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Objectives: Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy.Methods: Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation.Results: Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months.Conclusions: These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations. [ABSTRACT FROM AUTHOR]

Background: No pharmacokinetic data about remifentanil in preterm infants exist, although remifentanil is increasingly used in this especially vulnerable subgroup of pediatric patients. Unfortunately, ethical restrictions in the volume of blood that can be withdrawn for kinetic sampling nearly prohibit pharmacokinetic studies in preterm infants., Methods: Because remifentanil is rapidly metabolized by nonspecific blood esterases, we collected umbilical cord serum of preterm and term infants to investigate whether the activity of nonspecific blood esterases depends on gestational age. Umbilical cord serum, buffer solution, ascorbic acid, and remifentanil were mixed in a glass vial placed in a shaking water bath at 37°C. Subsequently, serum samples were subjected to liquid chromatography-mass spectrometry-based analysis of remifentanil and its metabolite GR90291 after 0, 30, 60, 100, and 150 min., Results: We analyzed umbilical cord serum samples of 34 preterm infants (24-36 gestational weeks) and six term infants. The degradation rates of remifentanil to its major metabolite GR90291 were comparable in preterm and term infants. The overall median degradation half-life of remifentanil was 143 ± (interquartile range) 47 min (minimum, 76 min; maximum, 221 min) without significant differences between very preterm infants (less than 28 gestational weeks) and term infants. The remifentanil concentration remained stable in control runs without serum., Conclusions: Our study demonstrates that very preterm infants exhibit a high nonspecific esterase activity in umbilical cord blood that is comparable with that of term infants. These results support clinical experiences that remifentanil is rapidly metabolized by preterm infants without prolonged side effects.

Aim: In 2001, we implemented the 'surfactant without intubation' (SWI) method to administer surfactant during spontaneous breathing with nasal continuous positive airway pressure in preterm infants. To determine whether application of the SWI method in infants born at ≤ 27 weeks gestational age influences early school age outcome., Methods: A historical control cohort was compared to an interventional cohort, when the SWI method had become part of primary respiratory support. According to the overall results of psychometric and neurological examinations, children were classified as showing no functional impairment, minor or major impairments., Results: Out of 79 surviving children, 54 (68%, two children not completely classifiable) were assessed at a median age of 6 5/12 years [25 (32%) lost to follow-up]. Thirteen of 31 (42%, interventional cohort) vs. 8 of 21 (38%, control cohort) children had no functional impairment, 16 (52%) vs. 9 (43%) showed minor, and 2 (7%) vs. 4 (19%) major impairments., Conclusion: There was no statistically significant difference regarding neurodevelopmental school age outcome in children treated after implementing the SWI procedure, even though surviving infants had been more immature and survival rates had increased., (© 2010 The Author(s)/Acta Paediatrica © 2010 Foundation Acta Paediatrica.)