reactive protein levels (CRP), liver function tests, renal function tests, serum galactomannan (GM) values in patients, aged 0-18 years, admitted in a tertiary care hospital in Leuven, Belgium. Results show that voriconazole levels varied widely and no correlation were observed between trough levels and administered dosage.

Abstract: Introduction: Although of pharmacokinetic and -dynamic relevance, data on ontogeny of UDP-glucuronosyltransferase (UGT) activity in neonates are scant. We therefore wanted to assess the impact of both postnatal and postmenstrual age (PNA/PMA) on the interindividual variability of glucuronidation to overall tramadol urinary elimination in neonates. Methods: O-demethyl tramadol (M1) and M1-glucuronide (M1G) were determined in 24 hour urine collections during continuous intravenous tramadol administration in neonates. Glucuronidation fraction (%) was calculated by the ratio of M1G to the sum of M1G and M1 free (M1total). Fractions (%) in early (

Discusses the abstract of the research 'Desirudin: effect on blood coagulation tests in vitro and following a subcutaneous administration in healthy volunteers,' submitted to the Dutch Society for Clinical Pharmacology & Biopharmacy on April 19, 2002.

The article focuses on the study about the maturation of 0-demethyl tramadol glucuronidation in a cohort of neonates and young infants. The research shows that 0-demethyl tramadol-glucuronide is the most abundant glucuronidated phase II metabolite. A significant effect of postnatal and postmenstrual age was observed. There is also a significant increase in glucuronidation with increasing postnatal age based on a fast maturation in the first week of postnatal life.