Search

In this study, frequency-dependent seismic scattering and intrinsic attenuation parameters for the crustal structure beneath the W-Bohemia/Vogtland swarm earthquake region close to the border of Czech Republic and Germany are estimated. Synthetic seismogram envelopes are modelled using elastic and acoustic radiative transfer theory. Scattering and absorption parameters are determined by fitting these synthetic envelopes to observed seismogram envelopes from 14 shallow local events from the October 2008W-Bohemia/Vogtland earthquake swarm. The two different simulation approaches yield similar results for the estimated crustal parameters and show a comparable frequency dependence of both transport mean free path and intrinsic absorption path length. Both methods suggest that intrinsic attenuation is dominant over scattering attenuation in the W-Bohemia/Vogtland region for the investigated epicentral distance range and frequency bands from 3 to 24 Hz. Elastic simulations of seismogram envelopes suggest that forward scattering is required to explain the data, however, the degree of forward scattering is not resolvable. Errors in the parameter estimation are smaller in the elastic case compared to results from the acoustic simulations. The frequency decay of the transport mean free path suggests a random medium described by a nearly exponential autocorrelation function. The fluctuation strength and correlation length of the random medium cannot be estimated independently, but only a combination of the parameters related to the transport mean free path of the medium can be computed. Furthermore, our elastic simulations show, that using our numerical method, it is not possible to resolve the value of the mean free path of the random medium. [ABSTRACT FROM AUTHOR]

This review presents an overview of German and Dutch research institutions and their studies in the field of skin drug delivery and adjacent topics. In the Netherlands, the involved research groups are mainly localized in Leiden, whereas in Germany the skin research institutions are spread over the whole country. The scientific studies in the Netherlands focus on the in-depth analysis of human skin composition and its individual components as well as on the development and characterization of dermal drug delivery systems ranging from liquid crystalline systems and vesicles up to microneedles with an emphasis on examining the interactions of these drug delivery systems with the human skin in vitro and in vivo. In Germany, the individual areas of research span from in-depth investigations on various drug delivery systems intended for skin application and the development of novel in vitro models for skin absorption testing up to in vivo studies focusing on the biological performance of topically applied actives. Furthermore, sophisticated analytical techniques are applied for the elucidation of skin assembly and transport processes. In addition, experimentally derived data are correlated with advanced computational modelling. Even though the individual research topics in the Netherlands and Germany are quite diverse, the exchange of knowledge and interdisciplinary collaborations between the two neighbouring countries were and are still frequently made. In this context, the review aims at highlighting crosslinks between the different institutions and individual persons to complete the picture. For each institution, the principal investigators and their studies are presented and the upcoming young scientists are introduced as an outlook for the field. This review does not claim completeness, but is rather intended to give a general overview of Dutch and German research in the field of skin drug delivery and adjacent topics. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The Hörre Belt in the SE part of the Rhenish Massif has been regarded as autochthonous because of the apparent lack of metamorphic inversion. We have performed a K-white mica study using powder X-ray diffraction derived Kübler Index (KI) and K-white mica b cell dimension, and the spectrally derived wavelength of the 2,200 nm absorption feature ('2200wvl') of supposedly allochthonous units and the underlying par-autochthon. KI reveals a slight, but significant inversion of metamorphic grade, which shows that the Hörre Belt and the Hessische Schieferserie adjacent to the South were emplaced by thrusting after they had acquired peak metamorphism ( M) in deeper parts of the orogenic wedge. Only in the westernmost part of the study area, the par-autochthon and the allochthon show the same grade of anchizonal metamorphism. This observation, together with K-white mica b cell dimensions <9.000 Å and 2200wvl <2,204 nm, suggests a second, low-pressure metamorphism M subsequent to the emplacement of the allochthon. This is supported by an anomaly of published conodont alteration index data. Our results expand the original width of the Rheno-Hercynian passive margin to at least 580, more probably to 670 or even 750 km. Palinspastic restoration also reveals that the Givetian to Early Carboniferous volcanic belt of the Lahn/Dill area is not only younger than the Emsian MORB-type lavas of the Rheno-Hercynian ocean, but was also separated, from the latter, by a largely non-volcanic belt of at least c. 220 km width. Apparently, the Givetian to Early Carboniferous volcanic episodes were unrelated to the Rheno-Hercynian drift stage. [ABSTRACT FROM AUTHOR]

Abstract: Active and abandoned coal mines have a huge impact on the environment. The most challenging problem is caused by acid mine drainage (AMD). Using traditional methods such as single point measurements to determine and analyze mining lakes over the period of a few years is difficult due to the lakes'' high dynamic and inner differentiation. To overcome this difficulty, a new method has been successfully tested to additionally monitor residual lakes. Using a manifold data set (like images from the hyperspectral airborne scanner casi, ground truth data, spectral field and laboratory measurements), the optical properties (reflection, absorption and scattering) of acid mining lakes were defined for the first time ever. Furthermore, hydrochemical parameters in quality and quantity were ascertained in a two-stage process. First, optical properties of the mining lakes were analyzed and defined for each of the limnological stages of development. Second, based on the lakes'' optical properties, algorithms for classification of the hydrochemical parameters evolved and were reliably utilized. The new algorithms enable the monitoring of mining lakes from acidic to alkaline as well as the quantification of the hydrochemical properties inside the lake water. [Copyright &y& Elsevier]

Nilotinib (Tasigna), a highly selective and potent BCRABL tyrosine kinase inhibitor (TKI), is administered orally and has pH-dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty-two participants (6 women, 16 men, mean age of 44.9 ± 12.9 years) were enrolled to receive nilotinib as a single oral 400-mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after nilotinib dosing, and nilotinib serum concentrations were determined by a validated liquid chromatography/tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, nilotinib Cmax was decreased by 27% and AUC0-∞ decreased by 34%. Nilotinib tmax was prolonged from 4.0 to 6.0 hours, but t1/2 was not altered. Mean gastric pH was 1.0 ± 0.5 at baseline and increased to 2.79 ± 2.50, 3.98 ± 2.27, 5.30 ± 1.70, 5.38 ± 1.26, and 5.31 ± 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors. [ABSTRACT FROM AUTHOR]

The fate of beta blockers (atenolol, acebutolol, bisoprolol, celiprolol, metoprolol, nadolol, pindolol, propranolol, and sotalol) was studied in surface water-sediment systems. A new analytical method was developed to determine the beta blockers in sediments by LC-ESI-tandem MS detection. The relative recoveries in sediments ranged from 89 ± 7% (acebutolol) to 102 ± 3% (nadolol) using deuterated surrogate standards. Beta blockers were present with concentrations up to 86 ng/g (bisoprolol) in the sediments of small German streams containing an elevated percentage of treated wastewater. Biotransformation studies and sorption isotherms of the beta blockers were performed with two natural river sediments ("Burgen", "Dausenau") differing in organic carbon content and particle size distribution. Biotransformation of beta blockers in the surface water-sediment systems exhibited a low to high persistence with 90% disappearance (DT90) ranging from 0.4-10 d (pindolol, atenolol) to >100 d (sotalol, propranolol or celiprolol). For sorption studies neither NaN3 addition nor autoclavation led to a complete mass balance of the beta blockers, probably due to biotransformation. Isotherms at 6 h (apparent equilibrium, measuring aqueous and sediment phase) fitted by the Freundlich equation show that sorption of all beta blockers to the Burgen sediment were linear or close to it (i.e., n-values between 0.93 and 1.13), while in the Dausenau sediment the sorptions were slightly non linear (i.e., n-values 0.77-0.91). In river water the sorbed fraction is negligible in comparison to the dissolved fraction. Nevertheless, beta blockers can be detected with concentrations up to 86 ng/g (bisoprolol) in sediments of small streams containing more than 50% treated wastewater. [ABSTRACT FROM AUTHOR]

Abstract: Fertilization with 2.5t/ha limestone: (83% CaCO3, 8% MgO, 6% K2O, 3% P2O5) reduces the 137Cs transfer from spruce forest soil into plants like fern (Dryopteris carthusiana) and blackberry (Rubus fruticosus) by a factor of 2–5 during at least 11 years as measured by the aggregated transfer factor Tag. In 1997 and 2006 these results were confirmed by additional measurements of the 137Cs transfer factor TF, related to the root zone (Oh horizon), which were explained by the selective sorption of 137Cs in the root zone by measurements of the Radiocaesium Interception Potential (RIP) in fertilized (RIP>179meq/kg) and non-fertilized soils (RIP<74meq/kg). [Copyright &y& Elsevier]

A method to estimate reactive transport parameters as well as geometric conduit parameters from a multitracer test in a karst aquifer is provided. For this purpose, a calibration strategy was developed applying the two-region nonequilibrium model CXTFIT. The ambiguity of the model calibration was reduced by first calibrating the model with respect to conservative tracer breakthrough and later transferring conservative transport parameters to the reactive model calibration. The reactive transport parameters were only allowed to be within a defined sensible range to get reasonable calibration values. This calibration strategy was applied to breakthrough curves obtained from a large-scale multitracer test, which was performed in a karst aquifer of the Swabian Alb, Germany. The multitracer test was conducted by the simultaneous injection of uranine, sulforhodamine G, and tinopal CBS-X. The model succeeds to represent the tracer breakthrough curves (TBCs) of uranine and sulforhodamine G and verifies that tracer-rock interactions preferably occur in the immobile fluid region, although the fraction of this region amounts to only 3.5% of the total water. However, the model failed to account for the long tailing observed in the TBC of tinopal CBS-X. Sensitivity analyses reveal that model results for the conservative tracer transport are most sensitive to average velocity and volume fraction of the mobile fluid region, while dispersion and mass transfer coefficients are least influential. Consequently, reactive tracer calibration allows the determination of sorption sites in the mobile and immobile fluid region at small retardation coefficients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The extension of biowaivers (drug product approval without a pharmacokinetic bioequivalence study) to drugs belonging to Class III of the Biopharmaceutics Classification System (BCS) is currently a subject of much discussion. OBJECTIVES: To assess the relationship between in vitro dissolution characteristics and in vivo absorption performance of immediate-release (IR) products containing cimetidine, a BCS Class III compound, in human subjects. To evaluate the feasibility and appropriateness of an extension of the biowaiver concept to BCS Class III compounds. STUDY DESIGN AND PARTICIPANTS: BCS-conform dissolution tests were carried out on ten marketed cimetidine products from Thailand and Germany, as well as cimetidine tablet formulations containing cimetidine 400mg manufactured by direct compression using methacrylate copolymer (Eudragit® RS PO) as a release-retarding agent to yield three batches with significantly different release profiles. Twelve healthy male subjects were enrolled in a randomised, open-label, single-dose schedule based on a five-way Williams' design balanced for carryover effects. Subjects received the following treatments, with 1-week washout periods between: (i) Tagamet® 400mg tablet; (ii) 7.5% methacrylate copolymer cimetidine tablet; (iii) 15% methacrylate copolymer cimetidine tablet; (iv) 26% methacrylate copolymer cimetidine tablet; and (v) Tagamet® (300mg/2mL) intravenous injection. The area under the plasma concentration-time curve from 0 to 12 hours (AUC12) and AUC from time zero to infinity (AUC∞), peak plasma concentration (Cmax), absolute bioavailability (F) and mean residence time (MRT) were evaluated and statistically compared among formulations. In vitro-in vivo correlation (IVIVC) analysis was then applied to elucidate the overall absorption characteristics of each tablet formulation. RESULTS: The release properties of the ten marketed cimetidine products were shown to comply with current US FDA criteria for rapidly dissolving drug products. As expected, the in vitro dissolution profiles of the cimetidine tablets containing different percentages of methacrylate copolymer differed considerably from one another. However, in vivo results showed no significant difference in AUC12, AUC∞, Cmax and F between the tablets manufactured with methacrylate copolymer and the innovator. The MRT values obtained from 26% methacrylate copolymer tablets were significantly longer than for the other two methacrylate copolymer formulations and the Tagamet® tablets. Furthermore, IVIVC analysis showed that the 26% methacrylate copolymer tablets exhibited dissolution rate-limited absorption, whereas the other formulations showed permeability rate-limited absorption. CONCLUSION: The results of the present study indicated that the absorption of cimetidine from IR tablets is, in general, limited by permeability rather than dissolution. IVIVC analysis demonstrated that only when the release was deliberately retarded (tablets containing 26% methacrylate copolymer), did the dissolution represent the rate-limiting step to drug absorption. On the in vitro side, it seems that 85% dissolution within 30 minutes, as currently required by the US FDA Guidance, is more than sufficient to guarantee bioequivalence of IR cimetidine products. For cimetidine and other BCS Class III drugs with a similar intestinal absorption pattern, application of the biowaiver concept seems to present little risk of an inappropriate bioequivalence decision. [ABSTRACT FROM AUTHOR]

Semi-classical molecular dynamics simulations of small rare gas clusters in short laser pulses of 100 nm wavelength were performed. For comparison, the cluster response to 800 nm laser pulses was investigated as well. The inner ionization dynamics of multi-electron atoms inside the cluster was treated explicitly. The simulation results underpin the belief that at XUV (extreme ultraviolet) wavelengths collisions play an important role in the energy absorption. The generation of the surprisingly high charge states of Xe atoms inside clusters, as they were observed in a free-electron laser experiment at DESY, Hamburg, Germany by Wabnitz et al. is due to the reduced ionization potential of atoms inside charged clusters, the ionization ignition mechanism, and collisions. [ABSTRACT FROM AUTHOR]

Kinetics of Eu sorption on sandy sediment from Gorleben, Germany, containing humic substances, was studied by radiotracer method in batch experiments at very low europium concentration (3.4.10-8 mol/l), with the aim to find kinetic parameters suitable for modeling Eu migration in bed of the sediment and to elucidate the mechanism of the sorption. Experiments were evaluated using a new simplified method taking into account simultaneous sorption/desorption of Eu on the walls of sorption vessel. Five kinetic functions were tested, of which that describing diffusion in inert surface layer of sorbent proved most suitable. The effects of pH (3.0-8.8) by addition of Aldrich humic acid (10 mg/l), addition of hydrogencarbonates (5.10-3 mol/l) and preequilibration of the sediment with solution or of Eu with solution were examined. From the results it has been concluded that the kinetics and mechanism of the sorption strongly depend on pH. At pH 4.8 Eu is sorbed mainly as humate complex from the solution of humic acid. The addition of humic acid accelerates the sorption. Carbonate complexes of Eu are the probable forms sorbed at pH 8.8. The presence of humic substances in the slightly alkaline solutions suppresses the rate of the sorption due to slow dissociation of Eu-humate complexes. [ABSTRACT FROM AUTHOR]

Panama, like most Latin American countries, has insufficient regulatory safeguards to ensure the safety and efficacy of all pharmaceutical products in the market, a situation that results in a two-tier system, where affluent citizens can afford innovator products while poor citizens must consume 'generics' of uncertain quality. Given that one lot of each drug product is analyzed every five years during registration while commercial lots are not, and since most products are not bioequivalent but simply copies or similars, there is a concern that commercial and registration lots of these 'generics' may not be of the same quality. The objective of this study was to assess the ability of various in vitro quality control tests to detect difference among five amlodipine products available in the Panamanian market: four 'generics', made in various countries, and the innovator, made in Germany and used as reference listed drug in Panama (Pan-RLD). The innovator manufactured in the United States (US-RLD) was used to compare the two RLDs. The Content Uniformity test, 30-min Dissolution test and multiple-pH Dissolution Profiles did not show any difference among the products. However, the in vitro dissolution absorption system 1 (IDAS1) showed a statistically significant difference in the amount dissolved between Pan-RLD and three out of the four 'generics', and significantly lower permeated amount for all the 'generics' compared with Pan-RLD; only US-RLD was similar to Pan-RLD. Thus, IDAS1 showed promise as a potential tool that authorities in weakly regulated markets can use to monitor for possible lot-to-lot product changes, which can help improve the quality of pharmaceutical products available to their entire populations. The significance of the similarity between the innovators made in Germany and the United States and their difference from the 'generics' (manufactured in other countries) is not known but deserves investigation. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ). Secondary objectives: • Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells - peripheral blood mononuclear cells (PBMCs). • Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes).Trial Design: Single centre, open-label, parallel group, two-arm, phase I drug-drug interaction trial.Participants: Healthy volunteers (18-60 years old) are treated in the Clinical Pharmacological Trial Center of Heidelberg University Hospital, Germany.Intervention and Comparator: • Participants are randomized in a group to either receive a nine-day course of pantoprazole, or to a control group without pantoprazole. All participants receive a single dose of HCQ 400 mg. • Additionally, CYP3A4 and CYP2D6 phenotyping with microdosed probe drugs is performed using midazolam and yohimbine as enzyme activity markers, respectively.Main Outcomes: Primary endpoint: Area under the curve (AUC)0-72 h and maximum concentration (Cmax) of a single oral dose of 400 mg HCQ with and without pantoprazole (changes in these two values describe relevant aspects of exposure to HCQ with and without administration of pantoprazole). Secondary endpoints: • AUC2-4 h, AUC0-6 h and Cmax of midazolam and yohimbine. • Correlation of HCQ concentrations in whole blood with concentrations in plasma and peripheral blood mononuclear cells (PBMC).Randomisation: Participants are assigned to treatment groups by using a randomisation list (1:1, block size = 4) and consecutive enrolment.Blinding (masking): The trial is an open-label trial, participants and investigators are not blinded.Numbers To Be Randomised (sample Size): A total number of 24 participants (12 per group) are planned to be randomised.Trial Status: Protocol version 2.1 dated 24/04/2020, first patient first visit. April 30th, 2020, recruitment ongoing, anticipated end of study June 30th, 2020.Trial Registration: EudraCT Number: 2020-001470-30 , registered on 31 March 2020 German Clinical trials register number / International Clinical Trials Registry Platform: DRKS00021573, registered on 27 April 2020 FULL PROTOCOL: The full trial protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full trial protocol. The trial protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). [ABSTRACT FROM AUTHOR]

In the last years a significant number of eye-safe single-wavelength backscatter lidars, oftenreferred to as ceilometers, was installed for unattended operation. Though the primaryreason for such ceilometer networks is the automation of synoptic observations, inparticular the determination of the cloud base height, the potential of quantitativeremote sensing of aerosols has been investigated for approximately 10 years. Oneof the main benefits is the very good spatial coverage that allows to track aerosollayers in real time. The optical characterization of aerosols is however limited tothe particle backscatter coefficient βp. In this context it was ignored for a longtime that most of the ceilometers work in a spectral range where water vapor isabsorbing, so that a correction is required if one aims at the quantitative retrieval ofβp. As a consequence we have investigated the relevance of water vapor absorption forceilometer signals and developed a numerical procedure to correct for it (Wiegner andGasteiger, 2015). Recently the validation of this correction scheme was attempted (Wiegneret al., 2018), based on data from the CeiLinEx2015 campaign in Lindenberg, Germany, whenseveral types of ceilometers and a reference lidar system were deployed. In this context itmust be considered that a strict validation is hardly possible as the optical properties ofparticles (backscatter and extinction) at the wavelength of the reference system (withoutwater vapor absorption, in our case at 1064 nm) and at the wavelength of the ceilometer(with absorption, around 910 nm) are different. They can only be estimated from sunphotometer data and the inversion of the reference lidar signal. Moreover, the emittedwavelength of the ceilometers is typically not exactly known due to missing technicalspecifications and possible drifts with temperature. Taking these uncertainties intoaccount it was demonstrated that the correction of CL51 (Vaisala) measurements istrustworthy. We want to emphasize that water vapor absorption does not play a significant role for theassessment of the mixing layer height (mlh) and the detection of (elevated) aerosol layers. Forthese applications the low signal-to-noise ratio and (possible) signal artefacts, but also theambiguity of most mlh-retrievals are more relevant. Nevertheless, we recommend monitoringthe emitted wavelength of the instrument to obtain new options of aerosol remotesensing. Wiegner, M. and Gasteiger, J.: Correction of water vapor absorption foraerosol remote sensing with ceilometers, Atmos. Meas. Tech., 8, 3971-3984,https://doi.org/10.5194/amt-8-3971-2015, 2015. Wiegner, M. et al.: Aerosol backscatter profiles from ceilometers: validation of watervapor correction in the framework of CeiLinEx2015, Atmos. Meas. Tech. Discuss.,https://doi.org/10.5194/amt-2018-307, in review, 2018. [ABSTRACT FROM AUTHOR]