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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 47 (1969), S. 1125-1130 
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary 1. Equilibrium dialysis, ultracentrifugation, and gel filtration on Sephadex are pointed out as being the most commonly used methods of quantitative determination of drug protein binding. 2. The interaction between proteins and substances of low molecular weight is governed by the law of mass action. It is the basis for the description of the results of binding experiments. The plotting of the data according to Scatchard (1949) is considered the most useful method. Also methods of plotting described by Scholtan (1962) and Krüger-Thiemer (1961) are used and offer advantages for special problems. 3. The binding of drugs to plasma proteins seems to take place mainly by hydrophobic mechanisms. The aromatic rings of the drugs apparently play an important part in their binding to proteins. 4. The bound drugs influence the structure of the proteins. 5. The binding of drugs to plasma proteins influences their action, tissue distribution, metabolism, and renal elimination. 6. The drug binding ability of plasma proteins can be changed in pathologic conditions. 7. Drugs can displace other drugs or physiological substances of low molecular weight from their binding sites on plasma proteins.
    Notes: Zusammenfassung 1. Auf Dialyse, Ultrazentrifugation und Sephadexgelfiltration als die gebräuchlichsten Methoden zur quantitativen Bestimmung der Eiweißbindung von Pharmaka wird hingewiesen. 2. Die Wechselwirkung von niedermolekularen Substanzen mit Proteinen folgt dem Massenwirkungsgesetz. Darauf beruht die Formulierung der Ergebnisse von Eiweißbindungsversuchen. Die Darstellung der Ergebnisse nach Scatchard (1949) wird als die wichtigste Methode angesehen. Daneben sind Darstellungsmethoden nach Scholtan (1962) und Krüger-Thiemer (1961) gebräuchlich, die für bestimmte Fragestellungen Vorteile bieten. 3. Die Bindung von Pharmaka an Plasmaproteine scheint vorwiegend hydrophoben Charakter zu besitzen. Dabei spielen offenbar die aromatischen Ringe der Arzneimittel eine wichtige Rolle. 4. Die gebundenen Arzneimittel beeinflussen die Struktur des Proteins. 5. Die Plasmaproteinbindung von Arzneimitteln beeinflußt deren Wirkung, Verteilung im Organismus, Stoffwechsel und renale Ausscheidung. 6. Das Bindungsvermögen von Plasma kann unter pathologischen Bedingungen verändert sein. 7. Arzneimittel können sich gegenseitig oder auch körpereigene Substanzen aus ihrer Plasmaproteinbindung verdrängen.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 52 (1974), S. 842-846 
    ISSN: 1432-1440
    Keywords: Neurotoxicity ; carbenicillin ; ampicillin ; benzylpenicillin ; EEG ; Neurotoxizität ; Carbenicillin ; Ampicillin ; Penicillin G ; EEG
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die neurotoxische Wirkung von Carbenicillin wurde am wachen Kaninchen untersucht. Die Neurotoxizität wurde bestimmt anhand von EEG-Veränderungen wie Spikes, Polyspikes and Spike-wave-Paroxysmen. Den Tieren wurden 2,4 g/kg Carbenicillin über 50 min intravenös infundiert. Bis 2 Std nach Infusionsbeginn wurden zu bestimmten Zeitpunkten die Carbenicillinblutspiegel gemessen. Spikes als erstes neurotoxisches Symptom waren regelmäßig bei Blutspiegeln von 3252±186 µg/ml zu beobachten. Nach Carbenicillin waren die toxischen Veränderungen wesentlich ausgeprägter als nach Ampicillin, jedoch deutlich geringer als nach Penicillin G. Diese Ergebnisse stehen im Einklang mit den in klinischen Fallberichten angegebenen Daten.
    Notes: Summary The neurotoxic effect of carbenicillin was studied in the conscious rabbit. The neurotoxicity was determined by EEG changes as spikes, polyspikes and spikewave paroxysms. The animals received 2.4 g/kg carbenicillin over 50 min by intravenous infusion. The carbenicillin blood levels were determined at certain intervals for 2 hours after the infusion had started. Spikes as the first neurotoxic symptoms were observed regularly at blood levels of 3252±186 µg/ml. With carbenicillin the neurotoxic changes were considerably more pronounced than with amicillin, however significantly less than with benzylpenicillin. These results agree with the data published in clinical case reports.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Phosphatic metabolite (perchloric acid extractable) concentrations of cerebral tissues were analyzed by phosphorus-31 nuclear magnetic resonance (P-31 NMR) spectfoscopy following external perfusion of the isolated rat brain (30 min or 60 min) under the following conditions: (a) constant perfusion pressure with either fluorocarbon-or erythrocyte-based medium, and (b) constant perfusate flow rate (3 ml/min) with the erythrocyte-based medium. Metabolite concentrations of control perfused brains were compared with those in nonperfused controls to provide a basis for detecting any qualitative or quantitative changes in cerebral metabolite composition. Metabolic responses of perfused brains to ischemia (incomplete ischemia, 83% reduction in flow for 10 min; transient complete ischemia for 1.5 or 2 min) were evaluated immediately after the ischemic episode and at selected time points during reperfusion (3 and 15 min). Alterations in cerebral metabolite levels induced by hypoxia were analyzed using a nonperfused rat brain model. Irrespective of the perfusion method employed, the phosphatic metabolites of control perfused rat brains were identical quantitatively to those of the nonperfused controls. Cerebral ischemia resulted in significantly increased levels of ADP, AMP + IMP, Pi, fructose 1,6-diphosphate, and glycerol 3-phosphate (global ischemia only), whereas ATP and phosphocreatine (PCr) levels declined significantly. The magnitude of these changes varied with the severity of the ischemia; however, following 15 min of control reperfusion metabolite levels had reverted to preischemic values. Significant perturbations in tissue phosphoethanolamine (3.848 resonance) content were evident at various time points during ischemia and postischemic recovery, which varied according to the perfusion conditions. In contrast to the changes observed in response to ischemia, hypoxia affected only cerebral high-energy phosphate levels. ATP and PCr levels were reduced, while a concomitant, essentially equimolar, increase in Pi and ADP was observed. The present studies indicate that in terms of phosphatic metabolites, the control equilibrated isolated perfused rat brain is quantitatively and qualitatively indistinguishable from the non-perfused rat brain in vivo regardless of the perfusion conditions (constant flow versus constant pressure). The metabolic responses to ischemia and hypoxia, as measured by P-31 NMR, were consistent with the pattern of changes reported elsewhere. Overall, P-31 NMR spectroscopic evaluation of the intact rat brain provides a potential experimental context for dynamic measures of cerebral metabolism under exogenously controlled conditions. The results reported herein from brain PCA extracts contribute a spectroscopic reference for understanding and interpreting the metabolic information contained in the P-31 profiles of the intact brain.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 19 (1972), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 24 (1975), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Staurosporine (0.03–0.5 µM) induced a dose-dependent, apoptotic degeneration in cultured rat hippocampal neurons that was sensitive to 24-h pretreatments with the protein synthesis inhibitor cycloheximide (1 µM) or the cell cycle inhibitor mimosine (100 µM). To investigate the role of Ca2+ and reactive oxygen species in staurosporine-induced neuronal apoptosis, we overexpressed calbindin D28K, a Ca2+ binding protein, and Cu/Zn superoxide dismutase, an antioxidative enzyme, in the hippocampal neurons using adenovirus-mediated gene transfer. Infection of the cultures with the recombinant adenoviruses (100 multiplicity of infection) resulted in a stable expression of the respective proteins assessed 48 h later. Overexpression of both calbindin D28K and Cu/Zn superoxide dismutase significantly reduced staurosporine neurotoxicity compared with control cultures infected with a β-galactosidase overexpressing adenovirus. Staurosporine-induced neuronal apoptosis was also significantly reduced when the culture medium was supplemented with 10 or 30 mM K+, suggesting that Ca2+ influx via voltage-sensitive Ca2+ channels reduces this apoptotic cell death. In contrast, neither the glutamate receptor agonist NMDA (1–10 µM) nor the NMDA receptor antagonist dizocilpine (MK-801; 1 µM) was able to reduce staurosporine neurotoxicity. Cultures treated with the antioxidants U-74500A (1–10 µM) and N-acetylcysteine (100 µM) also demonstrated reduced staurosporine neurotoxicity. These results suggest a fundamental role for both Ca2+ and reactive oxygen species in staurosporine-induced neuronal apoptosis.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 35 (1980), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: An isolated rat brain preparation was perfused using glucose-free (=aglycemic) media. The high-energy phosphates, substrates of the glycolytic pathway, free atnino acids, acetylcholine as well as the intracellular distribution of hexokinase activity were determined in brain tissues. The EEG was evaluated visually. The levels of glycolytic substrates, glutamate, and glutamine in cortical tissue decreased after aglycemic perfusion, whereas the aspartate level increased and the GABA level remained unchanged. The high-energy phosphate content seemed to be unaffected for about 15 min of aglycemic perfusion and fell significantly after 20 min. The EEG of the isolated brain changed rapidly after starting aglycemic perfusion and became isoelectric after 12–15 min. Hyperglycemic perfusion (35 mmol glucose per liter perfusion medium) did not alter the energy metabolism of the isolated brain. The breakdown of cerebral energy metabolism and of EEG activity was postponed when thiopental was added to the perfusion medium. The soluble hexokinase activity measured in cortical tissue was reduced after aglycemic perfusion and was enhanced after thiopental. Hyperglycemic perfusion did not influence the intracellular hexokinase distribution. The acetylcholine level in the striatum of the isolated rat brain was significantly decreased by aglycemia and was increased in hypothalamus by thiopental. It was suggested that hexokinase bound to the mitochondrial membrane may play an important role in the relationship of energy metabolism and neuronal activity.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1438-2199
    Keywords: Keywords: Amino acids – Organic acids – Glutaryl-CoA dehydrogenase deficiency – Excitotoxicity – NMDA receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Glutaryl-CoA dehydrogenase deficiency (GDD), which is one of the most frequent organic acid disorders, is characterized by a specific age- and regional-dependent neuropathology. We hypothesized that the distinct brain damage in GDD could be caused by the main pathologic metabolites, the organic acids glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids, through an excitotoxic sequence. Therefore, we investigated the effects of 3-OH-GA and GA on primary neuronal cultures from chick embryonic telencephalons. Here we report that 3-OH-GA and GA decreased cell viability concentration- and time-dependently, which could be only totally prevented by preincubation with MK-801, ifenprodil and NR2B antibodies. Furthermore, cell viability decreased in parallel with the increasing expression of NR2B subunit on cultured neurons from 2nd to 6th DIV. We conclude that GA and 3-OH-GA act as excitotoxic organic acids (EOA) specifically through NR1/NR2B and that the extent of induced neurotoxicity is dependent on NR1/NR2B expression during maturation.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1435-1463
    Keywords: Neuroprotection ; 5-HT1A agonists ; urapidil ; ischemia ; rat ; hypoxia ; excitotoxicity ; neuronal cell cultures
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of the present study was to evaluate the neuroprotective effect of the 5-hydroxytryptamine1A (5-HT1A) agnists, CM 57493 and urapidil, in vivo and in vitro, respectively. In vivo permanent occlusion of the middle cerebral artery (MCA) was performed in male Wistar rats. Forty-eight hours after electrocoagulation of the MCA and infarct volume was determined. Pretreatment of the rat with the 5-HT1A agonist urapidil significantly reduced infarct development. The neuroprotective effect of the agent was restricted to the cortical area; the striatal damage was not influence. As the stimulation of the 5-HT1A receptor by serotonin is supposed to induce inhibitory, hyperpolarizing effects by opening of a Ca2+-independent neuronal K+ ionophore, the efficacy of agonistic drugs directly on the neuron was investigated in vitro. Cyanide-induced cytotoxic hypoxia as well as glutamate-induced excitotoxicity were performedj using primary neuronal cell cultures from chick embryo cerebral hemispheres. Treatment with 5-HIT1A agonists urapidil and CM 57493 significantly increase protein content of hypoxic cultures. CM 57493 and added to the culture medium (1–10 μM) during and up to 24 h after glutamate exposure ameliorated viability of the neurons. The result demonstrate neuroprotective potency of the 5-HT1A agonists, urapidil and CM 57493, when applied under hypoxic, excitotoxic and ischemic conditions in vivo and in vitro, respectively. Both, presynaptically induced inhibition of glutamate release as well as postsynaptically induced inhibition of neuronal excitability could be discussed as possible mechanisms of action of the 5-HT1A receptor agonism.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 30 (1974), S. 924-926 
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Zusammenfassung Kaninchen überlebten die letale Dosis von 30 mg/kg Chlorpromazin (i.v.) nur zusammen mit einer Fettinfusion (0,5 ml/kg/min Lipofundin S 10®). Es konnte in vitro gezeigt werden, dass der Zusatz einer Fettemulsion (Lipofundin S 10®) zu Kaninchenblut (25 mg Fett/ml) den Anteil an freiem Chlorpromazin (Gesamtkonzentration 10−4 M) von 2,05% auf 0,87% herabsetzt.
    Type of Medium: Electronic Resource
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