A Three-Dimensional View on Soil Biogeochemistry: A Dataset for a Forested Headwater Catchment.

Current understanding of the variability in soil properties and their relationship to processes and spatial patterns in forested landscapes is limited due to the scarcity of datasets providing such information. Here we present a spatially highly resolved dataset () that provides detailed information on the three-dimensional variability of biogeochemical properties in the Wüstebach catchment (western Germany), a long-term environmental observation site of the TERENO (Terrestrial Environmental Observatories) project. High-resolution soil sampling was conducted, and physical and biogeochemical soil parameters were recorded per horizon. The dataset is helpful in the analysis of the spatial heterogeneity in biogeochemical properties within soil horizons and with depth through the soil profile. In addition, it shows links between hydrological and biogeochemical properties and processes within the system. Overall, the dataset provides a high-resolution view into (re)cycling, leaching, and storage of nutrients on the catchment scale in a forested headwater catchment.

A dose proportionality study of subcutaneously and intramuscularly administered recombinant human follicle-stimulating hormone (Follistim*/Puregon) in healthy female volunteers.

OBJECTIVE: To assess pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous (s.c.) administration of recombinant FSH in comparison with the intramuscular (i.m.) route. DESIGN: Open, group-comparative, randomized, multiple-dose study. SETTING: Phase I Clinical Research Unit.Volunteer(s): Forty-six healthy female volunteers. INTERVENTION(S): All volunteers were treated with Lyndiol contraceptive pills for 6 weeks to suppress pituitary function. After 3 weeks of Lyndiol, volunteers were randomized to 75 IU, 150 IU, or 225 IU s.c. or 150 IU i.m. of recombinant FSH, administered once daily for 7 days. Serum samples were collected to determine immunoreactive FSH, LH, and E(2) levels. Ultrasonography was performed for measurement of follicular growth. MAIN OUTCOME MEASURE(S): FSH pharmacokinetic parameters, number, and size of follicles. RESULT(S): The s.c. doses tested showed dose-proportional pharmacokinetics. Subcutaneous and i.m. administration of 150 IU of recombinant FSH were bioequivalent. For the 75-IU group almost no follicles >/=10 mm were found. The mean (+/-SD) number of follicles >/=8 mm on the day of maximum stimulation in the 150 IU and 225 IU s. c. and 150 IU i.m. groups were 14.0 +/- 7.1, 14.3 +/- 8.2, and 6.5 +/- 4.7. CONCLUSION(S): Pharmacokinetics of recombinant FSH were dose proportional within the dose range studied (75-225 IU). Subcutaneous and i.m. administration of 150 IU was bioequivalent with respect to pharmacokinetics, but after s.c. administration the number of growing follicles and estradiol response were higher.

Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part II. Dose-proportionality and gonadotropin suppression after multiple doses of ganirelix in healthy female volunteers.

OBJECTIVE: To assess the dose-proportionality and pharmacodynamic properties of multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands). DESIGN: Randomized, parallel, pharmacokinetic, and pharmacodynamic study. SETTING: Phase I clinical research unit. PATIENT(S): Three groups of 15 healthy female volunteers of reproductive age. INTERVENTION(S): Subcutaneous injections of 0.125 mg, 0.25 mg, or 0.50 mg of ganirelix were given once daily for 7 days. Blood samples were taken to assess serum ganirelix, LH, FSH, and E2 concentrations. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters and hormone suppression. RESULT(S): Steady-state levels were reached between days 2 and 3. Peak concentrations, which occurred approximately 1 hour after dosing, increased in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/mL for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Corresponding mean values for the area under the curve over one dosing interval (24 hours) were 33 ng x h/mL, 77.1 ng x h/mL, and 137.8 ng x h/mL, respectively. After the last 0.25-mg dose of ganirelix, serum LH, FSH, and E2 concentrations were maximally decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 hours after injection, respectively). Serum hormone levels returned to pretreatment values within 2 days after the last injection. CONCLUSION(S): The pharmacokinetics of ganirelix were dose-proportional within the dose range studied. Multiple injections resulted in immediate suppression of gonadotropins, which was rapidly reversed after treatment discontinuation.

Pharmacokinetics of mirtazapine from orally administered tablets: influence of a high-fat meal.

The effect of a high-fat meal on the pharmacokinetics of mirtazapine was studied in 19 healthy normal young male volunteers. In a randomized two-period crossover study, each volunteer received an oral dose of 15 mg of mirtazapine in the form of tablets, in the fasting state and after a high-fat meal, with a washout period of 14 days between the two doses. Serial blood samples were taken and pharmacokinetic parameters calculated and statistically analyzed from mirtazapine plasma levels. The extent of absorption of mirtazapine, as measured by the area under the plasma level versus time curve, was found to be equivalent for the fasting and the fed state. Food intake was shown to have no influence on the elimination of mirtazapine, as measured by its elimination half-life. The rate of mirtazapine absorption, as measured by the peak level (Cmax), was not altered by food. The peak time (tmax), however, in subjects in the fed state showed an increase: the 90%-confidence interval for the median difference ranged from 0.25 to 1.25 h. This was the only effect of food found in this study. It is considered to be of no clinical consequence.

Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins.

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.

Pharmacokinetics of two human menopausal gonadotrophin preparations after single intravenous administration during pituitary suppression.

A randomized study was performed in nine healthy women, to investigate pharmacokinetic parameters and bioequivalence of two human menopausal gonadotrophin preparations after i.v. administration. Endogenous gonadotrophin activity was suppressed by triptorelin administration. Humegon and Pergonal (225 IU of each) were injected i.v. in a cross-over way with an interval of 1 week. Blood samples were collected frequently and serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), specific LH, and human chorionic gonadotrophin (HCG) were determined by fluoroimmunoassays assays. Serum LH bioactivity was measured by an in-vitro bioassay. The area under curve (AUC) and half-life of FSH were respectively 431.5 IU h/l and 22.20 h for Humegon, and 402.6 IU h/l and 21.33 h for Pergonal. For both preparations, the (total) LH immunoactivity and in-vitro bioactivity of serum LH were very similar, and appeared to be a composite of specific LH and HCG activity. The AUC data of specific LH were 17.50 IU h/l for Humegon and 21.79 IU h/l for Pergonal respectively. The AUC and half-life of HCG were 153.7 IU h/l and 14.80 h for Humegon, and 134.1 IU h/l and 12.11 h for Pergonal. The two preparations were bioequivalent with respect to FSH and HCG immunoreactivity. Bioequivalence could not be proven for LH activity because of the small number of subjects.

Chloroquine interaction with inflammatory human polymorphonuclear leucocytes.

The molecular in vitro association of radiolabelled chloroquine (CQ) with both normal resting and inflammatory polymorphonuclear leucocytes (PMNs) was measured. For this purpose a suitable ligand-association assay was developed to measure the cell association and the intracellular concentration of CQ. Under the influence of inflammatory stimuli PMNs display altered interaction with CQ. The intracellular concentration of CQ is reduced with 30 to 40% under inflammatory (disease) states when compared with non-inflammatory conditions. The mechanisms of CQ-PMN interaction associated with these altered intracellular concentrations of CQ are considered, with particular attention to the effects of rheumatic disease. Association experiments of CQ with PMNs performed in the presence of different established transport inhibitors showed that both diffusive uptake and carrier-mediated transport are involved in the cell accumulation of CQ in inflammatory PMNs. From these results, emphasis is given to three explanations for the decrease of the intracellular CQ concentration in inflamed PMNs. a) the expansion of the PMN volume under inflammatory conditions; b) the cytoplasmic or lysosomal pH changes and activation of the PMN Na+/H+ antiport by inflammatory stimuli; and c) the exocytic release of the granules (degranulation). Our data suggest that all these mechanisms, based on the events involved in inflammatory responses, may be involved in the decrease of the intracellular CQ concentration in inflammatory PMNs.

The cellular association of sodium salicylate and indomethacin in peritoneal fluid of ascites bearing mice.

The degree of association of sodium salicylate and indomethacin with inflammatory cells was measured under in vivo conditions in ascites bearing mice. These animals had sufficient volume of inflammatory effusion in the peritoneal cavity which enabled measurement of drug concentrations extravascularly, both in the effusion and in the inflammatory cells. A single anti-inflammatory dose of 200 mg/kg sodium salicylate or 10 mg/kg indomethacin was administered orally or intraperitoneally. The peritoneal salicylate levels exceeded blood levels starting approximately 4 h following oral drug application. Indomethacin peritoneal levels were substantially lower within 6 h after oral drug intake and exceeded the blood levels at 24 h. Intraperitoneal dosing of salicylate resulted after approximately 4 h in similar vascular and extravascular drug concentrations. Indomethacin was slowly cleared from the peritoneal compartment after intraperitoneal administration. Salicylate and indomethacin accumulated under in vivo inflammatory conditions in peritoneal cells. The degree of accumulation (the intracellular concentration was at most 6 times the extracellular concentration) was dependent on compound, time of sampling, protein binding and administration route. These results were confirmed in in vitro cell association experiments. Protein appeared to affect the macro- and micropartition of these drugs. The differences in biodistribution at macro level (tissue distribution) and at micro level (cellular association) between sodium salicylate and indomethacin were sought in the apparent disparities in protein binding and affinity for protein in mouse serum and exudate.

An in vitro approach to study cellular kinetics of drugs.

We adapted different existing techniques in order to optimize the methodology for studying kinetic interactions between drugs and cells in vitro. Using the polymorphonuclear leukocyte as a target cell, we measured the binding of various ligands and intracellular drug concentrations. We also studied pharmacological modulation of drug transport under normal and inflammatory conditions. Our approach allows reproducible measurements on ligands with low affinity for association sites on polymorphonuclear leukocytes. We present data for various nonsteroidal antiinflammatory drugs and other ligands to validate our methodological approach. On the basis of the results thus obtained, we proposed a tentative model to fit data and concepts of drug-cell interactions.

Characteristics of the transport of ascorbic acid into leucocytes.

The degree and the mode of association of [14C]-ascorbic acid with leucocytes are examined. The degree of association of ascorbic acid with polymorphonuclear leucocytes (1-3%) is dependent on cell type, extracellular concentration of ascorbic acid, incubation temperature, intactness of the cells and the extracellular pH. All experiments are performed according to strict protocols as these compounds are labile in aqueous solutions. Further it is noticed that in all experiments an outward gradient of leucocyte endogenic ascorbic acid exists. The results suggest that the association process comprises at least one saturable pathway. The activation of polymorphonuclear leucocytes by phorbol myristate acetate increases the accumulation of ascorbic acid threefold.