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Abstract: The occurrence and fate of residues from the therapeutic use of the non-steroidal anti-inflammatory drug metamizole have been studied in investigations of sewage effluents from a military hospital, municipal sewers and a sewage treatment plant (STP) in Berlin, Germany. The loads of the metabolites aminoantipyrin (AA), 4-acetylaminoantipyrin (AAA) and 4-formyl-aminoantipyrin (FAA), rapidly formed after the application of metamizole, were predicted from pharmacokinetic data and based on the evaluation of extensive data sets of on the administration in hospitals and private households. In parallel, the actual concentrations were measured within three field trials. For the military hospital, the estimated average annual discharges of AA/AAA and FAA were 10.5 and 3.2kg, respectively. For the STP, annual loads of 333 and 133 kg were determined for AA/AAA and FAA, respectively. During sewage treatment, an average decrease of 26% of the loads was measured for AA/AAA whereas no changes were observed for FAA. Generally, the prediction of the loads resulted in an overestimation of the residue levels compared to those measured in the respective sewers. Thus, modeling of predicted loads or concentrations alone will not be sufficient for a realistic assessment. Concerns for human or other mammals’ health are not expected from the occurrence of metamizole residues in the aquatic system measured at concentrations up to 7μgl−1 in STP effluents. However, a rest of uncertainty remains as it was not possible to derive a no observed effect level for the induction of rare but potentially fatal toxicological side effects reported for metamizole. [Copyright &y& Elsevier]

Residues of phenazone-type pharmaceuticals originating from spills of a former pharmaceutical production plant have recently been detected in ground water in Berlin, Germany. The degradation pathways of phenazone, propyphenazone, and dimethylaminophenazone (DMAA) during water purification were enlightened in batch experiments with groundwater and filter material obtained from operating waterworks. For phenazone and propyphenazone a complete biological transformation into their respective metabolites 1,5-dimethyl-1,2-dehydro-3-pyrazolone (DP) and 4-(2-methylethyl)-1,5-dimethyl-1,2-dehydro-3-pyrazolone (PDP) was observed. Generally, removal of phenazone-type pharmaceutical residues during rapid sand filtration was almost exclusively caused by microorganisms only present in polluted raw water. DMAA applied to fresh filter materials was rapidly degraded into its metabolites 1-acetyl-1-methyl-2-phenylhydrazide (AMPH), acetoaminoantipyrine (AAA), formylaminoantipyrine (FAA), and 1-acetyl-1-methyl-2-dimethyloxamoyl-2-phenylhydrazide (AMDOPH). DMAA, AAA, and FAA were, however, only detected at low levels in a few samples of purified water from an operating water works. Whereas, the metabolites AMDOPH and DP were detected up to 1μgl−1. Propyphenazone was rapidly removed and AMPH, phenazone, and PDP were only measured with concentrations in the low ngl−1 range. The concentrations of the metabolites DP and PDP are even higher in the purified water than in the raw water caused by their formation during degradation of phenazone and propyphenazone. Reduction of filtration velocity on an experimental filter from 5mh−1 down to 2mh−1 resulted in improved removal of phenazone, propyphenazone and their metabolites DP and PDP, respectively. AMDOPH, however, was highly persistent in all experiments independent from filtration velocities and contact times. [Copyright &y& Elsevier]

The fate of two differently labelled radioactive forms of 17α-ethinylestradiol (EE2) was studied during the membrane bioreactor (MBR) process. The laboratory-scale MBR specially designed for studies with radioactive compounds was operated using a synthetic wastewater representative of the pharmaceutical industry and the activated sludge was obtained from a large-scale MBR treating pharmaceutical wastewater. By applying in MBR a concentration of 8 g/L mixed liquor solid suspension and a sludge retention time of 25 days over the whole test period (35 days), the removal performance of C-, N- and P-ranged between 80% and 95%. Balancing of radioactivity could demonstrate that real mineralization is <1%, while radioactivity mainly remained sorbed in the reactor, resulting in a removal of approximately 80%. The same metabolite pattern in the radiochromatograms for the two different labelling protocols led us to assume that the elimination pathway does not involve the removal of the ethinyl group from EE2 molecule. [Copyright &y& Elsevier]

The elimination has been studied of racemic and enantioenriched metalaxyl applied as an emulsifiable concentrate and wettable powder combined with copper in a Cameroonian field site. The kinetics of the degradation/dissipation of metalaxyl and its acid metabolite were investigated using reversed phase HPLC-MS/MS, while the enantiomeric ratios were measured by HPLC-MS/MS using a Chiralcel OD-H HPLC column. Some soil enzymes activities were determined concurrently for 120d. The elimination of racemic metalaxyl was shown to be enantioselective, with the R-enantiomer being degraded more slowly than the S-enantiomer. Dissipation followed approximate square root first-order kinetics (R >0.98) without lag phases. The enantiomers of metalaxyl have different elimination rates, with half-lives ranging from only 0.8 to 1.5 days. After application to soil, the elimination of metalaxyl in the copper containing formulation was slower. The activities of acid phosphatase, alkaline phosphatase, and alkaline glucosidase were monitored throughout the experiments. No significant influence of metalaxyl and copper could be observed on these parameters. The significantly shorter half-life values of all forms of metalaxyl under field conditions, compared to the previously reported laboratory derived ones, may have implications for the plant disease control with these fungicides in tropical rainforest areas. [Copyright &y& Elsevier]

Abstract: It has recently become clear that an isomer specific view of technical 4-nonylphenol (NP) is absolutely necessary for the evaluation of the biological behavior of NP, raising additional questions concerning enantiomer specific effects. For the first time, in this study enantioselective HPLC was applied to enantiomeric separation of chiral NP isomers. A semipreparative separation of two NP isomers could be achieved. A GC–MS method has been developed for the simultaneous detection of three chiral NP isomers in water samples. Investigation of influent and effluent samples from a wastewater treatment plant in Germany indicated that enantioselective degradation could occur in the environment. In one examined influent, an enantiomer ratio of 1.7 for two different isomers was determined. [Copyright &y& Elsevier]

During production of rivaroxaban, an orally administrated anticoagulant, process waste water is generated at several stages of manufacturing. Due to low biodegradability in conventional waste water treatment plants, it is currently incinerated. Thus, new pre-treatment methods for rivaroxaban-containing waste water could facilitate its subsequent biological processing. In this study, ozonation was investigated as the pre-treatment method, with special emphasis on the elimination of the target compound and the generation of its main transformation products. These were determined by high performance liquid chromatography – high resolution mass spectrometry (HPLC-HRMS). Our results show that the concentration of rivaroxaban in the ozonated waste water can be effectively reduced (below detection limit) under acidic conditions, whereas neutral or basic reaction environment proved less suitable. Four main transformation products were identified and their concentrations determined. Rivaroxaban and its most prominent transformation product acetoxamide were elucidated in multiple-stage mass spectrometry (MSn) experiments. Transformation products derived from the degradation of rivaroxaban were then compared to its natural (animal and human) metabolites as well as other known derivatives. In contrast to previously published rivaroxaban-derived metabolites, the presented ozonation experiments resulted in new transformation products. Unlabelled Image • Ozonation of original waste water from production of rivaroxaban • Identification of new rivaroxaban transformation products (incl. acetoxamide and oxazolinone acetamide) • Calculated pseudo first order rate constants for the degradation of rivaroxaban • Comparison of rivaroxaban ozonation products and its known metabolites • Improvement of the ecotoxicological parameters of rivaroxaban containing process waste water after ozonation [ABSTRACT FROM AUTHOR]

During production of active pharmaceutical ingredients, process waste water is generated at several stages of manufacturing. Whenever possible, the resulting waste water will be processed by conventional waste water treatment plants. Currently, incineration of the process waste water is the method to eliminate compounds with high biological activity. Thus, ozone treatment followed by biological waste water treatment was tested as an alternative method. Two prominent representatives of the large group of fluoroquinolone antibiotics (ciprofloxacin and moxifloxacin) were investigated, focussing on waste water of the bulk production. Elimination of the target compounds and generation of their main transformation products were determined by liquid chromatography – high resolution mass spectrometry (LC-HRMS). The obtained results demonstrated, that the concentration of moxifloxacin and its metabolites can be effectively reduced (>99.7%) prior entering the receiving water. On the contrary, the concentration of ciprofloxacin and its metabolites remained too high for safe discharge, necessitating application of prolonged ozonation for its further degradation. The required ozonation time can be estimated based on the determined kinetics. To assure a low biological activity the ecotoxicity of the ozonated waste water was investigated using three trophic levels. By means of multiple-stage mass spectrometry (MS n ) experiments several new transformation products of the fluoroquinolones were identified. Thus, previously published proposed structures could be corrected or confirmed. [ABSTRACT FROM AUTHOR]

Abstract: St. John''s Wort (Hypericum perforatum L.) was extracted with supercritical carbon dioxide (SC CO2) under 10, 15 and 20MPa and at 313 and 323K. The influence of SC CO2 density (400–800kg/m3) was examined with respect to extraction yield as well as to hyperforin and adhyperforin content, which was determined using a highly selective LC/MS/MS analytical method. A high concentration (up to 526mg/g total extract) of two phloroglucinol derivatives was determined in this study showing that the absolute extracted amount of hyperforin and adhyperforin (mg per 1g of dry plant) is almost constant not depending on total yield of extract, i.e. on density of SC CO2. Determination of the rate of hyperforin and adhyperforin extraction at 313K and 10MPa showed that the maximal rates correspond to consumption of 7–8.5g of CO2 per 1g of dry St. John''s Wort. Investigation of ultrasonic extraction of St. John''s Wort followed after pre-treatment of plant material (323K; 10MPa; 2h; without CO2 flow) indicated that obtained extract contains a higher amount (mg/g plant material) of two most important pharmacological active compounds of St. John''s Wort, hyperforin and hypericin, than the extract obtained by ultrasonic extraction only. [Copyright &y& Elsevier]

Abstract: The content of hypericins (hypericin and pseudohypericin), hyperforin, and flavonoids (rutin, hyperoside, quercitrin, and quercetin) and genetic profiles of eight accessions of Hypericum perforatum L., collected from different locations in India, have been determined. The secondary metabolite content was determined using a highly selective LC/MS/MS method. Pearson and Spearman''s correlation coefficient were used to investigate the relationships between the secondary metabolites and a significant positive correlation was found between hypericin and pseudohypericin contents. Genetic profiling was undertaken using the random amplification of polymorphic DNA (RAPD) and single sequence repeat (SSR) methods. Among the 49 random primers used for the initial screening, only nine yielded polymorphic RAPD profiles. The SSR analysis shows that seven out of the 11 primers were polymorphic. There exists only a partial correlation between the chemical content and genetic profiling data among the accessions under study. [Copyright &y& Elsevier]

Mycotoxin contamination of wheat kernels and diversity of fungal pathogens were monitored in a survey of 26 fields in Nakuru district, Kenya, in 2006. Sampling was performed twice; at mid-anthesis in July for leaves, stems and spikelets and at harvest in September for spikelets and kernels. Kernels were analysed for the occurrence of 32 mycotoxins using a high performance liquid chromatography – electrospray tandem mass spectrometry (LC-ESI-MS/MS) method. Fungi were isolated from surface-sterilized tissues and differentiated morphologically to the genus level. Fusarium isolates were identified based on the sequence of translation elongation factor 1-alpha gene. Eleven Fusarium-related mycotoxins were quantified with deoxynivalenol being detected at highest frequency (69%) and highest concentrations. Occurrence of enniatins in wheat (50%) is reported for the first time in Kenya. Non- Fusarium mycotoxins detected included aflatoxin G2, ochratoxin A, alternariol and alternariol monomethyl ether. Prevalence of Fusarium species on different wheat parts was 100% at both growth stages. Nineteen Fusarium species were identified with seven species – Fusarium chlamydosporum, Fusarium boothi, Fusarium poae, Fusarium scirpi, Fusarium arthrosporioides, Fusarium oxysporum and Fusarium graminearum– accounting for 80% of infections. At anthesis, spikelets and leaves were the most and least susceptible tissue, respectively. At harvest, infection of spikelets was 59% higher than that of kernels. [ABSTRACT FROM AUTHOR]

Abstract: The phenolic constituents and antioxidant activity of ethanol and water extract of the flowers of Hypericum venustum, collected in Turkey, were investigated. The extracts possess strong reducing power, free radicals and hydrogen peroxide scavenging activity, as well as metal chelating ability. [Copyright &y& Elsevier]

[isolation and structure elucidation of 2-hydroxydihydronigerone (I)]. [ABSTRACT FROM AUTHOR]