Loading of itraconazole into porous silica and silicon microparticles: characterization and dissolution tests

Most new drug molecules discovered today suffer from poor bioavailability. Poor oral bioavailability results mainly from poor dissolution properties of hydrophobic drug molecules, because the drug dissolution is often the rate-limiting event of the drug’s absorption through the intestinal wall into the systemic circulation. During the last few years, the use of mesoporous silica and silicon particles as oral drug delivery vehicles has been widely studied, and there have been promising results of their suitability to enhance the physicochemical properties of poorly soluble drug molecules. Mesoporous silica and silicon particles can be used to enhance the solubility and dissolution rate of a drug by incorporating the drug inside the pores, which are only a few times larger than the drug molecules, and thus, breaking the crystalline structure into a disordered, amorphous form with better dissolution properties. Also, the high surface area of the mesoporous particles improves the dissolution rate of the incorporated drug. In addition, the mesoporous materials can also enhance the permeability of large, hydrophilic drug substances across biological barriers. T he loading process of drugs into silica and silicon mesopores is mainly based on the adsorption of drug molecules from a loading solution into the silica or silicon pore walls. There are several factors that affect the loading process: the surface area, the pore size, the total pore volume, the pore geometry and surface chemistry of the mesoporous material, as well as the chemical nature of the drugs and the solvents. Furthermore, both the pore and the surface structure of the particles also affect the drug release kinetics. In this study, the loading of itraconazole into mesoporous silica (Syloid AL-1 and Syloid 244) and silicon (TOPSi and TCPSi) microparticles was studied, as well as the release of itraconazole from the microparticles and its stability after loading. Itraconazole was selected for this study because of its highly hydrophobic and poorly soluble nature. Different mesoporous materials with different surface structures, pore volumes and surface areas were selected in order to evaluate the structural effect of the particles on the loading degree and dissolution behaviour of the drug using different loading parameters. The loaded particles were characterized with various analytical methods, and the drug release from the particles was assessed by in vitro dissolution tests. The results showed that the loaded drug was apparently in amorphous form after loading, and that the loading process did not alter the chemical structure of the silica or silicon surface. Both the mesoporous silica and silicon microparticles enhanced the solubility and dissolution rate of itraconazole. Moreover, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. Finally, the mesoporous silicon particles loaded with itraconazole were found to be unstable under stressed conditions (at 38 qC and 70 % relative humidity).

Wind drift of snowfall between the radar volume and ground

This study evaluates how the advection of precipitation, or wind drift, between the radar volume and ground affects radar measurements of precipitation. Normally precipitation is assumed to fall vertically to the ground from the contributing volume, and thus the radar measurement represents the geographical location immediately below. In this study radar measurements are corrected using hydrometeor trajectories calculated from measured and forecasted winds, and the effect of trajectory-correction on the radar measurements is evaluated. Wind drift statistics for Finland are compiled using sounding data from two weather stations spanning two years. For each sounding, the hydrometeor phase at ground level is estimated and drift distance calculated using different originating level heights. This way the drift statistics are constructed as a function of range from radar and elevation angle. On average, wind drift of 1 km was exceeded at approximately 60 km distance, while drift of 10 km was exceeded at 100 km distance. Trajectories were calculated using model winds in order to produce a trajectory-corrected ground field from radar PPI images. It was found that at the upwind side from the radar the effective measuring area was reduced as some trajectories exited the radar volume scan. In the downwind side areas near the edge of the radar measuring area experience improved precipitation detection. The effect of trajectory-correction is most prominent in instant measurements and diminishes when accumulating over longer time periods. Furthermore, measurements of intensive and small scale precipitation patterns benefit most from wind drift correction. The contribution of wind drift on the uncertainty of estimated Ze (S) - relationship was studied by simulating the effect of different error sources to the uncertainty in the relationship coefficients a and b. The overall uncertainty was assumed to consist of systematic errors of both the radar and the gauge, as well as errors by turbulence at the gauge orifice and by wind drift of precipitation. The focus of the analysis is error associated with wind drift, which was determined by describing the spatial structure of the reflectivity field using spatial autocovariance (or variogram). This spatial structure was then used with calculated drift distances to estimate the variance in radar measurement produced by precipitation drift, relative to the other error sources. It was found that error by wind drift was of similar magnitude with error by turbulence at gauge orifice at all ranges from radar, with systematic errors of the instruments being a minor issue. The correction method presented in the study could be used in radar nowcasting products to improve the estimation of visibility and local precipitation intensities. The method however only considers pure snow, and for operational purposes some improvements are desirable, such as melting layer detection, VPR correction and taking solid state hydrometeor type into account, which would improve the estimation of vertical velocities of the hydrometeors.

Postoperative Volume Therapy in Cardiac Surgery : Effects on Hemostatic and Circulatory Variables

Background: Patients may need massive volume-replacement therapy after cardiac surgery because of large fluid transfer perioperatively, and the use of cardiopulmonary bypass. Hemodynamic stability is better maintained with colloids than crystalloids but colloids have more adverse effects such as coagulation disturbances and impairment of renal function than do crystalloids. The present study examined the effects of modern hydroxyethyl starch (HES) and gelatin solutions on blood coagulation and hemodynamics. The mechanism by which colloids disturb blood coagulation was investigated by thromboelastometry (TEM) after cardiac surgery and in vitro by use of experimental hemodilution. Materials and methods: Ninety patients scheduled for elective primary cardiac surgery (Studies I, II, IV, V), and twelve healthy volunteers (Study III) were included in this study. After admission to the cardiac surgical intensive care unit (ICU), patients were randomized to receive different doses of HES 130/0.4, HES 200/0.5, or 4% albumin solutions. Ringer’s acetate or albumin solutions served as controls. Coagulation was assessed by TEM, and hemodynamic measurements were based on thermodilutionally measured cardiac index (CI). Results: HES and gelatin solutions impaired whole blood coagulation similarly as measured by TEM even at a small dose of 7 mL/kg. These solutions reduced clot strength and prolonged clot formation time. These effects were more pronounced with increasing doses of colloids. Neither albumin nor Ringer’s acetate solution disturbed blood coagulation significantly. Coagulation disturbances after infusion of HES or gelatin solutions were clinically slight, and postoperative blood loss was comparable with that of Ringer’s acetate or albumin solutions. Both single and multiple doses of all the colloids increased CI postoperatively, and this effect was dose-dependent. Ringer’s acetate had no effect on CI. At a small dose (7 mL/kg), the effect of gelatin on CI was comparable with that of Ringer’s acetate and significantly less than that of HES 130/0.4 (Study V). However, when the dose was increased to 14 and 21 mL/kg, the hemodynamic effect of gelatin rose and became comparable with that of HES 130/0.4. Conclusions: After cardiac surgery, HES and gelatin solutions impaired clot strength in a dose-dependent manner. The potential mechanisms were interaction with fibrinogen and fibrin formation, resulting in decreased clot strength, and hemodilution. Although the use of HES and gelatin inhibited coagulation, postoperative bleeding on the first postoperative morning in all the study groups was similar. A single dose of HES solutions improved CI postoperatively more than did gelatin, albumin, or Ringer’s acetate. However, when administered in a repeated fashion, (cumulative dose of 14 mL/kg or more), no differences were evident between HES 130/0.4 and gelatin.

The thickness and volume of lake ice in Finland

Yhteenveto: Järvijään paksuus ja volyymi Suomessa jaksolla 1961-90

Scientific Journal Publishing – Yearly Volume and Open Access Availability

Introduction. We estimate the total yearly volume of peer-reviewed scientific journal articles published world-wide as well as the share of these articles available openly on the Web either directly or as copies in e-print repositories. Method. We rely on data from two commercial databases (ISI and Ulrich's Periodicals Directory) supplemented by sampling and Google searches. Analysis. A central issue is the finding that ISI-indexed journals publish far more articles per year (111) than non ISI-indexed journals (26), which means that the total figure we obtain is much lower than many earlier estimates. Our method of analysing the number of repository copies (green open access) differs from several earlier studies which have studied the number of copies in identified repositories, since we start from a random sample of articles and then test if copies can be found by a Web search engine. Results. We estimate that in 2006 the total number of articles published was approximately 1,350,000. Of this number 4.6% became immediately openly available and an additional 3.5% after an embargo period of, typically, one year. Furthermore, usable copies of 11.3% could be found in subject-specific or institutional repositories or on the home pages of the authors. Conclusions. We believe our results are the most reliable so far published and, therefore, should be useful in the on-going debate about Open Access among both academics and science policy makers. The method is replicable and also lends itself to longitudinal studies in the future.

Analysts' Accuracy of Estimation and the Relative Trading Volume

This study contributes to the neglect effect literature by looking at the relative trading volume in terms of value. The results for the Swedish market show a significant positive relationship between the accuracy of estimation and the relative trading volume. Market capitalisation and analyst coverage have in prior studies been used as proxies for neglect. These measures however, do not take into account the effort analysts put in when estimating corporate pre-tax profits. I also find evidence that the industry of the firm influence the accuracy of estimation. In addition, supporting earlier findings, loss making firms are associated with larger forecasting errors. Further, I find that the average forecast error increased in the year 2000 – in Sweden.

Estimation of cutting volume with three inventory methods for harvest planning in Canadian boreal forests.

Two methods of pre-harvest inventory were designed and tested on three cutting sites containing a total of 197 500 m3 of wood. These sites were located on flat-ground boreal forests located in northwestern Quebec. Both methods studied involved scaling of trees harvested to clear the road path one year (or more) prior to harvest of adjacent cut-blocks. The first method (ROAD) considers the total road right-of-way volume divided by the total road area cleared. The resulting volume per hectare is then multiplied by the total cut-block area scheduled for harvest during the following year to obtain the total estimated cutting volume. The second method (STRATIFIED) also involves scaling of trees cleared from the road. However, in STRATIFIED, log scaling data are stratified by forest stand location. A volume per hectare is calculated for each stretch of road that crosses a single forest stand. This volume per hectare is then multiplied by the remaining area of the same forest stand scheduled for harvest one year later. The sum of all resulting estimated volumes per stand gives the total estimated cutting-volume for all cut-blocks adjacent to the studied road. A third method (MNR) was also used to estimate cut-volumes of the sites studied. This method represents the actual existing technique for estimating cutting volume in the province of Quebec. It involves summing the cut volume for all forest stands. The cut volume is estimated by multiplying the area of each stand by its estimated volume per hectare obtained from standard stock tables provided by the governement. The resulting total estimated volume per cut-block for all three methods was then compared with the actual measured cut-block volume (MEASURED). This analysis revealed a significant difference between MEASURED and MNR methods with the MNR volume estimate being 30 % higher than MEASURED. However, no significant difference from MEASURED was observed for volume estimates for the ROAD and STRATIFIED methods which respectively had estimated cutting volumes 19 % and 5 % lower than MEASURED. Thus the ROAD and STRATIFIED methods are good ways to estimate cut-block volumes after road right-of-way harvest for conditions similar to those examined in this study.

Physical properties of a boreal clay soil under differently managed perennial vegetation

The physical properties of surface soil horizons, essentially pore size, shape, continuity and affinity for water, regulate water entry into the soil. These properties are prone to changes caused by natural forces and human activity. The hydraulic properties of the surface soil greatly impact the generation of surface runoff and accompanied erosion, the major concern of agricultural water protection. The general target of this thesis was to improve our understanding of the structural and hydraulic properties of boreal clay soils. Physical properties of a clayey surface soil (0 - 10 cm, clay content 51%), with a micaceous/illitic mineralogy subjected to three different management practices of perennial vegetation, were studied. The study sites were vegetated buffer zones located side by side in SW Finland: 1) natural vegetation with no management, 2) harvested once a year, and 3) grazed by cattle. The soil structure, hydraulic properties, shrinkage properties and soil water repellency were determined at all sites. Two distinct flow domains were evident. The surface soil was characterized by subangular blocky, angular blocky and platy aggregates. Hence, large, partially accommodated, irregular elongated pores dominated the macropore domain at all sites. The intra-aggregate pore system was mostly comprised of pores smaller than 30 μm, which are responsible for water storage. Macropores at the grazed site, compacted by hoof pressure, were horizontally oriented and pore connectivity was poorest, which decreased water and air flux compared with other sites. Drying of the soil greatly altered its structure. The decrease in soil volume between wet and dry soil was 7 - 10%, most of which occurred in the moisture range of field conditions. Structural changes, including irreversible collapse of interaggregate pores, began at matric potentials around -6 kPa indicating, instability of soil structure against increasing hydraulic stress. Water saturation and several freezethaw cycles between autumn and spring likely weakened the soil structure. Soil water repellency was observed at all sites at the time of sampling and when soil was dryer than about 40 vol.%. (matric potential < -6 kPa). Therefore, water repellency contributes to water flow over a wide moisture range. Water repellency was also observed in soils with low organic carbon content (< 2%), which suggests that this phenomenon is common in agricultural soils of Finland due to their relatively high organic carbon content. Aggregate-related pedofeatures of dense infillings described as clay intrusions were found at all sites. The formation of these intrusions was attributed to clay dispersion and/or translocation during spring thaw and drying of the suspension in situ. These processes generate very new aggregates whose physical properties are most probably different from those of the bulk soil aggregates. Formation of the clay infillings suggested that prolonged wetness in autumn and spring impairs soil structure due to clay dispersion, while on the other hand it contributes to the pedogenesis of the soil. The results emphasize the dynamic nature of the physical properties of clay soils, essentially driven by their moisture state. In a dry soil, fast preferential flow is favoured by abundant macropores including shrinkage cracks and is further enhanced by water repellency. Increase in soil moisture reduces water repellency, and swelling of accommodated pores lowers the saturated hydraulic conductivity. Moisture- and temperature-related processes significantly alter soil structure over a time span of 1 yr. Thus, the pore characteristics as well as the hydraulic properties of soil are time-dependent.