Fühner-Wieland's Sammlung von Vergiftungsfällen

Previous studies suggested that the rabbit is much more susceptible to the teratogenic action of 13-cis-retinoic acid (13-cis-RA) than the mouse or the rat, while the teratogenicity of all-trans-RA was comparable in these species. In the present study we investigated if pharmacokinetics can explain these species- and structure-related differences. The embryotoxic and teratogenic potential of all-trans-retinoid acid (all-trans-RA) and 13-cis-RA were evaluated in the Swiss hare rabbit after oral administration of daily doses of the two drugs throughout organogenesis, from gestation day (GD) 6 to 18 (plug day=GD 0). All-trans-RA was given at dose levels of 0.7, 2 or 6 mg/kg body weight per day and 13-cis-RA at 3, 7.5 or 10 mg/kg per day. The doses needed to elicit a minimum teratogenic response were found to be 6 mg/kg per day for all-trans-RA and 10 mg/kg per day for 13-cis-RA. Using these doses, transplacental pharmacokinetics of all-trans- and 13-cis-RA were performed. Pregnant rabbits were treated once daily from GD 7 to 12 and plasma and embryo samples were collected for HPLC analysis at various time intervals after the final dose. The main plasma metabolites of all-trans-and 13-cis-RA were all-trans-β-glucuronide (all-trans-RAG) and 13-cis-4-oxo-RA, respectively. The elimination of 13-cis-RA and its metabolites from maternal plasma were much slower than of all-trans-RA resulting in accumulation of the 13-cis-isomers in plasma. Marked differences in the placental transfer of the two drugs and their metabolites were observed. All-trans-RA and all-trans-4-oxo-RA were efficiently transferred to the rabbit embryo, reaching concentrations similar to the plasma levels. On the contrary, the 13-cis-isomers reached the embryo to a lesser extent. Despite its limited placental transfer, a considerable embryonic exposure to 13-cis-RA and 13-cis-4-oxo-RA was noticed after treatment with isotretinoin, as indicated by their area-under-the-concentration-time-curve (AUC) values in the embryo, which were in the same range as the corresponding AUC value of all-trans-RA after treatment with the all-trans-isomer. Our results suggest that the high sensitivity of the rabbit to the teratogenic effects of 13-cis-RA can be attributed mainly to the 13-cis-isomers and not to isomerization to all-trans-RA. The significant exposure of the rabbit embryo to 13-cis-RA and its 4-oxo metabolite is a result of their very slow excretion rates from the maternal organism. Furthermore, this study supports the view that embryonic AUC values should be considered as the most suitable pharmacokinetic correlate to retinoid induced teratogenesis.

Im Mageninhalt von E 605-Suicidfällen, der bei Zimmertemperatur aufbewahrt worden war, ließ sich noch nach 8 Monaten der Wirkstoff des E 605 mit Hilfe der spezifischen UV-Absorptionskurve nachweisen. Bei Versuchen mit kleineren zugesetzten Mengen an E 605 zu Mageninhalt, war die Nachweisbarkeitsdauer mit der beschriebenen Methode kürzer. Nach dreiwöchigem Erdgrab konnte im Mageninhalt von Kaninchen der Wirkstoff noch durch den Kurvenverlauf nachgewiesen werden. Die Zersetzung der Mageninhaltsstoffe bei mehrmonatigem Stehen bei Zimmertemperatur hat keinen wesentlichen Einfluß auf die Nachweisbarkeitsdauer mit Hilfe der Messung der Extinktionskurven des Esters wie des p-Nitrophenol. In den Fällen, bei denen der spezifische Kurvenverlauf der Extinktion für die zu ermittelnden Substanzen nicht mehr zu erhalten war, konnte p-Nitrophenol nach einer einfachen Anreicherungsmethode noch nachgewiesen werden.

Das Gift von Latrodectus Tredecimguttatus, das an der demyelisierten motorischen Faser Acetylcholin freizusetzen vermag, verlängert an Mäusen mit Vergiftung durch Botulinus-Toxin A signifikant die Überlebenszeit.

To investigate the effect of enzymatically modified isoquercitrin (EMIQ) on hepatocellular tumor promotion induced by phenobarbital (PB), male rats were administered a single intraperitoneal injection of 200 mg/kg N-diethylnitrosamine (DEN) and then fed with a diet containing PB (500 ppm) for 8 weeks, with or without EMIQ (2,000 ppm) in the drinking water. One week after PB administration, rats underwent a two-thirds partial hepatectomy. The PB-induced increase in the number and area of glutathione S-transferase placental form-positive foci and the proliferating cell nuclear antigen-positive ratio was significantly suppressed by EMIQ. Real-time reverse transcription–polymerase chain reaction analysis revealed increases in mRNA expression levels of Cyp2b2 and Mrp2 in the DEN-PB and DEN-PB-EMIQ groups compared with the DEN-alone group, while the level of Mrp2 decreased in the DEN-PB-EMIQ group compared with the DEN-PB group. There were no significant changes in microsomal reactive oxygen species (ROS) production and oxidative stress markers between the DEN-PB and DEN-PB-EMIQ groups. Immunohistochemically, the constitutive active/androstane receptor (CAR) in the DEN-PB group was clearly localized in the nuclei, but its immunoreactive intensity was decreased in the DEN-PB-EMIQ group. These results indicate that EMIQ suppressed the liver tumor-promoting activity of PB by inhibiting nuclear translocation of CAR, and not by suppression of oxidative stress.

Groups of male C57Bl and CD-1 mice were exposed to benzene via inhalation using two different exposure protocols. One protocol consisted of repetitive week-long exposures to 300 ppm benzene (6 h/d×5 d/wk) interrupted by 2 weeks of non-exposure. The exposure pattern (1 week of exposure followed by 2 weeks of non-exposure) was continued until the death of the last exposed animal. The second protocol consisted of exposures to 1200 ppm benzene (6 h/d×5 d/wk) for 10 weeks. Exposures were then terminated and the animals allowed to live out their lives. For each protocol, appropriate age-matched control mice received comparable exposures to filtered, conditioned air. The discontinuous exposure patterns mimic the patterns of exposure often encountered in the workplace and, in addition, prolong the survival of exposed animals so as to maximize potential tumorigenic responses. Both exposure protocols were markedly hematotoxic to both mouse strains as measured by peripheral blood counts. Both strains of mice responded to the intermittent 300 ppm benzene exposures with elevated incidences of malignant tumors. Particularly noteworthy was a 35% incidence of zymbal gland tumors in the C57Bl mice. In contrast, only the CD−1 mice responded to the 1200 ppm benzene exposures delivered over 10 weeks with elevated tumor incidences. A 46% incidence of lung adenoma was particularly striking in these mice. Neither of the benzene exposure protocols induced elevated incidences of leukemia/lymphoma in either strain. These studies demonstrate that discontinuous exposures to benzene are tumorigenic and that a lifetime exposure to benzene, even if delivered at a lower concentration and in an intermittent exposure pattern, is more tumorigenic than a short-term exposure to benzene.

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.

Human exposure to PM2.5 (particulate matter with an aerodynamic diameter below 2.5 μm) is known to be responsible for airway inflammation and may also induce airway remodelling. In respiratory epithelial cells exposed to PM2.5, releases of pro-inflammatory cytokines such as granulocyte macrophage-colony stimulating factor (GM-CSF) and growth factor ligands of the epidermal growth factor receptor (EGFR) are increased. The present study aimed at determining the involvement of EGFR ligands by autocrine effects in PM2.5-induced GM-CSF release. PM2.5 exposure triggers GM-CSF release by human bronchial epithelial (HBE) cells. This release is dependent on EGFR activation by ligand binding as it is inhibited by AG1478, an inhibitor of EGFR tyrosine kinase activity as well as by a neutralizing anti-EGFR antibody. The use of conditioned medium from cells previously exposed to PM2.5 demonstrates that PM2.5-exposed cells release soluble EGFR ligands able to induce GM-CSF release by an autocrine manner. It was further demonstrated by inhibiting tumour-necrosis factor-alpha converting enzyme (TACE) that is involved in some EGFR ligand shedding. TAPI-2 and GM-6001, two TACE inhibitors, prevented the PM2.5-induced GM-CSF release as well as the silencing of TACE by siRNA. We provide evidence that the pro-inflammatory response induced by PM2.5 exposure on HBE cells, results from an autocrine effect of EGFR ligands released by TACE activity. This autocrine loop by eliciting and sustaining inflammation could contribute to exacerbation of airway remodelling in respiratory-compromised individuals.