Membrane Separation of Chicken Byproduct Hydrolysate for Up-Concentration of Bioactive Peptides.

Membrane processes, such as microfiltration, ultrafiltration, and nanofiltration, are increasingly used for various applications in both upstream and downstream processing. Membrane-based processes play a critical role in the field of separation/purification of biotechnological products, including protein production/purification. The possibility of using membranes to separate peptides from a chicken byproduct hydrolysate and the effect of the performed downstream processing on the DPP-IV dipeptidyl peptidase IV (DPP-IV) inhibitory activity of mechanical deboning chicken residue (MDCR) has been investigated. The chicken byproduct hydrolysate was prepared by enzymatic hydrolysis followed by microfiltration (MF), ultrafiltration (UF), nanofiltration (NF), and reverse osmosis (RO) separation. Comparing all separation treatments, hydrolysates processed only by MF and UF show the best DPP-IV inhibition (59.5-60.0% at 1 mg/mL and 34.2-40.7% at 0.5 mg/mL). These samples show dose-responsive behavior. Bioactivity was correlated with molecular weight distribution profiles and average molecular weights. The nanofiltration process notably decrease the inhibitory activity, and these permeates show low DPP-IV inhibition (9.5-21.8% at 1 mg/mL and 3.6-12.1% at 0.5 mg/mL). The size-exclusion chromatography-organic carbon detection-organic nitrogen detection (LC-OCD-OND) analysis confirms that NF and RO would retain the bioactive peptides in the concentrate in comparison to MF and UF. Bioactivity was correlated with molecular weight distribution profiles and average molecular weights. Permeates after ultrafiltration show an IC50 value of 0.75 mg/mL, comparable to other potent DPP-IV inhibitors derived from various food sources, and significantly more potent compared to the microfiltration sample, which shows an IC50 value of 1.04 mg/mL. The average molecular weight of the permeates calculated from the SEC chromatograms was 883 g/mol for UF and 1437 g/mol for MF. Of the four membranes studied, the UF membrane shows the best separation properties with respect to maximizing the yield and up-concentration of the bioactive peptides. Overall, UF was demonstrated to be a feasible technology for the removal of the undesired high-molecular-weight substances and up-concentration of small-molecular-weight bioactive peptides from chicken byproduct hydrolysate. These peptides might exhibit biological activity and could offer several health benefits. There is a high potential for the use of bioactive peptides, and more research in this field can lead to promising results that have significant effects in the food and medical industries.

Removal and release of microplastics and other environmental pollutants during the start-up of bioretention filters treating stormwater.

Untreated stormwater is a major source of microplastics, organic pollutants, metals, and nutrients in urban water courses. The aim of this study was to improve the knowledge about the start-up periods of bioretention filters. A rain garden pilot facility with 13 bioretention filters was constructed and stormwater from a highway and adjacent impervious surfaces was used for irrigation for ∼12 weeks. Selected plants (Armeria maritima, Hippophae rhamnoides, Juncus effusus, and Festuca rubra) was planted in ten filters. Stormwater percolated through the filters containing waste-to-energy bottom ash, biochar, or Sphagnum peat, mixed with sandy loam. Influent and effluent samples were taken to evaluate removal of the above-mentioned pollutants. All filters efficiently removed microplastics >10 µm, organic pollutants, and most metals. Copper leached from all filters initially but was significantly reduced in the biochar filters at the end of the period, while the other filters showed a declining trend. All filters leached nutrients initially, but concentrations decreased over time, and the biochar filters had efficiently reduced nitrogen after a few weeks. To conclude, all the filters effectively removed pollutants during the start-up period. Before being recommended for full-scale applications, the functionality of the filters after a longer period of operation should be evaluated.

Bioequivalence Evaluation in Healthy Volunteers: New Generic Formulations of Sitagliptin and Sitagliptin-Metformin Fixed-Dose Combination Compared with the Originator Products.

INTRODUCTION: Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100 mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850 mg, 50/1000 mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. METHODS: The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48 h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUC0-t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0-t and Cmax were within BE acceptance range of 80.00-125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). RESULTS: Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100 mg), 26/25 (FDC 50/850 mg), and 26/24 (FDC 50/1000 mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0-t and Cmax were 95.83-100.37% and 91.85-109.56% (sitagliptin 100 mg); 100.84-103.69% and 93.44-105.10% (FDC 50/850 mg), and 101.26-105.20% and 98.71-112.89% (FDC 50/1000 mg); respective values for metformin were 94.23-101.89% and 91.66-99.38% (FDC 50/850 mg) and 98.45-104.89% and 96.79-105.62% (FDC 50/1000 mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. CONCLUSIONS: The new generic tablet formulations of sitagliptin 100 mg and the FDCs sitagliptin/metformin 50/850 mg and 50/1000 mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). TRIAL REGISTRATION: EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).

Calculating expected effects of treatment effectivity and river flow rates on the contribution of WWTP effluent to the ARG load of a receiving river.

Concentrations of genetic markers for antibiotic resistance genes (ARGs) were measured in the effluents of three Norwegian wastewater treatment plants (WWTPs) and in a receiving river upstream and downstream of the discharge point of one WWTP. Calculations based on mass balances were carried out to evaluate the impact of river flow rates and treatment effectivity on the WWTP's contribution to the load of genetic markers in the river. At average river flow rates, the WWTP effluent contributes 5-15% to the genetic marker load of the respective river. However, at minimum river flow rates, the WWTP effluent contributes 22-55% to the loads of different genetic markers. Scenarios of an improved or worsened removal of genetic markers in the WWTP showed that a further 1-log removal using additional treatment would be sufficient to improve considerably the river water quality with respect to genetic markers. Then, at an average flow rate, the contribution of the WWTP effluent to the load of the river would be less than 2%. However, in the case of low treatment effectivity or malfunction of the WWTP, the marker load of the river would increase dramatically. Even at average flow rate, 75-92% of the marker load would then originate from the WWTP. The results demonstrate the importance of considering the flow rates and hydrologic characteristics of the recipient water body when deciding on priorities regarding the upgrade of WWTPs for further removal of ARGs.

Water quality aspects related to domestic drinking water storage tanks and consideration in current standards and guidelines throughout the world - a review.

In many parts of the world, drinking water storage takes place in near-house or in-house tanks. This can impact drinking water quality considerably. International and numerous national standards and guidelines addressing the construction, installation and operation of domestic drinking water storage tanks are reviewed on their consideration of water quality aspects and the minimisation of health risks associated with drinking water storage. Several national and international standards and guidelines are reviewed in terms of drinking water quality requirements. Factors that have an impact on water quality in relation to the use of domestic drinking water storage tanks are summarised comprehensively. The impact of the domestic storage of drinking water on water quality, the points and locations of use, their positioning, the materials they are made of, their design and operation, as well as aspects of how they are operated and maintained is outlined and discussed in detail. Finally, the incorporation of aspects regarding water quality in drinking water storage tanks in standards and guidelines is presented and assessed. To make the use of domestic drinking water storage tanks safer and more efficient, recommendations for modifications, improvements and extensions of respective standards are made.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Atacicept in a Randomized Trial in Healthy Caucasian and Japanese Subjects.

BACKGROUND AND OBJECTIVE: Atacicept is an inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), and is being studied in relation to immunological disease. Currently, limited data on atacicept are available in non-Caucasian subjects. Pharmacokinetic data from earlier studies of atacicept were derived using an enzyme-linked immunosorbent assay (ELISA), which was subsequently found to have inadequacies. Hence, a new bioanalytical ELISA for total atacicept was developed and validated. We conducted this randomized, double-blind, placebo-controlled phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of atacicept in healthy Japanese and Caucasian subjects while generating pharmacokinetic data using the new ELISA. METHODS: Japanese subjects aged ≥ 18 to ≤ 55 years (n = 24) were randomized (1:1:1:1) to a single subcutaneous dose of atacicept 25, 75, or 150 mg or placebo. Caucasian subjects were then enrolled to match the Japanese subjects' gender, body weight (± 20%), and height (± 15%). RESULTS: Atacicept was well tolerated and there were no clinically significant differences in treatment-emergent adverse events (TEAEs), vital signs, or laboratory parameters between the Japanese and Caucasian subjects. Most (90%) TEAEs were mild; no severe or serious TEAEs or deaths occurred. Weight-adjusted atacicept exposure was comparable between ethnicities and across doses: the Japanese/Caucasian ratio of the area under the serum concentration-time curve from time zero to the last sampling point (AUC0-t) was 107.21% (90% CI 93.42-123.02%) and the Japanese/Caucasian ratio of maximum serum concentration (Cmax) was 95.74% (90% CI 74.26-123.43%; ANCOVA). Median time to reach Cmax (tmax) was 20-60 h across all subjects. Dose-exposure relationships were comparable for the two ethnicities, with dose-normalized AUC0-t decreasing with increasing dose, indicating nonlinear pharmacokinetics for the doses examined. There were no statistically significant differences between ethnicities in the pharmacokinetics-dose relationship. Some transient dose-related decreases in mean serum immunoglobulin (Ig)A and IgM, but not IgG, were observed after atacicept administration. There were small transient increases in peripheral B cell numbers in the first 4 days after dosing that were larger with atacicept than with placebo, with no apparent dose relationship. No anti-atacicept antibodies were detected. CONCLUSION: The safety, pharmacokinetic, and pharmacodynamic profiles of atacicept in healthy Japanese subjects were comparable to those in healthy Caucasian subjects. EudraCT-ID: 2013-002703-34.

Editorial for the Special Issue on 'Application and Behavior of Nanomaterials in Water Treatment'.

The simultaneous population explosion and the growing lack of clean water today requires disruptively innovative solutions in water remediation [...].

Impact of Different Combinations of Water Treatment Processes on the Concentration of Disinfection Byproducts and Their Precursors in Swimming Pool Water.

To mitigate microbial activity in swimming pools and to ensure hygienic safety for bathers, pool systems have a recirculating water system ensuring continuous water treatment and disinfection by chlorination. A major drawback associated with the use of chlorine as disinfectant is its potential to react with precursor substances present in pool water to form harmful disinfection byproducts (DBPs). In this study, different combinations of conventional and advanced treatment processes were applied to lower the concentration of DBPs and their precursors in pool water by using a pilot-scale swimming pool model operated under reproducible and fully controlled conditions. The quality of the pool water was determined after stationary concentrations of dissolved organic carbon (DOC) were reached. The relative removal of DOC (Δc cin-1) across the considered treatment trains ranged between 0.1  ±  2.9% and 7.70  ±  4.5%, where conventional water treatment (coagulation and sand filtration combined with granular activated carbon (GAC) filtration) was revealed to be the most effective. Microbial processes in the deeper, chlorine-free regions of the GAC filter have been found to play an important role in the degradation of organic substances. Almost all treatment combinations were capable of removing trihalomethanes to some degree and trichloramine and dichloroacetonitrile almost completely. However, the results demonstrated that effective removal of DBPs across the treatment train does not necessarily result in low DBP concentrations in the basin of a pool. This raises the importance of the DBP formation potential of the organic precursors, which has been shown to depend strongly on the treatment concept applied. Irrespective of the filtration technique employed, treatment combinations employing UV irradiation as a second treatment step revealed higher concentrations of volatile DBPs in the pool compared to those employing GAC filtration as a second treatment step. In the particular case of trichloramine, results confirm that its removal across the treatment train is not a feasible mitigation strategy because it cannot compensate for the fast formation in the basin.

N2 yields from monochloramine conversion by granular activated carbons are decisive for effective swimming pool water treatment.

Inorganic chloramines (mono-, di- and trichloramine) are formed in swimming pool water from the unintended reaction of free chlorine with ammonia that is introduced by bathers. Monochloramine is of particular interest as it is known to react further in pool water forming harmful DBPs, such carcinogenic N-nitrosodimethylamine (NDMA). During pool water treatment with granular activated carbon (GAC) filters, monochloramine is transformed by chemical reactions on the carbon surface to N2 and ammonia. As ammonia is led back into the pool where it is chlorinated again under the renewed formation of inorganic chloramines, it is recommended to use GACs with a high N2 yield for monochloramine transformation in pool water treatment. In this study, yields of N2 and ammonia from monochloramine conversion by commercially available GACs were determined using a fixed-bed reactor system under conditions that are typical for swimming pool water treatment. The N2 yields remained constant with on-going exposure of the GAC to monochloramine and ranged from 0.5% to 21.3%, depending on the type of GAC used. Correlation analyses were conducted to identify carbon properties that can determine the N2 yield for monochloramine conversion, such as the amount of oxygen groups, the elemental composition and the trace metal content. It was found that the N2 yield significantly correlates with the copper content of the tested carbons. Model calculations combining pool hydraulics with formation/abatement of inorganic chloramines and NDMA as well as chloramine transformations in GAC filters showed that the concentration of inorganic chloramines and carcinogenic NDMA can be decreased by a factor of ∼2, if the tested GACs could be modified to convert up to ∼50% of the monochloramine to N2.

Removal of antibiotic resistant E. coli in two Norwegian wastewater treatment plants and by nano- and ultra-filtration processes.

The effectivity of different treatment stages at two large wastewater treatment plants (WWTPs) located in Oslo, Norway, to remove antibiotic resistant Escherichia coli from municipal wastewater was investigated. The WWTPs were effective in reducing the total cultivable E. coli. The E. coli in WWTP samples were mainly resistant to ampicillin (6-27%) and trimethoprim-sulfamethoxazole (5-24%), and, to a lesser extent, tetracycline (3-14%) and ciprofloxacin (0-7%). In the first WWTP, a clear decrease in the percentage of E. coli resistant to these antibiotics was found, with the main removal occurring during physical/chemical treatment. In the second WWTP, the percentage of cultivable resistant E. coli did not display a considerable change. During laboratory-scale membrane filtration of WWTP effluents using ultrafiltration (UF) and nanofiltration (NF) membranes, all E. coli, including those resistant to antibiotics, were removed completely. The results imply that UF and NF processes are potent measures to remove antibiotic resistant bacteria (ARB) during post-treatment of WWTP effluents, thus reducing the potential spread of antibiotic resistance in the receiving aquatic environment.

Pore diffusion limits removal of monochloramine in treatment of swimming pool water using granular activated carbon.

Overall apparent reaction rates for the removal of monochloramine (MCA) in granular activated carbon (GAC) beds were determined using a fixed-bed reactor system and under conditions typical for swimming pool water treatment. Reaction rates dropped and quasi-stationary conditions were reached quickly. Diffusional mass transport in the pores was shown to be limiting the overall reaction rate. This was reflected consistently in the Thiele modulus, in the effect of temperature, pore size distribution and of grain size on the reaction rates. Pores <2.5 times the diameter of the monochloramine molecule were shown to be barely accessible for the monochloramine conversion reaction. GACs with a significant proportion of large mesopores were found to have the highest overall reactivity for monochloramine removal.

Single-dose pharmacokinetic study comparing the pharmacokinetics of recombinant human chorionic gonadotropin in healthy Japanese and Caucasian women and recombinant human chorionic gonadotropin and urinary human chorionic gonadotropin in healthy Japanese women.

Purpose: Recombinant hCG (r-hCG) was approved in Japan in 2016. As a prerequisite for a Phase III study in Japan related to this approval, the pharmacokinetic (PK) profile of r-hCG was investigated. Methods: An open-label, partly randomized, single-center, single-dose, group-comparison, Phase I PK-bridging study was done that compared a single 250 µg dose of r-hCG with a single 5000 IU dose of urinary hCG (u-hCG) in healthy Japanese women, as well as comparing a single 250 µg dose of r-hCG in Japanese and Caucasian women. The Japanese participants were randomized 1:1 to receive either r-hCG or u-hCG, while the Caucasian participants were weight-matched to the Japanese participants who were receiving r-hCG in a 1:1 fashion. The primary PK parameters were the area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC 0-∞) and the maximum serum concentration (Cmax). Results: The mean serum hCG concentration-time profiles of r-hCG in the Japanese and Caucasian participants were a similar shape, but the level of overall exposure was ~20% lower in the Japanese participants. For the Japanese participants, r-hCG resulted in an 11% lower Cmax but a 19% higher AUC 0-∞ compared with u-hCG. No new safety signal was identified. Conclusion: This study cannot exclude a potential difference in the PK profile of r-hCG between Japanese and Caucasian participants. However, this study does not indicate that there are clinically relevant differences in the serum PK of r-hCG and u-hCG in the Japanese participants.

New levothyroxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials.

OBJECTIVE: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95-105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox ) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation. METHODS: The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600 µg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50 µg, 100 µg, and 200 µg L-T4 tablets, at a total dose of 600 µg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (Cmax) of thyroxine (T4) in plasma. RESULTS: In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC0-72,adj was 99.3% (90% confidence interval [CI]: 95.6-103.2) and the Cmax,adj was 101.7% (90% CI: 98.8-104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9-1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8-1.25): the three dose strengths were dosage form proportional. CONCLUSIONS: The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.

The practical influence of rapid mixing on coagulation in a full-scale water treatment plant.

This study focuses on the effect of rapid mixing on the coagulation efficiency in a full-scale drinking-water treatment plant and discusses the mechanisms involved in the floc-formation process. The results refer to three periods of operation of the waterworks when no mechanical mixing was provided in the tanks for coagulant dosing due to mechanical failure of the rapid mixers. Although a certain deterioration of the subsequent flocculation process was observed, as assessed using the data for suspended solids, turbidity, and chemical oxygen demand, the overall water treatment performance was not affected. This suggests an insignificant role for intense rapid mixing in sweep flocculation during full-scale water treatment and reveals the potential to reduce the required energy costs for mechanical mixers.

A variable reaction rate model for chlorine decay in drinking water due to the reaction with dissolved organic matter.

A second order kinetic model for simulating chlorine decay in bulk water due to the reaction with dissolved organic matter (DOM) was developed. It takes into account the decreasing reactivity of dissolved organic matter using a variable reaction rate coefficient (VRRC) which decreases with an increasing conversion. The concentration of reducing species is surrogated by the maximum chlorine demand. Temperature dependency, respectively, is described by the Arrhenius-relationship. The accuracy and adequacy of the proposed model to describe chlorine decay in bulk water were evaluated and shown for very different waters and different conditions such as water mixing or rechlorination by applying statistical tests. It is thus very well suited for application in water quality modeling for distribution systems.

A multicenter phase 1 study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody targeting αv integrins, in progressive castration-resistant prostate cancer with bone metastases after chemotherapy.

BACKGROUND: EMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the αv subunit of human integrins. Blocking αv integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis. OBJECTIVE: Evaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments. DESIGN, SETTING, AND PARTICIPANTS: A phase 1 open-label study in 26 patients (four European centers). Eligible patients (≥ 18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate-specific antigen (PSA) values. INTERVENTION: Patients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500 mg every 2 wk). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used. RESULTS AND LIMITATIONS: Patients were treated for a mean of 16.8 ± 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for ≥ 18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials. CONCLUSIONS: No DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500 mg every 3 wk were chosen. TRIAL REGISTRATION: NCT00958477 (EMR 62242-002).

Safety, tolerability, and pharmacokinetics of the novel αv-integrin antibody EMD 525797 (DI17E6) in healthy subjects after ascending single intravenous doses.

PURPOSE: We evaluated the safety, tolerability, and pharmacokinetics (PK) of EMD 525797 (DI17E6), a humanized monoclonal antibody targeting αv-integrins, in healthy subjects. METHODS: In this first-in-human, double-blind, placebo-controlled, randomized Phase 1 study, healthy male volunteers were consecutively assigned to 6 ascending single-dose cohorts of 35, 100, 250, 500, 1000, or 1500 mg. Per dose cohort, EMD 525797 or placebo was administered over 1 h as an intravenous 250-mL infusion to 6 and 3 volunteers, respectively. Escalation to the next dose level was based on evaluation of safety, tolerability, and PK data. RESULTS: Fifty-five subjects (aged 18-45 years) were randomized. Twenty-seven of 37 (73 %) subjects receiving EMD 525797 reported a total of 61 adverse events (AEs), including 38 events (in 17 subjects) considered by the investigator to be treatment related. A total of 35 AEs were reported by 14 of 18 (78 %) placebo-treated subjects. The most commonly occurring AEs were gastrointestinal disorders, abnormal laboratory values, and increased or decreased biochemistry and/or hematology values, as well as headaches, which occurred at a slightly higher frequency in the EMD 525797 group compared with placebo. There were no serious AEs or deaths. EMD 525797 PK appeared to be dose dependent, especially at lower doses. CONCLUSION: Ascending single doses of EMD 525797 were shown to be safe and well tolerated. No safety concerns were identified. This study supports the ongoing investigation of EMD 525797.

Impact of backwashing procedures on deep bed filtration productivity in drinking water treatment.

Backwash procedures for deep bed filters were evaluated and compared by means of a new integrated approach based on productivity. For this, different backwash procedures were experimentally evaluated by using a pilot plant for direct filtration. A standard backwash mode as applied in practice served as a reference and effluent turbidity was used as the criterion for filter run termination. The backwash water volumes needed, duration of the filter-to-waste period, time out of operation, total volume discharged and filter run-time were determined and used to calculate average filtration velocity and average productivity. Results for filter run-times, filter backwash volumes, and filter-to-waste volumes showed considerable differences between the backwash procedures. Thus, backwash procedures with additional clear flushing phases were characterised by an increased need for backwash water. However, this additional water consumption could not be compensated by savings during filter ripening. Compared to the reference backwash procedure, filter run-times were longer for both single-media and dual-media filters when air scour and air/water flush were optimised with respect to flow rates and the proportion of air and water. This means that drinking water production time is longer and less water is needed for filter bed cleaning. Also, backwashing with additional clear flushing phases resulted in longer filter run-times before turbidity breakthrough. However, regarding the productivity of the filtration process, it was shown that it was almost the same for all of the backwash procedures investigated in this study. Due to this unexpected finding, the relationships between filter bed cleaning, filter ripening and filtration performance were considered and important conclusions and new approaches for process optimisation and resource savings were derived.

Impact of shear stress and pH changes on floc size and removal of dissolved organic matter (DOM).

The impact of shear stress and increases in pH on the release of natural dissolved organic matter (DOM) from Fe-DOM and Al-DOM flocs was investigated for a high organic matter, low turbidity raw water by application of a dynamic extinction probe (DEP) and liquid chromatography organic carbon detection (LC-OCD). It was shown that high shear forces resulted in a breakage of Fe-DOM flocs. Re-growth took place during subsequent low shear phases. However, re-growth was limited. The flocs regained a size of about 50% of the size after initial coagulation. Cyclic shearing resulted in slower re-growth rates. A new insight was that when enough time was given, similar sizes of the re-grown flocs were regained. As shown by bulk DOC, only an insignificant release of DOM took place when flocs were exposed to shear. Increase in shear stress resulted in smaller flocs with higher specific outer surface area. However, DOM removal did not change. Thus, there was no increase in adsorption capacity due to floc breakage. Consequently, DOM must be adsorbed inside the amorphous flocs rather than on the outer surface. Also, as shear results in more compact flocs, compaction does not have an effect on DOM removal. A pH increase of 0.5, as it can happen during water treatment after coagulation, resulted in a release of DOM. Humic substances accounted for the largest proportion of total DOM released. The increase in pH did not affect floc size. Consequently, DOM removal is mainly governed by the dependence of DOM properties on pH with the final pH determining the degree of DOM removal and not the path on which this pH is reached. The physical properties of the flocs have no impact on DOM removal.

Changes in blood pressure after administration of hydroxocobalamin: relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers.

OBJECTIVE: To assess the relationship between blood pressure changes following infusion of antidotal doses of hydroxocobalamin and plasma concentrations of total and free cobalamins-(III). METHODS: Independent groups of healthy volunteers received single intravenous doses of 2.5, 5, 7.5, or 10 g hydroxocobalamin over 7.5 to 30 minutes. RESULTS: In the pharmacokinetic population (n = 41), hydroxocobalamin caused short-lived mean blood pressure increases. Blood pressure increased shortly after initiation of infusion and returned nearly to baseline by 4 hours post-infusion. The time course of blood pressure changes coincided with that of changes in plasma total and free cobalamins-(III). Change in mean arterial pressure (MAP) was strongly correlated with plasma area-under-the-concentration-time curves (AUCs) of total and free cobalamins-(III) during infusion (r > 0.7) but not through 24 hours post-infusion (r < or = 0.36). CONCLUSION: The short-lived increase in mean blood pressure during administration of antidotal doses of hydroxocobalamin is closely linked to initial exposure to total and free cobalamins-(III).