A Case Report of a Carbamazepine Overdose With Focus on Pharmacokinetic Aspects.

In this article a case of carbamazepine overdose is reported. It is common to use immuno-based methods in the field of therapeutic drug monitoring but it might be difficult to adapt such values to toxicological cases. For carbamazepine overdoses it is recommended also to determine the metabolite carbamazepine-10,11-epoxide. Especially for critical conditions a definite substance identification should be performed. In addition, quantifying main metabolites is recommended for an acute clinical toxicological assessment.

Transpapillary retrieval of a proximally migrated stent using a three-prong polyp retrieval device in a 2-years-old girl.

Endoscopic retrieval of proximally migrated biliary stents is sometimes challenging. We report on the successful use of a three-prong colon polyp retrieval device in a two year old child.

Effect of enlarged glutathione on zinc-mediated toxicity in lung-derived cell lines.

Zinc-mediated toxicity has been linked to cellular glutathione content in isolated cells. In addition, treatment of alveolar epithelial type II cells with glucocorticoids diminishes cellular glutathione content, and this is followed by an increase in zinc-mediated toxicity. The question arises whether an increase in glutathione synthesis might decrease zinc-mediated toxicity. For this purpose an administration of 200 micromol/l N-acetyl-L-cysteine (NAC) was given to the cells, while cysteine was used up to 100 micromol/l. Zinc-mediated toxicity was assessed by measuring protein synthesis inhibition and glutathione dependent parameters. De novo synthesis of glutathione was assessed as compared to controls by N-acetyl-D-cysteine (NADC) treatment. Comparing NAC and NADC treatment no differences in zinc-mediated toxicity were found. Furthermore only in one (of three) cell line tested a significant increase in GSH content by NAC as compared to NADC treatment was achieved. But even in this cell line no changes by zinc-mediated toxicity were found. It is concluded that the cell lines tested can use other sources of cys for glutathione synthesis. Furthermore the increased zinc-mediated toxicity due to hydrocortisone was abolished in the alveolar epithelial cell lines by the NADC/NAC treatment. It is therefore discussed that additionally to glutathione some other antioxidative defence mechanisms can influence zinc-mediated toxicity as well.

In vitro embryotoxicity assessment with dental restorative materials.

OBJECTIVES: Resin (co)monomers may be released from restorative dental materials and can diffuse into the tooth pulp or the gingiva, and can reach the saliva and the circulating blood. Genotoxic potential of some dental composite components has been clearly documented. The genotoxic effects of xenobiotics can represent a possible step in tumor initiation and/or embryotoxicity/teratogenesis. A modified fluorescent mouse embryonic stem cell test (R.E.Tox) was used to test the embryotoxic potential of following dental restorative materials: Bisphenol A glycidylmethacrylate (BisGMA), urethanedimethacrylate (UDMA), hydroxyethylmethacrylate (HEMA), and triethyleneglycoldimethacrylate (TEGDMA), as well as some of their metabolic intermediates 2,3-epoxy-2-methyl-propionicacid-methylester (EMPME), methacrylic acid (MA), and 2,3-epoxy-2-methylpropionic acid (EMPA). METHODS: Mouse embryonic stem (ES) cells stably transfected with a vector containing the gene for the green fluorescent protein under control of the cardiac alpha-myosin heavy chain promoter were differentiated in the presence of various concentrations of the test compounds for 12 days. Fluorescence was measured using the TECAN Safire and values were expressed as percent of control values. To distinguish between cytotoxic and embryotoxic effects, all compounds were tested in a standard MTT assay. RESULTS: HEMA, TEGDMA and EMPME did not influence the differentiation process of ES cells towards cardiac myocytes. No cytotoxic effects were observed at any of the concentration levels tested. Exposure to BisGMA resulted in a 50% decrease in cell survival and a very strong inhibition of cell differentiation at 10(-5)M (p<0.01). Embryotoxic effects were also present at 10(-6) and 10(-7)M (p<0.05). EMPA induced a decrease in ES cell differentiation at 10(-5)M (p<0.01) without cytotoxic effects. No embryotoxic effects were induced at lower concentrations. Exposure to UDMA resulted in a slight decrease of cell differentiation at 10(-5)M (p<0.05). Exposure of cells to MA resulted in an increase of cardiac differentiation up to 150% (p<0.05) at 10(-5)M without cytotoxic effects. CONCLUSIONS: BisGMA induced a significant high embryotoxic/teratogenic effect over a large range of concentration. Therefore attention should be focused on this dental monomer, which should be investigated further by in vivo experiments.

[Brain death diagnosis after sedation with propofol or sufentanil. Recommendations for the usage of toxicological analytics]. / Hirntoddiagnostik nach Gabe von Propofol oder Sufentanil. Empfehlungen zum Umgang mit toxikologischer Analytik.

BACKGROUND: Before the clinical diagnosis of brain death is made, toxicological analyses are often performed for the exclusion of effective serum levels of previously applied sedating drugs. For propofol and sufentanil there are no uniform recommendations for the usage of toxicology test results. OBJECTIVES: To develop a standard practice in the diagnosis of brain death after therapeutic application of one of these drugs. MATERIAL AND METHODS: Based on the current literature and the available analytical assays, an ad hoc working group consisting of specialists in toxicology and intensive care medicine compiled recommendations for the usage of toxicological analytics in the diagnosis of brain death at the Rostock University Hospital. RESULTS: For propofol, current analytical assays allow the quantification of serum concentrations of 0.2 µg/ml and lower; the execution of clinical brain death diagnostics is recommended by the ad hoc group only at propofol serum levels lower than 0.4 µg/ml. For sufentanil, the currently prevalent assays set lower determination limits of about 0.2 ng/ml in serum and 0.1 ng/ml in urine, which is above the cautiously adopted lower therapeutic serum concentration of 0.02 ng/ml. Therefore after negative determination of sufentanil (< 0.2 ng/ml) in blood serum, the following alternative procedures are recommended: (1) the execution of clinical brain death diagnostics under administration of naloxone; or (2) at intact renal function the additional negative determination of sufentanil in urine (< 0.1 ng/ml). If an assay allowing the detection of sufentanil at ≤ 0.01 ng/ml is available, brain death diagnostics should be carried out only at a serum level lower than 0.02 ng/ml. CONCLUSION: These recommendations may serve as a proposal for similar standards in other hospitals.

Cytotoxicity of dental composite components and mercury compounds in pulmonary cells.

The cytotoxic potentials of the dental composite components triethyleneglycoldimethacrylate (TEGDMA) and 2-hydroxy-ethylmethacrylate (HEMA) as well as mercuric chloride (HgCl2) and methyl mercury chloride (MeHgCl) were investigated. Proliferating A549 and L2 cell monolayers were cultured in the absence or presence of composite components or mercurials. Twenty-four hours later the tetrazolium salt XTT (sodium 3'-[1-phenyl-aminocarbonyl)-3,4-tetrazolium]bis(4-methoxy-6-nitro)benzenesulphonic acid) was added. Formazan formation was quantified using a microtiter plate reader. EC50 values were obtained as half-maximum-effect concentrations from fitted curves. EC50 values were in A549 cells (mean values +/- standard deviation; n = 12; micromol/l); HEMA 8854+/-1882; TEGDMA 1821+/-529; HgCl2 41+/-7 and MeHgCl 27+/-3. EC50 values in L2 cells were: HEMA 191+/-28; TEGDMA 112+/-16; HgCl2 25+/-6 and MeHgCl 8+/-6. All tested substances induced a dose-dependent loss of viability in A549 and L2 cells after 24 h. The EC50 values of both mercurials were significantly (p < 0.05) lower compared to the values of both composite components. TEGDMA was about 5-fold (A549 cells) and about 2-fold (L2 cells) more toxic compared to HEMA. It is to be assumed that the risk of lung cell damage by dental composite components is even more unlikely.

Biological clearance of HEMA in guinea pigs.

No toxicokinetic data are available about the dental composite component 2-hydroxyethylmethacrylate (HEMA) in vivo in the literature. Therefore, the excretion of HEMA in feces and urine in vivo and, using the pendular perfusion technique with segments of jejunum and colon, in the biliary and enteric excretion in situ were investigated in anesthetized guinea pigs. In the in situ experiments, guinea pigs (n = 4) received HEMA (0.02 mmol/kgbw labelled with a tracer dose 14C-HEMA 0.3 kBq/gbw) injected into the jugular vein. In the in vivo experiments, guinea pigs (n = 4) received HEMA (+ 14C-HEMA, same dose as above) via gastric tube. Urine and feces were collected for 24h. In the in situ experiments, organs from guinea pigs were removed 60 min after the beginning of the experiment, and then the 14C-radioactivity was measured. During the 60 min perfusion period the calculated amount of 14C-activity excreted into the total jejunum and colon was 6.0 +/- 1.0% and 2.7 +/- 0.7% of the dose administered, respectively (mean +/- sem). Of the 14C-HEMA dose, 5.3 +/- 0.3% was found in the bile. Significantly (p < 0.05) higher bile/blood concentration ratios were found at 10-40 min after the injection of HEMA, as compared to the ratio at 60 min. The total 14C-recovery in all organs tested was 20.0 +/- 2.6%. During 24h the amounts of 14C-activity excreted in the feces and urine were 1.1 +/- 0.1% or 17.1 +/- 1.50% of the dose administered, respectively (mean +/- sem). The total 14C-recovery in all organs tested was 11.6 +/- 0.6%. In a second series of in vivo experiments, exhaled air from the animals was captured during the 24h experimental period. 14C was exhaled to 63.6 +/- 2.11% of the administered 14C-HEMA dose (mean +/- sem; n = 4) as 14C-carbondioxide. The results indicate a rapid clearance of 14C-HEMA and/or 14C-HEMA metabolite(s) from the organism, exhalation being the major route of elimination.

Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) and myelodysplastic syndromes (MDS) are disorders of pluripotent stem cells resulting in haematopoietic insufficiency which can be cured by marrow transplantation. The extent of myeloablative conditioning necessary for elimination of the non-malignant and premalignant clones is not known. We report our results of marrow transplantation with and without myeloablative conditioning in two patients with PNH and seven patients with MDS. Conditioning was not used in a patient with PNH and a monozygotic twin as donor. In this patient the disease remained unchanged. Myeloablative treatment with busulphan (BUS) in addition to immunosuppression with cyclophosphamide (CY) was used for conditioning in a patient with PNH and a 2-year-old boy with chronic myelomonocytic leukaemia (CMML). Fractionated total body irradiation (FTBI) and CY was used in six patients with refractory anaemia with excess of blasts (RAEB) and RAEB in leukaemic transformation (RAEB-T). Haematopoiesis was fully restored in all patients conditioned with myeloablative treatment except for a patient in leukaemic transformation with myelofibrosis and a HLA-DR-incompatible donor. Chimerism was complete in all patients except for the 2-year-old boy conditioned with BUS and CY. Our results and those reviewed in the literature indicate that myeloablative conditioning with either BUS or FTBI is advantageous for marrow transplantation in PNH and MDS.

Distribution and excretion of TEGDMA in guinea pigs and mice.

The monomer triethyleneglycoldimethacrylate (TEGDMA) is used as a diluent in many resin-based dental materials. It was previously shown in vitro that TEGDMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of 14C-TEGDMA applied via gastric, intradermal, and intravenous administration at dose levels well above those encountered in dental care were examined in vivo in guinea pigs and mice as a test of the hypothesis that TEGDMA reaches cytotoxic levels in mammalian tissues. 14C-TEGDMA was taken up rapidly from the stomach and small intestine after gastric administration in both species and was widely distributed in the body following administration by each route. Most 14C was excreted within one day as 14CO2. The peak equivalent TEGDMA levels in all mouse and guinea pig tissues examined were at least 1000-fold less than known toxic levels. The study therefore did not support the hypothesis.

Influence of zinc on protein metabolism in various lung cell lines.

Toxic cellular effects after exposure to elevated zinc concentrations affect protein metabolism. We separated proteins by 2D-PAGE after cellular zinc exposure in order to decide whether changes in protein metabolism of specific proteins by elevated zinc might be a main critical cellular effect. The investigation was performed with fibroblast-like (11Lu, 16Lu) and alveolar epithelial (L2, A549) lung cell lines. Silver staining and autoradiography after radiolabelled methionine incorporation of 2D gels of cellular proteins was executed in order to look for specific changes in protein content. Methionine incorporation decreased in a concentration- and time-dependent manner to values of 10% with 100 mumzinc chloride for 3hr in the non-malignant cell lines, while about 20% was reached with 200 mum after 4hr of incubation in the malignant A549 cells. In silver stained 2D gels of zinc-exposed cells only few differences as compared to controls were detectable. Autoradiograms of 2D gels after methionine incorporation showed few additional spots that could be heat shock proteins in alveolar epithelial cell lines after zinc exposure. Autoradiographically detectable methionine in 2D-gels obtained after exposure of cells to high zinc concentrations for time intervals greater than 1hr showed a time-dependent decrease in all cell lines. This decrease was accompanied by an increase of three characteristic spots at 28/9 (kDa/pI), 32/8 and 42/7.5 respectively, amounting to 15-30% of all incorporated radioactivity after 2-4hr of zinc exposure. When cells were allowed to recover from zinc poisoning, similar 2D gel spot patterns as compared to controls without zinc exposure were obtained in all cell lines tested.

Antioxidative vitamins decrease cytotoxicity of HEMA and TEGDMA in cultured cell lines.

OBJECTIVES AND METHODS: In a previous study it was postulated that toxicity of 2-hydroxyethylmethacrylate (HEMA) and triethleneglycoldimethacrylate (TEGDMA) is based on oxidative metabolites. In this study the influence of antioxidative vitamins (including uric acid) on the toxicity of HEMA or TEGDMA was tested. Toxicity of HEMA and TEGDMA was determined in rat alveolar epithelial L2, human malignant A549, and human fibroblast-like 11Lu cells by inhibition of methionine incorporation (as a marker of protein synthesis inhibition) and by determination of glutathione depletion, as well as by measurement of GSSG increase. RESULTS: Toxicity of the composite components HEMA and TEGDMA was demonstrated by GSH depletion as the most sensitive method. Five hundred micromoles per litre Vitamin C or 250 micromol/l Vitamin E were mostly able to decrease toxicity of HEMA and TEGDMA in the cell lines tested. In addition, 250 micromol/l Vitamin A was only effective in L2 cells impairing HEMA toxicity and 250 micromol/l uric acid impairing TEGDMA toxicity as assessed by decreased GSH depletion. In A549 cells only methionine incorporation inhibition but not GSH depletion was significantly affected. By contrast, in 11Lu cells methionine incorporation inhibition was not significantly changed, but GSH depletion was. CONCLUSIONS: The postulated mechanism of HEMA or TEGDMA toxicity based on radical metabolites is supported by the effectivity of the antioxidative substances tested in mitigating toxicity and by the greater susceptibility of the glutathione redox system as compared to protein synthesis inhibition in assessing toxicity.

Cytotoxicity of dental composite components and mercury compounds in lung cells.

OBJECTIVE: The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA), as well as mercuric chloride (HgCl2) and methylmercury chloride (MeHgCl) was investigated on the release of lactatedehydrogenase (LDH) from alveolar epithelial lung cell lines in vitro. METHODS: The confluent cell layers from the A549 (human, malignant) and the L2 cells (rat) were incubated with various concentrations of HEMA, TEGDMA, MeHgCl and HgCl2 at 37 degrees C in 2% (v/v) CO2 atmosphere for 8h. In further experiments the L2 cells were incubated with the same compounds for 6-48 h. LDH release was measured and the values were expressed as percentage of the LDH content. The values were plotted on a concentration log-scale and the substance concentration at the maximum slope was assessed as effective concentration (EC50). RESULTS: A significant (p<0.05) increase in the LDH release was found in the L2 cells after 8-h incubation with HEMA (4 mmol/l), TEGDMA (2 mmol/l), MeHgCl (0.01 mmol/l) and HgCl2 (0.015 mmol/l), and in A549 cells with HEMA (14 mmol/l), TEGDMA (15 mmol/l), MeHgCl (0.15 mmol/l) and HgCl2 (0.05 mmol/l), compared to controls. The EC50 values from compounds in the L2 cells are shown in the following table (mean; sem in parentheses; n=3-6; #n=1): [see text]. SIGNIFICANCE: The toxic effect of HgCl2 and MeHgCl from the L2 cells was about 100-700-fold higher than of the dental composite components. A significant (p<0.05) time dependent increase of toxicity was observed with TEGDMA, HEMA and MeHgCl.

Zinc toxicity in various lung cell lines is mediated by glutathione and GSSG reductase activity.

In a previous work, it was shown that in cells after a decrease of cellular glutathione content, toxic zinc effects, such as protein synthesis inhibition or GSSG (glutathione, oxidized form) increases, were enhanced. In this study, zinc toxicity was determined by detection of methionine incorporation as a parameter of protein synthesis and GSSG increase in various lung cell lines (A549, L2, 11Lu, 16Lu), dependent on enhanced GSSG reductase activities and changed glutathione contents. After pretreatment of cells with DL-buthionine-[R,S]-sulfoximine (BSO) for 72 h, cellular glutathione contents were decreased to 15-40% and GSSG reductase activity was increased to 120-135% in a concentration-dependent manner. In BSO pretreated cells, the IC50 values of zinc for methionine incorporation inhibition were unchanged as compared to cells not pretreated. The GSSG increase in BSO pretreated cells by zinc was enhanced in L2, 11Lu, and 16Lu cells, whereas in A549 cells, the GSSG increase by zinc was enhanced only after pretreatment with the highest BSO concentration. Inhibition of GSSG reductase in alveolar epithelial cells was observed at lower zinc concentrations than needed for methionine incorporation inhibition, whereas in fibroblastlike cells, inhibition of GSSG reductase occurred at markedly higher zinc concentrations as compared to methionine incorporation inhibition. These results demonstrate that GSSG reductase is an important factor in cellular zinc susceptibility. We conclude that reduction of GSSG is reduced in zinc-exposed cells. Therefore, protection of GSH oxidation by various antioxidants as well as enhancement of GSH content are expected to be mechanisms of diminishing toxic cellular effects after exposure to zinc.

Decreased zinc toxicity resulting from doxorubicin without increased GSSG export in three human lung cell lines.

Zinc-mediated cytotoxicity is recognized, at least in part, by a decrease of reduced glutathione (GSH) and an increase in the oxidized form of glutathione (GSSG). Doxorubicin is a common inducer of multidrug-resistance-associated proteins and such proteins might, furthermore, be associated by an increased GSSG export rate. Therefore, zinc-mediated toxicity should be abolished after doxorubicin pretreatment. In the present study, zinc toxicity was characterized by methionine incorporation, glutathione content, and the GSSG/GSH ratio. Experiments were performed in three established lung cell lines comparing doxorubicin-pretreated cells with controls. Zinc-mediated toxicity was significantly decreased after pretreatment with doxorubicin as assessed by methionine-incorporation inhibition, GSH depletion, and/or GSSG increase in the two nonmalignant cell lines. Unexpectedly, zinc-associated GSSG export was not increased after doxorubicin pretreatment. This inconsistency might be explained as a result of a decreased zinc content in these cells, probably because of an increased export rate of zinc. The findings are in contradiction to the opinion of metal excretion by multidrug-resistance-associated proteins, matched to GSH conjugate excretion, as it is discussed for cadmium, for example.

Influence of glutathione on zinc-mediated cellular toxicity.

The effect of zinc on various pulmonary cell lines has been studied by measuring the depletion of total cellular glutathione after exposure to zinc(II) chloride at different concentrations. Total cellular glutathione (cGS) was measured at 31+/-3 nmol/mg, 3.8+/-0.6 nmol/mg, and 3.7+/-1.2 nmol/mg protein in A549, L2, and 11Lu cells, respectively. After treatment with buthionine sulfoximine (BSO), the cGS levels decreased by 20% in A549 cells and below 0.2 nmol/mg in L2 and 11Lu cells. Exposure of A549 cells to 25-200 microM ZnCl2 for 4 h alone decreased the cGS content to 60-80%. There was little additional effect in BSO-pretreated cells. In L2 and 11Lu cells, the decrease of cGS was 70-85% following exposure to 15-150 microM ZnCl2 for 2 h. If BSO was also used, the decrease in cGS was 85-95% in L2 cells and 75-85% in 11Lu cells. Exposure to 25-250 microM ZnCl2 for 2 h diminished protein synthesis as determined by radiolabeled methionine incorporation, with half-maximum inhibition (EC50) from 40-160 microM ZnCl2. To attain similar EC50 values in BSO-pretreated cells, only about half the zinc concentrations were required as compared to cells without pretreatment. The decrease of cGS was accompanied by an increased ratio of oxidized: reduced glutathione that was more pronounced in cells with low glutathione content.

Effect of low level zinc pretreatment on zinc-mediated toxicity in different lung cell lines.

Reduced toxicity of high zinc exposure was observed after pretreatment of various lung cells with nonlethal zinc concentrations. This effect became significant when various parameters of cytotoxicity were assessed (e.g., inhibition of protein synthesis, depletion of reduced glutathione [GSH], increase of oxidized glutathione [GSSG], release of lactate dehydrogenase [LDH]). Similar protective effects by zinc have already been shown by several investigators for a variety of toxicity studies dealing with cadmium, in vitro and in vivo. Zinc-induced toxicity has been linked to glutathione metabolism and cellular GSH contents. Activity of glutathione reductase (GR) and rates of glutathione synthesis were identified as determinants of zinc (cyto)toxicity. However, these variables were virtually unaffected in our adapted cells. Consequently, another variable appears to be crucial for modulating cellular suscepticibility in zinc pretreated cells. Protection in our cells was achieved by pretreatment with 80-120 micromol/L zinc chloride for 24-72 h, roughly 10-fold more zinc in the medium than is normally found in human plasma. Protection was not observed when the cells were concomitantly exposed to cycloheximide, an inhibitor of protein synthesis, or actinomycin D, an inhibitor of RNA synthesis, but it was found in the presence of amanitin, an inhibitor of mRNA synthesis. It is therefore concluded that the altered zinc tolerance of pretreated cells is not attributable to the induction of metallothionein.

Inhibition of protein synthesis by zinc: comparison between protein synthesis and RNA synthesis.

Inhalation of zinc fumes may lead to the acute respiratory distress syndrome. The mechanisms of pulmonary zinc toxicity are not yet understood. Therefore we investigated zinc-dependent depression of protein and RNA synthesis in rat and human lung cell lines. 1. After exposure to 120 or 150 micromol/l zinc, RNA synthesis as assessed by uridine incorporation decreased by 60-70% between 0 and 2 h exposition in rat alveolar type II cells (L2 cells) and human fibroblast-like cells (11Lu and 16Lu cells), and by 90% between 0 and 4 h in carcinoma-derived cells (A549 cells). 2. After 2 h exposure, L2, 11Lu, and 16Lu cells were half-maximally inhibited by 50 micromol/l zinc, whereas A549 cells were more resistant with half-maximal inhibition at 100 micromol/zinc. 3. Protein and RNA synthesis was inhibited in parallel in L2, 11Lu, and A549 cells as indicated by simultaneous determination of uridine and amino acid incorporation. In 16Lu cells, the decline in protein synthesis preceded RNA synthesis inhibition. Pretreatment with RNA synthesis inhibitors (amanitin or actinomycin D) had no effect on time curve and intensity of RNA synthesis inhibition. Taken together, our results indicate that the suppression of RNA and protein synthesis likely are independent phenomena, due to direct zinc effects on these biosynthetic pathways.

Lack of effects of hydrocortisone pretreatment on zinc-induced changes in protein assemble.

Inhalational zinc intoxication may lead to the development of acute respiratory distress syndrome (ARDS). Pharmacological treatment of ARDS is based on glucocorticoids, while the efficiency of glucocorticoid treatment is discussed controversially. Glucocorticoid pretreatment of lung cell lines is known to cause disparate effects with regard to zinc susceptibility. Both substances are known to each interact with protein metabolism. In the present study, zinc effects were examined on hydrocortisone (HC)-pretreated lung cell lines by detection of content and synthesis of different proteins after two-dimensional (2D) gel electrophoresis. (1) In HC- pretreated fibroblast-like 11Lu and alveolar epithelial L2 cells, no zinc-mediated changes after silver staining of 2D gels were seen. Few differences occurred in HC-pretreated alveolar epithelial A549 cells that might be explained by the appearance of heat shock proteins (hsp) after zinc exposure. (2) In autoradiographs after 35S-Met incorporation only in 11Lu cells, small differences occurred after HC treatment as compared to controls without HC. (3) All cell lines tested demonstrated the same zinc-mediated changes in autoradiographs with a nearly complete loss of synthesized proteins and an appearance of a few new spots. These changes were reversible in all cell lines after washing out of external zinc. The new spots were transiently expressed for a few hours after zinc exposure. (4) The overall effect of HC pretreatment was rather unimpressive. The virtual lack of major effects does not support the hypothesis that a gross interaction between glucocorticoids and zinc at the cellular protein synthesis level would be an important mechanism of influence in zinc-induced lung injury.

Are we ready to replace dimercaprol (BAL) as an arsenic antidote?

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication-especially with lipophilic organoarsenicals-may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (= Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL whenever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of-no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

[The adolescent psychiatric service in the Saxony free state and its contribution to health promotion]. / Der Jugendärztliche Dienst im Freistaat Sachsen und sein Beitrag zur Gesundheitsförderung.

The tasks of the Public Health Service with particular reference to children and teenagers in the German Federal Land of Saxonia are laid down by legislation enacted by the Ministry for Culture on health care in schools (30.7.92). It is the main task of health promotion in schools to prevent health disorders and disturbed development in children and teens. The following tasks must be performed, among others: medical examination before admittance to school and in the classes 2, 5 and 9; public hours of consultation; and statistical documentation. All the essential demands on modern public health service for children and teens are part of current legislation in Saxonia.