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  • 1
    Digitale Medien
    Digitale Medien
    s.l. : American Chemical Society
    Journal of the American Chemical Society 110 (1988), S. 2643-2644 
    ISSN: 1520-5126
    Quelle: ACS Legacy Archives
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 2
    ISSN: 1432-2072
    Schlagwort(e): Clozapine ; Schizophrenia ; Tardive dyskinesia ; Efficacy ; Adverse effects ; Neuroleptics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Medical charts of 387 in-patients (schizophrenia n=284, tardive dyskinesia, TD, n=48), were analyzed to evaluate efficacy and adverse effects of clozapine. These patients were previously treated with between two and four other neuroleptics and were either therapy resistant or had severe side effects. Schizophrenic patients were treated with clozapine for 48±35 (TD 49±40) days, dosage was 189±119 (TD 220±176) mg. Four per cent showed worsening, 13% no change, 38% slight improvement, 42% marked improvement and 3% nearly total reduction of symptoms. In TD, 44% showed marked improvement, but only in 17% the drug was superior to previous neuroleptics. Adverse effects occurred in 56% of patients. Most frequent were sedation (17%), EEG alterations (16%), increase of liver enzymes (8%), hypotension (7%), hypersalivation (5%), fever (5%), ECG alterations (4%), tachycardia (3%), gastro-intestinal (3%) and delirious states (2%). A gradual increase in dosage seems to considerably reduce the incidence of some side effects. Clozapine treatment had to be discontinued because of severe side effects in 5.9%. In none of these patients did serious complications such as agranulocytosis occur. Only EEG alterations were significantly related to clozapine dosage (P〈0.0005). At dismissal, most patients continued to receive clozapine; only in 22% (TD 20%) was it replaced by another neuroleptic. Thus, the ratio benefit/risk of clozapine treatment seems to be satisfactory in most of the negatively selected patients. Never-theless, a gradual increase in dosage and careful control of hematological and other variables is highly recommended.
    Materialart: Digitale Medien
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  • 3
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 99 (1989), S. S101 
    ISSN: 1432-2072
    Schlagwort(e): Clozapine adverse effects ; AMÜP study ; Clozapine + benzodiazepines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Adverse effects related to clozapine were assessed within a post-marketing drug surveillance program, the AMÜP study, in two university psychiatric departments. In a randomly selected sample of patients (intensive drug monitoring) ADRs of any type were observed in 76% of clozapine-treated inpatients. Sedation, hypersalivation, increase in transaminases, and EEG changes were most frequently observed, but only rarely required changes in therapy. In 8.1% of 959 patients exposed to clozapine in the total inpatient population of the participating hospitals ADR led to withdrawal of clozapine; in 3.9% reactions judged as severe and potentially life-threatening occurred. Among these latter toxic delirium prevailed. In addition, four cases of severe cardiovascular and respiratory dysregulation were observed with the combination of clozapine and benzodiazepines. These cases and one case of sudden death under clozapine and haloperidol treatment are presented in some detail. The results obtained for clozapine are compared to data from this drug surveillance program for other neuroleptics.
    Materialart: Digitale Medien
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  • 4
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 406-407 
    ISSN: 1432-1912
    Schlagwort(e): 3H-Isoprenaline ; Extraneuronal efflux ; K+ Gradient ; Rat heart ; Carrier-mediated efflux
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary After loading of the extraneuronal tissues of the perfused rat heart with 3H-isoprenaline the elevation of extracellular K+ concentration (from 2.7 to 15 mmol/1) in the perfusion solution about doubled the rate constant for efflux of the 3H-amine. As this increase was not seen in the presence of 100 μmol/13-O-methyl-isoprenaline (OMI, a potent inhibitor of the uptake2-carrier), it is concluded that the change in the concentration of K+ modulates OMI-sensitive outward transport of 3H-isoprenaline by uptake2, not the diffusional efflux of the amine.
    Materialart: Digitale Medien
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 397-405 
    ISSN: 1432-1912
    Schlagwort(e): Rat cerebral cortex ; Brain COMT ; 3Hisoprenaline ; Central O-methylating system ; Central non-neuronal uptake
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The O-methylation and accumulation of 3H-isoprenaline in slices of the rat cerebral cortex were studied before and after inhibition of COMT. 1. Inhibition of COMT by μmol/l U-0521 virtually abolished the O-methylation and increased the accumulation of 3H-isoprenaline; hence, there is evidence for the existence of a central O-methylating system (with a transport mechanism and intracellular COMT). 2. Experiments were carried out with selective uptake inhibitors for uptake, (cocaine and desipramine) or uptake2 (corticosterone and OMI), with phenoxybenzamine (known to inhibit both carriers) and with changes in the ionic composition of the incubation medium. They revealed that the central carrier differed from both, uptake, and uptake2, although exhibiting some resemblance with uptake2 (lack of dependence on Na+ and Cl−, sensitivity to K+ and phenoxybenzamine, ability to transport 3H-isoprenaline). 3. Although the central carrier was rather sensitive to inhibition by beta-adrenoceptor antagonists (propranolol, carteolol), the effect of propranolol was not stereoselective; hence, beta-adrenoceptors do not seem to be involved. 4. Virtually identical IC30-values were obtained for inhibitors, when determined with or without inhibition of COMT. Only OMI was found to inhibit COMT as well as the central transport system; hence it was more potent in inhibiting the O-methylation than the accumulation of 3H-isoprenaline. 5. IC50-values (against initial rates of accumulation of 3H-isoprenaline; COMT inhibited) were determined for various substrates and inhibitors of peripheral uptake2. There was no correlation with the IC50-values determined earlier for uptake2 in rat heart (Grohmann and Trendelenburg 1984). 6. Unlabelled catecholamines half saturated the intracellular COMT when slices were incubated with 0.22 μmol/l [(±)-dobutamine] to 4.9 μmol/l [(−)-noradrenaline]. As the presence of unlabelled catecholamines increased tissue levels of 3H-isoprenaline, catecholamines are substrates of the central carrier. 7. The carrier of the central O-methylating system differs from uptake2 of peripheral organs, although it resembles the peripheral carrier in some respects.
    Materialart: Digitale Medien
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  • 6
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 338 (1988), S. 180-184 
    ISSN: 1432-1912
    Schlagwort(e): 3H-7-(−)Noradrenaline ; 3H-7,8-(−)Noradrenaline ; 3H-2,5,6-(−)Noradrenaline ; Isotope effect ; Neuronal and extraneuronal deamination and O-methylation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The neuronal disposition of the side chain-labelled 3H-7-(−)noradrenaline and the ring-labelled 3H-2,5,6-(−)noradrenaline of relatively high specific activity was compared in the (incubated) rabbit aorta, the extraneuronal one in the (perfused) rat heart. Furthermore, the metabolism by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) of the labelled amines was studied in rat heart homogenates. In addition, some of the experiments were also carried out with the side chain-labelled 3H-7,8-(−)noradrenaline that is an inferior substrate of MAO. 1. In agreement with several other studies, the present results revealed the known differences between the two side chain-labelled amines brought about by the poorer deamination of 3H-7,8-(−)noradrenaline. This fording also indicated that the 3H-7-(−)noradrenaline used in this study was of the desired quality, i. e. was labelled exclusively in position 7. 2. In contrast to earlier findings, no differences between the side chain-labelled 3H-7-(−)noradrenaline and the ring-labelled 3H-2,5,6-(−)noradrenaline were observed with regard to neuronal and extraneuronal amine handling (intact tissues) and metabolism by MAO and COMT in rat heart homogenates. Hence, there is no reason to avoid the ring-labelled amine with high specific activity and, consequently, with slightly more than one tritium substituent per catecholamine molecule in experiments designed to analyse the neuronal and extraneuronal fate of (−)noradrenaline.
    Materialart: Digitale Medien
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  • 7
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 336 (1987), S. 139-147 
    ISSN: 1432-1912
    Schlagwort(e): 3H-catecholamines ; Neuronal deamination ; Extraneuronal deamination ; Extraneuronal O-methylation ; k enzyme rat heart
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In a comparative study the neuronal and extraneuronal metabolism of several 3H-catecholamines (all of which were tritiated in the C-7 position of the side chain only) was determined in isolated rat hearts perfused at a concentration of the 3H-amines of 50 nmol/1. While the neuronal MAO activity was determined after inhibition of extraneuronal uptake (100 μmol/1 OMI) and COMT (10 μmol/1 U-0521), the extraneuronal MAO activity was estimated after inhibition of neuronal uptake (30 μmol/1 cocaine) and COMT. The extraneuronal COMT activity was determined under conditions of inhibition of both neuronal uptake and MAO (pretreatment with pargyline). Hearts were perfused with the 3H-catecholamines until the rate of appearance of the various 3H-metabolites in the venous effluent has reached a steady state. From these rates (v st-st) and the steady-state content of the unchanged 3H-catecholamines in the tissue (S i), the rate constants (V max/K m) for the unsaturated intracellular enzymes COMT (κCOMT) and MAO (κMAO) were calculated. The κCOMTvalues for all four catecholamines, (−)-noradrenaline, dopamine, (−)-adrenaline and (±)-isoprenaline exhibit a range from 0.24 to 0.78 min−1; the metabolism of the catecholamines by the COMT differs: (-)-noradrenaline = dopamine 〈 (−)-adrenaline 〈 (±)-isoprenaline. The extraneuronal MAO activity was low for all three catecholamines, (−)-adrenaline, (−)-noradrenaline and dopamine (range of κMAOfrom 0.05 to 0.28 min−1) and declined in the order: (−)-adrenaline 〈 (−)-noradrenaline 〈 dopamine. The neuronal MAO activity for (−)-adrenaline, (−)-noradrenaline and dopamine was slightly higher than that in the extraneuronal cells (range of kMAO from 0.08 to 0.35 min−1), but the ranking order showed the same pattern: (−)-adrenaline 〈 (−)-noradrenaline = dopamine.
    Materialart: Digitale Medien
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  • 8
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 329 (1985), S. 264-270 
    ISSN: 1432-1912
    Schlagwort(e): 3H-Catecholamines ; Perfused rat heart ; Stereoselectivity ; Extraneuronal O-methylating system ; Catechol-O-methyl transferase
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In a comparative study, the handling of five catecholamines by the extraneuronal O-methylating system of the rat heart was determined; all rats were pretreated with reserpine, monoamine oxidase and neuronal uptake were inhibited in all experiments. 1. Hearts were perfused for 7 min with a tracer concentration of 3H-(±)-isoprenaline, either in the absence or in the presence of unlabelled catecholamines (which reduced the O-methylation of the tracer amine). IC50's were determined for unlabelled catecholamines and then converted to “half-saturating outside concentrations”, i.e., to those concentrations in the perfusion fluid that halfsaturate the intracellular catechol-O-methyl transferase (COMT). The values for the (-)-isomers of dobutamine, isoprenaline, adrenaline and noradrenaline and that for dopamine were low and rather similar (between 0.67 and 2.7 μmol/l). Stereoselectivity for isoprenaline probably reflected the preference of uptake2 for the (-)-isomer. 2. The effects of (-)- and (+)-dobutamine indicated that both isomers are a) transported by uptake2 and b) good substrates of COMT. 3. The V max for O-methylation [determined for 3H-(±)-isoprenalina, 3H-(±)-adrenaline, 3H-(±)-noradrenaline and 3H-dopamine] was rather similar for all four catecholamines. 4. It is concluded that the extraneuronal O-methylating system of the rat heart handles the five catecholamines in a similar manner, although the K m for uptake2 had been found to increase substantially in the order: dobutamine 〈 isoprenaline 〈 adrenaline 〈 noradrenaline 〈 dopamine (Grohmann and Trendelenburg 1984b).
    Materialart: Digitale Medien
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  • 9
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 159-163 
    ISSN: 1432-1912
    Schlagwort(e): Extraneuronal monoamine oxidase ; Uptake2 ; Rat heart ; Extraneuronal deaminating system ; Catecholamines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The handling of five amines by the extraneuronal deaminating system was studied in perfused hearts of rats (pretreated with reserpine; COMT and neuronal uptake inhibited). Hearts were perfused with 50 nmol/l 3H-noradrenaline for 30 min, in the presence of increasing concentrations of unlabelled (−)-adrenaline, (−)-noradrenaline, dopamine, tyramine and 5-HT. IC50's were determined as those concentrations of unlabelled amines which halved the steady-state rate of deamination of 3H-noradrenaline. After correction for changes in the tissue/medium ratio for 3H-noradrenaline, “half-saturating outside concentrations” were obtained. They increased in the order (−)-adrenaline (15 μmol/l) — tyramine — dopamine — noradrenaline —5-HT (53 μmol/l). The V max for extraneuronal deamination was determined for 3H-(−)-adrenaline, 3H-(−)-noradrenaline and 3H-dopamine, as well as (by HPLC and electrochemical detection) for tyramine and 5-HT. It was low for (−)-adrenaline, intermediate for (−)-noradrenaline, dopamine and 5-HT, high for tyramine. For the three catecholamines the half-saturating outside concentrations of the extraneuronal deaminating system clearly exceeded those for the extraneuronal O-methylating system of the same organ (see Grohmann and Trendelenburg 1985), although the two enzymes appear to co-exist in the same cells, so that the same transport system is involved.
    Materialart: Digitale Medien
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  • 10
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 332 (1986), S. 34-42 
    ISSN: 1432-1912
    Schlagwort(e): Neuronal deamination ; Extraneuronal deamination ; Isotope effects ; 3H-catecholamides
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The neuronal and extraneuronal disposition of3H-7,8-and3H-7-labelled (−)-noradrenaline and dopamine was compared in in vitro studies. 1. In agreement with earlier studies, the present results show that the presence of a tritium label in position 8 (i.e., on the alpha-carbon) has two consequences: a) the rate of deamination declines and b) part of the deamination results in the formation of an unlabelled aldehyde plus tritium water; tritium water is recovered from the OMDA-fraction of the column chromatographic procedure of Graefe et al. (1973). 2. Whenever the deamination of a3H-catecholamine is reduced (by tritium in position 8), the intraneuronal3H-catecholamine concentration is increased. This increase, in turn, partly masks the decline in neuronal deamination (rat vas deferens). Irrespective of whether one dertermines the spontaneous efflux, the release of3H-noradrenaline by nerve stimulation or the release of3H-(−)-noradrenaline by the reserpine-like compound Ro 4-1284, the presence of tritium in position 8 distorts the results (experiments with rat vasa deferentia and/or rabbit aorta). 3. In the extraneuronal system of the rat heart, two intracellular enzymes inactivate3H-(−)-noradrenaline and3H-dopamine: catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO). Any hindrance of deamination (by tritium in position 8, COMT intact) leads to a shift of the metabolism of the3H-catecholamines from the exclusively deaminated to the exclusively O-methylated metabolites. 4. No differences between3H-7,8-and3H-7-labelled catecholamines were found after inhibition of MAO and COMT (extraneuronal accumulation and rate constant for efflux from the extraneuronal compartment III of the rat heart). 5. These results indicate that the presence of tritium in position 8 of catecholamines introduces errors, if monoamine oxidase is active. This is important for the interpretation of earlier results, since virtually all samples of “3H-(−)-noradrenaline” and “3H-dopamine nominally labelled in position 7” were contaminated with varying amounts of tritium in position 8. 6. In some experiments, also3H-7-(−)-adrenaline was used. For adrenergic nerve endings, the rate of metabolism (deamination) declined in the order:3H-7-dopamine 〉 3H-7-(−)-noradrenaline 〉 3H-7-(−)-adrenaline. For the extraneuronal disposition the ranking order was:3H-7-(−)-adrenaline 〉 3H-7-(−)-noradrenaline=3H-7-dopamine. However, in the extraneuronal disposition of3H-(−)-adrenaline, O-methylation predominated over deamination.
    Materialart: Digitale Medien
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