Comparison between a high-resolution single-stage Orbitrap and a triple quadrupole mass spectrometer for quantitative analyses of drugs.

The capabilities of a high-resolution (HR), accurate mass spectrometer (Exactive-MS) operating in full scan MS mode was investigated for the quantitative LC/MS analysis of drugs in patients' plasma samples. A mass resolution of 50,000 (FWHM) at m/z 200 and a mass extracted window of 5 ppm around the theoretical m/z of each analyte were used to construct chromatograms for quantitation. The quantitative performance of the Exactive-MS was compared with that of a triple quadrupole mass spectrometer (TQ-MS), TSQ Quantum Discovery or Quantum Ultra, operating in the conventional selected reaction monitoring (SRM) mode. The study consisted of 17 therapeutic drugs including 8 antifungal agents (anidulafungin, caspofungin, fluconazole, itraconazole, hydroxyitraconazole posaconazole, voriconazole and voriconazole-N-oxide), 4 immunosuppressants (ciclosporine, everolimus, sirolimus and tacrolimus) and 5 protein kinase inhibitors (dasatinib, imatinib, nilotinib, sorafenib and sunitinib). The quantitative results obtained with HR-MS acquisition show comparable detection specificity, assay precision, accuracy, linearity and sensitivity to SRM acquisition. Importantly, HR-MS offers several benefits over TQ-MS technology: absence of SRM optimization, time saving when changing the analysis from one MS to another, more complete information of what is in the samples and easier troubleshooting. Our work demonstrates that U/HPLC coupled to Exactive HR-MS delivers comparable results to TQ-MS in routine quantitative drug analyses. Considering the advantages of HR-MS, these results suggest that, in the near future, there should be a shift in how routine quantitative analyses of small molecules, particularly for therapeutic drugs, are performed.

Population pharmacokinetics in chronic myeloid leukaemia patients: observations under field-conditions

Introduction: Therapeutic drug monitoring (TDM) of imatinib has been increasingly proposed for chronic myeloid leukaemia (CML) patients, as several studies have found a correlation between trough concentrations (Cmin) >=1000ng/ml and improved response. The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to increase the availability of imatinib TDM, standardize labs, and validate proposed Cmin thresholds. Using the collected data, the objective of this analysis was to characterize imatinib Population pharmacokinetics (Pop-PK) in a large cohort of European patients, to quantify its variability and the influence of demographic factors and comedications, and to derive individual exposure variables suitable for further concentration-effect analyses.¦Methods: 4095 PK samples from 2478 adult patients were analyzed between 2006 and 2010 by LC-MS-MS and considered for Pop-PK analysis by NONMEM®. Model building used data from 973 patients with >=2 samples available (2590 samples). A sensitivity analysis was performed using all data. Available comedications (27%) were classified into inducers or inhibitors of P-glycoprotein, CYP3A4/5 and organic-cation-transporter-1 (hOCT-1).¦Results: A one-compartment model with linear elimination, zero-order absorption fitted the data best. Estimated Pop-PK parameters (interindividual variability, IIV %CV) for a 40-year old male patient were: clearance CL = 17.3 L/h (37.7%), volume V = 429L (51.1%), duration of absorption D1 = 3.2h. Outliers, reflecting potential compliance and time recording errors, were taken into account by estimating an IIV on the residual error (35.4%). Intra-individual residuals were 29.1% (proportional) plus ± 84.6 ng/mL (additive). Female patients had a 15.2% lower CL (14.6 L/h). A piece-wise linear effect of age estimated a CL of 18.7 L/h at 20 years, 17.3 L/h at 40 and 13.8 L/h at 60 years. These covariates explained 2% (CL) and 4.5% (V) of IIV variability. No effect of comedication was found. The sensitivity analysis expectedly estimated increased IIV, but similar fixed effect parameters.¦Conclusion: Imatinib PK was well described in a large cohort of CML patients under field conditions and results were concordant with previous studies. Patient characteristics explain only little IIV, confirming limited utility of prior dosage adjustment. As intra-variability is smaller than inter-patient variability, dose adjustment guided by TDM could however be beneficial in order to bring Cmin into a given therapeutic target.

Multivariate analyses of genotype x environment interaction of popcorn

The objectives of this work were to evaluate the genotype x environment (GxE) interaction for popcorn and to compare two multivariate analyses methods. Nine popcorn cultivars were sown on four dates one month apart during each of the agricultural years 1998/1999 and 1999/2000. The experiments were carried out using randomized block designs, with four replicates. The cv. Zélia contributed the least to the GxE interaction. The cv. Viçosa performed similarly to cv. Rosa-claro. Optimization of GxE was obtained for cv. CMS 42 for a favorable mega-environment, and for cv. CMS 43 for an unfavorable environment. Multivariate analysis supported the results from the method of Eberhart & Russell. The graphic analysis of the Additive Main effects and Multiplicative Interaction (AMMI) model was simple, allowing conclusions to be made about stability, genotypic performance, genetic divergence between cultivars, and the environments that optimize cultivar performance. The graphic analysis of the Genotype main effects and Genotype x Environment interaction (GGE) method added to AMMI information on environmental stratification, defining mega-environments and the cultivars that optimized performance in those mega-environments. Both methods are adequate to explain the genotype x environment interactions.

Longitudinal analyses of renal lesions due to acute pyelonephritis in children and their impact on renal growth.

PURPOSE: Acute pyelonephritis is a common condition in children, and can lead to renal scarring. The aim of this study was to analyze the progression of renal scarring with time and its impact on renal growth. MATERIALS AND METHODS: A total of 50 children who had renal scarring on dimercapto-succinic acid scan 6 months after acute pyelonephritis underwent a repeat scan 3 years later. Lesion changes were evaluated by 3 blinded observers, and were classified as no change, partial resolution or complete disappearance. Renal size at time of acute pyelonephritis and after 3 years was obtained by ultrasound, and renal growth was assessed comparing z-score for age between the 2 measures. Robust linear regression was used to identify determinants of renal growth. RESULTS: At 6 months after acute pyelonephritis 88 scars were observed in 100 renal units. No change was observed in 27%, partial resolution in 63% and complete disappearance in 9% of lesions. Overall, 72% of lesions improved. Increased number of scars was associated with high grade vesicoureteral reflux (p = 0.02). Multivariate analysis showed that the number of scars was the most important parameter leading to decreased renal growth (CI -1.05 to -0.35, p <0.001), and with 3 or more scars this finding was highly significant on univariate analysis (-1.59, CI -2.10 to -1.09, p <0.0001). CONCLUSIONS: Even 6 months after acute pyelonephritis 72% of dimercapto-succinic acid defects improved, demonstrating that some of the lesions may be not definitive. The number of scars was significantly associated with loss of renal growth at 3 years.

2015 Iowa Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the State Hygienic Laboratory (SHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. From 1983 to 2014, this monitoring effort was known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Beginning in 2015, the only statewide fish contaminant-monitoring program in Iowa was changed to the Iowa Fish Tissue Monitoring Program (IFTMP). The IFTMP is administered by IDNR and the tissue analyses are completed at the SHL. Historically, the data generated from the IFTMP have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The IFTMP incorporates five different types of monitoring sites: 1) status, 2) follow-up, 3) trend, 4) turtle, and 5) random.

2014 Iowa Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the State Hygienic Laboratory (SHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. From 1983 to 2014, this monitoring effort was known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Beginning in 2015, the only statewide fish contaminant-monitoring program in Iowa was changed to the Iowa Fish Tissue Monitoring Program (IFTMP). The IFTMP is administered by IDNR and the analyses are completed at the SHL. Historically, the data generated from the IFTMP have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The IFTMP incorporates five different types of monitoring sites: 1) status, 2) follow-up, 3) trend, 4) turtle, and 5) random.

2013 Iowa Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the State Hygienic Laboratory (SHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The Iowa RAFT monitoring program incorporates five different types of monitoring sites: 1) status, 2) follow-up, 3) trend, 4) turtle, and 5) random.

2012 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the State Hygienic Laboratory (SHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The Iowa RAFT monitoring program incorporates five different types of monitoring sites: 1) status, 2) follow-up, 3) trend, 4) turtle, and 5) random.

2011 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the State Hygienic Laboratory (SHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The Iowa RAFT monitoring program incorporates five different types of monitoring sites: 1) status, 2) trend, 3) follow-up, 4) turtle, and 5) random.

2010 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the State Hygienic Laboratory (SHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The Iowa RAFT monitoring program incorporates five different types of monitoring sites: 1) status, 2) trend, 3) random, 4) follow-up and 5) turtle.

2009 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the University of Iowa Hygienic Laboratory (UHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The Iowa RAFT monitoring program incorporates four different types of monitoring sites: 1) status, 2) trend, 3) random and 4) follow-up. New for 2009 was the one-time inclusion of snapping turtle tissue as part of the Iowa RAFT sampling program.

2008 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the University of Iowa Hygienic Laboratory (UHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006). The Iowa RAFT monitoring program incorporates four different types of monitoring sites: 1) status, 2) trend, 3) random and 4) follow-up.

2006/2007 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the University of Iowa Hygienic Laboratory (UHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (RAFT). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans (see IDNR 2006a). The Iowa RAFT monitoring program incorporates four different types of monitoring sites: 1) status, 2) trend, 3) random and 4) follow-up.

2005 Regional Ambient Fish Tissue Monitoring Program Summary of Analyses

To supplement other environmental monitoring programs and to protect the health of people consuming fish from waters within this state, the state of Iowa conducts fish tissue monitoring. Since 1980, the Iowa Department of Natural Resources (IDNR), the United States Environmental Protection Agency Region VII (U.S. EPA), and the University of Iowa Hygienic Laboratory (UHL) have cooperatively conducted annual statewide collections and analyses of fish for toxic contaminants. Beginning in 1983, this monitoring effort became known as the Regional Ambient Fish Tissue Monitoring Program (the RAFT program). Currently, the RAFT program is the only statewide fish contaminant-monitoring program in Iowa. Historically, the data generated from the RAFT program have enabled IDNR to document temporal changes in contaminant levels and to identify Iowa lakes and rivers where high levels of contaminants in fish potentially threaten the health of fish-consuming Iowans. The Iowa RAFT monitoring program incorporates three different types of monitoring sites: 1) status, 2) trend, and 3) follow-up.