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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Journal of molecular medicine 60 (1982), S. 767-772 
    ISSN: 1432-1440
    Schlagwort(e): Diabetes mellitus ; Diabetic glomerulosclerosis ; Clinical symptoms ; Proteinuria ; Insulin ; Diabetes mellitus ; diabetische Glomerulosklerose ; Klinik ; Proteinurie ; Insulin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Beschreibung / Inhaltsverzeichnis: Zusammenfassung 111 Fälle (bioptisch erfaßtn=106, autoptisch erfaßtn=5) werden in drei Gruppen eingeteilt: Diffuse diabetische Glomerulosklerose (n=74), gemischt diffus-noduläre Glomerulosklerose (n=14) und noduläre diabetische Glomerulosklerose (n=23). Die klinischen Parameter, Angaben über Dauer des Diabetes und Dauer der Nierenerkrankung sowie über Therapieformen werden zu den einzelnen morphologischen Gruppen korreliert. Dabei ergibt sich unter anderem: Die noduläre Glomerulosklerose tritt besonders häufig bei Frauen auf, geht häufig mit einer Diabetes-Manifestation jenseits des 40. Lebensjahres einher, ist mit der längsten Diabetes-Dauer korreliert und weist einen häufig meist stark erhöhten Serumkreatinin-Spiegel auf. Die Proteinurie ist mit rund 90% häufigstes und erstes Symptom der diabetischen Glomeruloskerose. Eine Insulinbehandlung hat offenbar einen günstigen Einfluß auf die Proteinurie. Zusammenfassend muß jedoch betont werden, daß die Variabilität der klinischen Symptomatik sehr groß ist, so daß eine Diagnose allein auf der Basis klinischer Befunde nicht immer möglich ist.
    Notizen: Summary One hundred and eleven cases of diabetic glomerulosclerosis (biopsiesn=106, autopsiesn=5) are divided into three groups: Diffuse diabetic glomerulosclerosis (n=74), mixed diffuse-nodular glomerulosclerosis (n=14) and nodular diabetic glomerulosclerosis (n=23). The clinical parameters, data concerning duration of diabetes and of renal disease, as well as types of therapy, were correlated with the different morphologic groups. The following results could be observed: nodular glomerulosclerosis very frequently occurs in women, often accompanied by a diabetes-manifestation beyond the fourth decade of life. This correlated with the longest duration of diabetes and frequently showed a greatly increased serum-creatinine level. Proteinuria of about 90% is the most frequent and first symptom of diabetic glomerulosclerosis. Therapy with insulin apparently shows an advantageous influence on proteinuria. In summary, however, the variability of clinical symptoms and signs should be emphasised, preventing in some cases a diagnosis being made on clinical findings alone.
    Materialart: Digitale Medien
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  • 2
    Digitale Medien
    Digitale Medien
    Springer
    Journal of molecular medicine 60 (1982), S. 429-444 
    ISSN: 1432-1440
    Schlagwort(e): Skeletal muscle ; Capillary blood flow ; Glucose ; Insulin ; Kinins ; Prostaglandins ; Skelettmuskel ; Kapillardurchblutung ; Glucose ; Insulin ; Kinine ; Prostaglandine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Beschreibung / Inhaltsverzeichnis: Zusammenfassung Anpassungen des Energiestoffwechsels wie sie im kontrahierenden Skelettmuskel auftreten, werden im Anschluß an die Phase der anaeroben Glycolyse über Änderungen des kapillaren Blutflusses vorgenommen, der Substrate und Sauerstoff für die Energiegewinnung heranträgt. Da zu Beginn der Leistung die Sauerstoffversorgung limitiert ist, scheint Glucose das geeignete Substrat, da sie sowohl anaerob zur Energiegewinnung benützt werden kann als auch pro Molekül Sauerstoff mehr Energie als Fettsäuren liefert. Neben der Glucose werden auch Aminosäuren für eine beschleunigte Proteosynthese und Muskelhypertrophie benötigt. Aus diesem Grunde muß die Erweiterung des kapillaren Gefäßnetzes von einer Modulation der Wirkung von Insulin begleitet sein, das häufig z.B. nach einem Übernachtfasten nur in niedrigen Konzentrationen vorliegt. Dieses Ziel wird auf dreierlei Weise erreicht: 1. Durch Erweiterung des kapillaren Gefäßnetzes, was zu einer verbesserten Versorgung mit Insulin und zu einem größeren Angebot an Insulinrezeptoren führt, 2. durch einen beschleunigten Transport von Insulin durch die kapillaren Gefäßwände, so daß mehr Insulin im interstitiellen Raum und an den Plasmamembranen des Gewebes vorhanden ist. 3. durch einen Effekt auf molekularer Ebene am „Insulin-Rezeptor-Messenger“-Mechanismus. Diese Adaptationen sind Teile eines selbstregulatorischen Prozesses, der durch die Freisetzung von Metaboliten aus dem arbeitenden Muskel in Gang gesetzt wird. Aus neueren Studien gibt es zunehmend Hinweise, daß Kinine und Prostaglandine beteiligt sind. Die ersteren werden bei Bedarf aus ihrem Präkursorprotein Kininogen proteolytisch freigesetzt und tragen als Gewebshormone das Signal des arbeitenden Muskelgewebes über den interstitiellen Raum zur glatten Gefäßmuskelzelle der Kapillaren. Daraufhin werden Prostaglandine aus Plasmamembranlipiden freigesetzt, die als Zellmediatoren zusammen mit den Kininen die verschiedenen Adaptationsmechanismen hervorrufen. Verstärkersysteme dieser Art dürfen nicht nur im Muskel, sondern auch in anderen Geweben eine Rolle spielen, in denen eine adäquate Kinin- und Prostaglandin-Freisetzung unter den verschiedensten klinischen Bedingungen, z.B. im Schock, beim Herzinfarkt, bei Wundheilung etc. für die adäquate Bereitstellung von Sauerstoff, energiereichen Substraten und Aminosäuren als Bausteinen sorgt.
    Notizen: Summary Adaptations of energy metabolism, as they occur during contractions of skeletal muscle besides by anaerobic glycolysis are achieved via changes in capillary blood flow providing substrates and oxygen for combustion. Since, initially, oxygen supply is restricted in the working muscle, glucose would seem to be the adequate fuel as it may be used anaerobically and yields more energy per mole of oxygen than fatty acids under such circumstances. Besides glucose, amino acids are also required for accelerated proteosynthesis according to the work load. Therefore, an enlargement of the capillary net has to be accompanied by an amplification of the action of insulin, which is often present in only small amounts, e.g., after an overnight fast. This aim is met in three ways: (1) enlargement of the capillary net with accelerated blood flow increasing the supply of insulin and the number of receptor sites for insulin binding; (2) accelerated transport of insulin through the capillary wall, providing more insulin in the interstitial space and at the plasma membranes; (3) a molecular mechanism directly involving the insulin-receptor-messenger complex, localized at the plasma membrane of the working muscle cell. These mechanisms resemble a self-regulatory process, set in motion by the release of metabolites from the working tissue. From recent studies there is accumulating evidence that kinins liberated from their precursors are involved as tissue hormones by carrying the signal across the interstitial space to the smooth muscle cells of the capillary vessels. Concomitantly, prostaglandins are released intracellulary to bring about, in cooperation with kinins, the various adaptive mechanisms. Amplifying systems of this kind may play a role not only in muscle but also in other tissues where adequate kinin or prostaglandin release would appear beneficial under several clinical conditions such as shock, coronary infarction, would healing, etc.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1433-8580
    Schlagwort(e): Liver regeneration ; Liposomes ; Portosystemic shunt ; Insulin ; Glucagon
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The regenerative activity of the liver parenchyma after two-thirds hepatectomy was examined in normal rats and rats with a fresh or 7-day-old portocaval shunt. The parameter for regeneration was the incorporation of3H-thymidine into DNA. The exogenous supply of insulin and glucagon—both potential stimulators of regeneration—by permanent infusion into the portal vein, or by several injections of the liposome-encapsulated hormones, did not significantly stimulate the rate of regeneration normally controlled by endogenous pancreatic hormones.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1433-8580
    Schlagwort(e): H2-Receptor ; Somatostatin ; Pancreatic polypeptide ; Gastrin ; Insulin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The effect of histamine H2-receptor stimulation via the infusion of impromidine was assessed with regard to postprandial plasma insulin, pancreatic polypeptide (PP), somatostatin, and gastrin levels. The effect of impromidine was assessed in the postprandial state during a liver extract/sucrose test meal which had a buffer capacity to maintain the intragastric pH at a constant level for the time impromidine was infused. Postprandial plasma insulin and gastrin levels were not changed by impromidine (10µg/kg·h−1). Plasma somatostatin levels rose significantly, whereas the postprandial increase of plasma PP levels was attenuated. The effects on somatostatin and PP were antagonized by the infusion of cimetidine, a specific histamine H2-receptor blocker. In conclusion the present data demonstrate that in the postprandial state activation of H2-receptors stimulates somatostatin and inhibits PP release while insulin and gastrin release are not affected.
    Materialart: Digitale Medien
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    Diabetologia 23 (1982), S. 365-373 
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; proinsulin ; granule ; vesicle ; rat ; islet cell tumour ; insulinoma ; subcellular fractionation ; electrophoresis ; ultrastructure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Density gradient centrifugation techniques, using iso-osmotic colloidal silica suspensions (Percoll), were developed for the isolation of insulin secretory granules from a transplantable rat islet cell tumour. These procedures were readily completed within 7 h and from each animal yielded approximately 1 mg of granule protein. The isolated granules were essentially free of other subcellular organelles as evaluated by their contents of marker proteins, electron microscopy and by electrophoretic analyses. Their susceptibilities to lysis at low osmotic strength, at pH values above 7 or in media containing sodium ions were similar to those of granules partially purified from islets. Insulin comprised 50–60% of the total granule protein when determined by immunoassay or by densitometry of electrophoretic profiles. The proinsulin content was marginally higher than that of islets, as was the ratio of insulins I to II. Electrophoretic analyses revealed that the secretory granules contained 150 or more proteins besides insulin-related peptides. The majority of these had acidic isoelectric points and were located both within the granule interior and its enveloping membrane.
    Materialart: Digitale Medien
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  • 6
    Digitale Medien
    Digitale Medien
    Springer
    Diabetologia 23 (1982), S. 381-385 
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; insulin activity ; insulin association ; crosslinking ; receptor clustering
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The extensive association of mammalian insulins in solution and the aggregation of insulin receptors in cell membranes are well documented. The hypothesis advanced here is that a direct connection exists between these observations. It is postulated that, after binding to its receptor, an insulin monomer can interact with another similarly bonded hormone-receptor complex through those groups on the insulin monomer faces utilized for dimer-dimer contacts in the crystal and in solution. Regarded thus, the insulin molecules are effectively bivalent as required for the formation of cross-links between receptors, with the accompanying enhancement of biological activity. A number of properties of native insulins from different animals, and of modified insulins, are considered in the light of this suggestion. It is shown to have considerable power in reconciling a diversity of such observations and to provide a plausible model for the experimentally observed receptor clustering phenomenon.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; insulin absorption ; plasma insulin ; blood glucose ; exercise ; growth hormone ; urinary catecholamines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Insulin was absorbed faster from the abdomen than from the thigh under resting conditions and during exercise. Exercise enhanced the rate of insulin absorption marginally. The fall of blood glucose during rest and exercise was not significantly different after insulin injection into either site. The faster absorption of insulin from the abdomen during rest and exercise was reflected in a sharper rise of serum growth hormone levels and urinary adrenaline excretion. Therefore exercise should not be taken immediately after injection of a large dose of soluble insulin, particularly into the abdomen.
    Materialart: Digitale Medien
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  • 8
    Digitale Medien
    Digitale Medien
    Springer
    Diabetologia 22 (1982), S. 106-110 
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; insulin antibody ; diabetic control
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In a single blind randomised cross-over study, 40 patients were changed from ordinary bovine to highly purified porcine insulins for a period of 6 months. Half were later rechallenged with bovine insulin. Sequential determinations of IgG insulin binding capacity for bovine insulin were correlated with insulin dose and diabetic control. After changing to highly purified insulins the following correlations were observed between percentage change in insulin dose and change in insulin binding capacity: at 2 months r = 0.35 (p 〈 0.05), at 4 months r = 0.38 (p 〈 0.02) and at 6 months r=0.37 (p 〈 0.02). When the patients who showed substantial changes in HbA1 were removed from the analysis, the remaining 29 demonstrated a clearer relationship between these two variables (r = 0.56, p 〈 0.01). Removal of patients with a low initial insulin binding capacity left 18 patients with stable diabetes, and changes in insulin binding capacity and insulin dose showed an even closer correlation for this group (r = 0.77, p 〈 0.001). A similar degree of positive correlation was observed after rechallenge with bovine insulin. We conclude that the level of circulating insulin antibody affects the dose of insulin required to maintain stable diabetic control.
    Materialart: Digitale Medien
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  • 9
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; insulin receptors ; mouse skeletal muscle ; rat hepatocytes ; human lymphocytes ; photoaffinity labelling
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Using the photoreactive, biologically active insulin analogue, B2-(2 nitro, 4-azidophenylacetyl)des-PheB1 insulin, which can be covalently bound to receptor molecules upon photolysis, the insulin receptor has been studied in three different types of cells or tissues: isolated rat hepatocytes, intact murine soleus muscle and cultured human lymphocytes. When compared with native insulin, this analogue displayed a slightly reduced binding affinity. Accordingly, the biological potency of the photoreactive analogue was decreased by approximately 30% compared with native insulin when tested for its ability to stimulate amino acid transport in hepatocytes, and deoxyglucose uptake in soleus muscles. It was as effective as insulin, however, at maximally stimulating concentrations and therefore is a full insulin agonist. This photoprobe was used to specifically label the insulin receptor in the three tissues: after ultra-violet irradiation, sodium dodecyl sulphatepolyacrylamide gel analysis of extracts under reducing conditions revealed that most of the radioactivity was associated with a 130,000 dalton band. In isolated hepatocytes, two bands at 125,000 and 23,000 daltons were also specifically labelled. In three different cell types from three different animal species, the 130,000 dalton band appeared to be the major subunit of the insulin receptor.
    Materialart: Digitale Medien
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  • 10
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; glucose ; glucose tolerance ; rat ; portal blood flow ; pancreatic transplantation ; pancreatic islets ; streptozotocin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The effect on glucose metabolism of altering the site of the venous drainage of an isograft of isolated adult islets implanted beneath the renal capsule, from the systemic circulation to the portal circulation was determined in streptozotocin-induced diabetic rats. Reversal of diabetes was accomplished by the transplantation of 1000–1200 isolated islets beneath the left kidney capsule. The rate of fall of the glucose concentration (as expressed by the K value) was found to be significantly decreased in transplanted animals (1.7 ± 0.5%/min; mean ± SD) compared with normal animals (2.4 ± 0.5%/min). Draining the left renal vein into the portal circulation restored the K value to that of normal animals (2.5 ± 0.4%). However the fasting glucose concentration was significantly higher and the basal insulin levels lower in both normal and transplanted rats with a renoportal shunt.
    Materialart: Digitale Medien
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  • 11
    Digitale Medien
    Digitale Medien
    Springer
    Diabetologia 22 (1982), S. 1-5 
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; calcium ; calmodulin ; cyclic nucleotides ; phosphorylation ; phenothiazines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Conclusion It is clear that calcium ions are of considerable importance as a second messenger in insulin secretion. There is increasing evidence that calmodulin, a ubiquitous intracellular regulatory protein that mediates calcium-dependent processes, has a fundamental role in stimulus-secretion coupling. Calmodulin is present in the B cell and the secretion of insulin is inhibited by phenothiazines which bind to and inhibit the action of calmodulin. The evidence strongly suggests that phenothiazines influence insulin secretion by their effect on calmodulin which probably mediates calcium-dependent insulin release. It seems likely that calmodulin acts at several points in stimulus-secretion coupling, influencing cyclic nucleotide metabolism, protein phosphorylation and exocytosis. The discovery of calmodulin and the increasing clarification of its roles in cellular metabolism represent major steps towards our understanding of the mechanisms which influence the secretion of insulin.
    Materialart: Digitale Medien
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  • 12
    ISSN: 1432-0428
    Schlagwort(e): Insulin ; insulin degradation ; kinetics of insulin disappearance ; constant infusion technique
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary To investigate the mechanism of insulin degradation in normal subjects, a kinetic model of insulin disappearance was constructed: insulin was assumed to be extracted from plasma by two independent processes, one saturable and one non-saturable. On the basis of these assumptions, a linear (non-proportional) relationship between steady-state plasma insulin concentration and steady-state plasma disappearance rate was predicted over the concentration range studied. Constant infusion experiments were performed on eight healthy normal subjects, normoglycaemia and fasting plasma C-peptide concentrations being maintained during the experiments. Agreement was found between the predictions of the model and the experimental results, and it is concluded that insulin degradation in normal subjects may be described in terms of two processes: one that is saturated at physiological plasma insulin concentrations and one that is apparently non-saturable over a wide concentration range.
    Materialart: Digitale Medien
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  • 13
    ISSN: 1432-0428
    Schlagwort(e): Glibenclamide ; pharmacokinetics ; high performance liquid chromatography ; plasma insulin ; blood glucose
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary A simple high performance liquid Chromatographic assay for the determination of plasma glibenclamide concentrations is described. This resolved glibenclamide from normal plasma constituents. The calibration curve of the assay was linear over the range 10–500 μg/1 and the minimum level of detection was 2 μg/1. Within-assay coefficients of variation were 11.6% (20 μg/1); 5.3% (50 μg/1); 6.8% (100 μg/1); between-assay coefficients of variation were 8.4% (20 μg/1); 4.7% (50 μg/1) and 7.4% (100 μg/1). The assay was used to study the pharmacokinetics of a 1 mg intravenous dose of glibenclamide in eight normal subjects. The mean half-life was found to be 1.47±0.42 h (SD) and no evidence for a non-linear β-phase or slowly equilibrating ‘deep’ compartment was found although this could not be rigorously excluded. The mean systemic drug clearance was 78±29 ml·h-1·kg-1 and the apparent volume of distribution in the β-phase was 155±44 ml/kg. The median time of maximum response of plasma immunoreactive insulin was 25 min and the median time of maximum blood glucose response was 53 min. No correlation could be found between the pharmacokinetics of glibenclamide and these responses in fasted normal individuals.
    Materialart: Digitale Medien
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  • 14
    ISSN: 1432-1238
    Schlagwort(e): Trauma ; Protein sparing ; Glucose ; Insulin ; Amino acids
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The metabolic effects of TPN were studied in a selected group of trauma patients. Nineteen patients were randomly divided into two groups: the first was treated with glucose and insulin, the second with glucose, insulin and amino acids. Each patient in both groups received TPN isocaloric with respect to daily energy output and the treatment lasted five days. Each group was further divided into two subsets (severe or moderate catabolism) according to fasting energy output with respect to the expected energy expenditure. During the acute flow phase, both in moderate as well as in severe catabolism, glucose and insulin were effective for protein sparing; the maximum protein sparing effect was reached when giving a caloric intake equal to 130% of daily energy output. Glucose, insulin and amino acids were effective in replacement of nitrogen losses. In moderately catabolic patients nitrogen balance was significantly better than in severely catabolic patients. This study shows that early and short-term TPN is effective in controlling the flow phase of trauma. Glucose and insulin appear to be the determinants of the protein sparing effect when given in amounts equal to those needed; amino acids provided protein replacement when given in amounts equal to about 20% of energy output. Energy supply higher than 120–130% of daily energy output does not increase protein sparing and protein replacement, the only effect being a further increase in metabolism, which is possibly dangerous in critically ill patients.
    Materialart: Digitale Medien
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  • 15
    Digitale Medien
    Digitale Medien
    Springer
    Intensive care medicine 8 (1982), S. 209-213 
    ISSN: 1432-1238
    Schlagwort(e): Hormones ; Sepsis ; Insulin ; Glucagon ; Ureagenesis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract This is a brief review of the observed hormonal alterations following trauma and sepsis. The major changes noted in the metabolic status of the stressed patient have been characterized by deranged carbohydrate metabolism, altered metabolic rate as measured by oxygen consumption and increased ureagenesis. Each of these phenomena are regulated to a large extent by the specific hormonal profile of the patient. Failure of insulin and growth hormone production have been associated with glucose intolerance, excessive urinary nitrogen loss and a fatal outcome. Glucagon, cortisol and catecholamines exhibit sustained elevation and have been associated with increased metabolic rate and excessive ureagenesis. These changes are usually self limited following trauma but will persist if the patient enters a septic phase. The use of specific nutritional support, namely hypertonic glucose versus a balanced fat emulsion system in the face of sepsis is considered.
    Materialart: Digitale Medien
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  • 16
    ISSN: 1432-1912
    Schlagwort(e): Adenosine ; Adenosine-5′-N-Ethylcarboxamide ; Isolated pancreas ; Glucagon ; Insulin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The effect of adenosine-5′-N-ethylcarboxamide, (NECA), a long-lasting adenosine derivative with pronounced vasoactivity was investigated on glucagon and insulin release from the in situ isolated blood perfused pancreas in the anesthetized dog: NECA (10−9 to 10−5 mol/l) led to a dose-dependent glucagon release. Insulin release was inhibited by NECA at low concentrations, but significantly increased at higher concentrations of the adenosine analogue. Similar effects were observed with infusion of adenosine at 10−7 and 10−6 mol/l. Aminophylline (10−4 mol/l) produced a 10-fold attenuation of the actions of NECA. The preponderance of glucagon release at low concentrations of NECA and adenosine in contrast to that of insulin release at high concentrations may represent a local pancreatic regulatory mechanism of adenosine in glucose homeostasis.
    Materialart: Digitale Medien
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  • 17
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 320 (1982), S. 63-66 
    ISSN: 1432-1912
    Schlagwort(e): β-Adrenoceptor antagonists ; Intrinsic sympathomimetic activity ; Glucose tolerance test ; Insulin ; Glucose
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The effect of β-adrenoceptor antagonists on the intravenous glucose tolerance test was investigated in conscious dogs. dl-Celiprolol (cardioselective with ISA=intrinsic sympathomimetic activity) 200 and 1000 μg/kg i.v., dl-metoprolol (cardio-selective without ISA) 200 and 1000 μg/kg i.v., dl-pindolol (non-selective with ISA) 5 and 25 μg i.v. and l-bupranolol (non-selective without ISA) 10 and 50 μg/kg i.v. were used in the study. The influence of β-adrenoceptor antagonists on the plasma glucose and immunoreactive insulin following the intravenous glucose tolerance test were evaluated by calculating the respective areas under the plasma curve. The present investigtion clearly demonstrates the marked difference between the various β-adrenoceptor antagonists on heart rate and, especially on metabolic parameters. dl-Metoprolol, a β-adrenoceptor antagonist with cardioselectivity and without ISA can be assumed not to alter plasma insulin level and glucose assimilation. l-Bupranolol, a non-selective β-adrenoceptor antagonist without ISA reduces plasma insulin level and probably enhances peripheral glucose uptake, resulting in an “unchanged” glucose tolerance. dl-Celiprolol or dl-pindolol, β-adrenoceptor antagonists with ISA, but cardioselective or non-selective enhance both, basal insulin level and insulin level after glucose stimulation but must be assumed to decrease peripheral glucose uptake since here too glucose tolerance was unchanged.
    Materialart: Digitale Medien
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  • 18
    Digitale Medien
    Digitale Medien
    Springer
    Pflügers Archiv 393 (1982), S. 227-231 
    ISSN: 1432-2013
    Schlagwort(e): Isolated perfused rat kidney ; Insulin ; Metabolic clearance rate ; Radioimmunoassay ; Filtering nonfiltering kidney
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract 1. Renal handling of pig-and rat-insulin was studied in the isolated perfused rat kidney. 2. Metabolic clearance rates of both pig- and rat-insulin excceded GFR. 3. Peritubular uptake of pig-insulin accounted for 13%, of rat-insulin for 31% of the total metabolic clearance. 4. The nonfiltering kidney does not remove insulin from the peritubular circulation. 5. Metabolic clearance rates of pig- and rat-insulin are directly related to GFR. 6. The filtration process seems to be necessary for the uptake of insulin at the peritubular site.
    Materialart: Digitale Medien
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  • 19
    Digitale Medien
    Digitale Medien
    Springer
    European journal of pediatrics 138 (1982), S. 226-230 
    ISSN: 1432-1076
    Schlagwort(e): Hepatic glycogenoses ; Growth ; Somatomedins ; Insulin ; Growth hormone ; Cortisol ; Glucagon
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The biochemical and endocrine responses of 13 patients with hepatic glycogen storage disease (HGSD) (type I-six patients, type Ib-two, type III-three, type IX-two patients) to an oral glucose load have been investigated. Longitudinal growth data was available in all patients. The height velocity standard deviation score (HVSDS) was positively correlated with the plasma somatomedin and inversely correlated with the glucose-insulin ratio, plasma cortisol and plasma growth hormone concentrations. There was no correlation between plasma glucagon and HVSDS. Free fatty acid and lactate concentrations were highest in the older untreated patients who were growing slowly. In four patients improvement in the HVSDS with treatment was accompanied by a rise in plasma somatomedin and a fall in growth hormone and cortisol. In two patients the glucose-insulin ratio decreased. Growth retardation in HGSD can be explained as part of the adaptation to the inability to maintain normal glucose homeostasis.
    Materialart: Digitale Medien
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  • 20
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 287-291 
    ISSN: 1432-1041
    Schlagwort(e): tolmesoxide ; hypertension ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Tolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined β-blocker and diuretic therapy (average supine blood pressure 178/103 mm Hg) the addition of tolmesoxide (300–900 mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 µg/ml compared to 2.97 µg/ml) and a significant increase in the time to reach peak plasma concentration (1.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.
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  • 21
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 307-310 
    ISSN: 1432-1041
    Schlagwort(e): piretanide ; renal failure ; high dose ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics of piretanide was studied in patients with renal failure. After oral administration of a high dose of piretanide (96 mg), the pharmacokinetic parameters were: elimination rate constant 0.346±0.072 h−1, half life 2.00±0.35 h, and total plasma clearance 119.55±35.90 ml · min−1. Compared to the values obtained in adults with normal renal function, these results show a decrease in total plasma clearance, but conservation of the metabolic clearance which amounts to 45% of the total clearance in the healthy adult.
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  • 22
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 397-402 
    ISSN: 1432-1041
    Schlagwort(e): ergotamine ; migraine ; radioimmunoassay ; clinical effects ; adverse effects ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headachefree state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6h. Their mean plasma levels at 30 min (0.33ng/ml) and 1h (0.40ng/ml) were significantly higher than those (0.06 and 0.08ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11ng/ml) responders appeared later (at 3h) than in good responders (at 1h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20ng/ml or more is achieved within 1 hour after oral or rectal administration.
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  • 23
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 343-350 
    ISSN: 1432-1041
    Schlagwort(e): orphenadrine ; single dose ; multiple doses ; bioavailability ; pharmacokinetics ; N-demethylorphenadrine ; metabolism ; dog ; man
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
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  • 24
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 273-279 
    ISSN: 1432-1041
    Schlagwort(e): amoxycillin ; i.v. administration ; pharmacokinetics ; two- and three-compartment models
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetic characteristics of amoxycillin were studied in healthy volunteers after intravenous injection of 250 mg, 500 mg and 1,000 mg, and infusion of 2 g and 5 g. Serum concentrations were fitted using either bi- and tri- exponentional equations. Comparison of the regression curves obtained revealed that the three-compartment model gave a better fit to the serum concentration versus time curve. It was evident that there was a third, slow, dose dependent phase of disposition. This result has been confirmed by the fact that the terminal half life of amoxycillin on cessation of a continuous infusion is significantly greater than after acute administration.
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  • 25
    ISSN: 1432-1041
    Schlagwort(e): indapamide ; bioavailability ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 µg-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly greater maximum blood concentration (263 vs 231 ng/ml) and a significantly shorter time of maximum blood concentration (2.3 vs 3.5 h). Cmax (333 ng/ml) and tmax (0.7 h) values for the solution were significantly higher than either tablet. The average half-life (β-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.
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  • 26
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 257-264 
    ISSN: 1432-1041
    Schlagwort(e): TRIS buffer ; metabolic acidosis ; pharmacokinetics ; cellular uptake ; renal excretion ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg=1 mmol/kg; pH 7.4) and to 20 patients suffering from metabolic acidosis (109–376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,β=5.6 h) and patients with intact renal function (t0.5,β=16.3–45.6 h). The final volume of distribution (Vβ) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.
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  • 27
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 75-80 
    ISSN: 1432-1041
    Schlagwort(e): psoriasis ; 8-methoxypsoralen ; food influence ; suction blister fluid ; serum ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The influence of food on the kinetics of 8-methoxypsoralen (8-MOP) in serum and suction blister fluid was evaluated in a cross-over study in 19 psoriatic patients under PUVA treatment. The peak serum concentration of 8-MOP was reached 1.5 h after ingestion on an empty stomach, and in suction blister fluid the maximum concentration was already present in the first sample taken after 2 h, the time when UVA radiation was given. The postprandial kinetics of 8-MOP in serum and suction blister fluid differed, the highest levels being reached, respectively, at 2.4 and 3 h after intake, i.e. in both body fluids after irradiation had started. The side effects of 8-MOP, such as nausea and dizziness, in the two groups were similar. The present results indicate that to optimize the therapeutic effect of PUVA in individual patients, 8-MOP should be given on an empty stomach.
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  • 28
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 189-195 
    ISSN: 1432-1041
    Schlagwort(e): befunolol ; propranolol ; pharmacokinetics ; pharmacodynamic effects ; beta-adrenoceptor blocking agent
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Repeated doses of a new β-adrenoceptor blocking agent, befunolol, were administered orally to adult male volunteers for a cross-over comparison with propranolol. The β-adrenoceptor blocking activity of befunolol was greater than that of propranolol when assessed by the percentage reduction in exercise-induced tachycardia. The elimination half-life of drug was significantly prolonged on repeated administration of propranolol, but not of befunolol. The percentage reduction in exercise-induced tachycardia was highly correlated with the log plasma level of each drug. Both drugs produced a significant reduction in pre-exercise systolic and diastolic blood pressure, and significant attenuation of exercise-induced rise in systolic blood pressure.
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  • 29
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 235-240 
    ISSN: 1432-1041
    Schlagwort(e): ergotamine ; pharmacokinetics ; migraine ; plasma drug levels ; i.v. administration ; i.m. administration ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg−1 min−1, and the volume of distribution (Vdβ ) was 1847.6 ml kg−1. Individual t1/2β showed a positive linear correlation with the individual Vdβ . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).
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  • 30
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 327-330 
    ISSN: 1432-1041
    Schlagwort(e): bendroflumethiazide ; cantharides plasters ; blister fluid ; plasma levels ; pharmacokinetics ; compartmental analysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of bendroflumethiazide (BFT) was investigated following the oral administration of 10 mg to 3 healthy volunteers. Each subject participated twice in the study. BFT was determined in plasma and cantharides blister fluid from 1/2 to 30 h post administration. Blister fluid was obtained from blisters 10–22 h old. Plasma levels were fitted to a tri-exponential equation and the concentration of the drug in the peripheral compartment was calculated from the microscopic rate constants. In 5 of 6 cases investigated, cantharides blister fluid levels paralleled the concentration of the drug in the peripheral compartment. The mean blister fluid levels exceeded the calculated concentration in Compartment 2 1.46 fold. In one case, the blister fluid level paralleled the plasma level. This subject clearly differed from the others as more than 10 h were required for blister formation in her. The results suggest that following the administration of BFT, cantharides blister fluid behaves as part of the peripheral compartment. The possible value of studying blister fluid levels in pharmacokinetic investigations is discussed.
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  • 31
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 343-347 
    ISSN: 1432-1041
    Schlagwort(e): valproic acid ; fatty acids ; plasma protein binding ; pharmacokinetics ; drug metabolism
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p〈0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p〈0.01) than in fasting samples (10–50%,p〈0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p〈0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
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  • 32
    ISSN: 1432-1041
    Schlagwort(e): L-threo-3,4-dihydroxyphenylserine ; familial amyloid polyneuropathy ; pharmacokinetics ; norepinephrine ; pressor response
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of oralL-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was studied in 7 normal subjects and 7 patients with familial amyloid polyneuropathy. Each person swallowed a single 300 mg dose in the fasting state, andL-threo-DOPS in plasma and urine was determined by high performance liquid chromatography with an electrochemical detector after separation on a boric acid gel column.L-threo-DOPS was slowly absorbed by normal subjects; the maximum plasma concentration occurred 3 h after administration and 20% of the oral dose was recovered unchanged in the urine within 12 h. It induced a substantial elevation of plasma norepinephrine levels, the peak being attained at 5 h, but without any change in blood pressure. In the patients, the absorption and metabolism ofL-threo-DOPS were delayed, and a prolonged pressor response was observed, with a peak after 8 h. It was concluded that the effects on plasma norepinephrine and blood pressure of oralL-threo-DOPS were essentially equal to those of twice as large a dose ofDl-threo-DOPS.
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  • 33
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 501-504 
    ISSN: 1432-1041
    Schlagwort(e): cimetidine ; uraemia ; dosing regimen ; prediction ; computer program ; old age ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Using a recently developed computer program based on a correlation between methods to predict the elimination half-life and apparent volume of distribution of cimetidine and actual data from patients, ideal dosage regimens were generated for patients with renal impairment and for geriatric patients, together with the corresponding maximum and minimum steady state concentrations. Using the ideal dosage regimens, practical regimens with feasible dosing intervals of 6, 8 and 12 h were computed, which should result in therapeutic concentrations of 0.4 to 1.3 µg/ml. For uraemic patients and geriatric patients above the age of 75 years it would be desirable to have an additional oral 100 mg dosage form.
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  • 34
    ISSN: 1432-1041
    Schlagwort(e): amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (〉500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
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  • 35
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 1-5 
    ISSN: 1432-1041
    Schlagwort(e): clonidine ; noradrenaline ; pharmacokinetics ; arterial blood pressure ; plasma concentration
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (Cmax) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels.
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  • 36
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 43-47 
    ISSN: 1432-1041
    Schlagwort(e): timolol ; pharmacokinetics ; pharmacodynamics ; healthy subjects ; cardiac infarction patients ; i.v. therapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Disappearance pharmacokinetics, pharmacodynamics and general tolerance of i.v. timolol were compared in 12 healthy volunteers and 10 patients with a definite or proven acute myocardial infarction. The drug was administered to the patients immediately on arrival at the hospital after a median delay time of 4 h. Tolerance to the injections was good in both volunteers and patients. The study revealed disappearance pharmacokinetics that were similar in volunteers and patients.
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  • 37
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 293-301 
    ISSN: 1432-1041
    Schlagwort(e): metipranolol ; deacetyl metipranolol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6–25 mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20 mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40 mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20 mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of β-blocking agents.
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  • 38
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 315-323 
    ISSN: 1432-1041
    Schlagwort(e): bendroflumethiazide ; propranolol ; hydralazine ; pharmacokinetics ; thin-layer chromatography ; fluorimetry ; fixed combination product
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Bendroflumethiazide (Bft) was administered to 6 healthy subjects at 3 different dose levels (2.5, 5 and 10 mg) in a cross-over design, either as capsules (2.5 mg) or as tablets (5 mg). Its pharmacokinetics were evaluated then and following administration of a fixed combination of Bft with propranolol and hydralazine to a further 7 volunteers. Plasma and urinary concentrations of Bft were determined by a new fluorimetric — thin-layer chromotography procedure. Peak plasma levels occurred after 2–3 h and averaged 15, 27 and 45 µg/l in the three dose groups. Areas under the plasma concentration — time curves (AUC0→12), which were 75, 147 and 250 µg l−1 h respectively, and cumulative urinary recovery (20%) were independent of the dose administered and the type of formulation. Thus Bft kinetics proved to be linear within the dose range evaluated. The plasma clearance was calculated to be 505 ml/min, renal clearance 108 ml/min and nonrenal clearance 396 ml/min. Bioavailability of Bft was not altered following administration of the fixed combination. The amount of propranolol found in the circulation did not change, whereas that of hydralazine (determined as apparent hydralazine) increased by 59% when the fixed combination was administered.
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  • 39
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 421-425 
    ISSN: 1432-1041
    Schlagwort(e): benzodiazepine ; lormetazepam ; lormetazepam glucuronide ; transfer to milk ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The concentrations of lormetazepam and its glucuronide in plasma and milk were determined during administration of 10 daily doses of lormetazepam 2 mg (2 tablets of NOCTAMID® - 1) to five mothers delivered by Caesarian section. Their babies were breast-fed throughout the study, and the plasma levels of lormetazepam and its glucuronide were determined three times in the babies. At 12 and 24h after administration, the plasma level of lormetazepam was about 3.5 ng/ml and 1.8 ng/ml in mothers, and below 0.09 ng/ml in the children. In milk the lormetazepam concentration was below 0.2 ng/ml. The plasma level of glucuronide varied between 24 ng/ml at 12h and 11 ng/ml 24h after administration. Almost no accumulation of unchanged lormetazepam was observed (factor: 1.3). The ratio of the levels of lormetazepam in milk and plasma was estimated to be below 0.06, and for the glucuronide the ratio was 0.04. The quantity of free and conjugated active ingredient transferred to the children via breast milk was calculated to be at most 100 ng/kg, corresponding to 0.35% of the maternal dose, which is regarded as tolerable.
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  • 40
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 499-504 
    ISSN: 1432-1041
    Schlagwort(e): gentamicin ; malnutrition ; pharmacokinetics ; infant
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of gentamicin was investigated in normal and malnourished infants aged 4–10 months. Neither mean “elimination” nor “distribution half life” show any difference, but the volume of distribution was higher in malnourished babies, probably due to their larger total body water.
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  • 41
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 423-428 
    ISSN: 1432-1041
    Schlagwort(e): pindolol ; renal failure ; metabolism ; pharmacokinetics ; 14C-pindolol ; blood metabolites ; urinary metabolites
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Increased metabolism of pindolol in renal impairment has previously been suggested by pharmacokinetic calculations. The present study was a pharmacokinetic and metabolic investigation in 7 patients with severe renal impairment (endogeneous creatinine clearance below 5 ml/min). All the patients received pindolol 5 mg t.d.s. 5 days. On the sixth day, after an overnight fast, 14C-pindolol 5 mg was given orally as a solution to drink. Blood samples were taken for up to 72 h and urine was collected at intervals up to 96 h for measurement of unchanged pindolol by a fluorimetric method and total radioactivity by liquid scintillation counting. Metabolites in blood and urine were analysed after separation by HPLC. It was found that the plasma levels following a single dose of 14C-pindolol were similar to those observed in healthy volunteers, but the elimination half-life was slightly increased up to 11.5 h. The observed steady state plasma concentrations of pindolol were twice as high but they are still in the therapeutic range of 10 to 100 ng/ml. Therefore, the dose of pindolol could have been reduced by a factor 2, but the reduction was not essential. No active metabolite of pindolol was found in plasma or urine, but elimination of the metabolites was decreased. The elimination half-life following multiple doses was prolonged compared to normal and it was quite comparable to that found for the pharmacodynamic half-life in renal patients. The discrepancy between the present findings and the previous results for metabolism and pharmacodynamic half-life was probably due to the sensitivity of the fluorimetric assay of pindolol.
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  • 42
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 155-160 
    ISSN: 1432-1041
    Schlagwort(e): amikacin ; pharmacokinetics ; development ; neonate ; infant ; child
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The disposition kinetics of a single i.v. dose of amikacin was studied in 6 neonates (6–25 days old), 10 infants (4–18 months) and 8 young children (3–11 years). There was a progressive change in the distribution and elimination kinetics during development. The distribution coefficient of the antibiotic averaged of 0.429, 0.320 and 0.210 l/kg in the newborns, infants and young children, respectively and serum half-life (t1/2 β) in these three groups averaged 2.812, 1.803 and 1.196 h, respectively. Significant differences in certain pharmacokinetic parameters were found between the values in paediatric patients and in adults receiving the same dose. A linear relationship was established between the distribution volume of the antibiotic and the weight of the patients, as defined by the following equation: $${\text{Vd}}_{{\text{ss}}} \left( 1 \right) = 0.976 + 1.140 \cdot {\text{TBW}}\left( {{\text{kg}}} \right);r = 0.954$$ The results suggest that a regimen of very frequent administrations should be employed in infants and young children in order to maintain a therapeutic level throughout treatment.
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  • 43
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 161-169 
    ISSN: 1432-1041
    Schlagwort(e): mebendazole ; hydatid disease ; Echinococcus granulosus ; hepatic disease ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The plasma concentrations of mebendazole and its metabolites have been monitored in twelve patients after receiving a 10 mg/kg dose for cystic hydatid disease. The mebendazole plasma concentration-time profiles differed considerably between patients; elimination half-lives ranged from 2.8–9.0 h, time to peak plasma concentration after dosing ranged from 1.5–7.25 h and peak plasma concentrations ranged from 17.5 to 500 ng/ml. The mean peak plasma concentration of mebendazole after an initial dose (69.5 ng/ml) was lower than found in patients during chronic therapy (137.4 ng/ml). The plasma AUCTs for the major metabolites of mebendazole (methyl 5-(α-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5 benzoylbenzimidazole) were about five times the plasma AUCT found for mebendazole in patients on chronic therapy. It is suggested that the slower clearance of these polar metabolites relative to mebendazole results from enterohepatic recycling. Since mebendazole is also highly plasma protein bound, caution should be observed in administering mebendazole to patients with liver disease. Concentrations of mebendazole found in the tissue and cyst material collected from two patients during surgery ranged from 59.5 to 206.6 ng/g wet weight.
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  • 44
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 173-176 
    ISSN: 1432-1041
    Schlagwort(e): melperone ; neuroleptic drug ; dose dependent kinetics ; i.m. injection ; i.v. injection ; pharmacokinetics ; oral application
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of melperone (Buronil®, Ferrosan, Sweden) was studied after administration of various parenteral and oral doses to man. After parenteral administration, the data could be fitted to a two-compartment model, but after oral dosing the distribution phase could not be separated from the elimination phase, and so an one-compartment model gave the best fit. The half-lives were about 3–4 h, except after intramuscular injection, when the half-life was about 6 h. The bioavailability of oral doses was about 60% of the intravenous injection. After the highest oral dose of 100 mg, the pharmacokinetics, expressed as AUC or Cmax, showed non-linearity, possibly due to saturation of the hepatic elimination system.
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  • 45
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 331-333 
    ISSN: 1432-1041
    Schlagwort(e): ketoconazole ; vaginal candidosis ; oral antimycotic ; distribution ; pharmacokinetics ; vaginal tissue concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma samples and biopsies of vaginal tissue were obtained from 23 healthy women undergoing operative sterilization, 1 to 6 h after a single oral dose of ketoconazole 200 mg. Drug concentrations in plasma and tissue, were measured by a specific gas chromatographic method. The vaginal tissue concentration averaged 2.4 times less than the corresponding plasma levels. Equilibrium between tissue, and plasma was established within 1 h after dosing, when vaginal tissue levels exceeded 1 µg/g. Ketoconazole concentrations decayed monoexponentially over the time interval studied (1–6 h), with the similar half-lives of 1.2 and 1.4 h in plasma and tissue, respectively. Following an oral 200 mg dose, a tissue concentration not less than 0.01 µg/ml was maintained over a 12 h period. This concentration has been shown to prevent outgrowth of the invasive (pseudo) mycelial form ofCandida albicans. Hence, a b.i.d. or t.i.d. dosage schedule of ketoconazole in vaginal candidosis would give continuously effective levels at the site of infection. Ketoconazole concentrations in vaginal fluid are thought to be much higher than in the tissue because of ion-trapping. The present data may explain the efficacy of oral ketoconazole in the treatment of vaginal candidosis.
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  • 46
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 303-306 
    ISSN: 1432-1041
    Schlagwort(e): furosemide ; renal failure ; haemodialysis ; pharmacokinetics ; children ; dosage schedule
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Furosemide was measured by gas-liquid chromatography in blood and dialysis fluid from 7 children with chronic renal failure, undergoing regular haemodialysis. It was administered chronically, in two or three daily doses (4.2–9.4 mg/kg). Two children received 1 mg/kg intravenously for determination of the pharmacokinetics. The half-life was longer than in adults and in anephric patients on haemodialysis. Systemic and renal clearance were also much lower. Plasma protein binding in 2 out of 6 cases was reduced as campared to normal adults. The data do not suggest any need to modify the present dosage schedule despite the 4–5 fold increase in the half-life of furosemide. The contribution of haemodialysis to drug clearance was minimal, and accounted for less than 10% of the total clearance.
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  • 47
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 331-334 
    ISSN: 1432-1041
    Schlagwort(e): diclofenac sodium ; rheumatoid disease ; healthy subjects ; serum albumin ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Pharmacokinetic data for diclofenac sodium has been well established in healthy volunteers, whereas in patients with rheumatoid arthritis very little information is available in the literature. A single oral dose of enteric-coated diclofenac sodium was given to 10 patients with active rheumatoid disease, adopting the same procedures used for a group of 10 healthy volunteers in whom pharmacokinetic data was already available. Plasma specimens were collected over a period of 8h following administration and concentrations of diclofenac determined by GLC. Resulting plasma concentration curves were similar to those obtained in the healthy subjects in that areas under curves and terminal half-lives were comparable. However, peak concentrations of diclofenac were significantly reduced in the rheumatoid patients. The lower peak concentrations were correlated with the lower serum albumin levels in the patients which are associated with active rheumatoid disease.
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  • 48
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 47-52 
    ISSN: 1432-1041
    Schlagwort(e): apnoea ; caffeine ; premature infants ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of caffeine was examined in 13 premature infants (gestational age 25–34 weeks, birth weight 920–2060 g, postnatal age 1–42 days) who received the drug for treatment of opnoea. Caffeine (1% aqueous solution) was given i.v. in single doses; guided by the clinical response infants received between one and seven (mean 2.6) doses of 15 mg/kg. Mean (± SE; range) Clb was extremely slow − 8.5 ml/kg/h (±0.4; 5.8–12.2), t1/2 was prolonged − 65.0 h (±3.7; 48.2–87.5 h) and Vd was 0.781/kg (±0.04; 0.47–1.01). No significant correlation was found between Clb, t1/2 and postnatal age in the whole group or in individual infants. Effective plasma concentrations varied over a wide range (12–36 µg/ml) and overlapped with subtherapeutic concentrations (⩽24 µg/ml). Single doses of 15 mg/kg i.v. or p.o. prevented apnoea in most cases, if necessary followed by additional doses. Monitoring the blood level of caffeine in infants receiving frequent repeated doses is necessary to prevent toxicity.
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  • 49
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 359-365 
    ISSN: 1432-1041
    Schlagwort(e): chlorpheniramine ; pharmacokinetics ; oral absorption ; half-life ; bioavailability ; volume of distribution
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma and urinary levels of chlorpheniramine (CPM) and its 2 demethylated metabolites were measured by HPLC after i.v. and oral dosing. In 5 mg (maleate) i.v. bolus studies in 2 subjects, plasma CPM levels were fitted to triexponential equations with terminal half-lives (t 1/2) of 23 and 22 h and area of 3.6 and 3.21/kg, respectively. Intravenous data predicted hepatic blood extraction ratios for the 2 subjects to be 0.06 and 0.07, respectively. Absolute bioavailability from oral solution (10 mg) was 59 and 34%, and from tablets (8 mg) 44 and 25%, respectively, indicating extensive gut first-pass metabolism. Mean t 1/2 from 7 oral fasting studies in 5 subjects was 28 h (19–43 h). Mean absorption lag time was 0.7 h (0.4–1.3 h), and mean peak time was 2.8 h (2–4 h). In 2 subjects, 6 mg solutions were given every 12 h for 9 doses; good correlation between single and multiple dose kinetics was found. Significant accumulation was demonstrated in simulation studies with frequent daily dosing. Estimated accumulation ratios vary from 4.1 to 9.4 (mean 6.5). The t 1/2 from urinary data (collected for 12 days) was consistent with plasma data. The above results suggest the need to reexamine the current practice of frequent daily dosing and the use of sustained or controlled release dosage forms of this drug. The possible cause of reduced plasma clearance of CPM in renal patients is discussed.
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  • 50
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 93-97 
    ISSN: 1432-1041
    Schlagwort(e): tolmesoxide ; vasodilator ; hypertension ; pharmacokinetics ; haemodynamics ; plasma renin activity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The haemodynamic response and pharmacokinetics of single dose oral tolmesoxide were studied at various dose levels in 4 patients with severe hypertension. There was a reproducible fall in mean arterial pressure from baseline of 24.2% and a rise in heart rate of 37.6% following administration of tolmesoxide. The onset of antihypertensive action occurred within 1 h, with a peak effect at 3 h after dosing. The mean duration of action was up to 12.0 h. Tolmesoxide had a mean half-life of 3.0 h. It was rapidly absorbed with a mean peak plasma level occurring at 1.0 h. Plasma levels correlated well with the doses administered. Side-effects included mild nausea, facial flushing and postural symptoms.
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  • 51
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 37-42 
    ISSN: 1432-1041
    Schlagwort(e): metoprolol ; propranolol ; oxprenolol ; pharmacokinetics ; acetubolol ; diacetolol ; oral contraceptive
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Plasma concentrations of metoprolol, propranolol oxprenolol, acebutolol and its metabolite diacetolol were measured after single oral doses in young healthy volunteers. In order to assess the inter-and intra-subject variability the following pharmacokinetic parameters were compared: AUC o 24 , Cmax, tmax and t1/2. The smallest variation in inter-subject variability was seen with oxprenolol and acebutolol: intrasubject variability was more uniform. Female volunteers taking an oral contraceptive generally had higher AUC o 24 and Cmax values than those not. This finding reached statistical significance only for metoprolol AUC o 24 .
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  • 52
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 49-57 
    ISSN: 1432-1041
    Schlagwort(e): verapamil ; norverpamil ; pharmacokinetics ; atrial fibrillation ; oral administration ; i.v. administration
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin® 2 ml), and oral verapamil 80 mg (Isoptin® 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination phase (t1/2β=5.79 h), corresponding to a plasma clearance of 0.26 1/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t1/2β=5.53 h). The oral bioavailability was 10.5%±7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atrial fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration — effect data from all the patients were pooled (r=0.59,n=71;p〈0.0005).
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  • 53
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 123-127 
    ISSN: 1432-1041
    Schlagwort(e): theophylline ; bronchiolitis ; infants ; pharmacokinetics ; single dose ; multiple doses ; HPLC
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Theophylline pharmacokinetics were studied in 12 infants (age 3 weeks–6.5 months) with bronchiolitis. 9 of the 12 patients received a single dose of aminophylline (5.0–8.5 mg/kg) whereas the remainder were at steady-state receiving multiple doses (2.5–5.0 mg/kg) of aminophylline. The dose was administered IV over 0.5–1.0 h. An HPLC method was used to measure theophylline concentrations in serum and urine. Peak serum concentrations of theophylline measured by HPLC ranged from 8.48–21.6 µg/ml. Total, renal and nonrenal clearance of theophylline ranged from 4.66 to 19.25, 1.07 to 5.76 and 3.59 to 16.83 ml/min/m2, respectively. Mean apparent volume of distribution and elimination half-life were 8.75 l/m2 and 11.38 h, respectively. Although no significant correlation was observed between age and theophylline kinetic parameters, clearance appeared to increase and half-life decrease with age. Our patients had a substantially lower clearance and longer half-life as compared to published data in children 〉1 year of age. A five-fold variation in theophylline clearance demonstrates the need for monitoring theophylline serum concentration to minimize the risk of potential toxicity.
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  • 54
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 129-134 
    ISSN: 1432-1041
    Schlagwort(e): theophylline ; ethinylestradiol ; oral contraceptives ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The effect of chronic oral contraceptive (OC) usage on the disposition of theophylline was examined. Aminophylline solution (4 mg/kg) was given orally to 8 healthy female non-OC users and to 8 healthy women who were chronic (〉6 months) OC users. The OC user group had a significantly lower total plasma clearance of theophylline than women not using OC (35.1±5.6 vs. 53.1±14.5 ml/h/kg). The t1/2 was also significantly prolonged in the OC group (9.79±1.43 vs. 7.34±1.75 h) while the volume of distribution was similar between the 2 groups. The serum ethinylestradiol (EE) concentrations after oral OC administration were measured simultaneously. The apparent clearance of EE was about 30% lower in the OC users. A significant positive correlation was found between the apparent clearance of EE and the plasma clearance of theophylline. The effects of OC are predominantly due to chronic use with decreased elimination of both theophylline and EE.
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  • 55
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 167-172 
    ISSN: 1432-1041
    Schlagwort(e): ticarcillin ; probenecid ; excretion ; pharmacokinetics ; automated chemical assay method
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [35S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.
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  • 56
    ISSN: 1432-1041
    Schlagwort(e): dipyridamole ; platelets ; plasma levels ; pharmacokinetics ; adenosine uptake
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Two preparations of dipyridamole have been studied by oral administration to 11 normal volunteers. The plasma levels of dipyridamole and its glucuronide were determined simultaneously by high performance liquid chromatography. The instant form (I.F., 100 mg) was administered four times daily and the slow release preparation (SRP, 200 mg) twice daily, for 3 days. Multiple blood samples were collected on Days 1–4 to provide plasma for assay, and simulteneously, platelet rich plasma was prepared for ex vivo study of the effect of dipyridamole on platelet uptake of adenosine. The pharmacokinetics of absorption and distribution of dipyridamole were described using a two compartment model with lag time and prolonged absorption. Strong inhibition of the platelet adenosine uptake was observed at therapeutic plasma levels. The inhibition of platelet adenosine uptake may be related to some of the pharmacological properties of dipyridamole.
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  • 57
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 349-351 
    ISSN: 1432-1041
    Schlagwort(e): indomethazine ; rheumatoid arthritis ; pharmacokinetics ; tolerance ; side effects ; slow-release tablets
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (tmax 3.7 h and 〈 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.
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  • 58
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 335-341 
    ISSN: 1432-1041
    Schlagwort(e): phenylephrine ; pharmacokinetics ; bioavailability ; first-pass metabolism ; phenolic conjugates ; m-hydroxymandelic acid ; intravenous ; oral
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary 7-3H-phenylephrine was given to 15 volunteers by a short-infusionn=4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 1/h, and the volume of distribution of 340l. Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.
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  • 59
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 315-320 
    ISSN: 1432-1041
    Schlagwort(e): furosemide ; cirrhotic patients ; ascitic fluid ; diuretic effect ; pharmacokinetics ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 µg/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.
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  • 60
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 325-330 
    ISSN: 1432-1041
    Schlagwort(e): cimetidine ; renal failure ; cimetidine sulphoxide ; pharmacokinetics ; haemodialysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary A single intravenous dose of cimetidine 200mg was administered to 6 patients with severe chronic renal failure one hour prior to haemodialysis. The plasma concentrations of cimetidine and its sulphoxide metabolite at the start of haemodialysis were 2.74±0.12 and 0.76±0.08 µg/ml, and after dialysis for 4h 1.08±0.10 and 0.51±0.08 µg/ml, respectively (mean ± SE). The average haemodialysis clearance (ClHDa) of cimetidine during dialysis was 46–92ml/min at a dialysate flow rate of 320ml/min and blood flow rates in the 6 patients between 160–240ml/min. The mean ClHDa of the sulphoxide metabolite was 44% higher than that of cimetidine, and ranged between 49–148ml/min. During haemodialysis the mean plasma elimination half-life (t1/2) of cimetidine was 3.24h (range 2.08–5.08) and of the sulphoxide metabolite 9.49h (range 4.70–14.39). There was a significant relationship between the elimination rate constant (β) and ClHDa of the sulphoxide metabolite (p〈0.01), but no such relationship was found between β and ClHDa of cimetidine. However, there was a tendency to a relationship between β of cimetidine and the capacity to metabolise the drug, expressed as the ratio between the plasma concentrations of the sulphoxide metabolite and cimetidine after dialysis for 4h. These ratios ranged between 0.23–0.76, and the lowest ratio was seen in the patient with the lowest β value of cimetidine. Thus, the large variations in the plained by differences in their capacity to metabolise the drug. The mean total amount of cimetidine eliminated during dialysis was 27.3mg (range 17.9–31.8), which was 9.0–15.9% of the given dose. Between 12.2–21.2mg (mean 15.3) of the sulphoxide metabolite was eliminated in the dialysate. Major adjustment of the dose of cimetidine on days of dialysis is not necessary.
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  • 61
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 351-354 
    ISSN: 1432-1041
    Schlagwort(e): lithium ; plasma level decay curve ; elimination ; pharmacokinetics ; psychiatric patients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Chronic treatment with conventional lithium carbonate was interrupted in a selected group of 40 psychiatric patients of mixed sex and race. All patients had normal renal function. Serum samples were taken 12, 24, 36 and 48 h after the last dose and lithium was assayed by atomic absorption spectrophotometry. Decay rates calculated for the 12–24 h and 36–48 h periods yielded different values. This was ascribed to the presence of an incomplete redistribution phase during the earlier period. The distribution of elimination rates determined during the later period gave a more symmetrical spread and approximated a normal distribution. The mode, median, mean and standard deviation of the lithium elimination half-lives were 12.5, 14, 18.2 and 7.3 h and 22.5, 24.5, 29.8 and 10.1 h for the two periods, respectively. The results contrast sharply with another report of the distribution spread of elimination half-lives in a much larger sample. The current values have implications for dosage prediction, serum level monitoring and dosage formulation, especially sustained-release preparations. The evidence was against the possibility that some individuals ‘retain’ lithium.
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  • 62
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 373-377 
    ISSN: 1432-1041
    Schlagwort(e): propranolol ; sotalol ; thyrotoxicosis ; bioavailability ; serum tri-iodothyronine ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p〈0.05) and its clearance was increased (p〈0.005), whereas there was no difference in its serum t1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.
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  • 63
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 21 (1982), S. 433-441 
    ISSN: 1432-1041
    Schlagwort(e): antipyrine ; antipyrine metabolites ; drug metabolism ; route of administration ; healthy volunteers ; urinary excretion ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8±1.9% of the dose was excreted in urine as unchanged antipyrine in 48h, 24.9±6.3% as 4-hydroxyantipyrine, 16.5±3.2% as norantipyrine, 13.0±2.2% as 3-hydroxymethyl-antipyrine and 5.8±1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.
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  • 64
    ISSN: 1432-1041
    Schlagwort(e): clomipramine ; desmethylclomipramine ; depressive syndrome ; plasma level ; pharmacokinetics ; clinical response ; benzodiazepines
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Thirty one in-patients suffering from depression were treated orally with clomipramine (Cl) at various dosage, for 28 days, after a “wash-out” period of three days. In 17 patients receiving 75 mg per day of Cl, steady state plasma levels of Cl were reached at Day 14, and steady state plasma levels of its active metabolite, desmethylclomipramine (DMCl), were reached at Day 21. In contrast, in 7 other patients receiving a dosage increasing to 150 mg per day at Day 7, mean plasma levels of Cl and DMCl continued to rise during the entire treatment period. At the steady state, a correlation was found between Cl dosage expressed as mg kg body weight and the plasma concentration of Cl and DMCl. Factors such as tobacco and alcohol consumption seem to modify the Cl/DMCl ratio. A comparison of clinical response with plasma levels of Cl, DMCl and Cl + DMCl showed a significant negative linear correlation.
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  • 65
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 77-84 
    ISSN: 1432-1041
    Schlagwort(e): allopurinol ; oxipurinol ; benzbromarone ; hydrochlorothiazide ; pharmacokinetics ; bioavailability ; interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary An high-pressure liquid chromatographic method was used to measure allopurinol and oxipurinol in plasma and urine in 6 healthy volunteers after a single intravenous or oral dose of allopurinol. The influence of coadministrated benzbromarone and hydrochlorothiazide on the pharmacokinetics of allopurinol and oxipurinol was also investigated. After intravenous injection of allopurinol 300 mg the plasma disappearance was biexponential, with a mean distribution half-life of 2.32±1.08 min $$(\bar x \pm SD)$$ and an elimination half-life of 47.8±10.6 min. The total clearance of allopurinol was 11.37±2.70 ml/min/kg, whereas its renal clearance was only 1.73±0.79 ml/min/kg. Oxipurinol disappeared monoexponentially from plasma ith a mean half-life of 12.2±2.6 h. Its renal clearance was 0.42±0.091 ml/min/kg. After oral administration of allopurinol 300 mg the peak plasma concentration of 2.1±0.6 µg/ml (1.5×10−5 M) was reached within 30 to 120 min. The peak level of oxipurinol of 5.8±1.5 µg/ml (3.8×10−5 M) was found within 2 to 5 h after intravenous and oral allopurinol. The bioavailability of oral allopurinol computed from plasma data was 90.4±8.7%. The total recovery from urine was 77% (allopurinol 8%, oxipurinol 69%) after oral and 88% after i.v. administration. It was concluded that about 10% of the oral dose was not absorbed and that 12% was eliminated by an unknown mechanism, presumably as riboside. The pharmacokinetics of allopurinol and oxipurinol were not significantly influenced by coadministration of benzbromarone or hydrochlorothiazide.
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  • 66
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 343-349 
    ISSN: 1432-1041
    Schlagwort(e): methadone ; opiate addicts ; pharmacokinetics ; single and multiple doses ; stable isotope technology ; methadone maintenance therapy ; deuterium technique
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Deuterated methadone (M-d30) and GC-MS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d3 was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n=6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n=6). Plasma and urinary levels of M and M-d3 were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1–2 and 24–26. The oral bioavailability of a methadone solution was found to be between 81 and 95%; elimination half-life in the β-phase varied between 19 and 58 h; the volume of distribution was 4.1±0.65 l/kg; and total body clearance of M was 54–195 ml/min and its renal clearance 3.4–34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first days of MMT as compared with after one month. In 4/12 of the patients dispositional tolerance was developed to methadone during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness
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  • 67
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 515-521 
    ISSN: 1432-1041
    Schlagwort(e): tienilic acid ; uricosuria ; pharmacokinetics ; pharmacodynamics ; uric acid ; diuretic ; plasma level assay
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary A simple and reliable HPLC method for the determination of tienilic acid ((TA) Selacryn®, Selcryn®, Diflurex®, Ticrynafen®) and its alcoholic metabolite in plasma and urine has been developed. In 8 healthy adult volunteers the plasma and urinary levels of tienilic acid and its alcoholic metabolite, and plasma and urinary levels of sodium, creatinine and uric acid were measured after oral administration of tienilic acid 250 mg. The pharmacokinetic parameters found differed only slightly from those reported in the literature, as there was faster absorption and a shorter half-life. TA is probably excreted by a saturable renal tubular transport mechanism. The pharmacodynamic effects of tienilic acid developed quickly, the uricosuric effect being very impressive and the natriuretic effect moderate. These effects disappeared in about 8 h. An inverse relationship was found between the starting plasma uric acid level in an individual and the maximal uric acid clearance — the higher the plasma uric acid level, the lower was the maximum effect. Plasma tienilic acid level and natriuretic effect were correlative within individuals and intra-individually (p〈0.05). Urinary tienilic acid level and natriuretic effect were correlated, too (p〈0.05 top〈0.001), but only intraindividually. No correlation between drug level and uricosuric effect was found.
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  • 68
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 535-539 
    ISSN: 1432-1041
    Schlagwort(e): noscapine ; pharmacokinetics ; absorption ; bioavailability ; intravenous application ; oral application ; ion exchange resin tablet
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Noscapine was administred to five healthy volunteers in a randomized crossover design, as an intravenous infusion of 66 mg, and as an oral 150 mg dose of either rapidly dissolving tablets or a tablet containing ion exchange resin-bound noscapine. After i.v. administration, the disposition of noscapine was bi-exponential with an elimination half-life of 2.6 h; the total plasma clearance was 22 ml/min/kg and the volume of distribution (Vdarea) was 4.7 l/kg. The absolute oral bioavailability was 30%, with a 3.6-fold interindividual variation. There was no pharmacokinetic evidence to support a prolonged action of the ion exchange resin tablet.
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  • 69
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 417-422 
    ISSN: 1432-1041
    Schlagwort(e): theophylline ; aminophylline ; obstructive airways disease ; short-term i.v. infusion ; log-normal distribution ; pharmacokinetics ; serum concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, Vd=0.451 (0.258–0.789) l/kg ideal body weight, and t1/2(el)=7.1 (2.6–19.1) h.
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  • 70
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 249-252 
    ISSN: 1432-1041
    Schlagwort(e): mecillinam ; bacmecillinam ; pivmecillinam ; pharmacokinetics ; pro-drug ; healthy volunteers ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (±SD) peak levels of plasma mecillinam were 1.43±0.34, 2.73±0.43, and 4.62±1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38±0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21±0.19, 3.99±0.63, and 7.74±1.38 mg·h·l−1 for bacmecillinam and 5.35±0.93 mg·h·l−1 for pivmecillinam. The elimination half-lives were 0.8–1.1h for bacmecillinam and 0.7h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p〈0.001), AUC (p〈0.001) and urinary recovery (p〈0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p〈0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.
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  • 71
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 267-270 
    ISSN: 1432-1041
    Schlagwort(e): terodiline ; human volunteers ; pharmacokinetics ; serum clearance ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of terodiline HCl was studied in nine healthy volunteers given 12.5 mg i.v. and p.o. or 20 mg i.v. and 25 mg p.o. on two different occasions. The serum concentrations were measured by gas chromatography — mass spectrometry, using deuterated terodiline HCl as the internal standard. After i.v. administration the kinetics could be described by a two-compartment model with a mean distribution half life of 0.3 h and a mean elimination half life of 63 h. The serum clearance and apparent volume of distribution varied about 4-fold with mean values of 4.8 l/h and 417 l, respectively. After oral administration, the mean half life of absorption was 0.7 h and that of elimination 65 h. The absolute bioavailability varied between 64% and 105% with a mean of 92%. The long serum half life of terodiline should permit its once daily administration.
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  • 72
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 369-372 
    ISSN: 1432-1041
    Schlagwort(e): neuromuscular blockade ; pancuronium ; non-depolarizing neuromuscular blocking agent ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Pancuronium in bolus doses of 40 to 350 µg/kg was administered to surgical patients in order to evaluate the linearity of its pharmacokinetics. The profile of the plasma decay curve and of its urinary elimination were compared with reference to the administered dose. It was possible to superimpose the dose-normalized plasma decay-curves. The parameters of the two compartment-open model used to describe the pharmacokinetics of pancuronium were not influenced by the dose. The elimination half-life was 89±20 min and the plasma clearance was 1.84±0.38 ml/min/kg. The profiles of cumulative urinary excretion were also dose-independent. After 6 and 24 h, 57% and 69% of the administered dose, respectively, had been excreted in the urine. The results indicate that the pharmacokinetics of pancuronium is linear.
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  • 73
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 523-527 
    ISSN: 1432-1041
    Schlagwort(e): endralazine ; acetylator phenotype ; hydralazine ; pharmacokinetics ; plasma concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC 0 ∞ ) was 18.2% lower (p〈0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p〉0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC 0 ∞ of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p〈0.01).
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  • 74
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 265-272 
    ISSN: 1432-1041
    Schlagwort(e): pharmacokinetics ; variation of absorption ratios ; bioavailability ; dissection of variation due to absorption and intermediate processes ; oral drug application
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Differences in the plasma concentrations of drugs after oral administration are caused by two main factors: variation in absorption ratios and in the distribution processes in the body. A new method for the dissection of both types of factors is discussed. The method uses a reference regression of the AUC-values to the corresponding values after intravenous infusion of graded doses. The reference regression is estimated from an appropriate trial. Deviation of the determined AUC-values from the regression curve afford an estimate of the residual variance due to varying distribution volumes or similar random biological effects. For the estimation of absorption ratios after oral administration the drug is given orally to another sample of subjects and their AUC-values are calculated. The deviation of these AUC values due to the above mentioned random effects are simulated using the residual variance of the reference regression, and are subtracted from the observed AUC-values. Then, the differences in the corresponding absorbed doses are transformed by inverting the reference regression. From these doses the empirical distribution function and statistical parameters (e.g. quantiles) are determined. The method has the advantage that no restrictive assumptions are required, such as first order processes, dose linearity, homogeneity of variance or normal distribution of absorption ratios. Its applicability to substances with qualitative differences in their pharmacokinetics is demonstrated by appropriate examples.
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  • 75
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 22 (1982), S. 337-342 
    ISSN: 1432-1041
    Schlagwort(e): methadone ; pharmacokinetics ; urinary pH ; RBC level ; saliary level ; mass fragmentography
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The influence of urinary pH on the acute disposition of methadone in man was studied in five healthy volunteers. A cross-over experiment was performed in each subject. In the first experiment the subjects were treated with ammonium chloride (urinary pH ≈ 5.2) and in the other the urine was made alkaline (pH ≈ 7.8) by treatment with sodium hydrogen carbonate. d, 1-Methadone-HCl 10 mg (M) was administered intramuscularly on each occasion and blood, saliva and urine levels of M were determined by mass fragmentography. Plasma half-lives, volumes of distribution and body clearances of M were calculated in both experiments. The plasma half-lives in the β-phase were 19.5±3.6 h (acidic urine) and 42.1±8.8 h (alkaline urine), respectively (p〈0.001). The volumes of distribution were increased when the pretreatment was changed from ammonium chloride to sodium bicarbonate, namely from 3.51±0.41 l/kg to 5.24±0.83 l/kg (p〈0.01). The body clearance decreased from 134±21 ml/min (acidic) to 91.9±9.1 ml/min (alkaline urine) (p〈0.01). The ration Mplasma/MRBC was about 2.3 and the elimination of M from RBCs was in good agreement with the plasma kinetics of M under both experimental conditions. The salivary levels of M did not reflect the plasma kinetics and considerable variation was seen in the ratio Msaliva/Mplasma (0.26–2.98). Thus, the present experiments demonstrate that pretreatment either with ammonium chloride or bicarbonate had profound effects on both the distribution and elimination kinetics of methadone.
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  • 76
    Digitale Medien
    Digitale Medien
    Springer
    European journal of clinical pharmacology 23 (1982), S. 435-440 
    ISSN: 1432-1041
    Schlagwort(e): erythromycin ; haemodialysis ; dosage adjustment ; pharmacokinetics ; protein-binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Erythromycin kinetics were studied in 17 patients with end stage renal failure treated with maintenance haemodialysis and 9 normal volunteers to discover if dialysis patients needed a modified dose. The elimination half life in dialysis patients (on dialysis days) was similar to that reported in normal subjects. Only small amounts of drug appeared in the dialysate, no patient loosing more than 9 mg in one dialysis. Both patients and volunteers had similar plasma concentrations 8 h after the end of a 5-day course. Protein-binding did not change significantly during dialysis and was similar to that reported in normal subjects. We conclude that dialysis patients requiring 1.5 g of erythromycin stearate daily or less can be given normal doses.
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  • 77
    Digitale Medien
    Digitale Medien
    Springer
    Protoplasma 110 (1982), S. 20-22 
    ISSN: 1615-6102
    Schlagwort(e): Hormone-receptors ; Insulin ; Plant seed development ; Serotonin ; Triiodothyronine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Summary Treatment with insulin, triiodothyronine or serotonin resulted in increases of root length, root weight, coleoptile weight and mitotic index of germlings from barley seeds at concentration of 10−8 M. All three hormones were superior in activity to the natural and synthetic plant hormones (3-indoleacetic acid, naphthylacetic acid, trichlorophenoxyacetic acid) tested for comparison. The experimental observations suggest that plant cells also have receptors to which hormones of vertebrates can bind, and that plants cells also respond to such hormones.
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  • 78
    ISSN: 1439-6327
    Schlagwort(e): Glucose delivery ; Insulin ; Muscle metabolites ; Gastrocnemius ; Soleus
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary A modified rat hindlimb perfusion technique, aimed at studying factors of importance for glucose uptake at rest and during exercise, is presented. The modifications involved cannulation of the femoral artery and femoral vein in the groin, instead of the aorta and caval vein. This modification gives a number of advantages, among others the possibility of using the contralateral leg as control, perfused or nonperfused. The muscle tissue was well preserved after 40 min of perfusion, as judged from normal levels of muscle metabolites. The glucose uptake at rest was dependent on glucose delivery (glucose concentration times blood flow) as well as insulin concentration. During exercise, induced by sciatic nerve stimulation, glucose uptake, lactate production and oxygen uptake increased. The glucose uptake during exercise was closely related to the metabolic state of the muscle tissue. Thus, the glucose uptake was negatively correlated with the ATP/ADP ratio and the creatine phosphate level, and positively correlated to the lactate level in both soleus and gastrocnemius muscle. The results suggest that the level of the glucose uptake in exercising muscles is determined by the energy state of the muscle tissue.
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  • 79
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 94 (1982), S. 1069-1071 
    ISSN: 1573-8221
    Schlagwort(e): pharmacokinetics ; alcohol ; alcohol abstinence
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Materialart: Digitale Medien
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  • 80
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 94 (1982), S. 1373-1375 
    ISSN: 1573-8221
    Schlagwort(e): pharmacokinetics ; phenazepam ; 3-hydroxyphenazepam ; cats ; blood ; metabolic model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Materialart: Digitale Medien
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  • 81
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 94 (1982), S. 1689-1692 
    ISSN: 1573-8221
    Schlagwort(e): ethanol preference ; endogenous ethanol ; pharmacokinetics ; estrous cysle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Materialart: Digitale Medien
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  • 82
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 465-494 
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; pharmacokinetics ; bioavailability ; metabolite ; half-life ; protein binding ; disease states ; drug-drug interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Current information on the pharmacokinetics of disopyramide is reviewed with emphasis on the implications for antiarrhythmic therapy. The absolute bioavailability, the disposition half-life, the plasma clearance, and the renal clearance for normal subjects and patients are discussed. Drug-drug interactions are discussed, and a new flexible intravenous dosing schedule is proposed.
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  • 83
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 335-348 
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; bioavailability ; growth ; literature growth ; logistic function
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The literature growth in pharmacokinetics and bioavailability between the years 1964 and 1980 is analyzed. During much of this period, the literature doubled approximately every 1.6 years. However, during the period 1978–1980, little or no growth was observed. During the period 1950–1967, the total chemical literature increased exponentially with a half-life of 8.28 years; between 1968 and 1980, the half-life was 12.4 years. Thus, the pharmacokinetic literature increased at a much more rapid pace than did the total chemical literature in general. The subject of growth is considered in a general context, particularly as influenced by psychological, sociological, political, and economic factors. It is concluded that while mathematical functions may adequately describe past literature trends, they have little if any utility in predicting future trends in specific research areas such as pharmacokinetics.
    Materialart: Digitale Medien
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  • 84
    ISSN: 1573-8744
    Schlagwort(e): chloramphenicol-3-monosuccinate ; chloramphenicol-1-monosuccinate ; chloramphenicol ; bioavailability ; pharmacokinetics ; intravenous administration ; adult patients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of chloramphenicol (CAP) and total chloramphenicol succinate (CAPS) were studied in eight hospitalized adult patients with normal renal and hepatic function receiving intravenous chloramphenicol sodium succinate therapy. The steady-state peak concentrations of CAP (8.4–26.0 μg/ml) occurred at an average of 18.0 min (range 5.4–40.2) after cessation of the chloramphenicol sodium succinate infusion. Unhydrolyzed CAPS prodrug, representing 26.0±7.0% of the dose, was recovered unchanged in the urine indicating that the bioavailability of CAP from a dose of intravenous chloramphenicol succinate is not complete. A pharmacokinetic model was developed for simultaneous fitting of CAP and CAPS plasma concentration data. Pharmacokinetic parameters determined by simultaneous fitting were: V, 0.81±0.18 liters/kg; t1/2, 3.20 ±1.02 hr; CLB, 3.21±1.27 ml/min/kg for chloramphenicol; and V, 0.38±0.13 liters/kg; t1/2, 0.57±0.12hr; CLB, 7.72±1.87 ml/min/kg for total chloramphenicol succinate.
    Materialart: Digitale Medien
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  • 85
    ISSN: 1573-8744
    Schlagwort(e): antiarrhythmic compound ; experimental arrhythmia ; pharmacokinetics ; three compartment model ; pharmacological response ; combined pharmacokinetic pharmacodynamic model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. ke0, a measure of the lag time of pharmacological response behind changes in plasma concentration, and Ce (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.
    Materialart: Digitale Medien
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  • 86
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 231-245 
    ISSN: 1573-8744
    Schlagwort(e): nitrazepam ; i.v. ; oral ; rectal administration ; protein binding ; pharmacokinetics ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.
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  • 87
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 27-51 
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; models ; plasma protein binding ; nonlinear processes ; Sulfaethidole
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Sulfaethidole distribution and elimination in the rat was studied over a 90-fold dose range. This experimental design produced marked nonlinearity in the binding of Sulfaethidole to proteins in both interstitial fluid and plasma. Using a multicompartmental model consisting of binding of Sulfaethidole to plasma and interstitial fluid proteins, Sulfaethidole distribution in the body could be simulated. Urinary and biliary elimination of Sulfaethidole depended on the unbound drug mass in the plasma and urine flow. The results confirm the central role of the unbound species in the distribution and elimination of drugs with marked binding to plasma proteins.
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  • 88
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 559-574 
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; steady state predictions ; sensitivity analysis ; parameter estimates ; optimum sampling strategies
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The sensitivity theory is applied to derive a linear approximation to the functional dependence of some steady state quantities of therapeutic significance on pharmacokinetic parameters obtained from the biexponential response to a single drug dose. The error of a steady state prediction depends in general on two terms. The first one may be viewed as an approximate sensitivity of the prediction to the parameter errors, and this depends solely on the algebraic relation between the prediction and the parameters. The second term is the relative error in parameters, and this may be affected by experimental design and the method of data analysis. Comparisons are made with Monte Carlo simulations and “a posteriori”estimates of variance of a prediction.
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  • 89
    ISSN: 1573-8744
    Schlagwort(e): theophylline ; pharmacokinetics ; variability ; disposition rate constant ; man
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract After administering a single 300 mg dose of theophylline in oral solution to 12 healthy adults, the dose-normalized area under the plasma concentration-time curve was 97.2±20.1 % (mean±SD) of that after giving a 500 mg dose and statistically indistinguishable. Similarly, these areas multiplied by the individual's terminal disposition rate constant (β) were statistically indistinguishable between 300 and 500mg doses (99.1±10.3%), giving no evidence of dose-dependence for theophylline kinetics at the levels below 15 μg/ml observed in these individuals. After an intravenous dose, a shortlived distribution phase (t1/2α) is sometimes seen. An a phase, however, is hardly discernible in over 250 profiles arising from oral doses administered during five single dose bioavailability studies. Almost all such profiles appear to follow single-compartment model predictions. With precautions to avoid a potential a phase, a terminal log-linear slope can be fitted by least squares analysis with a relative standard error in the slope determination almost always less than 6%. Covariance analysis confirms statistically that 39 of the 60 participating individuals varied in their β on the different occasions each was required to take a dose during the course of a crossover bioavailability trial. In one study, even though each individual was observed on only two occasions, 9 out of 12 showed statistically identifiable variation in β. Fluctuations in β of 60% can be seen. Changes of 30% or greater are common and can occur within 3 or 4 days. Thus real, large, and potentially frequent changes in β of theophylline have been identified in a majority of normal subjects. These changes do not appear to be confined to either sex, to smokers or nonsmokers, or to heavier or lighter individuals. No chronological pattern has, as yet, been recognized in the intraindividual variability in β.
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  • 90
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 147-156 
    ISSN: 1573-8744
    Schlagwort(e): intravenous hydrocortisone ; blood concentrations ; pharmacokinetics ; endogenous hydrocortisone suppression
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of hydrocortisone were examined following single intravenous doses of 5, 10, 20, and 40 mg hydrocortisone, as the sodium succinate salt, to healthy male volunteers. Endogenous hydrocortisone was suppressed by administration of 2 mg dexamethasone the night before hydrocortisone injection. Plasma samples obtained serially during 8 h after hydrocortisone injection were assayed by reversephase HPLC using a fixed wavelength (254 nm) ultraviolet detector. Initial concentrations of hydrocortisone in plasma were proportional to dose size. The subsequent decline in hydrocortisone concentrations was biphasic, and individual data sets were adequately described in terms of the pharmacokinetic two-compartment open model. Values of pharmacokinetic parameters were similar from the 5, 10, and 20 mg doses. Following the 40 mg dose, the overall elimination rate constant decreased, while the distribution volume, Vdss,and plasma clearance increased, in comparison with the values obtained from lower doses. Changes in the pharmacokinetics of hydrocortisone at high doses may be related to drug concentrationdependent changes in the binding of hydrocortisone to plasma proteins. Previously reported dosedependent changes in some pharmacokinetic parameters following oral hydrocortisone are attributed to absorption rather than distribution or elimination effects.
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  • 91
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 15-26 
    ISSN: 1573-8744
    Schlagwort(e): cefroxadin ; pharmacokinetics ; man
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of cefroxadin have been studied after the administration of single oral and intravenous doses to healthy volunteers. Cefroxadin was assayed by HPLC. The kinetics in plasma following i.v. administration were described by using a three-compartment model. An additional disposition phase was observed following oral administration that could not be detected after the low i.v. dose. The terminal half-life was 1.03 h. The apparent volume of distribution at the steady state was consistent with a diffusion of the antibiotic in all extracellular fluids. The AUCafter oral administration was linearly related to the dose. The urinary excretion amounted to 95% of the dose with virtually complete absorption of orally administered drug.
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  • 92
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 1-14 
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; pharmacokinetics ; antiarrhythmic, healthy subjects
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects, the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (α), these are the only parameters which can be reported without qualification as to the concentration. The mean ± SD total body clearance of unbound drug in the eight subjects was 5.40± 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of α, while the renal clearance of total disopyramide is dependent upon α.
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  • 93
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 201-227 
    ISSN: 1573-8744
    Schlagwort(e): interspecies variations ; scaling ; heterogony ; allometry ; pharmacokinetics ; physiological time ; pharmacokinetic time ; maximum lifespan potential
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Interspecies variation in pharmacokinetics is considered and treated as a property and consequence of body size (allometry). Consequently, it is possible to reference (scale) pharmacokinetic parameters to the organism's individual anatomy, biochemistry, and/or physiology in such a manner that differences between species are nullified. Thus, in the mouse, rat, dog, monkey, and human, methotrexate plasma clearance always equals 133% of creatinine clearance and as such becomes invariant. Pharmacokinetic time (a variable in terms of chronological time) is shown to be a form of physiological time in which a pharmacokinetic event becomes the independent variable, e.g., disposition halflife. A relationship between pharmacokinetic time and body size is demonstrated. It is suggested that man's lesser quantitative ability to metabolize many drugs may be correlated with his enhanced longevity.
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  • 94
    ISSN: 1573-8744
    Schlagwort(e): diuretic ; bumetanide ; pharmacokinetics ; pharmacodynamics ; normals
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics and pharmacodynamics of bumetanide (1 mg) administered either orally or intravenously were studied in a group of normal subjects using high-pressure liquid chromatography. A two-compartment model adequately fitted the intravenous data. Renal clearance (85 ml min−1 contributed 65% to the total elimination of bumetanide irrespective of whether a model-dependent or model-independent method was used. Oral administration of bumetanide elicited a greater and a more prolonged pharmacological response than did intravenous bumetanide. An attempt is made to relate the pharmacokinetics of the drug to its pharmacodynamics.
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  • 95
    Digitale Medien
    Digitale Medien
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 65 (1982) 
    ISSN: 0018-019X
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 96
    ISSN: 0018-019X
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The Avileurekanoses A and C and Further Degradation Products of the Avilamycins A and CAlkaline hydrolysis of the orthosomycin antibiotics, avilamycins A ad C products similar t those earlier described for flambamycin. Among these avileurekanose c (15) became of particular importance because its acetate prisms suitable for an X-ray structural determination. For the avilamycins A and C structural formulae 2 and 3, respectively, can now be drawn, in which only the configuration at C (16), one out of 32 asymmetric C-atoms, is not yet determined.
    Zusätzliches Material: 1 Ill.
    Materialart: Digitale Medien
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  • 97
    ISSN: 0018-019X
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: The complexation of Cue2+ with 1, 8-diamino-3, 6-diaza-2, 7-octanedione (—N, N′-diglycyl-1, 2-ethanediamine, DED) and with 1, 9-diamino-3, 7-diaza-2, 8nonanedione (—N, N′-diglycyl-1, 3-propanediamine, DPD) has been studied by potentiometric and by spectrophotometric titration. With both ligands L the complexation to Cue2+ leads to relatively complicated equilibria with CuLH3+, CuL2+, CuLH-2, and dimeric Cu2L24+ complexes. With DED, another dimeric species, Cu2L2H-22+, is formed in addition. Independent numerical treatment of spectrophotometric and poteritiometric titrations was used to obtain a satisfactory model for the complexation and to test the relative discriminatory power of the two methods. Titrations of glycine ethylamide (GEA) were used as an additional test and as a model for DED and DPD. It was shown that in each case spectrophotometric titrations give results of similar reproducibility and have a discriminatory power equal to or better than potentiometric titrations, provided that optimum mathematical algorithms are used in the numerical treatment.
    Zusätzliches Material: 3 Tab.
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  • 98
    ISSN: 0018-019X
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Heterocyclic and Carbocyclic 12-π-and 14-π-Systems, 47th Commnunication1. Synthesis of 7,9-Dimethyl-4,5-dihydro-3H-benz[cd]azualene-3-one and 7,9-Dimethyl-3H-benz[cd]azulene-3-one. A Simple Synthesis of Azulenopseudophenalenons4, 6, 8-Trimethylazulene (3) reacts after metalation with lithiumdiisopropyl-amide in ether with bromoacetic acid to the 6, 8-dimethylaltulene-4-propionic acid (4), which undergoes cyclization to the 7, 9-dimethyl-4, 5-dihydro-3H-benz [cd]-azulene-3-one (5) in the presence of p-toluenesulfonic acid; oxidation of 5 with 2, 3-dichloro-5, 6-dicyanobenzoquinone yields 7, 9-dimethyl-3H-benz [cd]azulene-3--one (1b). Alkylation of 1b with triethyloxonium tetrafluoroborate in CH2C12 gives the 3-ethoxy [cd]benzazulenium tetrafluoroborate (6).
    Zusätzliches Material: 1 Ill.
    Materialart: Digitale Medien
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  • 99
    Digitale Medien
    Digitale Medien
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 65 (1982), S. 317-324 
    ISSN: 0018-019X
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Doubts that have recently been expressed [1] about the currently accepted (+)-(R), (-)-(S) [2] absolute configuration of indane-1-carboxylic acid appear to be unwarranted. Our ORD. values for 1-methylindane [12] are in error.
    Zusätzliches Material: 1 Tab.
    Materialart: Digitale Medien
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  • 100
    Digitale Medien
    Digitale Medien
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 65 (1982), S. 365-370 
    ISSN: 0018-019X
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Synthesis of [16,16,16,16′,16′,16′ 2H6]LycopeneLycopene having at both ends the deuteriated methyl groups trans to the chain has been synthesized for further biochemical experiments aimed to elucidate the stereochemistry of the cyclization step.Incidentally a gas-chromatographic separation of the isotopisomers 1 and 2g has been observed.
    Zusätzliches Material: 1 Ill.
    Materialart: Digitale Medien
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