Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial

Conclusions: HX575 and the comparator epoetin alfa were bioequivalent with respect to their PK/PD, supporting the conclusion that both, when administered subcutaneously, will be equally efficacious and may be interchangeable as therapy. Copyright © 2008 S. Karger AG, Base

Phenotyping of N -acetyltransferase type 2 and xanthine oxidase with caffeine: when should urine samples be collected?

Objectives: Individual activities of N-acetyltransferase 2 (NAT2) and of xanthine oxidase (XO) can be assessed using ratios of urinary caffeine metabolites. We investigated how ratios changed over time and which urine collection interval would be the best for NAT2 and XO activity assessments. Methods: On two occasions separated by 14days, 16 healthy male Caucasians collected urine before and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16 and 16-24h after a dose of 150mg caffeine given in the framework of a phenotyping cocktail study. The metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U) were quantified with LC-MS/MS. The molar ratio (AFMU + AAMU)/(1X + 1U + AFMU + AAMU) was used as a NAT2 metric, while the ratio 1U/(1X + 1U) served as XO metric. Results: The NAT2 ratios were stable in the intervals 4-24h after caffeine dosing. Mean intra-individual coefficients of variation were 11-23% starting 4h post-dose, while inter-individual variability reached 37-75%. The XO ratios increased gradually by 14% from the 2-4 to the 16-24h interval. The mean intra- and inter-individual coefficients of variation of XO activity were 3-18 and 7-10% respectively. No significant differences between study occasions were observed. Conclusions: Any sampling interval at least 4h after caffeine dosing is suitable for NAT2 and XO activity assessments. XO activities can only be compared between volunteers and studies if the same urine collection schedule has been respected. The low intraindividual variability allows for sample sizes of 16 and 6 participants in crossover interaction studies of NAT2 and XO activity respectivel

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not kn

In Vitro Recovery of Sufentanil, Midazolam, Propofol, and Methylprednisolone in Pediatric Cardiopulmonary Bypass Systems

Objectives: To evaluate in vitro drug recovery in cardiopulmonary bypass (CPB) systems used for pediatric cardiac surgery. Design: Observational in vitro study. Setting: Single-center university hospital. Participants: In vitro CPB systems used for pediatric cardiac surgery. Interventions: Three full neonatal, infant, and pediatric CPB systems were primed according to hospital protocol and kept running for 6 hours. Midazolam, propofol, sufentanil, and methylprednisolone were added to the venous side of the systems in doses commonly used for induction of general anesthesia. Blood samples were taken from the postoxygenator side of the circuit immediately after injection of the drugs and after 2, 5, 7, 10, 30, 60, 180, and 300 minutes. Measurements and Main Results: Linear mixed model analyses were performed to assess the relationship between log-transformed drug concentration (dependent variable) and type of CPB system and sample time point (independent variables). The mean percentage of drug recovery after 60 and 180 minutes compared with T1 was 41.7% (95% confidence interval [CI] 35.9-47.4) and 23.0% (95% CI 9.2-36.8) for sufentanil, 87.3% (95% CI 64.9-109.7) and 82.0% (95% CI 64.6-99.4) for midazolam, 41.3% (95% CI 15.5-67.2) and 25.0% (95% CI 4.7-45.3) for propofol, and 119.3% (95% CI 101.89-136.78) and 162.0% (95% CI 114.09-209.91) for methylprednisolone, respectively. Conclusions: The present in vitro experiment with neonatal, infant, and pediatric CPB systems shows a variable recovery of routinely used drugs with significant differences between drugs, but not between system categories (with the exception of propofol). The decreased recovery of mainly sufentanil and propofol could lead to suboptimal dosing of patients during cardiac surgery with CPB

4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here, we show that the inhibition of HA-synthesis by 4-MU or genetic deletion of Has2/Has3 improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved prescription-free drug, could be repurposed to treat obesity and diabetes

Caffeine, Paraxanthine, Theophylline, and Theobromine Content in Human Milk

This study aimed to assess the content of caffeine and its metabolites—paraxanthine, theophylline, and theobromine—in breast milk according to selected factors. Samples of human milk were collected from 100 women living in the east–northeast region of Poland. Information on the consumption of beverages and foods containing caffeine was collected using a 3 day food record. The determination of caffeine and its metabolite content was performed using liquid chromatography–mass spectrometry (LC–MS/MS). This study research showed that more caffeine was found in the milk of women living in cities, with secondary education, aged 34–43, and also in milk from the 3rd and 4th lactation periods (p ≤ 0.05). Factors such as place of residence, level of education, age, and stage of lactation influenced the nutritional choices of breastfeeding women, which had an impact on the level of caffeine and its metabolites in breast milk. A positive correlation was found between the consumption of caffeine with food and drinks and its level in human milk

Quantification of adefovir and pitavastatin in human plasma and urine by LC-MS/MS: A useful tool for drug-drug interaction studies

As a tool to be used in transporter-mediated drug-drug interaction studies, a sensitive LC-MS/MS method for the simultaneous quantification of adefovir and pitavastatin in human plasma and adefovir in urine was developed and successfully validated. Plasma samples were processed by protein precipitation using methanol with a subsequent concentrating step. Urine samples were diluted using 0.1% formic acid. Separation was achieved on a Synergy Polar-RP reversed phase column (50 x 4.6 mm, 2.5 mu m) in gradient elution using a mobile phase composed of water and 0.1% formic acid and a mixture of methanol and acetonitrile (50:50, v/v) containing 0.1% formic acid at a flow rate of 1.0 mL/min. The linear range covered concentrations from 0.273 to 52.6 ng/mL for adefovir and from 0.539 to 104.2 ng/mL for pitavastatin in human plasma, respectively. The calibration curve for adefovir in urine ranged from 0.104 to 10.0 mu g/mL. The weighted linear regression (1/conc(2)) implied excellent linearity with correlation coefficients >= 0.999

A HILIC-MS/MS assay for the quantification of metformin and sitagliptin in human plasma and urine: A tool for studying drug transporter perturbation

This article describes the development and validation of a HILIC-MS/MS method for the simultaneous quantification of metformin and sitagliptin from human plasma and urine. The presented method uses quick sample preparation and fast chromatography allowing for high sample throughput. The quantification is performed using multi-reaction monitoring and ESI positive mode with stable isotope labelled internal standards for both metformin and sitagliptin. Excellent linearity in the selected calibrations ranges, low inter-day variability (CV% <6.7%), and high accuracy (95.5-104.1%) were obtained. Adequate retention was attained for both analytes by hydrophilic interaction liquid chromatography using a plain silica column in combination with a mobile phase composed of ammonium formate, acetonitrile, formic acid and water in gradient separation mode. (C) 2019 Elsevier B.V. All rights reserved