(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in ...animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of (14)Cdapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.
While systematic reviews (SRs) are often perceived as a "gold standard" for evidence synthesis in environmental health and toxicology, the methodological rigour with which they are currently being ...conducted is unclear. The objectives of this study are (1) to provide up-to-date information about the methodological rigour of environmental health SRs and (2) to test hypotheses that reference to a pre-published protocol, use of a reporting checklist, or being published in a journal with a higher impact factor, are associated with increased methodological rigour of a SR. A purposive sample of 75 contemporary SRs were assessed for how many of 11 recommended SR practices they implemented. Information including search strategies, study appraisal tools, and certainty assessment methods was extracted to contextualise the results. The included SRs implemented a median average of 6 out of 11 recommended practices. Use of a framework for assessing certainty in the evidence of a SR, reference to a pre-published protocol, and characterisation of research objectives as a complete Population-Exposure-Comparator-Outcome statement were the least common recommended practices. Reviews that referenced a pre-published protocol scored a mean average of 7.77 out of 10 against 5.39 for those that did not. Neither use of a reporting checklist nor journal impact factor was significantly associated with increased methodological rigour of a SR. Our study shows that environmental health SRs omit a range of methodological components that are important for rigour. Improving this situation will require more complex, comprehensive interventions than simple use of reporting standards.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary ...goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5′ upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.
The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We ...performed a meta‐analysis on data from 4,973 tamoxifen‐treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow‐up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
Clinical Pharmacology & Therapeutics (2014); 95 2, 216–227. doi:10.1038/clpt.2013.186
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aims: To investigate whether glucose lowering with the selective sodium glucose transporter 2 (SGLT2) inhibitor dapagliflozin would prevent or reduce the decline of pancreatic function and disruption ...of normal islet morphology. Methods: Female Zucker diabetic fatty (ZDF) rats, 7-8 weeks old, were placed on high-fat diet. Dapagliflozin (1 mg/kg/day, p.o.) was administered for ~33 days either from initiation of high-fat diet or when rats were moderately hyperglycaemic. Insulin sensitivity and pancreatic function were evaluated using a hyperglycaemic clamp in anaesthetized animals (n = 5-6); β-cell function was quantified using the disposition index (DI) to account for insulin resistance compensation. Pancreata from a matched subgroup (n = 7-8) were fixed and β-cell mass and islet morphology investigated using immunohistochemical methods. Results: Dapagliflozin, administered from initiation of high-fat feeding, reduced the development of hyperglycaemia; after 24 days, blood glucose was 8.6 ± 0.5 vs. 13.3 ± 1.3 mmol/l (p < 0.005 vs. vehicle) and glycated haemoglobin 3.6 ± 0.1 vs. 4.8 ± 0.26% (p < 0.003 vs. vehicle). Dapagliflozin improved insulin sensitivity index: 0.08 ± 0.01 vs. 0.02 ± 0.01 in obese controls (p < 0.03). DI was improved to the level of lean control rats (dapagliflozin 0.29 ± 0.04; obese control 0.15 ± 0.01; lean 0.28 ± 0.01). In dapagliflozin-treated rats, β-cell mass was less variable and significant improvement in islet morphology was observed compared to vehicle-treated rats, although there was no change in mean β-cell mass with dapagliflozin. Results were similar when dapagliflozin treatment was initiated when animals were already moderately hyperglycaemic. Conclusion: Sustained glucose lowering with dapagliflozin in this model of type 2 diabetes prevented the continued decline in functional adaptation of pancreatic β-cells.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Reunion Island (21° S, 55° E), situated in the Indian Ocean at about 800 km east of Madagascar, is appropriately located to monitor the outflow of biomass burning pollution from Southern Africa and ...Madagascar, in the case of short-lived compounds, and from other Southern Hemispheric landmasses such as South America, in the case of longer-lived species. Ground-based Fourier transform infrared (FTIR) solar absorption observations are sensitive to a large number of biomass burning products. We present in this work the FTIR retrieval strategies, suitable for very humid sites such as Reunion Island, for hydrogen cyanide (HCN), ethane (C2H6), acetylene (C2H2), methanol (CH3OH), and formic acid (HCOOH). We provide their total columns time-series obtained from the measurements during August–October 2004, May–October 2007, and May 2009–December 2010. We show that biomass burning explains a large part of the observed seasonal and interannual variability of the chemical species. The correlations between the daily mean total columns of each of the species and those of CO, also measured with our FTIR spectrometer at Reunion Island, are very good from August to November (R 0.86). This allows us to derive, for that period, the following enhancement ratios with respect to CO: 0.0047, 0.0078, 0.0020, 0.012, and 0.0046 for HCN, C2H6, C2H2, CH3OH, and HCOOH, respectively. The HCN ground-based data are compared to the chemical transport model GEOS-Chem, while the data for the other species are compared to the IMAGESv2 model. We show that using the HCN/CO ratio derived from our measurements (0.0047) in GEOS-Chem reduces the underestimation of the modeled HCN columns compared with the FTIR measurements. The comparisons between IMAGESv2 and the long-lived species C2H6 and C2H2 indicate that the biomass burning emissions used in the model (from the GFED3 inventory) are probably underestimated in the late September–October period for all years of measurements, and especially in 2004. The comparisons with the short-lived species, CH3OH and HCOOH, with lifetimes of around 5 days, suggest that the emission underestimation in late September–October 2004, occurs more specifically in the Southeastern Africa-Madagascar region. The very good correlation of CH3OH and HCOOH with CO suggests that, despite the dominance of the biogenic source of these compounds on the global scale, biomass burning is their major source at Reunion Island between August and November.
The selective inhibition of sodium‐glucose cotransporter 2 (SGLT2) has recently become a focus of potential type 2 diabetes mellitus (T2DM) therapeutics. This review describes the mechanism of ...SGLT2‐induced urinary glucose excretion (UGE) and its effects on parameters of glycemic control in animal models, healthy humans, and patients with T2DM. Key questions on various aspects of the development of SGLT2 inhibitors are discussed, as well as insights regarding this field.
Clinical Pharmacology & Therapeutics (2011) 89 4, 621–625. doi:10.1038/clpt.2011.16
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Main text
The CCQM-K154.b comparison was coordinated by the Bureau International des Poids et Mesures (BIPM) and the Chinese National Institute of Metrology (NIM) on behalf of the Organic Analysis ...Working Group (OAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) for National Measurement Institutes (NMIs) and Designated Institutes (DIs) which provide measurement services in organic analysis under the 'Comité International des Poids et Mesures' Mutual Recognition Arrangement (CIPM MRA) and/or have participated in the BIPM's Mycotoxin Metrology Capacity Building and Knowledge Transfer (MMCBKT) project as part of its "Metrology for Safe Food and Feed in Developing Economies" Capacity Building Programme.
Gravimetrically-prepared solutions having an assigned mass fraction of specified organic analytes are routinely used to calibrate measurement processes for the quantification of the same analytes in matrix samples. Appropriate assignments of the property value and associated uncertainty of calibration solutions thus underpin the traceability of routine analysis and are critical for accurate measurements. Evidence of successful participation in relevant international comparisons is needed to document calibration and measurement capability claims (CMCs) made by national metrology institutes and designated institutes. In total, eleven NMIs/DIs participated in the Track C, Model II, Key Comparison CCQM-K154.b Gravimetric preparation and value assignment of aflatoxin B1 (AfB1) in acetonitrile (ACN) for emerging areas of global interest and innovation. Participants were requested to gravimetrically prepare calibration solutions and value assign the mass fractions, expressed in mg/kg, of aflatoxin B1 (AfB1) in the acetonitrile (ACN) solution. Study samples, with assigned values and associated uncertainties were prepared by the comparison participants and sent to the coordinating laboratory for comparison. The Key Comparison Reference Values (KCRVs), calculated form values measured by the coordinating laboratory based on calibrations obtained from independent gravimetrically prepared calibrant solutions, agreed with participants reported values, within their stated uncertainties.
AfB1 was selected to be representative of polar aflatoxins. Aflatoxins are a class of mycotoxins generally produced by fungi of the genus Aspergillus. It was anticipated to provide a challenge representative for the gravimetrical preparation and value assignment of calibration solutions in the mass fraction range of 2 mg/kg to 50 mg/kg of mycotoxins with broadly similar structural characteristics.
Nine participants of the MMCBKT programme were provided with a stock solution having a known AfB1 mass fraction and expanded uncertainty to use to gravimetrically prepare and value assign a calibration solution. Three NMIs/DIs also participated using their own calibration solutions. The use of in-house solutions required an additional capacity to undertake a fit-for-purpose purity assessment. NIM was the only NMI participating using both the MMCBKT based and their own in-house assigned solutions in order to connect the two different groups.
It was decided to propose separate KCRVs for each of the two ampoules provided by the participating NMIs/DIs based on the AfB1 mass fraction. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to gravimetrically prepare calibration solutions and to assess the AfB1 mass fraction.
The majority of the AfB1 mass fraction KCRVs (wKCRV) for CCQM-K154.b spanned a mass fraction range of 2.02 mg/kg to 31.57 mg/kg. The relative expanded uncertainties U(wKCRV) ranged from 0.69 % to 2.93 %.
Inspection of the degree of equivalence plots for the AfB1 mass fraction assignments in CCQM-K154.b indicated that there was an excellent agreement of results. Solely, the AfB1 mass fraction assignments of INRAP did not agree with the KCRVs. It was found that the samples were altered as a result of an acid contamination.
To reach the main text of this paper, click on
Final Report
. Note that this text is that which appears in Appendix B of the BIPM key comparison database
https://www.bipm.org/kcdb/
.
The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
PharmGKB is a knowledge base that captures the relationships between drugs, diseases/phenotypes and genes involved in pharmacokinetics (PK) and pharmacodynamics (PD). This information includes ...literature annotations, primary data sets, PK and PD pathways, and expert-generated summaries of PK/PD relationships between drugs, diseases/phenotypes and genes. PharmGKB's website is designed to effectively disseminate knowledge to meet the needs of our users. PharmGKB currently has literature annotations documenting the relationship of over 500 drugs, 450 diseases and 600 variant genes. In order to meet the needs of whole genome studies, PharmGKB has added new functionalities, including browsing the variant display by chromosome and cytogenetic locations, allowing the user to view variants not located within a gene. We have developed new infrastructure for handling whole genome data, including increased methods for quality control and tools for comparison across other data sources, such as dbSNP, JSNP and HapMap data. PharmGKB has also added functionality to accept, store, display and query high throughput SNP array data. These changes allow us to capture more structured information on phenotypes for better cataloging and comparison of data. PharmGKB is available at www.pharmgkb.org
Summary
Pressure on financial margins in UK wheat production is driving a review of all inputs, and seed represents one of the largest financial inputs in wheat production. The potential savings ...through exploiting the crop's ability to compensate for reduced population are, therefore, attractive. Field experiments were carried out at ADAS Rosemaund (Herefordshire, UK) in 1996/97, 1997/98 and 1998/99 to investigate the effect of sowing date on dry matter growth and yield responses of winter wheat to reduced plant population. There were three target sowing dates (late‐Septembr, mid‐October and mid‐November), six seed rates (20, 40, 80, 160, 320 and 640 seeds m−2) and four varieties (Cadenza, Haven, Soissons and Spark). Grain yield was significantly affected by plant population with a mean reduction from 9.2 to 5.5 t ha−1 as plant number was reduced from 336 to 13 m−2. In addition, there was a significant interaction between plant density and sowing date. There was, however, no interaction between variety and plant population in terms of yield, except when lodging affected high plant populations of lodging susceptible varieties. The experiments demonstrated scope for reducing plant populations below the current target of 250–300 plants m−2; however, the degree of reduction was dependent on sowing date. Over the three years, the average economic optimum plant density was 62 plants m−2 for late‐September, 93 plants m−2 for mid‐October, and 139 plants m−2 for mid‐November sowings. Compensation for reduced population was due to increased shoot number per plant, increased grain number per ear and to a lesser extent increased grain size. Higher economic optimum plant densities at later sowing dates were due to reduced tiller production and hence ear number per plant. The other compensatory mechanisms were unaffected by sowing date.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
