[Card-based age control mechanisms at tobacco vending machines. Effect and consequences]. / Die kartenbasierte Alterskontrolle an Zigarettenautomaten. Wirkung und Folgen.

Until recently, 700,000 tobacco vending machines provided uncontrolled access to cigarettes for children and adolescents in Germany. On January 1, 2007, a card-based electronic locking device was attached to all tobacco vending machines to prevent the purchase of cigarettes by children and adolescents under 16. Starting in 2009, only persons older than 18 are able to buy cigarettes from tobacco vending machines. The aim of the present investigation (SToP Study: "Sources of Tobacco for Pupils" Study) was to assess changes in the number of tobacco vending machines after the introduction of these new technical devices (supplier's reaction). In addition, the ways smoking adolescents make purchases were assessed (consumer's reaction). We registered and mapped the total number of tobacco points of sale (tobacco POS) before and after the introduction of the card-based electronic locking device in two selected districts of the city of Cologne. Furthermore, pupils from local schools (response rate: 83%) were asked about their tobacco consumption and ways of purchase using a questionnaire. Results indicated that in the area investigated the total number of tobacco POSs decreased from 315 in 2005 to 277 in 2007. The rates of decrease were 48% for outdoor vending machines and 8% for indoor vending machines. Adolescents reported circumventing the card-based electronic locking devices (e.g., by using cards from older friends) and using other tobacco POSs (especially newspaper kiosks) or relying on their social network (mainly friends). The decreasing number of tobacco vending machines has not had a significant impact on cigarette acquisition by adolescent smokers as they tend to circumvent the newly introduced security measures.

Tissue distribution of radioiodinated FAUC113: assessment of a pyrazolo(1,5-a) pyridine based dopamine D4 receptor radioligand candidate.

AIM: Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-(131)I-FAUC 113 in Sprague-Dawley rats. METHODS: Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radio-hplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and ex-vivo autoradiography on a mu-Imager system. RESULTS: 7-(131)I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603 +/- 0.047% ID/g, n = 4) and liver (0.357 +/- 0.070% ID/g, n = 4) at 10 min p.i.; 7-(131)I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36 +/- 0.15 (n = 4). In-vivo stability of 7-(131)I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57 +/- 0.13 at 10 min p.i. (n = 6). Coinjection with L-750667 could not suppress any putative specific binding of 7-(131)I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand. CONCLUSIONS: Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brain barrier permeability.

[Drug addiction prevention in the workplace--feasibility study in a company from the chemical industry]. / Betriebliche Suchtprävention - Durchführbarkeitsstudie in einem Betrieb der chemischen Industrie.

INTRODUCTION: In recent years drug prevention at the place of work has became increasingly important for programmes focussing on health promotion at the place of work. Drug prevention programmes aim at reducing cost and protecting the employees from physical harm. There are virtually no reliable figures from surveys in companies. To date intervention programme in companies have hardly been verified. In this feasibility study we intended to examine the practicability of an evaluation of an intervention programme in a large chemical company by means of questionnaires and we present preliminary intervention effects. METHODS: In the context of a pilot study we conducted and evaluated a drug prevention programme at the place of work. Focus was on illegal designer drugs. The programme was conducted as a one-day workshop for trainers in superior management positions. We used a feedback form and a detailed questionnaire on drug prevention in the working place. 41 trainers who participated in the seminar were compared with a control group of 12 trainers who did not participate. RESULTS: The intervention programme was well accepted by the participants. Follow-up data demonstrated, that participants in the seminar had far better knowledge of the employment agreement on addiction and drugs and of the possible ways to get help and they were far more active in realising the employment agreement. CONCLUSION: To achieve a long-term improvement of drug abuse in companies it is not enough to include and implement a passage on drug abuse and addiction in the employment agreement. Well-instructed trainers talk far often with colleagues displaying abnormal or addictive behaviour, resulting in more rapid therapeutic interventions.

Epidermal growth factor and prostaglandin E(2) accelerate mucosal recovery from stress-induced gastric lesions via inhibition of apoptosis.

The repair of damaged gastric mucosa is a complex process involving prostaglandins (PG) and mucosal growth factors such as epidermal growth factor (EGF). Recently, we postulated that the increased occurrence of apoptosis in the gastric epithelium might be of pathophysiological importance in the development of stress lesions. The aim of the present study was to assess the effect of the pretreatment of rats, exposed to 3.5 h of water immersion and restraint stress (WRS), with EGF and PG (16,16 dmPGE(2)) on the number of stress lesions, recovery of gastric mucosa from stress and the expression of apoptosis related genes such as caspase-3 and antiapoptotic bcl-2. Rats were divided in following groups: (1) vehicle; (2) EGF 100 microg/kg i.p.; (3) 16,16 dm-PGE(2) (5 microg/kg i.g.) and caspase-1 inhibitor (ICE-I; 100 microg/kg i.p.). One hour later, the rats were exposed to 3.5 h of WRS and then sacrificed immediately (0 h) or at 6, 12, or 24 h after WRS. The number of acute gastric lesions was determined. Gastric epithelial apoptosis was assessed by TUNEL staining. In addition, mRNA expression of caspase-3, Bcl-2 and proinflammatory cytokines (IL-1 beta, TNFalpha) was assessed by RT-PCR. PGE(2) generation in gastric mucosa and luminal EGF were determined by RIA. Exposure to WRS resulted in the development of multiple acute stress erosions ( approximately 18) which almost completely healed during 24 h. The gastric blood flow was significantly reduced (approximately 70% of intact mucosa) immediately after WRS. The expression of mRNA for IL-1 beta and TNF alpha reached their peak at 12 h after stress exposure. The apoptosis rate was highest at 6 h after WRS and was accompanied by the highest caspase-3 expression. In rats pretreated with EGF or 16,16 dm-PGE(2), a significant decrease in caspase-3 mRNA and upregulation of bcl-2 mRNA as observed as compared to vehicle controls. Caspase-1 inhibitor significantly reduced the number of stress lesions. We conclude that EGF and PGE(2) accelerate healing of stress-induced lesions due to the attenuation of apoptosis via upregulation of bcl-2 in gastric mucosa. Inhibitors of apoptosis accelerate healing of stress lesions and may be potentially effective agents in the healing of damaged gastric mucosa.

Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213).

Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments. According to our schematic molecular model, the intrinsic activity of the regioisomers investigated is controlled by the ability of the heterocyclic unit to interact with both elements of the D4 binding-site crevice, the aromatic microdomain in TM6, and a serine residue in TM5.

Pharmacokinetics of gatifloxacin and interaction with an antacid containing aluminum and magnesium.

The pharmacokinetics of gatifloxacin (400 mg orally) and the influence of the antacid aluminum magnesium hydroxide (20 ml of Maalox 70) on the bioavailability of gatifloxacin in 24 healthy volunteers were assessed. In an open, randomized, six-period crossover study, the volunteers received either gatifloxacin alone (treatments A and D); aluminum magnesium hydroxide concomitant with gatifloxacin (treatment C); or aluminum magnesium hydroxide 2 h before (treatment B), 2 h after (treatment E), or 4 h after gatifloxacin administration (treatment F). Gatifloxacin concentrations were measured by a validated bioassay and high-performance liquid chromatography. Pharmacokinetics of a single 400-mg dose of gatifloxacin alone were characterized as follows (mean +/- standard deviation): peak concentration (Cmax), 3.8 +/- 0. 5 (treatment A) and 3.4 +/- 0.9 (treatment D) microgram/ml; time to Cmax, 1.4 +/- 0.8 (treatment A) and 1.7 +/- 0.7 (treatment D) h; area under the curve from time zero to infinity (AUC0-infinity), 33. 5 +/- 5.9 (treatment A) and 31.4 +/- 3.4 (treatment D) microgram. h/ml; urine recovery, (83 +/- 6)% (treatment A) and (84 +/- 8)% (treatment D). Comparison of the results obtained by bioassay showed a good correlation. Aluminum magnesium hydroxide administration 2 h before (treatment B) or concomitant with (treatment C) gatifloxacin decreased the Cmax by 45% (2.1 +/- 1.2 microgram/ml) or even 68% (1.2 +/- 0.4 microgram/ml) highly significantly (P < 0.01). AUC0-infinity was significantly reduced from 33.5 +/- 5.9 to 19.4 +/- 6.9 microgram. h/ml (by 42%) or even to 11.9 +/- 3.3 microgram. h/ml (by 64%) (P < 0. 01). If aluminum magnesium hydroxide was given 2 h after gatifloxacin (treatment E), there was no significant reduction of concentration in serum but AUC0-infinity was significantly reduced from 31.4 +/- 3.4 to 25.9 +/- 5.3 microgram. h/ml (18%) (P < 0.01). Aluminum magnesium hydroxide given 4 h after gatifloxacin (treatment F) showed no influence on the gatifloxacin pharmacokinetics. Therefore, the optimal time between gatifloxacin application and the intake of an aluminum-containing antacid should be 4 h.

Azaindole derivatives with high affinity for the dopamine D4 receptor: synthesis, ligand binding studies and comparison of molecular electrostatic potential maps.

Piperazinylmethyl substituted pyrazolo[1,5-a]pyridines and related heterocycles were synthesized and found to recognize selectively the dopamine D4 receptor. For the most potent derivative 10d a Ki value of 2.0 nM was observed. SAR studies including the comparison of molecular isopotential surfaces were performed.

[Some problems in standardization of fructosamine tests]. / Zu einigen Problemen bei der Standardisierung des Fructosamin-Tests.

The degree of nonenzymatic glycation of serum proteins was estimated in 500 nondiabetic subjects and in 124 Type 2 diabetic out-patients. The values were evaluated in relation to a DMF calibration curve, a secondary glycated protein standard and to serum protein concentrations. Neglecting the evaluation with respect to the protein concentration 0.4% of the samples from nondiabetics and 9% from diabetic patients would have been incorrectly interpreted. The fructosamine values from nondiabetic subjects showed a Gaussian distribution. The use of secondary protein standards is a premise to a widespread application of the fructosamine assay in diabetic care. The calibration of such secondary glycated protein standards results in some problems when using DMF protein mixtures as primary standards, because albumin preparations from the same or different suppliers gave variable standardization curves.

[What is the fructosamine test and what is its clinical significance?]. / Was ist der Fructosamin-Test, worin besteht seine klinische Bedeutung?

The clinical usefulness of the fructosamine assay is reviewed. Problems of external standardization are discussed and possibilities to circumvent these problems are considered.

Effect of glutathione depletion on aminopyrine and formaldehyde metabolism.

In previous studies, diethylmaleate (DEM)- and phorone-induced hepatic glutathione (GSH) depletion in rats was accompanied by impaired evolution of 14CO2 from the N-14C-labeled methyl groups of aminopyrine, which in turn was attributed to impaired generation of formaldehyde, its subsequent oxidation to formate, or to some combination of both. In the present study, l-buthionine sulfoximine (BSO)-induced hepatic GSH depletion was also accompanied by decreased evolution of CO2 from aminopyrine, but the extent of the fall in CO2 was less than that induced by DEM or phorone, even though the decrease in hepatic GSH was comparable with all three GSH-lowering compounds. Incubation of freshly prepared normal hepatic microsomes in vitro with the GSH-lowering agents resulted in impaired aminopyrine-N-demethylase (APDM) activity with inhibition by phorone greater than DEM greater than BSO. By contrast, hepatic microsomes prepared from rats pretreated with these compounds had normal APDM activity. 14CO2 evolution from i.p. administered [14C]formaldehyde was not impaired by any of the GSH-lowering compounds. Thus, assessment of APDM activity and formaldehyde metabolism did not unequivocally establish the mechanism(s) by which CO2 evolution from aminopyrine is depressed by DEM, phorone and BSO, although low GSH is likely to impair metabolism of formaldehyde formed in liver after demethylation of aminopyrine. Quantitative differences in the degree of depression of CO2 evolution suggest that at least DEM and phorone exert an additional inhibitory effect by a GSH-independent mechanism. This may involve inhibition of aminopyrine-N-demethylase activity.