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Summary Background The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. Methods PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). Findings Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). Interpretation In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. Funding AOP Orphan Pharmaceuticals AG.

Vancomycin is the first-choice antibiotic for infants with β-lactam-resistant gram-positive bacterial infection. Despite long experience of prescribing of this drug optimal dosing is still challenging. This study aimed at investigating variables predicting vancomycin clearance in order to propose optimal maintenance dosing in infants treated for suspected or culture-proven sepsis.Vancomycin pharmacokinetics was calculated in a one-compartmental model based on serum concentrations. A linear regression model was used to explore relationships between vancomycin clearance and expected covariates.Twenty-two patients were enrolled into the study. Median (IQR) postnatal age was 157 (112-238) days. The median (IQR) volume of distribution and clearance for vancomycin were 0.50 (0.39-0.94) L/kg and 0.112 (0.095-0.133) L/h/kg, respectively. Vancomycin clearance was associated with actual body weight, height, body surface area, gestational age, postnatal age, postmenstrual age and estimate glomerular filtration rate. Actual body weight was the best predictive variable for vancomycin clearance. Daily maintenance dose (mg) calculated as 76.28 × actual body weight (kg) - 41.57 most closely approximated optimal dosing based on individual pharmacokinetics. This relationship was used to construct a dosing nomogram.We developed an easy-to-use dosing nomogram for maintaining a vancomycin average steady-state concentration of 22.5 mg/L based on actual body weight.

The aim of this study was to investigate longitudinal changes of the pulmonary inflammatory process as a result of mechanical stress due to mechanical ventilation. The concentrations of IL-8, TNF-α, MIP-1β, nitrites/nitrates, and inducible nitric oxide synthases (iNOS) were investigated indicate in bronchoalveolar lavage (BAL). Twenty-three piglets were divided into three groups. Group I: animals breathing spontaneously; group II: mechanical ventilation (tidal volume (TV) = 7 mL/kg, PEEP = 5 cmH(2)O); group III: mechanical ventilation (TV = 15 mL/kg, PEEP = 0 cmH(2)0). Concentrations of BAL nitrites/nitrates from groups II and III increased during the first hour of mechanical ventilation (P = .03 and .02, respectively). The highest expression of iNOS was observed during the first hour in groups II and III. IL-8 concentration increased significantly in groups II and III. Production of TNF-α increased significantly in group III during the second and third hour (P = .01). Concentration of MIP-1β was significantly increased in groups II and III after the first hour (P = .012 and P = .008, respectively).

A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for enantiomeric determination of tramadol and its primary phase metabolite O-desmethyltramadol in human plasma has been developed. Tramadol hydrochloride-(13)C, d(3), was used as an isotopic labeled internal standard for quantification. The method involves a simple solid phase extraction. The analytes and internal standard were separated on Lux Cellulose-2 packed with cellulose tris(3-chloro-4-methylphenylcarbamate) using isocratic elution with hexane/isopropanol/diethylamine (90:10:0.1, v/v/v) at a flow rate of 1.3 mL/min. The APCI positive ionization mass spectrometry was used with multiple reaction monitoring of the transitions at m/z 264.2-->58.2 for tramadol, m/z 250.1-->58.2 for O-desmethyltramadol and m/z 268.2-->58.2 for internal standard. Linearity was achieved between 1-800 ng/mL and 1-400 ng/mL (R(2) > or = 0.999) for each enantiomer of tramadol and O-desmethyltramadol, respectively. Intra-day accuracies ranged among 98.2-102.8%, 97.1-109.1% and 97.4-102.9% at the lower, intermediate, and high concentration for all analytes, respectively. Inter-day accuracies ranged among 95.5-104.1%, 99.2-104.7%, and 94.2-105.6% at the lower, intermediate, and high concentration for all analytes, respectively. This assay was successfully used to determine the concentration of enantiomers of tramadol and O-desmethyltramadol in a pharmacogenetic study.

The authors examined two groups of children treated during neonatal period with high doses of Gentamycin. The reasons for Gentamycin treatment at the intensive care unit were infection of the CNS, pneumopaties, intracranial haemorrhagiae, cerebral oedema and other causes. The first group of children was treated in 1981, the second one in 1986. Both groups were examined in 1987. All children were evaluated to objective hearing tests, impedance audiometry by acoustically evoked potentials of the brain stem. Children of the first group examined during their fifth or sixth year were also submitted to a hearing test. The control group was formed by children born in 1986 treated at the intensive care unit with similar indications but who were not given Gentamycin. A total of 51 children were examined. Twenty-two children examined at the age of five had no hearing impairment. Acoustically evoked potentials of the brain stem have a wide variability which may be the manifestation of the disease which led to admission to the intensive care unit. Therefore it should be conceived as a screening examination and the revealed pathological findings should be verified by repeated examinations. Possible hearing disorders should be confirmed at a later age by conventional examinations.