287 research outputs found

    Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design

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    Penicillins are widely used to treat infections in children, however the evidence is continuing to evolve in defining optimal dosing. Modern paediatric pharmacokinetic study protocols frequently favour opportunistic, “scavenged” sampling. This study aimed to develop a small volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modelling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modelling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 hour remaining in the range of 98-103% of the original concentration. More rapid analyte degradation had already occurred after 4 hours with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 hours. Modelling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modelling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring

    Quantification of Plasma and Urine Thymidine and 2'-Deoxyuridine by LC-MS/MS for the Pharmacodynamic Evaluation of Erythrocyte Encapsulated Thymidine Phosphorylase in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy.

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    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disorder caused by mutations in TYMP, leading to a deficiency in thymidine phosphorylase and a subsequent systemic accumulation of thymidine and 2'-deoxyuridine. Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is under clinical development as an enzyme replacement therapy for MNGIE. Bioanalytical methods were developed according to regulatory guidelines for the quantification of thymidine and 2'-deoxyuridine in plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for supporting the pharmacodynamic evaluation of EE-TP. Samples were deproteinized with 5% perchloric acid (v/v) and the supernatants analyzed using a Hypercarb column (30 × 2.1 mm, 3 µm), with mobile phases of 0.1% formic acid in methanol and 0.1% formic acid in deionized water. Detection was conducted using an ion-spray interface running in positive mode. Isotopically labelled thymidine and 2'-deoxyuridine were used as internal standards. Calibration curves for both metabolites showed linearity (r > 0.99) in the concentration ranges of 10-10,000 ng/mL for plasma, and 1-50 µg/mL for urine, with method analytical performances within the acceptable criteria for quality control samples. The plasma method was successfully applied to the diagnosis of two patients with MNGIE and the quantification of plasma metabolites in three patients treated with EE-TP

    Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of ceftriaxone, metronidazole and hydroxymetronidazole in plasma from seriously ill, severely malnourished children.

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    We have developed and validated a novel, sensitive, selective and reproducible reversed-phase high-performance liquid chromatography method coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) for the simultaneous quantitation of ceftriaxone (CEF), metronidazole (MET) and hydroxymetronidazole (MET-OH) from only 50 µL of human plasma, and unbound CEF from 25 µL plasma ultra-filtrate to evaluate the effect of protein binding. Cefuroxime axetil (CEFU) was used as an internal standard (IS). The analytes were extracted by a protein precipitation procedure with acetonitrile and separated on a reversed-phase Polaris 5 C18-Analytical column using a mobile phase composed of acetonitrile containing 0.1% (v/v) formic acid and 10 mM aqueous ammonium formate pH 2.5, delivered at a flow-rate of 300 µL/min. Multiple reaction monitoring was performed in the positive ion mode using the transitionsm/z555.1→m/z396.0 (CEF),m/z172.2→m/z128.2 (MET),m/z188.0→m/z125.9 (MET-OH) andm/z528.1→m/z364.0 (CEFU) to quantify the drugs. Calibration curves in spiked plasma and ultra-filtrate were linear (r2≥ 0.9948) from 0.4-300 µg/mL for CEF, 0.05-50 µg/mL for MET and 0.02 - 30 µg/mL for MET-OH. The intra- and inter- assay precisions were less than 9% and the mean extraction recoveries were 94.0% (CEF), 98.2% (MET), 99.6% (MET-OH) and 104.6% (CEF in ultra-filtrate); the recoveries for the IS were 93.8% (in plasma) and 97.6% (in ultra-filtrate). The validated method was successfully applied to a pharmacokinetic study of CEF, MET and MET-OH in hospitalized children with complicated severe acute malnutrition following an oral administration of MET and intravenous administration of CEF over the course of 72 hours

    Approximate Minimum-Weight Matching with Outliers Under Translation

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    Our goal is to compare two planar point sets by finding subsets of a given size such that a minimum-weight matching between them has the smallest weight. This can be done by a translation of one set that minimizes the weight of the matching. We give efficient algorithms (a) for finding approximately optimal matchings, when the cost of a matching is the L_p-norm of the tuple of the Euclidean distances between the pairs of matched points, for any p in [1,infty], and (b) for constructing small-size approximate minimization (or matching) diagrams: partitions of the translation space into regions, together with an approximate optimal matching for each region

    Recovering 3D structural properties of galaxies from SDSS-like photometry

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    Because of the 3D nature of galaxies, an algorithm for constructing spatial density distribution models of galaxies on the basis of galaxy images has many advantages over surface density distribution approximations. We present a method for deriving spatial structure and overall parameters of galaxies from images and estimate its accuracy and derived parameter degeneracies on a sample of idealised model galaxies. The test galaxies consist of a disc-like component and a spheroidal component with varying proportions and properties. Both components are assumed to be axially symmetric and coplanar. We simulate these test galaxies as if observed in the SDSS project through ugriz filters, thus gaining a set of realistically imperfect images of galaxies with known intrinsic properties. These artificial SDSS galaxies were thereafter remodelled by approximating the surface brightness distribution with a 2D projection of a bulge+disc spatial distribution model and the restored parameters were compared to the initial ones. Down to the r-band limiting magnitude 18, errors of the restored integral luminosities and colour indices remain within 0.05 mag and errors of the luminosities of individual components within 0.2 mag. Accuracy of the restored bulge-to-disc ratios (B/D) is within 40% in most cases, and becomes worse for galaxies with low B/D, but the general balance between bulges and discs is not shifted systematically. Assuming that the intrinsic disc axial ratio is < 0.3, the inclination angles can be estimated with errors < 5deg for most of the galaxies with B/D < 2 and with errors < 15deg up to B/D = 6. Errors of the recovered sizes of the galactic components are below 10% in most cases. In general, models of disc components are more accurate than models of spheroidal components for geometrical reasons.Comment: 15 pages, 13 figures, accepted for publication in RA

    Pharmacokinetics of penicillin G in preterm and term neonates.

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    Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age 90% for MICs ≤2 mg/L with doses of 25,000 IU/kg/q12h. In neonates, regardless of GA, PK parameters of penicillin G are similar. The dose of 25,000 IU/kg/q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 hours of life

    Simultaneous Determination of Fluoroquinolones and Sulfonamides Originating from Sewage Sludge Compost

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    A simultaneous method for quantitative determination of traces of fluoroquinolones (FQs) and sulfonamides (SAs) in edible plants fertilized with sewage sludge was developed. The compounds were extracted from the plants by rapid and simple liquid extraction followed by extracts clean-up using solid phase extraction. The eluent additive 1,1,1,3,3,3-hexafluoro-2-propanol was used for liquid chromatographic detection to achieve separation of structurally similar antimicrobials like ciprofloxacin and norfloxacin. Identification and quantification of the compounds were performed using high-performance liquid chromatography with electrospray ionization mass spectrometry in selected reaction monitoring mode. Method was validated and extraction recoveries of FQs and SAs ranged from 66% to 93%. The limit of quantifications was from 5 ng/g in the case of ofloxacin to 40 ng/g for norfloxacin. The method precision ranged from 1.43% to 2.61%. The developed novel method was used to evaluate the plats antimicrobial uptake (potato (Solanum tuberosum L.), carrot (Daucus carota L.), lettuce (Lactuca sativa L.), and wheat (Triticum vulgare L.)) from soil and migration of the analytes inside the plants
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