Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.

Use of Data Driven Techniques for Short Lead Time Streamflow Forecasting in Mahanadi basin

Streamflow forecasts at daily time scale are necessary for effective management of water resources systems. Typical applications include flood control, water quality management, water supply to multiple stakeholders, hydropower and irrigation systems. Conventionally physically based conceptual models and data-driven models are used for forecasting streamflows. Conceptual models require detailed understanding of physical processes governing the system being modeled. Major constraints in developing effective conceptual models are sparse hydrometric gauge network and short historical records that limit our understanding of physical processes. On the other hand, data-driven models rely solely on previous hydrological and meteorological data without directly taking into account the underlying physical processes. Among various data driven models Auto Regressive Integrated Moving Average (ARIMA), Artificial Neural Networks (ANNs) are most widely used techniques. The present study assesses performance of ARIMA and ANNs methods in arriving at one-to seven-day ahead forecast of daily streamflows at Basantpur streamgauge site that is situated at upstream of Hirakud Dam in Mahanadi river basin, India. The ANNs considered include Feed-Forward back propagation Neural Network (FFNN) and Radial Basis Neural Network (RBNN). Daily streamflow forecasts at Basantpur site find use in management of water from Hirakud reservoir. (C) 2015 The Authors. Published by Elsevier B.V.

New Keynesian Model Features that Can Reproduce Lead, Lag and Persistence Patterns

This paper uses a new method for describing dynamic comovement and persistence in economic time series which builds on the contemporaneous forecast error method developed in den Haan (2000). This data description method is then used to address issues in New Keynesian model performance in two ways. First, well known data patterns, such as output and inflation leads and lags and inflation persistence, are decomposed into forecast horizon components to give a more complete description of the data patterns. These results show that the well known lead and lag patterns between output and inflation arise mostly in the medium term forecasts horizons. Second, the data summary method is used to investigate a rich New Keynesian model with many modeling features to see which of these features can reproduce lead, lag and persistence patterns seen in the data. Many studies have suggested that a backward looking component in the Phillips curve is needed to match the data, but our simulations show this is not necessary. We show that a simple general equilibrium model with persistent IS curve shocks and persistent supply shocks can reproduce the lead, lag and persistence patterns seen in the data.

Pulse NMR in solids : chemical shift, lead fluoride and thorium hydride

Part one of this thesis consists of two sections. In the first section the fluorine chemical shift of a single crystal CaF_2 has been measured as a function of external pressure up to 4 kilobar at room temperature using multiple pulse NMR techniques. The pressure dependence of the shift is found to be -1.7 ± 1 ppm/kbar, while a theoretical calculation using an overlap model predicts a shift of -0.46 ppm/kbar. In the second section a separation of the chemical shift tensor into physically meaningful "geometrical" and "chemical" contributions is presented and a comparison of the proposed model calculations with recently reported data on hydroxyl proton chemical shift tensors demonstrates, that for this system, the geometrical portion accounts for the qualitative features of the measured tensors.

Part two of the thesis consists of a study of fluoride ion motion in β-PbF_2 doped with NaF by measurement of the ^(19)F transverse relaxation time (T_2), spin lattice relaxation time (T_1) and the spin lattice relaxation time in the rotating frame (T_(1r)). Measurements over the temperature range of -50°C to 160°C lead to activation energies for T_1, T_(1r) and T_2 of 0.205 ± 0.01, 0.29 + 0.02 and 0.27 ± 0.01 ev/ion, and a T_(1r) minimum at 56°C yields a correlation time of 0.74 μsec. Pressure dependence of T_1 and T_2 yields activation volumes of <0.2 cm^3/g-mole and 1.76 ± 0.05 cm^3/g-mole respectively. These data along with the measured magnetic field independence of T_1 suggest that the measured T_1's are not caused by ^(19)F motion, but by thermally excited carriers.

Part three of the thesis consists of a study of two samples of Th_4H_(15), prepared under different conditions but both having the proper ratio of H/Th (to within 1%). The structure of the Th_4H_(15) as suggested by X-ray measurements is confirmed through a moment analysis of the rigid lattice line shape. T_1 and T_2 measurements above 390 K furnish activation energies of 16.3 ± 1.2 kcal/mole and 18.0 ± 3.0 kcal/mole, respectively. Below 350 K, T_(1r) measurements furnish an activation energy of 10.9 ± 0.7 kcal/mole, indicating most probably more than a single mechanism for proton motion. A time-temperature hysteresis effect of the proton motion was found in one of the two samples and is strongly indicative of a phase change. T_1 at room temperature and below is dominated by relaxation due to conduction electrons with the product T_1T being 180 ± 10 K-sec. Using multiple pulse techniques to greatly reduce homonuclear dipolar broadening, a temperature-dependent line shift was observed, and the chemical shift anisotropy is estimated to be less than 16 ppm.

On the arrival time, waiting time to unload, unloading time and waiting time for departure for purse seiners at Mangalore landing centre

Fifty four purse-seine boats at Mangalore landing centre were observed during different stages of unloading fish catch. It was found that a boat takes 75% of the berthing time to unload an average quantity of 2.4 tons of fish. Further, unloading period and catch were found to be directly related where it was estimated that 5 to 7 minutes are spent in unloading about half a ton of fish to a nearby tempo by employing 9 ± 2 laborers.

Development of a time and space resolved sampling probe diagnostic for engine exhaust hydrocarbons

In order to understand how unburned hydrocarbons emerge from SI engines and, in particular, how non-fuel hydrocarbons are formed and oxidized, a new gas sampling technique has been developed. A sampling unit, based on a combination of techniques used in the Fast Flame Ionization Detector (FFID) and wall-mounted sampling valves, was designed and built to capture a sample of exhaust gas during a specific period of the exhaust process and from a specific location within the exhaust port. The sampling unit consists of a transfer tube with one end in the exhaust port and the other connected to a three-way valve that leads, on one side, to a FFID and, on the other, to a vacuum chamber with a high-speed solenoid valve. Exhaust gas, drawn by the pressure drop into the vacuum chamber, impinges on the face of the solenoid valve and flows radially outward. Once per cycle during a specified crank angle interval, the solenoid valve opens and traps exhaust gas in a storage unit, from which gas chromatography (GC) measurements are made. The port end of the transfer tube can be moved to different locations longitudinally or radially, thus allowing spatial resolution and capturing any concentration differences between port walls and the center of the flow stream. Further, the solenoid valve's opening and closing times can be adjusted to allow sampling over a window as small as 0.6 ms during any portion of the cycle, allowing resolution of a crank angle interval as small as 15°CA. Cycle averaged total HC concentration measured by the FFID and that measured by the sampling unit are in good agreement, while the sampling unit goes one step further than the FFID by providing species concentrations. Comparison with previous measurements using wall-mounted sampling valves suggests that this sampling unit is fully capable of providing species concentration information as a function of air/fuel ratio, load, and engine speed at specific crank angles. © Copyright 1996 Society of Automotive Engineers, Inc.

Association of candidate genes with flowering time and water-soluble carbohydrate content in Lolium perenne (L.)

Sk?t, L., Humphreys, J., Humphreys, M. O., Thorogood, D., Gallagher, J. A., Sanderson, R., Armstead, I. P., Thomas, I. D. (2007). Association of candidate genes with flowering time and water-soluble carbohydrate content in Lolium perenne (L.). Genetics, 177 (1), 535-547. Sponsorship: BBSRC RAE2008

A generic time and space accurate numerical approach to closely coupled fluid-structure interaction problems

Fluid structure interaction, as applied to flexible structures, has wide application in diverse areas such as flutter in aircraft, flow in elastic pipes and blood vessels and extrusion of metals through dies. However a comprehensive computational model of these multi-physics phenomena is a considerable challenge. Until recently work in this area focused on one phenomenon and represented the behaviour of the other more simply even to the extent in metal forming, for example, that the deformation of the die is totally ignored. More recently, strategies for solving the full coupling between the fluid and soild mechanics behaviour have developed. Conventionally, the computational modelling of fluid structure interaction is problematical since computational fluid dynamics (CFD) is solved using finite volume (FV) methods and computational structural mechanics (CSM) is based entirely on finite element (FE) methods. In the past the concurrent, but rather disparate, development paths for the finite element and finite volume methods have resulted in numerical software tools for CFD and CSM that are different in almost every respect. Hence, progress is frustrated in modelling the emerging multi-physics problem of fluid structure interaction in a consistent manner. Unless the fluid-structure coupling is either one way, very weak or both, transferring and filtering data from one mesh and solution procedure to another may lead to significant problems in computational convergence. Using a novel three phase technique the full interaction between the fluid and the dynamic structural response are represented. The procedure is demonstrated on some challenging applications in complex three dimensional geometries involving aircraft flutter, metal forming and blood flow in arteries.

A study on the cost sharing model for supply lead time reduction with component commonality

This paper studies a two-level supply chain consisting of components supplier and product assembly manufacturer, while the manufacturer shares the investment on shortening supply lead time. The objective of this research is to investigate the benefits of cost sharing strategy and adopting component commonality. The result of numerical analysis demonstrates that using component commonality can help reduce the total cost, especially when the manufacture shares a higher fraction of the cost of investment in shortening supply lead time.

Variability in thermal and UV-B energy fluxes through time and their influence on plant diversity and speciation

Throughout Earth's history there have been temporal and spatial variations in the amount of visible and ultraviolet radiation received by ecosystems. This paper examines if temporal changes in these forms of energy receipt could have influenced the tempo and mode of plant diversity and speciation, focusing in particular upon Cenozoic time-scales. Evidence for changing patterns of plant diversity and speciation apparent in various fossil records and molecular phylogenies are considered alongside calculated changes in thermal and solar ultraviolet energy (specifically UV-B) over the past 50 Myr. We suggest that changes in thermal energy influx (amount and variability) affected the tempo of evolution through its influence upon community dynamics (e.g. population size, diversity, turnover, extinctions). It was not only the amount of thermal energy but also variability in its flux that may have influenced these processes, and ultimately the rate of diversification. We suggest that variations in UV-B would have influenced the mode and tempo of speciation through changes to genome stability during intervals of elevated UV-B. We argue, therefore, that although variability in thermal energy and UV-B fluxes through time may lead to the same end-point (changing the rate of diversification), the processes responsible are very different and both need to be considered when linking evolutionary processes to energy flux.

Population dynamics of the liver fluke, Fasciola hepatica: the effect of time and spatial separation on the genetic diversity of fluke populations in the Netherlands

An evaluation of the genetic diversity within Fasciola hepatica (liver fluke) may provide an insight into its potential to respond to environmental changes, such as anthelmintic use or climate change. In this study, we determined the mitochondrial DNA haplotypes of >400 flukes from 29 individual cattle, from 2 farms in the Netherlands, as an exemplar of fasciolosis in a European context. Analysis of this dataset has provided us with a measure of the genetic variation within infrapopulations (individual hosts) and the diversity between infrapopulations within a herd of cattle. Temporal sampling from one farm allowed for the measurement of the stability of genetic variation at a single location, whilst the comparison between the two farms provided information on the variation in relation to distance and previous anthelmintic regimes. We showed that the liver fluke population in this region is predominantly linked to 2 distinct clades. Individual infrapopulations contain a leptokurtic distribution of genetically diverse flukes. The haplotypes present on a farm have been shown to change significantly over a relatively short time-period.

Serological markers for coeliac disease:changes with time and relationship to enteropathy

Antigliadin antibodies (AGA) may be present in healthy adults. One previous study has reported that IgA-AGA detected by population screening may become negative after a 6-year follow-up period.

Lead contamination and associated disease in captive and reintroduced red kites Milvus milvus in England

Since 1989, a red kite Milvus milvus reintroduction programme has been underway in the United Kingdom, with 4-6 week old nestlings brought into captivity and held for 6-8 weeks before reintroduction. As scavengers, red kites may consume unretrieved game, and ingest shot or lead (Pb) fragments in their prey's flesh. We evaluated exposure to Pb in captive and wild red kites by taking blood samples from 125 captive young red kites prior to release, through analysing 264 pellets (regurgitated by wild birds) collected from under a roost site, and analysing Pb concentrations in livers and/or bones of 87 red kites found dead between 1995 and 2003. Lead isotope analyses of livers were also conducted in an effort to identify Pb exposure routes. Forty-six (36.8%) kites sampled prior to release had elevated blood Pb concentrations (201-3340 microg l(-1)). The source of this Pb was probably small fragments of lead ammunition in the carcasses of birds or mammals either fed to the nestlings by their parents or, more likely, subsequently whilst in captivity. Once released, kites were also exposed to lead shot in their food, and a minimum of 1.5-2.3% of regurgitated pellets contained Pb gunshot. Seven of 44 red kites found dead or that were captured sick and died within a few days had elevated (>6 mg kg(-1) dry weight [d.w.]) liver Pb concentrations, and six of these (14%) had concentrations of >15 mg kg(-1) d.w., compatible with fatal Pb poisoning. Post-mortem analyses indicated that two of these birds had died of other causes (poisoning by rodenticide and a banned agricultural pesticide); the remaining four (9%) probably died of Pb poisoning. Bone samples from 86 red kites showed a skewed distribution of Pb concentration, and 18 samples (21%) had Pb concentrations >20 mg kg(-1) d.w., indicating elevated exposure to Pb at some stage in the birds' life. Lead isotopic signatures (Pb (208/206); Pb (206/207)) in liver samples of the majority of kites were compatible with those found in lead shot extracted from regurgitated pellets. Lead isotope ratios found in the livers of kites with very low Pb concentrations were distinct from UK petrol Pb isotopic signatures, indicating that birds were exposed to little residual petrol Pb. We conclude that the primary source of Pb to which red kites are exposed is lead ammunition (shotgun pellets or rifle bullets), or fragments thereof, in their food sources; in some cases exposure appears sufficient to be fatal. We make recommendations to reduce Pb poisoning in both captive and wild red kites and other scavenging species.

Lead isotopes and lead shot ingestion in the globally threatened marbled teal (Marmaronetta angustirostris) and white-headed duck (Oxyura leucocephala)

Lead isotope ratios ((206)Pb/(207)Pb and (208)Pb/(207)Pb) and concentrations in the livers and bones of marbled teal and white-headed duck found dead or moribund were determined in order to establish the main lead source in these waterfowl species. Lead concentrations in bone (dry weight) and liver (wet weight) were found to be very high in many of the white-headed ducks (bone: geometric mean=88.9 ppm, maximum=419 ppm; liver: geometric mean=16.8 ppm, maximum=57.0 ppm). Some of the marbled teal had high lead levels in the bones but liver lead levels were all low (bone: geometric mean=6.13 ppm, maximum=112 ppm; liver: geometric mean=0.581 ppm, maximum=4.77 ppm). Ingested lead shot were found in 71% of the white-headed duck and 20% of the marbled teal. The (206)Pb/(207)Pb ratio in livers and bones of white-headed ducks and marbled teals showed no significant differences compared to the ratios obtained from lead shot. The (206)Pb/(207)Pb ratio in bones of marbled teal ducklings with the highest lead concentrations tended to resemble the ratios of lead shot, which supports our hypothesis that the lead was derived from the hens. We also found that the lead ratios of lead shot and lead ratios described for soils in the area overlapped, but also that the isotopic ratio (206)Pb/(207)Pb in lead shot used in Spain has a narrow range compared with those used in North America. The principal source of lead in many of these birds was, however, most likely lead shot, as supported by the similar isotopic ratios, high lead concentrations in tissues and evidence of ingested shot.