Search

Summary Reasons for performing study: The β2-agonist clenbuterol is commonly administered for therapeutic purposes in the horse, but its use an an anabolic agent is illegal. Clenbuterol can be detected in blood and urine for a relatively short period after administration and detection in hair could enhance the analytical range and be used to determine the history of clenbuterol application. Hypothesis: That detection in mane or tail hair is possible over an extended period. Methods: Four horses received 0.8 μg elenbuterol hydrochloride/kg bwt b.i.d. for 10 days. Four other horses were used as untreated controls. Blood, urine, mane and tail hair samples were taken on Day 0 (before) and 5, 10, 30, 35, 40, 60, 90, 120, 150 and 360 days after start of treatment. Gas chromotography/high resolution mass spectrometry (GC/HRMS) was developed for clenbuterol analysis: limit of detection was 0.2 pg/mg; intra-assay repeatability limit r = 0.06 (confidence level 95%); interassay repeatability limit r = 0.03 (confidence level 95%). Prior to treatment, clenbuterol was absent from all samples analysed. Results: Clenbuterol was detectable as early as Day 5 in tail and mane hair of Segment 1 (0–20 mm from the roots) and was maximal on Day 90. However, as time progressed, shift into lower 20 mm segments was observed. On Day 360, the maximum concentration (up to 21 pg/mg) was located in Segment 13, i.e. 26–28 cm from roots of hair. Clenbuterol was not detectable in blood or urine after Day 30. Mane and tail hair results were very similar. Conclusions: The study showed that the β-agonist clenbuterol can be found in mane and tail hair of horses after extended periods. Potential relevance: It will be possible to detect clenbuterol in breeding and show horses where anabolic drugs have been used illegally to improve conformation. This method may also be helpful to monitor therapeutic clenbuterol treatment.

Dopinganalytik kann als Teilgebiet der Toxikologischen Analytik angesehen werden, und die Beurteilung ihrer Ergebnisse sowie unter speziellen Umstanden (Todesfalle oder Spatschaden als vermutliche Folgen von Doping) der Korrelation von Ursache und Wirkung konnen forensisch-toxikologische und rechtsmedizinische Kompetenz erfordern. Trotz des sehr breiten Interesses auch der Offentlichkeit und einer in spektakularen Fallen zuweilen hysterischen Uberkommentierung besteht gegenuber Dopingproblemen haufig Unkenntnis gerade der elementaren Voraussetzungen des Dopingverbots und der Dopingkontrolle. Diese Unwissenheit ist viel haufiger Anlass zu dissenten Meinungen als spezielle Probleme etwa der analytischen Nachweisbarkeit. Der Artikel soll daher eine sehr allgemein gehaltene Ubersicht uber die Grundlagen, die Situation und die prinzipiellen Probleme der Dopingkontrolle vermitteln. Details und speziellere Fragen, die den Rahmen dieser Einfuhrung uberschreiten, sind z. B. aus der zitierten weiterfuhrenden Literatur zu ersehen.

Die Einschatzung der Handlungsfahigkeit eines todlich Vergifteten kann bei der Tatrekonstruktion sehr bedeutsam sein, insbesondere bei der Frage „Selbst- oder Fremdbeibringung des Giftes“. Klinische Publikationen gehen hierauf kaum ein. Deshalb wurden 27 Falle todlicher oraler Intoxikationen mit Cyan-Verbindungen der rechtsmedizinischen Institute Wurzburg, Hamburg, Munchen, Berlin (FU), Tubingen, Essen und Leipzig, bei denen eine Aussage zur Handlungsfahigkeit des spater Verstorbenen moglich war, sowie die dazugehorigen polizeilichen und staatsanwaltschaftlichen Akten unter dieser Fragestellung ausgewertet. Ergebnis: in der Mehrzahl der Falle betrug die Handlungsfahigkeit nur wenige Sekunden bis maximal 1 bis 2 Minuten. Im Untersuchungsgut und in der Literatur kamen allerdings auch Falle vor, bei denen die Handlungsfahigkeit uber ca. 5 bis 10 min erhalten war. Die Ergebnisse der Arbeit sollen dem Gutachter als Leitlinie bei der Klarung einschlagiger Falle dienen.

Die Einschatzung der Handlungsfahigkeit eines todlich Vergifteten kann bei der Tatrekonstruktion sehr bedeutsam sein, insbesondere bei der Frage „Selbst- oder Fremdbeibringung des Giftes“. Klinische Publikationen gehen hierauf kaum ein. Deshalb wurden 20 gerichtliche Obduktionen der Institute fur Rechtsmedizin der Universitat Wurzburg und Leipzig sowie die dazugehorigen polizeilichen und staatsanwaltschaftlichen Akten unter dieser Fragestellung ausgewertet. Ergebnis: in der Regel betrug die Handlungsfahigkeit bei todlichen Pflanzenschutzmittelintoxikationen 10 bis 15 Minuten. Im Untersuchungsgut und in der Literatur kamen allerdings auch Falle vor, bei denen die Handlungsfahigkeit deutlich langer erhalten war. Die Arbeit soll dem Gutachter eine Leitlinie bei der Klarung einschlagiger Falle sein.

If qualitative analysis is aimed to detect large, imprecisely confined groups comprising hundreds or thousands of compounds – like during the analysis of questionable poisoning cases without direct hints, the so called “general unknowns”–, the evaluation of the identification certainty becomes equally important like the associated estimation of the necessary information capacity of the analytical procedures to be applied [1–4]. On this basis, the authors have outlined factors, which influence the usable information provided by analytical principles or procedures depending of the number and types (analytical categories, differences and similarities, detectability) of the analytes to be detected or included. A correlation between the usable information (excess or deficiency) and the probability of failing identifications is defined, and the information loss by interfering analytical signals is discussed. The concepts of discrimination power DP, identification power IP, and mean list length MLL [4–7] are associated with these considerations. Examples of analytical tasks in this “general unknown” environment of toxicological analysis are presented.

A broad variety of atropisomeric biphenyl diphosphines have been synthesized via optically active 6,6'-dimethoxybiphenyl-2,2'-diyl-bis(diphenyl phosphonates), -bis@hosphonic dichlorides), -bis(phosphonous dichlorides) and -bis@rimary diphosphines). The usefulness of diphosphine variety in enantioselective hydrogenation was demonstrated by application to sub- strates of unconventional and unprecedented type such as an a-pyridyl ketone, yketo olefins, an a-pyrone and an enol ether of a p-keto lactam. Enantioselectivities and rates in these hydrogena- tions were markedly influenced by the electronic and steric properties of the diphosphine ligands. Of particular utility were the biphenyl diphosphines with a-fury1 and 3,5-di-t-butylphenyl groups on the P atoms. A synthesis of a tetrasulfonated biphenyl diphosphine carrying the sulfonato substituents in the paru position of the P-phenyl rings has also been developed. Ruthenium cata- lysts derived from this ligand proved highly efficient for several enantioselective hydrogenations in aqueous systems.

Die „Screening“-Stufe der Dopinganalytik erfast auser den zahlreichen verbotenen Dopingstoffen auch weitere Xenobiotika, die identifiziert werden mussen. Sofern diese nicht als erlaubte Medikamenteneinnahmen seitens des Probanden deklariert werden, ist sogar die Vermutung zu prufen, ob das Dopingverbot mittels zunachst nicht explizit verbotener Stoffe unterwandert werden soll. Nach fruheren „Grauzonen“-Fallen mit erlaubten, jedoch ohne medizinische Indikation und somit aus suspekten Motiven applizierten Medikamenten fiel 1996 in Atlanta das halblegale und inzwischen als Dopingmittel verbotene Pharmazeutikum Bromantan auf. 1997 gelang uns erstmals im Weltmasstab die massenspektrometrische Identifikation eines halblegal synthetisierten, weder regular toxikologisch gepruften noch registrierten Wirkstoffs, der als Designerdroge aus zwei Wirkstofftypen mit nootrop/psychotroper beziehungsweise analeptischer Wirkung anzusehen ist. Als „Carphedon“ unterliegt er inzwischen explizit dem IOC-Dopingverbot. Nachweis und Identifikation der bis 1997 weitgehend unbekannten Verbindung sowie die unmittelbaren Konsequenzen werden beschrieben.

The aim of our hGH application study with non-competitive athletes was the investigation of selected serum parameters from different processes affected by hGH. Fifteen athletes (age 21-33, mean 24) were treated with 0.06 IU hGH/kg BW per day or placebo (10 hGH, 5 placebo) respectively for 14 days. Blood samples were taken prior to, during and until 10 weeks after treatment. The concentrations of the following markers were determined in relevant serum samples: IGF-I, IGFBP-3, ALS, PIIINP, PINP, osteocalcin, and leptin. The IGF-I concentration increased rapidly within the hGH treatment group and showed significantly higher levels compared to baseline even 3 days after application. The response of the IGFBP-3 to the hGH applications was lower in comparison to IGF-I. The hGH group showed an increasing IGFBP-3 compared to baseline from day 4 till day 15. The response of PIIINP to hGH is clearly delayed compared to the IGF-I axis, but the PIIINP concentration remains on an increased level for a longer period (from day 4 until day 21). The time course and the extent of response varied strongly interindividually. PINP and osteocalcin showed only a small response to hGH applications. These parameters are characterised by a strong scattering of base values compared with the small response. In the hGH treatment group very different leptin concentrations were found at the beginning of the study, but after treatment decreasing leptin levels were observed in all cases. The determination of only one parameter will not be sufficient for detection of hGH abuse. A combination of markers by mathematical methods can be helpful to distinguish between placebo and hGH-treated athletes. By using the suggested discriminant function the data sets of hGH and placebo-treated athletes could be separated without false positive results.

This paper presents a GC-MS confirmation method, based on large-volume programmed-temperature vaporisation (PTV) injection, for the determination of cannabinoids in plasma samples (or whole blood) with deuterium-labelled internal standards using only 25 microl of biological fluid. The analytes, Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta 9-tetrahydrocannabinol (THC-COOH), were enriched by means of solid-phase extraction cartridges containing octadecyl-bonded silica and were, subsequently, methylated. A 20 microl aliquot of an extract in hexane was injected into a PTV in solvent split mode. Method development and the results of the analyses of standard reference material and real samples are presented and discussed. This micro-method is precise and sensitive enough to assess relevant cannabinoid levels in human blood for forensic investigations as well as for clinical applications.

Two lethal poisonings by butane and propane are described, and the corresponding concentrations in the body fluids and organ tissues are evaluated. One case appeared to be an accident after deliberate inhalation for butane, one was a suicide. The mechanism of the inhalation could be reconstructed in both cases. The concentrations in the biological material agreed well with observations in similar cases.

In the former GDR it was almost impossible to perform studies on environmental pollution. Therefore, a short time after the opening of the German interior border the authors started an investigation on the heavy metal burden of humans in the former District of Leipzig (Saxonia). In 1990/91 tissues from 57 deceased were collected from this region. The concentrations of cadmium were determined in specimens from the liver and renal cortex, of mercury in liver, renal cortex and grey matter of the cerebrum and of lead in samples of the pelvic bone and the cortical part of the femur. After sample pretreatment, the heavy metal concentrations were determined by GF-AAS or CV-AAS. The results were compared with studies recently performed by the authors in the region of Munich (southern Bavaria, FRG) and with values from the literature. It was found that the burden with cadmium was similar in both regions, whereas on the average, the bone lead concentrations in Leipzig were 10 times (!) higher than in Munich. Considering dental amalgam as main factor for the burdening with inorganic mercury, the mercury concentrations in the liver and the renal cortex were of the same order of magnitude in both regions. In contrast to this, significantly higher mercury concentrations were found in the brain samples from Leipzig than from Munich. Possible negative health effects of these elevated lead and mercury burden in the Leipzig area are discussed.

Both environment and health are terms of far-reaching meaning, which impedes a complete survey of their interactions. Originating from considerations about global phenomena, as e.g. the extinction of biological species, of the so called "forest dying", or of the extensive consumption of energy and material resources, on the hierarchy of effects on health of environmental damages on one hand or on the undisputable adaptivity of man in particular on the other, only actual examples are outlined. The groups of dioxins, asbestos and radon are outlined, considering them as representatives for the vast number of substances potentially harmful to the environment and for the complexity of the toxicological and oecological interactions with oecosphere, biosphere and man. By the examples, the principles of toxicological/oecological thinking are explained, finally never resulting in yes/no alternatives, but in compromises by sober balances of risk and benefit. The basically correct vigilance of the public against avoidable risks may not lead to hysteric reactions, impeding the concentration onto necessary and practicable solutions.

The predominating hydrophilic physiological body constituents are not interfering severely during the toxicological analysis for organic poisons in biological matrices, whereas coextracted lipids are usually well distinguishable from xenobiotics. But interfering substances increase strongly with autolysis, and some of them behave like toxicologically relevant compounds to be detected by the respective analytical methods. Attempts are reaching from the STAS' isolation procedure through the ptomaines to our chromatographical epoche, to phenomenologically compensate the matrix effects--increasing in the course of putrefaction--by the determination and generalisation of according analytical signals. The paper outlines on the background of Systematic Toxicological Analysis how far a systematic thanatochemical concept should be considered more closely for the futural more effective analytical elimination of such matrix effects.

Smooth muscle cell proliferation and formation of extracellular matrix in the intima of muscular arteries after vascular injury can lead to severe intimal hyperplasia and stenosis. Cilazapril reduces intimal hyperplasia induced by balloon catheterization of the rat carotid artery by 80%, and significantly decreases the surface area covered by proliferative lesions. We investigated the effects of angiotensin II (A II) on SMC proliferation in cell culture and A-II induction of selected growth factor or growth-related genes in SMC in culture: PDGF A chain, TGF-beta, thrombospondin, c-myc and c-fos, and compared the influence of cilazapril on these responses to A II. A-II induced SMC proliferation, stimulated mRNAs for c-myc and c-fos after 30 min, and stimulated mRNAs for PDGF A chain, TGF-beta, and thrombospondin somewhat later. The ACE inhibitor did not have detectable independent effects on the A-II induced proliferation or gene expression. Thus, these data support the conclusion that cilazapril suppresses SMC proliferation in vivo through the block of conversion of A I to A II, and that A II has a critical and central role in the control of the proliferative response after balloon catheter-induced vascular injury.

The Saarland and Saxony have not only been located at the western respectively at the eastern border of Germany (or of the then separated both German states). Different law regulations and lifestyles seemed to be an additional reason for different incidences of blood alcohol. Therefore, the blood alcohol cases of the university institutes for legal medicine of both provinces were statistically compared for 1989. Beyond some difficulties in the comparison itself due to different definitions and managements, equal or similar patterns dominated by far against discrepancies. The slightly different regulations for quality assurance were also compared with the expectation of their equalisation during the next future.

TV technology combined with a modern video-frame store is used to store the complete fringe pattern in digitized form in real time. A minicomputer connected to the store has direct access to any picture point in the store. In this manner, it is possible to evaluate the photoelastic-fringe pattern in the computer by special developed software.

Interessiert beim Entwurf von Stahlbetontragwerken ihr Verhalten im bruch- nahen Bereich, dann sind wegen der sehr verwickelten Vorgange bis jetzt kaum numerische Berechnungen moglich. Man ist auf Untersuchungen an Real- modellen angewiesen, die in allen Belastungsphasen bis zum Bruch der Hauptausfuhrung ahnlich sind. Von den Modellgesetzen ausgehend wird gezeigt, durch welche Masnahmen man einen geeigneten Modellbeton erhalt und wie die Modellbewehrung beschaffen sein mus, damit Ahnlichkeiten im Verbund und damit auch im Risbild vorhanden sind.

In recent years, the expanding panorama of congenital skeletal dysplasia has increased, of which the differential diagnosis is often difficult to establish. Here, we report a case of a young man suffering from a congenital skeletal dysplasia, associated with hyperphosphatasemia, who additionally developed an osteogenic sarcoma of the skull. Some diagnostic problems of congenital hyperphosphatasemia and the relationship between skeletal dysplasia and malignant bone tumors will be discussed.

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

A series of non-steroidal anti-inflammatory drugs (NSAID) and a few other agents were evaluated for their ability to: 1) reduce the acute toxicity of intravenously injected arachidonic acid (AA) in mice; 2) prevent castor oil-induced diarrhoea in mice; 3) enhance the formation of gastric mucosal erosions by a water stress in rats. A correlation between the activity in the three tests has been found for most NSAID studied, and the results point to inhibition of cyclooxygenase as a common mechanism of action.

Though liquid-liquid extraction is most widely used technique for isolating organic compounds (drugs, poisons), its fundamental parameters (partition constants and dissociation constants) are not determined explicitly in most cases; they are mostly estimated indirectly together with other factors in the form of resultants (total yield, detection sensitivities). For this reason we determined the partition quotients and their pH-dependence for more than 300 slightly volatile organic compounds (mainly drugs) in two-phase systems (aqueous buffer solution/solvent non-miscible with water). Nearly all the determinations were performed using diethyl ether and chloroform; other organic solvents were applied especially in studying slightly extractable compounds. The results obtained with 63 acidic compounds are reported.

Carprofen, a new non-steroidal anti-inflammatory agent, showed marked anti-inflammatory and analgesic effects in various relevant experimental models. The analgesic activity was restricted to conditions where pain was provoked by an inflammatory process. Induction of intestinal ulcers was the only side effect recognizable in animals and occurred only after high doses. Inhibition of prostaglandin (PG) synthesis by carprofen was slight in relation to its anti-inflammatory and analgesic potency. As ulcerogenicity of non-steroidal anti-inflammatory agents is correlated with inhibition of the PG-synthesis, the insignificant impairment of the PG-synthesis in therapeutically effective doses may explain the good gastrointestinal tolerance repeatedly reported for carprofen in clinical trials.

The synthetic trimethyl prostanoid Ro 22-6923 was studied for its effects on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. The prostanoid (at a p.o. dose as low as 0.05 mg/kg) produced significant inhibition of gastric acid secretion induced by 12 micrograms/kg/h of histamine for 5 h. A dose of 0.5 mg/kg p.o. produced a significant antisecretory effect within 45 min that lasted for 8.5 h. Cimetidine (5 mg/kg p.o.) produced an inhibitory effect on acid output equivalent to the 0.5-mg/kg dose of Ro 22-6923, but the duration of the cimetidine effect was less than 6 h. Administration of Ro 22-6923 i.v. (0.25 mg/kg) inhibited acid output for longer than 8 h. Against a 25-micrograms/kg/h histamine challenge, Ro 22-6923 (0.5 and 1.0 mg/kg) inhibited acid output to an equal degree but for a longer duration than cimetidine (5 mg/kg). Pepsin output was totally inhibited by 0.5 mg/kg of Ro 22-6923, whereas 5 mg/kg of cimetidine inhibited pepsin output by approximately 60%. Pepsin activity in the gastric juice was reduced by Ro 22-6923 and was increased by cimetidine. Blood flow, as estimated by the aminopyrine clearance technique, was reduced slightly by Ro 22-6923 and cimetidine. However, the ratio of clearance to acid secretory rate increased with both compounds, suggesting a direct effect of Ro 22-6923 and cimetidine on acid secretion at the parietal cell level. The results suggest that Ro 22-6923 may be a useful therapeutic agent for peptic ulcer disease in humans.

The synthetic prostanoid Ro 22-6923 was studied for its ability to inhibit gastric secretion and to protect the gastric mucosa against the injurious effects of stress, indomethacin and ethanol. Ro 22-6923 inhibited basal acid secretion when administered intragastrically or intraduodenally to animals with a gastric fistula. The pH of the gastric juice promptly increased and remained above 5 for 3 h after an intragastric dose of 10 micrograms/kg and the pH remained above 4 for more than 3 h after this dose given intraduodenally. The increase in pH was associated with reduction of acid concentration and H+ output. Ro 22-6923 inhibited histamine-stimulated gastric secretion in a perfused stomach preparation with an ED50 of 15 micrograms/kg compared to values of 43, 126 and 289 micrograms/kg for prostaglandin (PG)E2, ranitidine and cimetidine, respectively. The synthetic prostanoid protected the gastric mucosa from the injurious effects of stress (oral ED50 values of 0.2 and greater than 1.0 mg/kg for Ro 22-6923 and PGE2, respectively) and indomethacin (oral ED50 0.07 and 0.06 mg/kg for Ro 22-6923 and PGE2, respectively). Cimetidine and ranitidine, at high doses, were effective against the mucosal damage produced by stress (ED50 values greater than 100 mg/kg) and indomethacin (ED50 values greater than 10 mg/kg). Ro 22-6923, but not PGE2 or 16, 16-dimethyl PGE2, inhibited dibutyryl cyclic AMP-induced [14C]aminopyrine accumulation by isolated parietal cells, indicating that the prostanoid has a direct inhibitory effect on H+ secretion. The results on the antisecretory and cytoprotective properties of Ro 22-6923 suggest this drug could be potentially useful in the pharmacotherapy of peptic ulcer disease.

The novel antidepressant moclobemide is a reversible inhibitor of monoamine oxidase (MAO), preferentially of type A. Moclomide was active in three animal models considered predictive for antidepressant activity: 1) it prevented dose-dependently akinesia and blepharospasm induced in mice and rats by Ro 4-1284, a short-acting amine releasing agent. Prevention of akinesia by moclobemide also depended upon the dose of Ro 4-1284. For comparison also, effects of cimoxatone, harmaline, tranylcypromine and clorgyline are presented: 2) in cats, it selectively and dose-dependently suppressed rapid eye movement sleep without disturbing the sleep-wakefulness cycle; and 3) in the behavioral despair test in mice, it decreased the immobility score to a similar degree as amitriptyline or imipramine. In addition, moclobemide potentiated 5-hydroxytryptophan-induced stereotypies in rats with a potency similar to cimoxatone and with a duration of action of less than 24 hr. Moclobemide had almost no effect on the spontaneous behavior in mice, rats, cats and monkeys. Only in higher doses, marginal sedation and slight impairment in motor performance were seen. Moclobemide did not prevent pilcarpine-induced salivation in mice, demonstrating the absence of anticholinergic activity. Blood pressure and heart rate of freely moving, spontaneously hypertensive rats were only slightly decreased for less than 3 hr. Moclobemide moderately potentiated the pressor effect of p.o. tyramine in rats. In conclusion, the reversible MAO inhibitor moclobemide is active in animal models sensitive to all major drugs used in the treatment of depression. In contrast to imipramine-like antidepressants, it lacks anticholinergic activity and it differs from classic MAO inhibitors by potentiating only weakly the pressor effect of p.o. tyramine.