Anticlockwise Hysteresis Loops Research Articles

An integrated strategy to evaluate active substances of Astragali Radix-Carthami Flos combination on the treatment of cerebral ischemia reperfusion injury based on TQSM polypharmacokinetics and pharmacodynamics.

As a classic herb pair, Astragali Radix-Carthami Flos (AR-CF) has revealed good biological activity in the treatment of cerebral ischemia/reperfusion injury (CI/RI), which remained to be further clarified together with the underlying efficacy related compounds for material basis. In this study, the nine formulations were obtained by L9 (34) orthogonal array design of four active fractions (saponin and flavonoid extracted from AR, safflower yellow and safflower red extracted from CF). The concentrations of eleven components and the levels of four biochemical indicators in rat plasma were continuously detected after intragastric administration of nine formulations, respectively. The collected data were analyzed by sigmoid-Emax function to understand the polypharmacokinetics and pharmacodynamics (PK-PD) behaviors of multi-components. Using the total quantum statistic moment polypharmacokinetics and its similarity method, the importance of four active fractions from AR-CF in relieving CI/RI was discussed and the Q-markers were screened. The results represented that a reliable and robust liquid chromatography tandem mass spectrometry method been successfully established to simultaneously determine the concentrations of eleven components in rat plasma. The AUC and MRT values of components from flavonoid fraction had the greatest contribution to AUCT and MRTT values. The transitivity in vivo of calycosin-7-O-β-Dglucoside (CG), astragaloside IV (AIV) and hydroxysafflor yellow A (HYA) was closer to polypharmacokinetics behavior. All formulations up/down-regulated the levels of GSH-Px and ATP/ET and LDH to varying degrees, among which formulation 7 had the best regulating effect. By drawing the time-concentration-effect curve, clockwise hysteresis loops were presented in the time-concentration-effect relationships between eleven components and LDH/ET, while the relationship between eleven components and ATP/GSH-Px expressed as anticlockwise hysteresis loops. In conclusion, the combination based on the combination principle of formulation 7 produced the best alleviation effect on CI/RI, and flavonoid fraction might played key role in this process. The CG, AIV and HYA were identified as Q-markers. This research offered a novel strategy for exploring the active substances, and provided further understanding regarding the development of drugs for the treatment of cerebral ischemia-reperfusion injury.

Source availability and hydrological connectivity determined nitrate-discharge relationships during rainfall events in karst catchment as revealed by high-frequency nitrate sensing

Karst terrain seasonal monsoonal rainfall is often associated with high concentrations of nitrate-N in streams draining agricultural land. Such high concentrations can pose problems for environmental and human health. However, the relationship between rainfall events that mobilize nitrate and resulting nitrate export remains poorly understood in karst terrain. To better understand the processes that drive nitrate dynamics during rainfall events, the characteristics of individual rainfall events were analyzed using sensor technology. Thirty-eight rainfall events were separated from the high-frequency dataset spanning 19 months at a karst spring site. The results revealed that nitrate-discharge (N-Q) hysteresis in 79% of rainfall events showed anticlockwise hysteresis loop patterns, indicating nitrate export from long distances within short event periods. Karstic hydrological connectivity and source availability were considered two major determining factors of N-Q hysteresis. Gradual increase in hydrological connectivity during intensive rainfall period accelerated nitrate transportation by karst aquifer systems. Four principal components (PCs, including antecedent conditions PC1&3 and rainfall characteristics PC2&4 explained 82% of the cumulative variance contribution to the rainfall events. Multiple linear regression of four PCs explained more than 50% of the variation of nitrate loading and amplitude during rainfall events, but poorly described nitrate concentrations and hydro-chemistry parameters, which may be influenced by other factors, e.g., nitrate transformation, fertilization time and water-rock interaction. Although variation of N concentration during event flow is evident, accounting for antecedent conditions and rainfall factors can help to predict rainfall event N loading during rainfall events. Pollution of the karstic catchment occurred by a flush of nitrate input following rainfall events; antecedent and rainfall conditions are therefore important factors to consider for the water quality management. Reducing source availability during the wet season may facilitate to reduction of nitrogen loading in similar karst areas.

Monolithic In2Se3–In2O3 heterojunction for multibit non-volatile memory and logic operations using optoelectronic inputs

Stable ferroelectricity at room-temperature down to the monolayer limit, harnessed with strong sensitivity towards visible-to-near-infrared illumination in α-In2Se3, facilitates its potential as versatile building block for developing ultrathin multifunctional photonic integrated networks. Herein, we demonstrated a planar ferroelectric-semiconductor heterojunction (FeS-HJ) field-effect transistor (FET) fabricated out of α-In2Se3 and In2O3, where the ferroelectric-polarization state in α-In2Se3 is utilized to control the device characteristics. The robust in-plane (IP) polarization flipping triggered by out-of-plane (OOP) electrostatic field along with clear anticlockwise hysteresis loop were readily revealed by scanning Kelvin-probe force microscopy (KPFM) and electrical probing. The orthogonally tangled ferroelectric switching was used to manipulate the HJ channel conductance and thereby to realize non-volatile memory (NVM) states. Moreover, gate-tuneable diode-like characteristics and superior photoresponse in HJ compared to its individual constitutes were observed. Utilizing the concurrent ferro-photonic coupling, high bandwidth optical inputs further tailored the outputs into four distinguished current states induced by different polarization directions. Our results pave the way for developing advanced (opto) electronic devices with diverse signal modulation capability to realize next generation low-power neurocomputing, brain-inspired visionary systems, and on-chip optical communications.

Relationship between Concentration and Discharge on Storm Events: Case Study at Cakardipa Catchment, Cisukabirus Subwatershed, Upper Ciliwung Watershed, Bogor, West Java

River nutrient loadings rates are frequently determined from discharge and hydrochemistry relationships using regression techniques. Unfortunately such methods as a conventional technique are inadequate for dealing with the problem such as differences in shape and direction of loop forming in individual and seasonal storms. Besides the relationships are nonlinear and time-dependent, they also varies from site to site. There is a currently method to study hysteresis between discharge and concentration of hydrochemistry. The relationship between discharge and solute concentration was investigated at Cakardipa catchment, Upper Ciliwung watershed, between the years of 2009-2010. The characteristics of the hysteresis loops were used to evaluate the temporal variation of the relative contribution to stream flow of source waters at Cakardipa Catchment including groundwater (CG), soil water (CSO), and rain water (CR). Chemical water analysis was carried out on 497 water samples on storm event. The chemical analysis of storm event of Februari 14, 2010 was carried out for the concentrations of K+, Ca2+, Mg2+, Na+, SiO2, SO42-NO3-, Cl-, and HCO3-. Results of the experiment showed that concentrations displayed circular hysteresis loops during the events, highlighting the complex relation among solutes and discharge during storm hydrographs. The solutes of K, Na, and Ca produced concave curvature, anti-clockwise hysteresis loops, and positive trend, so that classified as A2 loops with components ranking were CR> CG> CSO. .The solutes of Mg, SO4, NO3 assumed to come from groundwater produced convex curvature, clockwise hysteresis loops, and positive trend, indicating a concentration component ranking of CG > CR > CSO (C2 model). While Si and Cl produced clockwise hysteresis loops, indicating a concentration component ranking of CG> CSO> CR which was C1 model.

Suspended sediment budget and intra-event sediment dynamics of a small glaciated mountainous catchment in the Northern Caucasus

The sediment dynamics of (peri-)glacial catchments can be highly variable and complex. Understanding these dynamics and their underlying causes is not only of interest from a scientific perspective but also required to address the practical problems with which they are often associated. In order to better understand the sediment dynamics of glaciated mountainous catchments, suspended sediment fluxes in the 9.1 km2 Djankuat catchment (North Caucasus, Russia) were monitored intensively during the 2017 ablation season. The intra-event suspended sediment dynamics were studied using a newly proposed simple hysteresis index (SHI), quantifying to what extent evolutions in sediment concentration are characterized by a clockwise or anticlockwise hysteresis loop. The resulting catchment suspended sediment yield was 1033 t km−2 year−1, with the glacier itself contributing 72% of the suspended sediment load. However, during rainfall events, also hillslope erosion in the proglacial area became a very significant sediment source. Clockwise hysteresis loops occurred in 61.8% of the events, while anticlockwise in 11.8%. On the other hand, only 47.8% of the total suspended sediment flux was transported during clockwise events. Our observations clearly indicate that events showing a stronger clockwise pattern (i.e., a higher SHI) are associated with a larger sediment input from the proglacial area. Overall, our results provide data and insights on sediment dynamics in an understudied environment. They illustrate that the type and characteristics of sediment concentration hysteresis loops are to some extent linked to the dominant sediment sources during the event. As such, the proposed methodology and SHI may also help with a better understanding of sediment dynamics in other environments.

Impact of soil freeze-thaw mechanism on the runoff dynamics of two Tibetan rivers

Soil freeze-thaw is typically not fully considered in quantifying the hydrology of seasonally frozen catchments located, for instance, on the Third Pole. We investigate the role of soil water content and freeze-thaw state on the runoff dynamics of the headwaters of the Yellow and Yangtze rivers, both situated on the eastern Tibetan Plateau. A version of augmented Noah land surface model (LSM) allowing reliable simulation of key hydrometeorological processes over the Tibetan Plateau is employed and further validated using measured monthly discharge records. From measurements supported by the Noah LSM simulations for more than thirty years (1979–2010), we deduce an annual hysteresis loop, viz. a time lag between measured/simulated runoff and precipitation for both catchments. Our simulation results with the augmented Noah LSM further demonstrate that annual anticlockwise (or clockwise) hysteresis loops are also observed for the liquid soil water (or soil ice). We infer from the LSM simulations that the amount of water stored in the soil is the factor driving the hysteresis between runoff and precipitation, whereby the state of the stored water plays a crucial role in the seasonality of the runoff regime. Further analyses illustrate that inclusion of soil freeze-thaw model physics effectively increases the thermal inertia of the soil column that dampens large variations of soil temperature and turbulent heat fluxes. These findings highlight the importance of soil freeze-thaw for the hydrology and runoff regime across the High Asia’s rivers as well as the need for a thorough understanding of this process to generate reliable projections.

Baclofen-induced encephalopathy in overdose – Modeling of the electroencephalographic effect/concentration relationships and contribution of tolerance in the rat

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Baclofen overdose may induce severe encephalopathy and electroencephalographic (EEG) abnormalities. Whether prior prolonged baclofen treatment may influence the severity of baclofen-induced encephalopathy in overdose has not been established. We designed a rat study to characterize baclofen-induced encephalopathy, correlate its severity with plasma concentrations and investigate the contribution of tolerance.Baclofen-induced encephalopathy was assessed using continuous EEG and scored based on a ten-grade scale.Following the administration by gavage of 116 mg/kg baclofen, EEG rapidly and steadily impaired resulting in the successive onset of deepening sleep followed by generalized periodic epileptiform discharges and burst-suppressions. Thereafter, encephalopathy progressively recovered following similar phases in reverse. Periodic triphasic sharp waves, non-convulsive status epilepticus and even isoelectric signals were observed at the most critical stages. Prior repeated baclofen administration resulted in reduced severity (peak: grade 7 versus 9; peak effect length: 382 ± 40 versus 123 ± 14 min, P = 0.008) and duration of encephalopathy (18 versus > 24 h, P = 0.0007), supporting the acquisition of tolerance. The relationship between encephalopathy severity and plasma baclofen concentrations fitted a sigmoidal Emax model with an anticlockwise hysteresis loop suggesting a hypothetical biophase site of action. The baclofen concentration producing a response equivalent to 50% of Emax was significantly reduced (8947 μg/L, ±11.3% versus 12,728 μg/L, ±24.0% [mean, coefficient of variation], P = 0.03) with prior prolonged baclofen administration.In conclusion, baclofen overdose induces early-onset and prolonged marked encephalopathy that is significantly attenuated by prior repeated baclofen treatment. Our findings suggest a possible role for the blood-brain barrier in the development of tolerance; however, its definitive involvement remains to be demonstrated.

Temporal variability of soil organic carbon transport in the Enxoé agricultural watershed

The temporal variability of particulate (POC) and dissolved (DOC) organic carbon concentrations was analyzed in the Enxoe temporary river, southern Portugal, between September, 2010 and August, 2013. The overall aim was to study the variability of those elements during storm events, and determine their origin and the main transfer mechanisms to the river. Twenty-one flood events were observed. An empirical model was used to describe changes in solute concentrations, and the magnitude and rotational patterns of the hysteretic loops during flood events. POC and DOC concentrations varied between 0.49–88.93 and 0.25–25.75 mg L−1, respectively. POC and DOC annual yields varied between 0.06–2.15 and 0.03–1.47 t km−2, respectively. Flood events had greater effect in POC than in DOC variability. POC had mostly a terrestrial origin, with exports being related to soil erosion and runoff. POC revealed a flushing behavior during the entire monitored period, and clockwise or anticlockwise trajectory loops whenever the predominant origin of the exports was in river bed deposits or arable lands, respectively. DOC had also a terrestrial origin, but it revealed a contrasting dilution behavior and, in general, anticlockwise hysteresis loops. DOC showed a delay in the arrival of solutes to the river, consistent with mass flow through subsurface flow. DOC exports were thus associated with soil weathering and crop mineralization. This work highlights the main processes involved in POC and DOC loads in a temporary river during flood events, with a precise quantification of those elements.

Mode Characteristics and Optical Bistability for AlGaInAs/InP Microring Lasers

Mode characteristics and optical bistability are investigated for an AlGaInAs/InP microring laser, with an outer radius of 10 μm and a ring width of 3 μm, connected with a 2-μm-wide radial output waveguide. A clockwise bistable hysteresis loop is observed with the continuous injection current from 20 to 28 mA at 289 K, measured through a single-mode optical fiber coupled to the output waveguide in the center position. The lasing spectra with main lasing wavelength difference of 0.022 nm are observed for the upper and lower states of the hysteresis. Furthermore, an anticlockwise bistable hysteresis loop is observed as the fiber is moved away from the center of the output waveguide to the secondary peak position of the coupled power. Comparing the experimental and simulation results, we attribute the bistability to the mode competitions between the near-degenerate symmetric and antisymmetric modes with different far-field emission characteristics.

Hybrid Nonvolatile Memory Devices with Ferroelectric Copolymers Based on ZnO Nanowire Field Effect Transistors

Zinc Oxide (ZnO) nanowire (NW) field effect transistors (FETs) have been increasingly popular recently as promising circuitry building blocks. ZnO NWs have a relatively good ohmic contact between the metal electrodes and semiconductor materials, which results in a high device performance and fabrication yield. At the same time, organic thin film transistors (OTFTs) with ferroelectric materials have been researched extensively owing to their nonvolatile memory effect, nondestructive readout and applications to flexible electronics [1, 2]. However, research works on ferroelectric memory devices based NW FETs are still limited [3, 4], while that on their thin film counterparts are relatively widespread [5].We will first introduce the nonvolatile memory device arrangement based on a ZnO NW FET. Single NW and network NW FET configurations are compared in terms of their associated ferroelectric memory properties. We will show our previous work on the ZnO NWs grown by a chemical vapor transport method on glass substrates [6] together with that by a hydrothermal method on flexible substrates, with the dimensions ranging from 100-300 nm in diameter and up to 5-10 um in length. Our ZnO NW FETs grown on flexible substrates directly shows a high current on/off ratio of up to 105-107with an anticlockwise hysteresis loop present on the transfer curve. The top-gate and bottom-gate structures have been prepared by spin coating a 5 wt% solution of ferroelectric PDVF-TrFE powders in cyclohexane. After spin coating, the ZnO NW FETs with PVDF-TrFE thin films have been thermally cured in a vacuum oven at 150°C for 5 hours. The device showed a memory window of at least 10-20 volts depending on the type of the substrates, which can be tuned by varying the sweep range of the gate voltages.[1] T. Sekitani et al., Science 326, 1516 (2009).[2] S.K. Hwang et al., Adv. Mater. 24, 5910 (2012).[3] D. Yeom et al., Nanotechnology 19, 395204 (2008).[4] Y.T. Lee et al., Adv. Mater. 24, 3020 (2012).[5] K.H. Lee et al., Adv. Mater. 21, 4287 (2009).[6] S. Nedic, et al., Appl. Phys. Letts. 104, 033101 (2014).

Contrasting Dynamics of Nitrate and Kjeldahl Nitrogen in a Stream Draining a Rural Catchment in Galicia (NW Spain)

In this study the temporal variability of nitrogen (N) transport in a small rural agroforestry catchment (16 km2) located in NW Spain is analyzed. Total annual N loss was 20.34 t, and the specific N yield was 8.16 kg ha−1 y−1. This rate is low in relation to rural catchments in other regions with similar size and distribution of land use. Nitrate (N-NO3), which represents about 78% of the N transported, was mainly mobilized during baseflow (59%), whereas most of the total Kjeldahl nitrogen (TKN) export occurred during runoff events (54%). A significant difference in the transport of N-NO3 and TKN within the catchment was observed. The relationship between N-NO3 concentrations and discharge within runoff events was mainly dominated by anticlockwise hysteresis loops, whereas in the case of TKN clockwise hysteresis loops predominated.

Climatic and geologic controls on suspended sediment flux in the Sutlej River Valley, western Himalaya

Abstract. The sediment flux through Himalayan rivers directly impacts water quality and is important for sustaining agriculture as well as maintaining drinking-water and hydropower generation. Despite the recent increase in demand for these resources, little is known about the triggers and sources of extreme sediment flux events, which lower water quality and account for extensive hydropower reservoir filling and turbine abrasion. Here, we present a comprehensive analysis of the spatiotemporal trends in suspended sediment flux based on daily data during the past decade (2001–2009) from four sites along the Sutlej River and from four of its main tributaries. In conjunction with satellite data depicting rainfall and snow cover, air temperature and earthquake records, and field observations, we infer climatic and geologic controls of peak suspended sediment concentration (SSC) events. Our study identifies three key findings: First, peak SSC events (≥ 99th SSC percentile) coincide frequently (57–80%) with heavy rainstorms and account for about 30% of the suspended sediment flux in the semi-arid to arid interior of the orogen. Second, we observe an increase of suspended sediment flux from the Tibetan Plateau to the Himalayan Front at mean annual timescales. This sediment-flux gradient suggests that averaged, modern erosion in the western Himalaya is most pronounced at frontal regions, which are characterized by high monsoonal rainfall and thick soil cover. Third, in seven of eight catchments, we find an anticlockwise hysteresis loop of annual sediment flux variations with respect to river discharge, which appears to be related to enhanced glacial sediment evacuation during late summer. Our analysis emphasizes the importance of unconsolidated sediments in the high-elevation sector that can easily be mobilized by hydrometeorological events and higher glacial-meltwater contributions. In future climate change scenarios, including continuous glacial retreat and more frequent monsoonal rainstorms across the Himalaya, we expect an increase in peak SSC events, which will decrease the water quality and impact hydropower generation.

Nonvolatile Memory Effect in a Au/Cu–ZnO/p-Si Type of Metal–Insulator–Semiconductor Structure

A low-cost insulating Cu-doped ZnO (Cu-ZnO) thin film has been utilized to form a Au/Cu-ZnO/p-Si type of metal-insulator-semiconductor (MIS) junction. The capacitance-voltage plot shows a nonvolatile memory effect through an anticlockwise hysteresis loop, indicating electron trapping and detrapping. The area of the hysteresis loop and the saturated capacitance value is found to be dependent on the frequency, indicating involvement of various trap states. A possible mechanism corresponding to the writing and erasing processes for the MIS structure has been discussed. The memory effect of the Cu-ZnO-based MIS device is novel and uniquely unconventional that we are reporting for the first time.

Using artificial fluorescent particles as tracers of livestock wastes within an agricultural catchment

Evidence for the movement of agricultural slurry and associated pollutants into surface waters is often anecdotal, particularly with relation to its ‘particulate’ components which receive less attention than ‘bio-available’ soluble phases. To assess the extent of movement of slurry particles artificial fluorescent particles were mixed with slurry and applied to a field sub-catchment within a headwater catchment. Particles were 2–60 μm in diameter and two different densities, 2.7 and 1.2 g cm –3 representing ‘inorganic’ and ‘organic’ material. Water samples from the field and catchment outlet were collected during two storm events following slurry application and analysed for particle and suspended sediment concentrations (SSC). SSC from the field and catchment outlet always formed clockwise hysteresis loops indicating sediment exhaustion and particles of the two densities were always found to be positively correlated. Particles from the field formed clockwise hysteresis loops during the first discharge event after slurry application, but anti-clockwise hysteresis loops during the second monitored event which indicated a depletion of readily mobilisable particles. Particles from the catchment outlet always formed anticlockwise hysteresis loops. Particle size became finer spatially, between field and catchment outlet, and temporally, between successive storm events. The results indicate that slurry particles may be readily transported within catchments but that different areas may contribute to pollutant loads long after the main peak in SSC has passed. The density of the particles did not appear to have any effect on particle transport however the size of the particles may play a more important role in the 2–60 μm range.

Spatial scale dependence of sediment dynamics in a gullied rolling loess region on the Loess Plateau in China

Sediment dynamics is still imperfectly understood, especially at spatial scale in the highly erodible region of the Loess Plateau, and few studies have been heretofore conducted. Using 5-year continuous water and sediment records, three plots and three basins in the gullied rolling loess region were selected and sediment dynamics at spatial scale was studied. Results showed that the floods, where the peak discharge (Qp) did not come earlier than the sediment peak, were predominant in slope zones, occupying >90 and >70% of the total for the Mao slope and for the Entire slope, respectively. However, in basins, most of the sediment peaks (Cp) lagged behind Qp, implying that slope zone was the main origin of sediment. More than 50% of the events presented clockwise hysteresis loops in the Mao slope area, while almost all the events had anticlockwise hysteresis loops in basins. This can be attributed to less occurring frequency of hyperconcentrated flow, as well as its instability in slope zones, compared to those in the basins. Within these contexts, gravitational erosion made the highest sediment concentration (C) in Tuanshangou basin and median developing status of C-discharge (C–Q) relationships in the Entire slope area. This study provides insights into the protection of slope surface and disruption of the development of hyperconcentrated flow to reduce soil loss.

Temporal changes in suspended sediment transport in a gullied loess basin: the lower Chabagou Creek on the Loess Plateau in China

AbstractSuspended sediment dynamics are still imperfectly understood, especially in the loess hilly region on the Loess Plateau, with strong temporal variability, where few studies heretofore have been conducted. Using a dataset up to eight years long in the Lower Chabagou Creek, the variability in suspended sediment load at different temporal scales (within‐flood variability, monthly–seasonal and annual) is analyzed in this paper. The results show that, on the within‐flood scale, most of the sediment peaks lag behind peak discharges, implying that slope zones are the main sediment source area; independent of the occurring sequences of the peaks of sediment and discharge, all the events could present an anti‐clockwise hysteresis loop resulting from the abundant material and the influence of hyperconcentrated flows on suspended sediment concentration. At monthly and seasonal scales, there is a ‘store–release’ process, i.e. sediment is prepared in winter, spring and late autumn, and exported in summer and early autumn. At the annual scale, the high variability in concentration and sediment yield are highly correlated with water yield, resulting from the number and magnitude of floods recorded yearly, and almost all the suspended load is transported during these events. Copyright © 2008 John Wiley & Sons, Ltd.

Pharmacokinetic and Pharmacodynamic Properties of Lafutidine after Postprandial Oral Administration in Healthy Subjects: Comparison with Famotidine

Lafutidine, a histamine H(2)-receptor antagonist, inhibits gastric acid secretion during the daytime, however, the relationship between the plasma concentration and the drug response remains unclear. The aim of this study was to compare the pharmacokinetic and pharmacodynamic properties of lafutidine and famotidine following postprandial oral administration. After a lafutidine tablet (10 mg), famotidine tablet (20 mg), or water only (control) was administered, blood samples were taken and intragastric pH was measured. The plasma concentrations of lafutidine and famotidine were determined by HPLC, and the median intragastric pH values per 30 min were used as the degrees of gastric acid suppression. Data were analyzed based on a one-compartment pharmacokinetic model and a sigmoid E(max) pharmacodynamic model. Lafutidine plasma concentrations rapidly increased after administration; famotidine required some time to increase the plasma concentrations, requiring an absorption lag time in the pharmacokinetic model. Between the plasma concentration and DeltapH (the difference in intragastric pH by the drug vs. control), lafutidine showed an anticlockwise hysteresis loop which indicated equilibration delay between the plasma concentration and effect site, requiring an effect site compartment in the pharmacodynamic model; famotidine showed more parallel relationship. These results indicated that the pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration were different from those of famotidine at least 4.5 h after dosing.

Dynamic response of HTS composite tapes to pulsed currents

Dynamic voltage–current characteristics of an HTS Ag/BiSCCO composite tape arestudied both experimentally and theoretically. The tape is subjected to pulsedcurrents with different shapes and magnitudes and voltage traces are measuredusing the four-point method with different locations of potential taps on thesample surface. Clockwise and anticlockwise hysteresis loops are obtained forthe same sample depending on the location of the potential taps. The dynamiccharacteristics deviate substantially from the DC characteristic, especially in the rangeof low voltages where a criterion for the critical current value is usually chosen(1–10 µV cm−1). The critical current determined from dynamic characteristics and its change with thepulse magnitude depend on the location of the potential taps and on the curvebranch chosen for the critical current determination (ascending or descending).The theoretical analysis is based on a model of the magnetic flux diffusion into a compositetape for a superconductor described by the flux creep characteristic. Numerical simulationbased on this model gives results in good agreement with the experimental ones andexplains the observed peculiarities of the dynamic characteristics of HTS composite tapes.The difference between the magnetic diffusion into a tape and a slab is discussed.

PRACTICAL APPLICATION OF GUINEA PIG TELEMETRY SYSTEM FOR QT EVALUATION

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of baclofen in mice.

The aim of this study was the development of a pharmacokinetic-pharmacodynamic (PK/PD) model of the antinociceptive effect of baclofen in mice. We studied the dose response curve of the analgesic action of baclofen in mice by hot plate test. Baclofen produced a dose dependent antinociceptive effect with doses between 1-3 mg/kg administered intraperitoneally (i.p.) (ED50: 1.94 mg/kg of racemate) and this effect fits to a linear pharmacodynamic model. Blood and brain concentrations of (-)3H-baclofen were determined by Thin-Layer Chromatography (TLC) and counted in the scintillation-counter. The PK/PD models were analyzed with the PC-TOPFIT V.2.0 and the tests for distinguishing between models were several adjustment parameters as Akaike information criterion (AIC), Imbimbo criterion (Ip), standard deviation (SD) and the correlation coefficient (r2). Accordingly with these adjustment parameters, a 2 compartment open model was selected where plasma is the central compartment and brain is in the peripheral compartment. In this model, the effect is linked to the peripheral compartment. When the antinociceptive effect of baclofen was plotted against blood concentration, the resulting curve exhibited an anticlockwise hysteresis loop, but on the other hand, when the antinociceptive effect was plotted against the brain concentration, the hysteresis was collapsed. These results confirmed the selected model in our study, as the best adjustment was shown when the pharmacological response was linked to the peripheral compartment.