[Release of antibiotics into urban wastewater: A secondary-data based analysis for the input assessment using the city of Dresden as an example]. / Antibiotikaeintrag in das urbane Abwasser : Eine sekundärdatenbasierte Analyse zur Eintragsabschätzung am Beispiel der Stadt Dresden.

Antibiotics are essential for the successful treatment of bacterial infections. Recently, the increasing number of resistant bacteria and the occurrence of residues of antibiotics in the environment has become the focus of scientific interest. The aim of the cooperative project ANTI-Resist was to investigate the release of antibiotics and the occurrence and distribution of antibiotic resistance in the urban waste water system of the city of Dresden.This article presents the main results of the secondary data analysis for the determination of outpatient and inpatient antibiotic consumption and provides an insight into the complexity of the topic antibiotics in waste water.Based on the data of outpatient prescriptions provided by the AOK PLUS for the period 2005 to 2013, thirteen focus substances were identified to estimate antibiotic consumption. Furthermore, delivery data from the pharmacies of three hospitals in Dresden were available.Depending on the substances investigated, seasonality and age dependency were determined. The results at a regional level were mostly in good accordance with general trends throughout Germany. It should be noted that the total amount of antibiotics used remained nearly constant over the whole period investigated, but the prescription of fluoroquinolones increased. This must be questioned when taking into account the increasingly critical situation in the treatment of Gram-negative bacteria in particular. Examinations of waste water conducted indicated that sewage treatment plants are not able to remove antibiotics or their metabolites completely from waste water. The residues are released into surface waters via the treatment plants. The impact cannot be assessed at the moment and further investigations are necessary.

Occurrence and removal of frequently prescribed pharmaceuticals and corresponding metabolites in wastewater of a sewage treatment plant.

The present study determines removal rates (RR) of 56 pharmaceuticals and metabolites, respectively, in an urban sewage treatment plant using mass flow analysis by comparing influent and effluent loads over a consecutive ten-day monitoring period. Besides well investigated compounds like carbamazepine and metoprolol, less researched targets, such as topiramate, pregabalin, telmisartan, and human metabolites of pharmaceuticals were included. Another aim was to determine the ratio of pharmaceuticals and corresponding metabolites in raw wastewater. Valsartan and gabapentin were detected at the highest average concentrations in influent (c(val) = 29.7 (± 8.1) µg/L, c(gab) = 13.2 (± 3.3) µg/L) and effluent (c(val) = 22.1 (± 5.1) µg/L, c(gab) = 12.1 (± 2.6) µg/L) samples. The comparison of mass loads in influent and effluent showed a significant removal (p<0.1) for 20 compounds but only enalapril, eprosartan, losartan, pregabalin, and quetiapine were removed from the aqueous phase by more than 50%. Another 20 compounds were determined without significant difference and for five compounds (clindamycin, lamotrigine, oxcarbazepine, O-desmethyl venlafaxine, triamterene), a significant higher mass load in the effluent than in the influent was observed. It has to be noticed that metabolites like 10,11-dihydro-10-hydroxy carbamazepine (MHD) are found in higher mass loads than the corresponding parent compound in the sewage samples. Furthermore, metabolites and parent compound behave differently in the sewage treatment process. While MHD (RR = 15.1%) was detected with lower mass load in the effluent than in the influent, oxcarbazepine (RR = -73.2%) showed the contrary pattern. When comparing expected and measured ratios of parent compound and metabolite in raw sewage, citalopram/N-desmethyl citalopram for example, showed good results. However, a major problem exists due to insufficient data regarding metabolism and excretion of many pharmaceuticals. This complicates the prediction of relevant metabolites and further efforts are needed to overcome this problem.

Development of a SPE-HPLC-MS/MS method for the determination of most prescribed pharmaceuticals and related metabolites in urban sewage samples.

Based on regional prescription data several pharmaceuticals with variable amounts of prescription and corresponding metabolites were selected and analyzed in influent and effluent samples of the sewage treatment plant (STP) in Dresden, Germany. Pharmaceuticals of the following most prescribed therapeutic groups were chosen: antibiotics, antifungals, anticonvulsants, antipsychotics, antidepressants, and cardiovascular active compounds like beta blockers and angiotensin-converting enzyme inhibitors. To analyze the selected compounds, a multi-target method was developed and applied to 24-h composite wastewater samples for three single days in May and June 2014. The method was based on a cleanup of a sample with a volume of 1mL using solid phase extraction followed by a high performance liquid chromatography coupled to a tandem mass spectrometer. Analytes were separated in a 15min chromatographic separation and quantified using 23 Internal Standards and a calibration curve in 40-fold diluted blank urine. The limit of quantification varied between 50 and 200ng/L and for all analytes good accuracy and precision as well as linearity for the calibration curve with the correlation coefficient R(2) higher than 0.99 was reached. A total of 41 and 40 of the selected 55 analytes were detected and quantified in the influent and effluent samples of the studied STP, respectively. Valsartan was the compound with the highest maximum concentration in influent (27.1µg/L) and effluent (15.7µg/L). Furthermore, analytes like bezafibrate, candesartan, carbamazepine, gabapentin, metoprolol, levetiracetam, pregabalin and telmisartan as well as the metabolite O-desmethyl venlafaxine were detectable in influent and effluent samples, respectively, with a concentration higher than 1µg/L.

Clinical pharmacology of antithrombotic drugs in coronary artery disease.

Coronary heart disease is the leading cause of death in the Western world. Antithrombotic therapy is the cornerstone of its successful treatment. Clinical trials have demonstrated that antithrombotic therapy reduces the risk for recurrent myocardial infarction and cardiovascular death. Antiplatelet drugs and anticoagulants interfere with haemostasis and thus bleeding is a major risk factor of these drugs. The benefit of antithrombotic therapy must therefore be carefully balanced with the risk of bleeding and other potential adverse reactions of these drugs. However, to date there is no firm evidence that dosage adaptation of aspirin or clopidogrel according to platelet aggregation testing translates directly into any clinical benefit. Resistance to antithrombotic drugs is a serious problem because these patients are at a higher risk of myocardial infarction, stroke and cardiovascular death. It has most recently been demonstrated that resistance to clopidogrel is at least in part caused by polymorphism of CYP2C19. Clinical trials have also demonstrated that optimal benefit in different settings depends unequivocally on the meticulous choice of the various drugs. Thus, profound knowledge of the clinical pharmacological profiles of the different antithrombotic drugs is indispensable for successful treatment.

[Drug safety of NSAIDs and COX-2 inhibitors]. / Zur Arzneimittelsicherheit von NSAR und COX-2-Hemmern.

In this review the risk-benefit ratio of COX-2 inhibitors and NSAIDs is compared. In the discussion of the safety of these two groups different evaluation standards are used, which is not a basis of a rational pharmacotherapy.

Baseline blood flow and bradykinin-induced vasodilator responses in the human forearm are insensitive to the cytochrome P450 2C9 (CYP2C9) inhibitor sulphaphenazole.

A substantial portion of the vasodilator response elicited by bradykinin in the human forearm is unaffected by the combined inhibition of nitric oxide (NO) synthases and cyclo-oxygenases. The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries. The aim of the present study was to determine the effect of sulphaphenazole on basal and bradykinin-induced NO/PGI2-independent changes in the forearm blood flow (FBF) of healthy subjects. Eleven healthy male volunteers participated in this placebo-controlled study. Test agents were infused into the brachial artery and FBF was measured by bilateral venous occlusion plethysmography. Sulphaphenazole (0.02-2 mg/min) alone did not affect basal blood flow. Inhibition of the NO synthases by NG-monomethyl-L-arginine (L-NMMA; 4 micromol/min) and cyclo-oxygenases by ibuprofen (1200 mg, orally) reduced FBF to 48 +/- 7% in the absence and 50 +/- 8% in the presence of sulphaphenazole (2 mg/min; P=not significant). After pretreatment with L-NMMA (16 micromol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation. We conclude that CYP2C9-derived metabolites (i) are not involved in the regulation of baseline blood flow, and (ii) do not mediate bradykinin-induced NO/PGI2-independent vasorelaxation in the human forearm. However, determining the contribution of this enzyme to regulation of blood flow in pathological conditions associated with endothelial dysfunction requires further studies.