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  • 1
    Keywords: PHASE ; PHASE-III ; - ; advanced breast cancer ; III TRIAL ; THERAPY ; CANCER ; BREAST-CANCER ; BREAST ; breast cancer ; TRIAL ; chemotherapy ; ONCOLOGY ; THERAPIES
    Type of Publication: Meeting abstract published
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  • 2
    ISSN: 1432-0738
    Keywords: Trichloroethylene ; Longterm inhalation ; Carcinogenicity ; Lymphomas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pure trichloroethylene (tri), stabilized by an amine base, was administered by inhalation at 0, 100, and 500 ppm for 6 h/day, 5 days/week, for 18 months to mice, rats and Syrian hamsters of both sexes. No significant increase in tumor formation was observed in any species or dosing group, except in malignant lymphomas, which were increased in female mice in the following incidence rates: 9/29 (controls), 17/30 (100 ppm), and 18/28 (500 ppm). Whether or not this high occurrence of lymphomas, which is peculiar to this strain of mice (NMRI) has any relationship to tri-exposure, cannot be decided upon by the present experiment. It is concluded that from these findings no indication for a carcinogenic potential of pure trichloroethylene can be deduced.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: 1,1-dichloroethylene (Vinylidene chloride) ; Metabolization rate ; Liver glutathione ; Hepatotoxicity ; Isolated perfused rat liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Der Leberglutathiongehalt wird nach oraler Gabe von 1,1-Dichloräthylen (Vinylidenchlorid = VDC; in Olivenöl gelöst) gemessen und seine Bedeutung für Metabolismus und Hepatotoxizität von VDC untersucht. Nach oraler Applikation von 1000 mg/kg VDC sinkt Glutathion in 4 Std auf 33% der Kontrollwerte ab. Nach 24 Std sind die Kontrollwerte wieder erreicht. Der Abfall ist bei 18 Std-Nüchterntieren, die um 21% erniedrigte Ausgangswerte aufweisen, gleich. Die Glutathiondepletion ist dosisabhängig. Die Metabolisierungsrate von VDC in der isoliert perfundierten Leber beträgt nach 3 Std Perfusion, mit 5000 ppm VDC in der Gasphase, 7,64 μmol/g Leber. Die Rate ist um 18% erniedrigt, wenn der Glutathiongehalt mit Diäthylmaleat (25 μmol direkt ins Perfusat) auf 15% der Kontrollwerte gesenkt wird. Unter diesen Perfusionsbedingungen wird nach Diäthylmaleatzugabe die Funktionsfähigkeit (als Parameter hierfür dient der Lactat/Pyruvatquotient) der Leber eingeschränkt. Die Funktionsfähigkeit der Leber und die Metabolisierungsrate von VDC wird durch 18stündiges Fasten der Tiere nicht beeinflußt. Die Konzentration von Serumglutamatoxalacetattransaminase (SGOT) und Serumglutamatpyruvattransaminase (SGPT) im Perfusat ist nicht erhöht. Diese Befunde deuten darauf hin, daß keine Beziehung zwischen dem Leberglutathiongehalt und der erhöhten Letalität von VDC mit Nüchterntieren besteht.
    Notes: Abstract The liver glutathione content was measured after oral administration of 1,1-dichloroethylene (vinylidene chloride = VDC; dissolved in olive oil) and its significance for the metabolism and hepatotoxicity of VDC was investigated. After treatment with 1000 mg/kg VDC p.o., glutathione decreased to 33% of the control values within 4 h but returned to the control level after 24 h. An identical fall in glutathione after VDC administration was found to occur in animals which had been fasted for 18 h. In these animals the baseline values of glutathione were lowered by 21%. The depletion of glutathione was dependent on the dosage of VDC. The conversion rate of VDC by the isolated perfused livers was 7.64 μmoles/g liver after 3 h-perfusion, if 5000 ppm of VDC were supplied in the gas phase. Lowering the glutathione content to 15% of the normal value (by diethylmaleate, 25 μmoles added directly to the perfusate) resulted in a reduction of VDC conversion by 18%. Furthermore the viability (with the lactate/pyruvate ratio serving as the parameter) of the liver was distinctly depressed. No effect on viability nor on metabolization rate was noted when perfusing the livers of 18-h fasted animals. The concentrations of the glutamate-oxaloacetate transaminase (SGOT) and glutamate-pyruvate transaminase (SGPT) in the perfusate failed to show an increase. These findings indicate that there is no correlation between the liver glutathione level and the increased lethality of VDC in fasted rats.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 37 (1976), S. 23-38 
    ISSN: 1432-0738
    Keywords: Dichloroacetylene ; Inhalation toxicity ; Neurotoxic effects ; Sensory trigeminal nucleus ; Dichloracetylen ; Inhalationstoxizität ; Sneurotoxische Wirkung ; ensibler Trigeminuskern
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung In Inhalationsversuchen mit letalen und subletalen Dosen von Dichloracetylen (126, 202 und 307 ppm/1 Std; 17 ppm/6 Std) wird die neurotoxische Wirkung dieses Stoffes bei Kaninchen mit histologischen und funktionellen Methoden untersucht. Histologisch finden sich in den Kernen des unpaaren Hirnstammes, an den sensorischen Cortexarealen und besonders an den Kernen der sensiblen Hirnnerven Chromatolyse, Tigrolyse sowie Nisslsubstanzsinterung und Zellschrumpfung in Abhängigkeit von den eingesetzten Dosen. Beim Kaninchen ist am stärksten der sensible Trigeminuskern betroffen, es folgen mit Abstand und in abnehmender Intensität der N. facialis, oculomotorius und der motorische Trigeminuskern; am wenigsten ist der N. acusticus verändert. — Erstmals wird im Tierversuch durch Prüfung der protopathischen Sensibilität mit Thermoreizen an der Gesichtshaut des Mandibularbereiches ein Sensibilitätsverlust des N. trigeminus nachgewiesen. Die neuropathologisch und funktionell gefundenen Ausfallserscheinungen können die bei DCA-Vergiftungen des Menschen beobachteten Hirnnervenschädigungen erklären; sie scheinen aber bei Versuchstieren vergleichsweise schwächer ausgeprägt zu sein.
    Notes: Abstract In inhalation tests involving lethal as well as sublethal doses of dichloroacetylene (DCA) (126, 202 and 307 ppm/1 h; 17 ppm/6 h) its neurotoxic effect was examined in rabbits by means of histologic and neurofunctional methods. Histologic examination revealed chromatolysis, disintegration of Nissl bodies, and cell shrinkage in proportion to the doses employed in the nuclei of the unpaired brain stem, in the sensory cortical regions and especially in the sensory cranial nerve nuclei. The sensory trigeminal nucleus was involved most severely, followed in decreasing intensity by the facial and oculomotor nerves and the motor trigeminal nucleus; the least changes were observed in the acoustic nerve. By testing the protopathic sensitivity of the facial skin it was possible for the first time to produce evidence of a sensory loss in the distribution of the trigeminal nerve by animal experimentation. The neuropathological and functional deficits observed may explain the cranial nerve lesions in human DCA intoxication; however, these lesions seem to be less distinct in experimental animals.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0738
    Keywords: 1,1-Dichloroethylene (Vinylidene chloride) ; Pharmacokinetics ; Biotransformation ; Mercapturic acid ; Molecular toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The excretion and biotransformation of [14C] 1,1-dichloroethylene (vinylidene chloride, VDC) after administration of a single oral dose has been investigated in female rats. Seventy-two hours after a dose of 0.5, 5.0, and 50.0 mg/kg, 1.26, 9.70, 16.47%, respectively, are exhaled as unchanged VDC, and 13.64, 11.35, 6.13% as 14CO2. The main pathway of elimination is through renal excretion with 43.55, 53.88, 42.11% of the administered radioactivity. Through the biliary system, 15.74, 14.54, 7.65% of the activity are eliminated. The isolation of the main metabolites of VDC from 24 h urine is accomplished through the combined application of solvent extraction, ion exchange chromatography and thin layer chromatography. Then gas chromatography and mass spectrometry are used for their identification. Three metabolites have been identified: thiodiglycolic acid, N-acetyl-S-(2-carboxymethyl)cysteine and methylthio-acetylaminoethanol. In addition, three smaller unidentified radioactive peaks have been found. Thiodiglycolic acid is the main metabolite in VDC metabolism. The simultaneous formation of an ethanolamine- and a cysteine-conjugation product points to different reaction pathways of the postulated intermediate reactive epoxide; ethanolamine probably originates from membrane lipids, which react with VDC-epoxide and/or its derivatives. This pathway could explain, in part, the parenchyma damaging effect of VDC.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0021-9673
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Food and Cosmetics Toxicology 16 (1976), S. 227-235 
    ISSN: 0015-6264
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: The method of two-dimensional exchange spectroscopy under condition of magic angle sample spinning (MAS) and synchronization of the mixing time with the rotor period is extended to spin I=1 nuclei. Theoretical equations are derived for the cross peak intensities as a function of the magnetic and kinetic parameters of the system and the method is demonstrated on a number of deuterated compounds. Dimethylmalonic acid–d6 is first used to illustrate the effect of rotor synchronization by the complete absence of cross peaks when no exchange takes place. The method is then applied to two dynamic systems, viz. dimethylsulfone–d6 and thiourea–C6D12 inclusion compound. The experimental results are compared with simulations as well as with analogous experiments on nonspinning samples. Since chemical shift effects are often negligible in deuterium NMR the time domain sampling can in principle be reduced to the number of the desired spinning sidebands, resulting in considerable time savings. The main advantage of the method is the gain in sensitivity at the expense of the characteristic ridge pattern of static two-dimensional exchange experiments. The gain in sensitivity may be sufficient for performing such experiments on deuterium in isotopically normal compounds. The feasibility of such experiments is demonstrated by the recording of a one-dimensional deuterium MAS spectrum of a nonenriched sample.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1246
    Keywords: Vinylidene chloride ; Isolated perfused liver ; Metabolism ; Mixed-function oxidases ; Hepatotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Uptake and hepatotoxicity of 1,1-dichloroethylene (vinylidene chloride, VDC) was investigated with the isolated perfused rat liver: 1. VDC, at concentrations of 670, 2150, 3400, 5000, and 6500 ppm, was evaporated in the thermostat and introduced into the perfusion medium for 3 hours under steady-state conditions. During this period the VDC concentration in the perfusate rose linearly from 4.8 to 34.8μg/ml. 2. The difference between the concentrations in the perfusate, determined before and after hepatic passage (prehepatic and posthepatic concentration, respectively) as a function of the hepatic flux was used to investigate VDC uptake. With increasing prehepatic concentrations of VDC, metabolization approached a saturation characteristic. At a concentration of 4.8μg/ml perfusate, 2.5 pmol/g liver is metabolized within 3 hours, and at 34.8μg/ml the respective value is 8.6μmol/g liver. 3. Inhibitors of microsomal cytochrome P-450-dependent drug metabolism, e.g., 2-diethylaminoethyl-2, 2-diphenylvalerate (SKF 525-A) or 6-nitro-1, 2, 3-benzotthiadiazole (0.02 mmol) decrease the uptake just slightly. Stronger inhibition (40 %) was achieved with pyrazole (200 mmol). 5,6-Dimethyl-1, 2, 3-benzothiadiazole was found inactive. 4. VDC uptake was significantly elevated (35 %) following pretreatment of rats with 1, 1, 1-trichloro-2, 2-bis (p-chlorophenyl)-ethane (DDT) and to a lesser degree after phenobarbital (10 %). This stimulation of the uptake rate was not correlated with enhanced hepatotoxicity of VDC, as evidenced by the concentrations of the serum glutamate-oxaloacetate transaminase (SGOT), the serum glutamate-pyruvate transaminase (SGPT) and they-glutamyl transpeptidase (γ-GT) in the perfusate.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1246
    Keywords: 1,1,1-Trichloroethane ; Methyl chloroform ; Vinylidene chloride ; 1,2-Epoxybutane ; Antioxidants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Gas chromatography and gas chromatography-mass spectrometry were employed to analyze 22 samples of technical grade 1,1,1-trichloroethane for impurities. Eighteen contained vinylidene chloride (1,1-dichloroethylene) (30–900 μg/ml) and further contaminants were identified as 1,1-dichloroethane (11), trichloroethylene (12), and 1,1,2-trichloroethane (9). Nitromethane (18), 1,2-epoxybutane (19), tert. butanol (7), and dioxane (10) were detected as stabilizers. It is recommended that the manufacturers should eliminate vinylidene chloride and stabilizers which carry a carcinogenic and/or mutagenic risk, from technical samples of 1,1,1-trichloroethane.
    Type of Medium: Electronic Resource
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