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  • pharmacokinetics  (465)
  • Development  (135)
  • Rheology
  • Springer  (603)
  • American Geophysical Union  (1)
  • American Geophysical Union (AGU)
  • American Physical Society
  • Nature Publishing Group
  • 1980-1984  (495)
  • 1970-1974  (109)
  • 1935-1939
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  • 1
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    American Geophysical Union
    In:  Bull., Polar Proj. OP-O3A4, Flow and Fracture of Rocks, Washington, D. C., American Geophysical Union, vol. 16, no. XVI:, pp. 29-53, (ISBN: 3-540-23712-7)
    Publication Date: 1972
    Keywords: Rheology ; Physical properties of rocks ; Inelastic ; Laboratory measurements ; Rock mechanics
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  • 2
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    Springer
    In:  Bull., Open-File Rept., Zahlenwerte und Funktionen aus Naturwiss. und Technik, L.B. V-1b, Berlin, Springer, vol. 81A, no. 16, pp. 141-238, (ISBN 0080419208)
    Publication Date: 1982
    Keywords: Textbook of geophysics ; Fracture ; Rock mechanics ; Rheology
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nutrition 22 (1983), S. 14-26 
    ISSN: 1436-6215
    Keywords: branched chain α-keto acids ; 4-methyl-2-oxopentanoate, 3-methyl-2-oxopentanoate ; 3-methyl-2-oxobutyrate ; dehydrogenation ; transamination ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Michaelis-Konstanten und Aktivitäten von Dehydrogenasen und Transaminasen der drei verzweigten α-Ketosäuren Keto-Valin, Keto-Leucin und Keto-Isoleucin in Leber, Niere, Skeletmuskel und Gehirn von Ratten werden mitgeteilt. Nach oraler Zufuhr passieren nur 11–22% der Ketosäuren unverändert die Leber. Aus pharmakokinetischen und Resorptions-Untersuchungen erhaltene Blutspiegel an Ketosäuren werden zu den Michaelis-Konstanten in Beziehung gesetzt. Bei den geringen Konzentrationen an Ketosäuren nach oraler Zufuhr kann angenommen werden, daß die oxidativen Prozesse in den nichthepatischen Geweben über die Transaminierung überwiegen. Daten über die Wachstumseffizienz von verzweigtkettigen α-Ketosäuren im Vergleich zu den entsprechenden Aminosäuren stimmen mit dieser Vorstellung überein. Bei intravenöser Verabreichung müßten die Voraussetzungen für Transaminierung besser sein als nach oraler Zufuhr. Auf der Basis von Daten aus der Literatur werden die Übertragbarkeit unserer Befunde auf den Menschen und die verschiedenen Faktoren, welche die Effizienz der verzweigten α-Ketosäuren durch Einwirkung auf ihren Stoffwechsel beeinflussen können, diskutiert.
    Notes: Summary Miehaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chainα-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11–22 % of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain α-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain α-keto acids are discussed in connection with data reported in the literature.
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  • 4
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    Springer
    Entomologia experimentalis et applicata 34 (1983), S. 174-178 
    ISSN: 1570-7458
    Keywords: Lepidoptera ; Pyralidae ; Maruca testulalis ; Pod borer ; Development ; Nutritional suitability ; Host plant ; Crotalaria ; Vigna unguiculata
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les possibilités de développement larvaire de Maruca testulalis sur les fleurs de huit espèces végétales ont été examinées en laboratoire. La comparaison a porté sur Crotalaria retusa, C. juncea, C. saltiana, C. misereniensis, C. mucronata, C. amazonas, Cajanus cajan et l'hôte principal de cette chenille, Vigna unguiculata. En tenant compte de la mortalité larvaire et des indices de croissance (G.I.), ces plantes ont été divisées en trois catégories principales: 1 celles provoquant une mortalité larvaire de 0–30% et ayant des G.I. ≥60%, constituent les plantes hôtes convenables (Vigna unguiculata seule); 2 les plantes qui provoquent une mortalité larvaire de 30≤50% et ont des G.I. de 30 à 60% de la plante hôte principale (Cajanus cajan, Crotalaria amazonas, C. saltiana, C. mucronata; 3 les plantes qui causent 50–100% de mortalité larvaire et dont les G.I. sont inférieurs à 30% de la plante hôte principale (Crotalaria retusa, C. juncea, C. misereniensis). Les résultats déjà publiés sur les choix du lieu de ponte des femelles et l'utilisation de C. juncea comme plante piège, sont discutés à la lumière de ces données nouvelles.
    Notes: Abstract Flowers of eight plant species were evaluated under laboratory conditions for their suitability as larval growth media for the cowpea pod borer, Maruca testulalis. The plants tested were Crotalaria retusa, C. juncea, C. saltiana, C. misereniensis, C. amazonas, Cajanus cajan and the principal host of the borer, Vigna unguiculata (cowpea), was included for comparison. Based on the data obtained on larval mortality and growth indices (GI) the plants were divided into 3 categories namely: I: Those causing 0–30% mortality and having GI value ≥60% form suitable host plants. This group only included V. unguiculata. — II: Those plant species causing 30≤50% larval mortality and having GI value 30%≤60% of the principal host plant (Cajanus cajan, Crotalaria amazonas, C. saltiana, C. mucronata). This group of species is marginally suitable as hosts. — III: Plants causing 50–100% larval mortality and having GI value ≤30% of principal host plant (C. retusa, C. juncea and C. misereniensis). Previously published data on the oviposition preference of the adult moth are discussed in the light of the present findings and the use of C. juncea as a possible trap crop.
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  • 5
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    Entomologia experimentalis et applicata 34 (1983), S. 251-256 
    ISSN: 1570-7458
    Keywords: Cyromazine ; Musca domestica ; Housefly ; Development ; Sensitivity ; Penetration ; Insect growth regulator
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé La cyromazine (N-cyclopropyl-1,3,5-triazine-2,4,6-triamine or CGA-72662) est un puissant inhibiteur de développement chez Musca domestica Le traitement des adultes par voie orale n'altère pas l'éclosion des œufs, mais inhibe fortement le développement des larves. Incorporée au milieu larvaire, elle donne une DL50 de 0.11 ppm. La sensibilité des pupes, traitées par application topique, décroit rapidement avec l'âge et est dépendante du solvant utilisé. Une heure après pupaison et avec le tétrahydrofuran comme vecteur, la DL50 est de 3 μg/g, soit 0.2 μg/g pour la pupe sans puparium. Comparé au méthanol. le tétrahydrofuran facilite la pénétration de la cyromazine pendant ce stade critique. La pénétration est également un facteur de la résistance des pupes agées. La toxicité de la cyromazine apparait rait donc principalement dépendante de sa vitesse de pénétration et de son accumulation dans l'organisme plutôt que de son métabolisme. Juste après pupaison, la jeune pupe chez M. domestica s'avère être un matériel sensible et pratique pour l'étude du mode d'action de la cyromazine.
    Notes: Abstract Cyromazine is a potent inhibitor of housefly (Musca domestica L.) larval development when administered orally to adults or incorporated into larval media, and of pupal metamorphosis on topical application shortly before or after pupariation. Pupae are most sensitive to cyromazine within 1 hr after pupariation and with tetrahydrofuran as the carrier solvent, giving topical LD50 values of 3 μg/g for the total puparium plus pupa and 0.2 μg/g calculated for the pupa only. Tetrahydrofuran is more effective than methanol in facilitating rapid cyromazine penetration during this critical pupal stage. The rate of cyromazine penetration or accumulation at sensitive stages appears to be more critical than the extent of metabolism in limiting cyromazine toxicity. Houseflies shortly after pupariation provide a sensitive and convenient organism for studies on cyromazine mode of action.
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  • 6
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    Calcified tissue international 12 (1973), S. 259-279 
    ISSN: 1432-0827
    Keywords: Osteocyte ; Calvarium ; Histology ; Development ; Calcium ; Phosphorus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Des cartes tissulaires ainsi que les caractéristiques et propriétés cellularires ont été relevées au cours d'une étude de microscopie optique du développement de la calotte cranienne de souris, avant la naissance, jusqu'au 26ème jour. Les population d'ostéocytes de moitiés droite et gauche de ces calottes sont semblables, mais décroissent avec le temps dans un volume donné. De petites plages limitées de matrice osseuse se colorent pour le phosphate (ou carbonate) de façon plus nette que la matrice environnante, qui se colore légèrement après coupe. Les divers types ostéocytaires se distinguent par les réactions histochimiques du calcium et du phosphate, qui sont associés dans les cellules osseuses de façon complexe, variant dans le temps et la localisation. Ces deux constituants ne sont pas toujours présent dans les cellules des diverses régions, ou dans la même localisation dans un type cellulaire donné. En tenant compte des changements visible dans les divers types cellulaires avec le temps, dans des régions données, une hypothèse de “charge” et “décharge” cellulaire est émise.
    Abstract: Zusammenfassung Anläßlich einer mikroskopischen Studie über die Entwicklung des Mäuse-Calvariums von der Pränatalperiode bis zu 26 Tagen nach der Geburt wurden auch die Gewebetopographie sowie die Charakteristica und Eigenschaften der Zellen aufgezeichnet. Die Osteocyten-populationen in der linken und rechten Hälfte des Calvariums waren sich gleich, nahmen jedoch bei einem gegebenen Volumen mit der Zeit ab. Kleine isolierte Stellen von Knochen-matrix konnten leichter auf Ph sphat (oder Carbonat) angefärbt werden, als die umgebende Matrix, welche sich wohl am Schnitt, nicht aber am ganzen Stück färben ließ. Die verschiedenen Typen von Osteocyten wurden aufgrund histochemischer Calcium- und Phosphat-reaktionen bestimmt. Calcium und Phosphat waren innerhalb der Knochenzellen auf komplexe Art miteinander verbunden, die je nach Zeit und Lagerung unterschiedlich war. Zellen in abgetrennten Bereichen enthielten nicht immer Calcium und Phosphat und beide waren bei einer bestimmten Zellenart auch nicht immer am gleichen Ort abgelagert. Aufgrund der an ausgewählten Stellen beobachteten, zeitlich bedingten Veränderungen innerhalb der verschiedenen Zelltypen wird vorgeschlagen, daß es sich dabei um eine Sequenz von “Ladung” und “Entladung” der Zellen handelt.
    Notes: Abstract Tissue maps, and cell characteristics and properties were recorded in a study under the optical microscope of the development of the mouse calvarium from pre-natal to 26 days. Osteocyte populations in left and right halves of the calvarium were similar, but decreased with time for a given volume. Small isolated areas of bone matrix stained for phosphate (or carbonate) in a more readily available form from that in the surrounding matrix, which could be stained after sectioning but failed to stain in bulk. Osteocyte types were defined on the basis of histochemical methods for calcium and phosphate, which were associated inside bone cells in a complex manner, varying with time and position. The calcium and phosphate were not always present within the cell in discrete regions and were not always present in the same place in a given cell type. On the basis of a study of changes in cell types with time in selected sites a sequence of “loading” and “unloading” is proposed.
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  • 7
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    Calcified tissue international 16 (1974), S. 209-217 
    ISSN: 1432-0827
    Keywords: Mucopolysaccharides ; Collagen ; Calvarium ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract Mucopolysaccharides (MPS) and collagen have been analyzed in different types of cartilage and some other tissues at various stages of prenatal and postnatal human development. The concentration of the chondroitin sulfate-type MPS increased from the 38th embryonal day, the 6-sulfate exceeding in amount the 4-sulfate. The increase in collagen concentration was accompanied by a decrease in the proportion of neutral salt-soluble collagen. There was no accumulation of chondroitin sulfates in the calvaria. A maximal concentration of MPS of a low molecular weight occurred in the skin and in the ear pinna after the 10th prenatal week. Postnatally, the MPS-concentration in the iliac crest and in the tibial articular cartilages decreased gradually, the highest values being reached in the newborn; the collagen-concentration showed an approximately reciprocal course.
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  • 8
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    Journal of molecular evolution 3 (1974), S. 109-113 
    ISSN: 1432-1432
    Keywords: “Custom Fitting” ; Development ; Evolution ; Antibody response ; Genetic Redundancy ; Perturbation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary When the complexity of a developmental system evolves to a certain point, appreciable variation must occur in the process. The problem the biologist faces is whether this point constitutes a limit to the evolution of complexity in developmental systems. If not, what mechanisms are employed to cope with the problem ? The problem—essentially one in “custom fitting” of parts, — and the possible solution(s) to it that have evolved are discussed. The antibody producing system appears to be one that “solves” the custom-fitting problem.
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  • 9
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    Development genes and evolution 188 (1980), S. 55-63 
    ISSN: 1432-041X
    Keywords: Drosophila ; Compound eye ; shibire ts ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have analysed the effect of temperature on both developing and adult eye cell clones homozygous forshi ST139, a temperature-sensitive mutant ofDrosophila melanogaster. The mutant gene, autonomous in its cellular expression, causes structural modifications of ommatidial cells when adult clones of cells are exposed to the restrictive temperature (29°C) for several days. However, the mutant phenotype reverses to normal within 4 days at the permissive temperature (20°C). The results of pulse, shift-up and shift-down experiments show that the temperaturesensitive period for developing compound eye cells is from the late second instar up to the early pupa. Cytodifferentiation of compound eye cells is blocked by restrictive temperature treatment during this period, whereas cell proliferation does not seem to be directly affected. These results are discussed with regard to the other known aspects of the phenotype observed in mutant individuals.
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  • 10
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    Development genes and evolution 191 (1982), S. 281-284 
    ISSN: 1432-041X
    Keywords: Mammals ; Brain cortex ; Gangliosides ; Glycoproteins ; AChE ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Developmental profiles of 11 gangliosides, concentration of lipid- and glycoprotein-bound sialic acid, and activity of AChE of the rat and mouse cerebral cortex were followed from the 7th day of gestation to the 21st postnatal day. There are three main changes in ganglioside concentration, which are similar in both species. The first occurs from gestation day 10 until birth: parallel to decreased proliferation, cell migration, and neuroblast differentiation, GM3 and GD3 in mouse cortex and GD3 in the rat's decreases in favor of GQ1b, GT1b, and GD1a. The second occurs from birth until the first postnatal week: Parallel to increased growth and arborization of dendrites and axons as well as synaptogenesis in rats and mice, there is a two-fold rise of GD1a, whereas GQ1b and GT1b remain on a nearly constant level. Concomitantly, GM3 and GD3 decreases. The third period of ganglioside changes starts in the second postnatal week, parallel to onset of myelination, and is characterized by an increase of GM1 in parallel with a decrease of the polysialogangliosides GT1b and GQ1b.
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  • 11
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    Development genes and evolution 191 (1982), S. 341-347 
    ISSN: 1432-041X
    Keywords: Physarum ; Development ; RNA ; Sequence complexity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Poly(A) RNA from S phase, G2 phase and starved macroplasmodia of Physarum contain mRNA sequences which when translated in vitro, yield similar patterns of polypeptides after fluorography. Reassociation of nick-translated DNA (Cot) allows the isolation of highly labeled single copy DNA which, after saturation hybridization with poly(A) RNA, gives values of 23% for growth and 17% for starvation. Homologous cDNA/poly(A) RNA hybridization reactions (Rot) indicate that 22–28% of the genome is transcribed during growth and 12% during starvation and that about half of the cDNA reacts with 0.1% of the genome and could represent 50–80 RNA species, each present in about 1,000 copies per nucleus. Up to 25,000 different RNA species, 1–5 copies each per nucleus, are estimated to be present during growth, and about 15,000 during starvation. Heterologous cDNA/poly(A) RNA hybridization reactions (Rot) indicate that the RNA sequences in S and G2 phase of the cell cycle are similar, with RNA sequences being more abundant in G2 phase. During starvation about 25% of the sequences present during growth cannot be detected and those sequences present during growth have become diluted during starvation.
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  • 12
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    Development genes and evolution 191 (1982), S. 159-162 
    ISSN: 1432-041X
    Keywords: Vitellogenin ; Hemagglutinin properties ; Yolk formation ; Insects ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The sugar binding properties of 2 important vitellogenic proteins in Colorado beetle hemolymph were demonstrated by hemagglutination and precipitation experiments. The agglutination of human red blood cells by the hemolymph of reproducing females was observed up to a hemolymph dilution of 1/256, irrespective of the blood-group. It increased significantly after trypsinization of the crythrocytes. Vitellogenin 1 was identified as the hemagglutinin. Hemagglutination and hemagglutination inhibition tests showed that this protein has a low affinity for hexosamines and a higher affinity for sulfated polysaccharides. Precipitation tests demonstrated that besides vitellogenin, another major yolk protein, chromoprotein 2, reacts with sulfated polysaccharides. The possibility that there is a specific reaction of the vitellogenic proteins with well defined saccharides on the oocyte surface is discussed. This lectintype reaction may explain the selectivity of yolk precursor endocytosis.
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  • 13
    ISSN: 1432-041X
    Keywords: Protein synthesis ; Development ; Antherea pernyi ; Follicles ; Specific ribonuclease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Crude, cell-free protein-synthesizing systems were prepared from follicles of two different stages of development in the ovariole of the silkmothAntherea pernyi. The efficiency of the translation of natural and synthetic mRNAs in these systems was compared with that in a cell-free wheat germ system. A postmitochondrial extract (S-30) from the follicles almost completely inhibited protein synthesis in a polyribosome-dependent, cell-free systems. A specific ribonuclease, obtained from the post mitochondrial extract by ammonium sulphate precipitation, heat denaturation and DEAE-cellulose chromatography, inhibited polyribosome-dependent protein synthesis. The effect of this specific ribonuclease on the structural integrity of radioactive RNAs and ribosomal subunits, which were isolated from Ehrlich ascites tumor cells, was also studied.
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  • 14
    ISSN: 1432-041X
    Keywords: Major haemolymph proteins ; Development ; Cuticle ; Immunocytochemistry ; Ceratitis capitata
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The developmental profile of the major haemolymph proteins (ceratitins) inCeratitis capitata was studied. Ceratitin concentration in the haemolymph decreases dramatically during the last days of pupal life, while the amounts of ceratitins in whole organism extracts remain unchanged. By electrophoretic, immunological and immunofluorescence techniques it was revealed that ceratitins are reabsorbed by the fat body and a fraction of them is deposited in the cuticle. The possible role of ceratitins is discussed.
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  • 15
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    Development genes and evolution 188 (1980), S. 205-213 
    ISSN: 1432-041X
    Keywords: Gangliosides ; Development ; Brain ; Chicken
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The developmental profiles of 15 different gangliosides of the optic lobes and cerebrum of the chicken were followed from the 6 th day of incubation to hatching and correlated to morphological development. Five of these gangliosides appearing in both structures between the sixth and tenth day, have not been reported previously in higher vertebrates. Three chromatographed on TLC-plates similarly to GT3, GT2, and GT1c gangliosides, which have been demonstrated in fish brain. One fraction moved just below GQ1b and is suggested, to contain GQ1c. These “novel” gangliosides, which are possibly related to a recently proposed separate and probably phylogenetically older biosynthetic pathway, contained up to 20% of total ganglioside sialic acid. The fifth “novel” fraction, containing up to 16% of total ganglioside-sialic acid, moved below the penta-sialoganglioside GP1 and is suggested to contain hexa-sialogangliosides. There were two main changes in ganglioside synthesis, which were identical in both structures. The first occurred from the sixth to the eleventh day, parallel to decreased proliferation, maximal cell migration and neuroblast differentiation, GD3 and GD2 decreased rapidly in favour of GQ1b, GP1, and to the “novel” fractions, described above. The second occurred from the eleventh to the eighteenth day, parallel to increased growth and arborization of dendrites and axons as well as functional establishment of synaptic contacts, there was a sharp rise in the amount of GD1b, GT1b, and GD1a. Concomitantly the “novel” gangliosides decreased. At hatching GD1a was the predominant ganglioside. GM3, GM2, and GM1 were always minor fractions, each accounting for less than 4% of total ganglioside-sialic acid. GM4 was never detected, indicating neglegible myelinisation until hatching.
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  • 16
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    Development genes and evolution 189 (1980), S. 171-180 
    ISSN: 1432-041X
    Keywords: Amino acyl-tRNA synthetases ; Development ; Nuclear-mitochondrial interactions ; Neurospora
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The specific activities of the branched chain amino acyl-tRNA synthetases from the cytosolic and mitochondrial fractions ofN. crassa were low in dormant conidia and increased during germination, reaching a maximum 8 h after inoculation. This stage of development is characterised by high rates of many other cellular activities. The increases in activity of synthetases of both cytosol and mitochondria are inhibited by cycloheximide indicating that they are synthesized on cytoplasmic ribosomes. The mitochondrial synthetases show a stimulation of their specific activity when mitochondrial RNA and protein synthesis are inhibited by either ethidium bromide or chloramphenicol suggesting that a mitochondrial translation product regulates the synthesis of the mitochondrial synthetases. The activities of amino acyl-tRNA synthetases are dependent on energy production. When respiration is uncoupled from oxidative phosphorylation, synthetase specific activities decrease although the activities of other mitochondrial enzymes like NADH-dehydrogenase increase. This phenomenon suggests that more than one mechanism regulates the synthesis of mitochondrial proteins which are formed on cytoplasmic ribosomes. The synthesis of branched chain amino acyl-tRNA synthetases ofNeurospora is neither repressed by their cognate amino acids, nor is there inhibition by the precursors of these amino acids, as has been observed in other amino acyl-tRNA synthetases of various organism includingNeurospora.
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  • 17
    ISSN: 1432-041X
    Keywords: Mollusca ; Cleavage ; Junctions ; Interaction ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In early cleavage stages ofLymnaea stagnalis, three kinds of intercellular junctions could be distinguished up to the sixth cleavage: intermediate, septate and gap junctions. The first two form “junctional belts” located on the cell border at the periphery of the embryo. For the purpose of our study we were most interested in gap junctions as they are alleged to be structures that allow cell-to-cell communication. Gap junctions first appear at the four cell stage. Up to the sixth cleavage no difference in the distribution pattern could be found between and within each of the four quadrants of the embryo. Some of the cell tiers along the animal-vegetal axis lack gap junctions either between the blastomeres within the tier or between the blastomeres from adjacent tiers. All gap junctions observed in freeze fracture replicas show plaques with an irregular IMP pattern. The average IMP diameter measures 12 nm (SD±2 nm). In stages fixed after the fifth cleavage, gap junctions are found between micromeres at the animal pole and the central 3D macromere. This is in agreement with the presumed interaction between these cells at this stage. The possibility of a transition of non-functional into functional gap junctions after the fifth cleavage is discussed.
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  • 18
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    Development genes and evolution 191 (1982), S. 143-148 
    ISSN: 1432-041X
    Keywords: Amphibia ; Junctions ; Interaction ; Development ; Freeze fracture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Using freeze-fracture electron microscopy and fluorescent dye injection we have analysed the contacts between cells of the deeper endoderm taken from neurulae ofXenopus laevis. Endodermal cells in situ have large 1.5 μm diameter gap junctions composed of 8 nm P-face particles and corresponding E-face pits. Beside gap junctions, particle aggregates typical of desmosomal plaques are present but there are no tight junctions. The dissociation of endoderm into single cells involves profound structural alterations in the surface membrane including the complete disappearance of junctional structures among them gap junctions. The reaggregation of endoderm cells leads to the restoration of the surface membrane IMP (Intra Membrane Particle) pattern and, after ca. 30 min, to the establishment of functional pathways allowing for the intercellular transfer of fluorescent dye. Concomitantly gap junctions reappear. The observation that the dissociation and reaggregation of endodermal cells involves IMP alterations which go beyond the cell junctions themselves is discussed as an adaptation of the plasma membrane to changing environmental conditions.
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  • 19
    ISSN: 1432-041X
    Keywords: Mollusca ; Interaction ; Development ; Dye-coupling ; Gap junctions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary During the early development of the molluscPatella, the dorsoventral axis is established after the fifth cleavage due to direct interaction between the animal micromeres and one of the vegetal macromeres. This vegetal macromere is thereby induced to become the mesentoblast mother cell (3D). In this study we have examined intercellular communication in earlyPatella embryos by monitoring the transfer of the fluorescent dye, Lucifer Yellow, upon iontophoretic injection into blastomeres between the second and sixth cleavage. Up to the fifth cleavage dye transfer is detectable neither inin toto embryos nor in serial sections. Shortly after the fifth cleavage dye-coupling between blastomeres becomes apparent. This occurs approximately 40 min before the interaction between animal micromeres and the future mesentoblast mother cell. Inspection of serially sectioned embryos after dye-iontophoresis in either animal micromeres or in the central macromere 3D showed the absence of direct dye-transfer between these cells at the stage of interaction. The reduced rate of dye-transfer from the 3D macromere to its dorsal neighbour 2d2 suggests a bilateral symmetrical transfer pattern, the axis of which corresponds with the dorsoventral axis at the sixth cleavage. Cell deletion experiments demonstrated that the establishment of dye-coupling between the vegetal macromeres occurs independently of the interaction between animal and vegetal blastomeres.
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  • 20
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    Development genes and evolution 190 (1981), S. 33-39 
    ISSN: 1432-041X
    Keywords: Ceratitis capitata ; Major haemolymph proteins ; Development ; Fat body ; Secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The accumulation of major haemolymph proteins (a group of proteins immunologically related to Calliphorin) their biosynthesis in vivo and in organ culture as well as their secretion, has been studied during the late larval stages and white pupae of the Mediterranean fruit flyCeratitis capitata. The accumulation of major haemolymph proteins in the haemolymph, shows a twenty fold increase from the 4-day old larvae to the white pupae stage, while in the fat body there is only a seven fold increase. It is evident from the in vivo and organ culture studies, that the major haemolymph proteins are synthesized during the late larval stage and their synthesis declines abruptly during the stage of white pupae. It seems also that each polypeptide has its own characteristic developmental kinetics of synthesis. The major haemolymph proteins are synthesized in the fat body and are very quickly secreted into the haemolymph.
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    Calcified tissue international 7 (1971), S. 267-276 
    ISSN: 1432-0827
    Keywords: Tech ; Development ; Enamel ; Enzyme ; Histochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé L'activité en naphtylamidase est étudiéc au niveau des incisives et molaires de rat, à divers stades de développement. Du L-leucyl-4-methoxy-2-naphtylamide, du L-alanyl-4-methoxy-2-naphtylamide, du L-leucyl-2-naphthylamide et du DL-alanyl-2-naphtylamide sont utilisés comme substrats: du bleu rapide B et du grenat rapide GBC sont employés comme sels de diazonium. Le naphtylamidase n'est pas visible au niveau de dents, en voie de dévelopment, au cours de la formation matricielle de l'émail. A la fin de ce stade, le naphtylamidase est présent au niveau de l'extrémité distale des améloblastes, près de la surface de l'émail. L'activité enzymatique reste identique jusqu'au moment de la fusion de l'épithélium dentaire et de l'épithélium buccal, au moment de l'éruption de la dent dans la cavité buccale. On ne rencontre pas de naphtylamidase au niveau d'autres tissues dentaires; cependant une activité marquée est observée dans les ostéoclastes au niveau des surfaces de résorption de l'os alvéolaire, entourant les dents, en voie de développement et d'éruption, et dans certaines régions du tissu conjonctif.
    Abstract: Zusammenfassung Die Aktivität der Naphthylamidase wurde in den Backen- und Schneidezähnen von Ratten in verschiedenen Entwicklungsstufen studiert. Als Substrate wurden L-leucyl-4-methoxy-2-naphthylamid, L-alanyl-4-methoxy-2-naphthylamid, L-leucyl-2-naphthylamid und DL-alanyl-2-naphthylamid verwendet; als Diazoniumsalze dienten Echtblau B und Echt-Granat GBC. Naphthylamidase konnte während der Schmelzmatrixbildung im Zahn nicht nachgewiesen werden. Nach Abschluß dieser Phase erschien Naphthylamidase in den distalen Enden der Ameloblasten, nahe bei der Schmelzoberfläche. Die Enzymtätigkeit blieb am selben Ort lokalisiert, bis das Zahnepithel, im Augenblick wo der Zahn in die Mundhöhle durchstößt, in das Mundepithel überging. Naphthylamidase wurde in anderen Zahngeweben nicht gefunden, aber eine deutliche Aktivität konnte in gewissen Bezirken des Bindegewebes sowie in den Osteoklasten der resorbierenden Oberflächen vom alveolären Knochen festgestellt werden, welcher die sich bildenden und die hervorstoßenden Zähne umgibt.
    Notes: Abstract Naphthylamidase activity was studied in rat molar and incisor teeth at different stages of development. L-leucyl-4-methoxy-2-naphthylamide, L-alanyl-4-methoxy-2-naphthylamide, L-leucyl-2-naphthylamide and DL-alanyl-2-naphthylamide were used as substrates and Fast blue B and Fast Garnet GBC as diazonium salts. Naphthylamidase was not demonstrable in the teeth during enamel matrix formation. After the termination of this stage, naphthylamidase was present in the ameloblasts in their distal ends close to the enamel surface. The enzyme activity retained this localization until the dental epithelium fused with the oral epithelium at the time of tooth eruption into the oral cavity. Naphthylamidase was not found in other dental tissues, but marked activity was found in osteoclasts at the resorbing surfaces of alveolar bone surrounding the developing and erupting teeth and in certain areas of the connective tissue.
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    Calcified tissue international 9 (1972), S. 122-130 
    ISSN: 1432-0827
    Keywords: Tetracycline ; Development ; Calcification ; Statolith ; Nematocysts ; Aurelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé L'effet de la tétracycline HCl sur la synthèse de statolithes de sulfate de calcium chezAurelia a été étudié. La tétracycline inhibe la synthèse de statolithes et nématocystes à un stade précoce de strobilation. La tétracycline, cependant, n'est pas incorporée dans les statolithes ou nématocystes en formation. Comme la tétracycline ne se combine pas avec le calcium des statolithes de sulfate de calcium dihydraté d'Aurelia, l'explication des effets d'inhibition sur la différenciation de statolithes et nématocystes ne semble pas liée avec un facteur en rapport avec l'incorporation. Des étudesin vitro de quatre systèmes inorganiques de calcium et de tétracycline montrent que le sulfate de calcium dihydraté (gypse) n'incorpore pas la tétracycline: il en est de même de son équivalent isostructural, le phosphate de calcium hydrogéné dihydraté (brushite). Le carbonate de calcium et le phosphate de calcium (apatite) incorpore la tétracycline. L'explication des différences de comportement du calcium peut être liée à la structure cristalline des composés respectifs, et, en particulier, au fait que l'ion Ca est prêt ou non à réagir avec la tétracycline.
    Abstract: Zusammenfassung Es wird über die Wirkung von Tetracyclinchlorhydrat auf die Synthese von Calciumsulfat-Statolithen beiAurelia berichtet. Wird das Tetracyclin in einem Frühstadium der Strobilation verabreicht, so hemmt es die Synthese der Statolithen und der Nematocysten. Das Tetracyclin wird jedoch nicht in die sich bildenden Statolithen oder Nematocysten eingebaut. Da sich das Tetracyclin nicht mit dem Calcium der Calciumsulfatdihydrat-Statolithen derAurelia verbindet, so kann dessen Hemmwirkung auf die Statolithen und die sich differenzierenden Nematocysten offenbar nicht mit einem einbaubedingten Faktor erklärt werden. Untersuchunge, die in vitro mit vier verschiedenen anorganischen Calciumsalzen und Tetracyclin ausgeführt wurden, zeigten, daß weder Calciumsulfatdihydrat (Gips), noch dessen isotrukturelles Aequivalent Calciumhydrogenphosphatdihydrat (Bruschit) Tetracyclin einbauen. Dagegen inkorporieren Calciumcarbonat und Calciumphosphat (Apatit) das Tetracyclin. Die Erklärung für dieses unterschiedliche Verhalten der Calciumsalze findet sich in der Kristallstruktur der betreffenden Verbindungen, d.h. es hängt davon ab, ob das Calciumion ür die Reaktion mit Tetracyclin leicht verfügbar ist.
    Notes: Abstract The effect of tetracycline HCl on synthesis of calcium sulphate statoliths inAurelia is reported. Tetracycline inhibits synthesis of statoliths and nematocysts when administered at an early stage of strobilation. The tetracycline, however, is not incorporated into the developing statoliths or nematocysts. As the tetracycline does not combine with the calcium of the calcium sulfate dihydrate statoliths ofAurelia, an explanation for its inhibitory effects on statoliths and nematocyst differentiation apparently does not rest with an incorporation-related factor. In vitro studies of four inorganic calcium systems and tetracycline revealed that calcium sulfate dihydrate (gypsum) did not incorporate tetracycline nor did its isostructural equivalent, calcium hydrogen phosphate dihydrate (brushite). Calcium carbonate and calcium phosphate (apatite) did incorporate tetracycline. The explanation for these different behaviors of calcium can be found in the crystal structure of the respective compounds, namely, whether or not the Ca ion is readily available to react with tetracycline.
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    Calcified tissue international 9 (1972), S. 173-178 
    ISSN: 1432-0827
    Keywords: Phosphatase ; Development ; Bone ; Growth ; Rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Une étude longitudinale, par séries, est effectuée pour déterminer les activités en phosphatases acide et alcaline dans les os longs et la mandibule. Le pH optimum des deux enzymes se situe respectivement à 10.2 et 5.4 pour les phosphatases alcaline et acide. Des portées synchronisées de rats sont sacrifiées, à raison d'une portée par jour, en commençant au premier jour jusqu'au 25ème jour post-partum. Les spécimens sont analysés en ce qui concerne leur concentration en protéine et leur activité en phosphatases. Une activité de types élevée et faible est observée au niveau du tissu osseux, ainsi qu'un type d'activité faible en phosphatase alcaline, au cours des pics d'activité en phosphatase acide, et vice-versa. Les pics observés suggèrent une concordance entre l'activité en phosphatase et les autres changements biochimiques de la croissance osseuse, au niveau de la matrice organique et la formation minérale. Une étude séparée, tenant compte de la possibilité d'une activité enzymatique rythmique, suggère l'existence d'un rythme diurne court chez les animaux jeunes.
    Abstract: Zusammenfassung Eine serienmäßige Longitudinaluntersuchung wurde unternommen, um die Aktivitäten der alkalischen und sauren Phosphatase in den Röhrenknochen und den Mandibulae von Ratten zu bestimmen. Das pH-Optimum der beiden Enzyme wurde für die alkalische Phosphatase bei 10,2 und für die saure Phosphatase bei 5,4 ermittelt. Synchronisierte und randomisierte Würfe wurden getötet, 1 Wurf pro Tag vom 1.–25. Tag post partum. Die Proben wurden auf ihren Proteingehalt und ihre Phosphatasenaktivität untersucht. Ein Muster niedriger und hoher Aktivität konnte in beiden Knochengeweben beobachtet werden, sowie ein Muster von niedriger Aktivität der alkalischen Phosphatase bei Spitzenwerten der sauren Phosphatase und umgekehrt. Die beobachteten Spitzenwerte lassen einen Zusammenhang vermuten zwischen der Phosphatasenaktivität und den anderen biochemischen Veränderungen, die im wachsenden Knochen auftreten, d. h. Bildung der organischen Matrix und des Minerals. Eine getrennte Untersuchung, welche sich mit der Möglichkeit rhythmischer Merkmale der Enzymaktivität befaßte, läßt vermuten, daß in den ersten Tagen ein schwacher Tagersrhythmus bestehen könnte.
    Notes: Abstract A serial longitudinal study was undertaken to determine the activities of the alkaline and acid phosphatases in the long bones and mandibles. The optimum pH of the two enzymes was recorded at 10.2 and 5.4 for alkaline and acid phosphatase, respectively. Synchronized and randomized litters of rats were killed, 1 litter daily, starting at day 1 to day 25 post partum. Samples were analyzed for protein concentration and activity of the phosphatases. A pattern of low and high activity was observed in both bony tissues, as well as a pattern of low alkaline phosphatase activity during acid phosphatase activity peaks, and vice versa. The observed peaks suggest a correspondence between phosphatase activity and the other biochemical changes occurring in the growing bone, i.e., organic matrix and mineral formation. A separate study, considering the possibility of rhythmic features of the enzyme activity suggests that there may be a small diurnal rhythm at an early age.
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    European journal of clinical pharmacology 5 (1972), S. 44-52 
    ISSN: 1432-1041
    Keywords: alprenolol ; serum drug level ; exercise ; man ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of alprenolol on heart rate and systolic blood pressure were studied in healthy subjects during standardized exercise on a bicycle ergometer. In one series of experiments, in which serum concentrations of alprenolol were also measured, the effects of single oral doses of 50, 100 and 200 mg of alprenolol and a placebo were compared by a double blind cross-over technique. In a second series of experiments 100 mg alprenolol was given four times in one day and the effect was followed for up to eighteen hours after the last dose. — Alprenolol diminished the expected increase in heart rate and systolic blood pressure during exercise. The reduction of exercise tachycardia in a given individual was linearly related to the logarithm of the dose or the serum concentration of alprenolol. The serum concentrations required for a given reduction of exercise tachycardia varied almost one hundred-fold amongst the subjects studied. The biological availability of alprenolol was dose-dependent, probably due to a limited capacity biotransformation of the drug before it entered the general circulation. After a single dose the serum level of alprenolol and its chronotropic effect diminished at a rate corresponding to an elimination half life of about two hours. This rate of elimination was consistent with that calculated from the results of the four dose study.
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    European journal of clinical pharmacology 5 (1973), S. 174-180 
    ISSN: 1432-1041
    Keywords: Tricyclic antidepressant ; nortriptyline ; metabolism ; urine ; pharmacokinetics ; twins ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The urinary excretion of nortriptyline (NT) and five of its metabolites was studied by quantitative gas chromatography in 22 twins and 7 unrelated healthy subjects after single (1 mg/kg) and multiple oral doses (0.4 mg/kg t.i.d.) of NT hydrochloride. A mean recovery of 62% of the dose was found after both single and multiple doses. The metabolite pattern in the urine was qualitatively and quantitatively identical in the two regimes, but there were marked variations in the pattern of metabolites between individuals. The disappearance rate of NT from the plasma was mainly determined by the metabolism of NT to 10-hydroxynortriptyline, which varied considerably between individuals. The data suggest that in certain rapid NT metabolizers, the upper limit for the overall clearance of NT from the plasma (if extrahepatic metabolism is assumed to be negligible) might be set by the blood flow through the liver.
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    European journal of clinical pharmacology 6 (1973), S. 268-270 
    ISSN: 1432-1041
    Keywords: Diphenhydramine ; orphenadrine ; gas-liquid chromatography ; N-selective detector ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A method is described for the assay of nanogram quantities of diphenhydramine and orphenadrine in human plasma. The procedure employs gas-liquid chromatography and a high sensitivity nitrogen detector. It has been used to assay diphenhydramine in plasma after oral administration of therapeutic doses.
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    European journal of clinical pharmacology 6 (1973), S. 234-238 
    ISSN: 1432-1041
    Keywords: Phenobarbital ; neonate ; maternal-fetal exchange ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of phenobarbital were measured in 18 newborn infants for one to two weeks after birth. The drug had been administered prenatally to the mothers as part of treatment for maternal hypertension or toxaemia. The plasma half-life of the drug in the infants (77–404 h) was inversely correlated with the extent of prenatal exposure to it. In three infants a bi-phasic plasma curve was found as there was a sudden change from slow to fast disappearance on the 5th to 7th day of life.
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    European journal of clinical pharmacology 7 (1974), S. 407-414 
    ISSN: 1432-1041
    Keywords: Diuretic ; indapamide ; human pharmacology ; toxicology ; pharmacokinetics ; TLC assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacology, toxicology and kinetics of a new diuretic indapamide, have been studied in six normal volunteers following a single oral dose of 40 mg. Pronounced diuresis was found, commencing three hours after ingestion, with a peak urinary flow at four to six hours, and continuing for a total of thirty-six hours. A fall in systolic standing blood pressure occurred twenty four hours after ingestion, coincident with the period of maximum dehydration. Free water clearance rose, accompanied by increased urinary losses of Na+, K+ and Cl− and alkalinisation of the urine comparable to the actions of benzothiadiazines. Total urinary losses of Ca2+, Mg2+ and PO 4 3− rose in spite of a fall in urinary concentrations of these ions. The Ca2+ effect compares with the acute ionic effects of other diuretics. No renal, hepatic or haematological toxic effect was demonstrated. The blood sugar level was not disturbed. Serum uric acid rose to abnormal levels although the change did not reach statistical significance. — A thin layer chromatographic method, with a sensitivity limit of 0.1 µg/ml., has been developed for the assay of indapamide in urine. The urinary excretion rates of the volunteers measured over forty-eight hours indicate that the drug is rapidly absorbed with a peak excretion, 2.9±1.3 µg/min occurring three hours after ingestion. The drug is eliminated bi-phasically with an initial short rapid elimination followed by a slower exponential decline with a mean elimination half-life of 10.3 ± 3.9 h. The mean urinary excretion of unchanged indapamide over forty-eight hours was 4.4±1.4% of the administered dose. — It is concluded that indapamide is an effective long-acting diuretic with comparable action to the benzothiadiazine diuretics, but without an effect on blood sugar level in single doses in normal subjects. In contrast with other diuretics, indapamide appears to be extensively metabolised in man, and its longer duration of action to be related to a longer elimination half-life.
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  • 29
    ISSN: 1432-1041
    Keywords: Oral antidiabetic drug ; butylbiguanide ; pharmacokinetics ; two-compartment open model ; plasma concentration ; liver concentration ; intestine concentration ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 50 mg14C-Butylbiguanide was administered intravenously to 4 diabetic patients and 100 mg14C-butylbiguanide orally to 5 further diabetics. The concentrations of the drug in plasma, intestinal fluid, intestinal epithelium and liver tissue were determined and the renal excretion of the biguanide measured. Irregularities in the plasma concentration curve were observed which appeared as systematic deviations from the ideal curve of a biexponential function. Because these deviations occurred only in the middle phase of the plasma concentration curve, it was nevertheless possible to calculate the pharmacokinetic parameters of butylbiguanide by use of a two-compartment open model. The principal pharmacokinetic parameters were determined according to this model after intravenous dosing and the following mean values were obtained:t 1/2 (β)=4.6 h (β=0.15 h−1),C P 0 =0.85µg/ml,V D =218 l,V T =157 l,V P =62 l,k 12=0.69 h−1,k 21=0.44 h−1,k el =0.54 h−1. Within 48 h after administration, an average of 72.4% of the intravenous and 74.4% of the oral dose had been excreted in the urine. Total clearance (Cl tot) averaged 536 ml/min and renal clearance (Cl ren) 393 ml/min. High concentrations of butylbiguanide were observed in the intestinal fluid (100–700 mg/ml) 20–40 min after oral administration. It was found that the drug accumulates in intestinal fluid, intestinal epithelium and liver tissue, and that it is secreted into the intestinal lumen. The concentrations of butylbiguanide in intestinal and liver tissue were 10–46 times higher than in plasma. The secretion of biguanide into the intestinal lumen may occur via the bile or the intestinal mucosa, but there is no evidence of significant biliary excretion of butylbiguanide.
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    European journal of clinical pharmacology 7 (1974), S. 295-305 
    ISSN: 1432-1041
    Keywords: Mestranol ; ethynyloestradiol ; contraceptive compounds ; demethylation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oestrogenic activity of mestranol depends on its demethylation to ethynyloestradiol. The reaction has been studied in man. The compound disappeared exponentially from plasma during the first 4 h after i.v. injection of [4-14C-] mestranol. The “metabolic clearance” for this phase amounted to 31.8 1/day per kg body weight. Methoxy-3H-labelled mestranol was prepared for the further studies, because if it is demethylated, the tritium would be transferred to HTO, which would equilibrate immediately with body water. The appearance in body water of tritium from [methoxy-3H-] mestranol could be described by two exponential functions, which corresponded to bi-phasic disappearance of the original compound from plasma. The rate constant of the first stage was: γ1=0.835 h−1, and of the second: γ2=0.034 h−1. HTO radioactivity was eliminated from the body by exchange of water. From the data obtained, a three-compartment model was constructed of the transfer of tritium from [methoxy-3H-] mestranolinto body water, which permitted computer simulation of the partial processes. The compartmental analysis suggested that mestranol differed from ethynyloestradiol mainly in the delayed and protracted manner in which hormonally active oestrogen entered the circulation. The proportion of [methoxy-3H-] mestranol demethylated to ethynyloestradiol (demethylation ratio) varied little, 53.7±5.0% (x±SD; n=6), and was consistent with clinical observations that mestranol is half as potent an oestrogen as ethynyloestradiol. Thus, the dose of mestranol required to produce a given effect has to be twice as large as that of ethynyloestradiol.
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    European journal of clinical pharmacology 6 (1973), S. 44-53 
    ISSN: 1432-1041
    Keywords: Nortriptyline ; pharmacokinetics ; plasma clearance ; gas chromatography — mass spectrometry ; pharmacogenetics ; twins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five identical (monozygotic) and 6 fraternal (dizygotic) sets of healthy twins between 47 and 53 years of age were given a single oral dose of nortriptyline (NT) hydrochloride 1 mg/kg. The plasma half-life, the apparent volume of distribution, and the plasma clearance of NT were estimated for each subject as well as the urinary excretion rate of conjugated and unconjugated 10-hydroxynortriptyline (10-OH-NT). “Steady-state” plasma levels predicted from the reciprocal single dose plasma clearance rate of NT agreed well with those observed in a previous study of the same twins 2 years previously. In the present study, there was a 5-fold range of the plasma half-lives and 2-fold variation in the apparent volume of distribution of NT (assuming complete availability on oral administration). No correlation was found between the plasma half-life and the apparent volume of distribution. Analysis of variance showed that most of the variability between persons in plasma half-life, apparent volume of distribution and conjugation of 10-OH-NT was genetically determined. The plasma half-life and apparent volume of distribution may contribute independently to the total interindividual variability of the “steady-state” plasma level of NT.
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    European journal of clinical pharmacology 4 (1971), S. 54-58 
    ISSN: 1432-1041
    Keywords: pharmacokinetics ; infusion ; plasma expander ; blood level fluctuation ; sulfonamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Description / Table of Contents: Summary A hypothetical pharmacokinetic model is reported which describes the decreasing fluctuations in the blood levels of a sulfonamide during infusion of a plasma expander. Its concentration in the serum increases reciprocally with the amount of plasma expander infused. These procedures can be described by simple equations, and it is possible therefore, to calculate the dose required to maintain a constant blood level during the infusion.
    Notes: Zusammenfassung Es wird über ein hypothetisch-pharmakokinetisches Modell berichtet, welches sich mit der absinkenden Serumkonzentration eines Sulfonamids nach Infusion eines Plasmaexpanders beschäftigt. Die Serumkonzentration fällt reziprok zur infundierten Menge des Plasmaexpanders ab. Die Vorgänge lassen sich durch einfache Gleichungssysteme beschreiben. Es gelingt daher, eine Zusatzdosis zu berechnen, welche den bei Infusionsbeginn bestehenden Plasmaspiegel annähernd konstant erhält.
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    European journal of clinical pharmacology 5 (1972), S. 58-61 
    ISSN: 1432-1041
    Keywords: Pralidoxime chloride ; pharmacokinetics ; anti-cholinesterase poisoning
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dose of 1.0 g (10.0–14.0 mg/kg body weight) of pralidoxime mixed with various cholinolytics was given by i.m. injection to 29 healthy male subjects. A concentration of pralidoxime in blood of 4 µg/ml was reached after 5 to 10 min with all the mixtures and was maintained for about 1 to 2 h. The calculated half lives of pralidoxime in three groups of subjects were 62.2, 60.0 and 61.8 min., respectively. — The urinary excretions of pralidoxime during the first 4 h after the injections averaged 75.0, 79.6 and 69.6 per cent, respectively, of the total amount given. — The results are compared with published information about similar oximes.
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    European journal of clinical pharmacology 7 (1974), S. 375-380 
    ISSN: 1432-1041
    Keywords: Tranexamic acid ; pharmacokinetics ; man ; antifibrinolytic agents ; renal clearance ; two-compartment model
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tranexamic acid has been investigated in two healthy volunteers. The behaviour of the drug can be described in terms of a two compartment open model; the disposition (biological) half-life was 2.7 h and 1.9 h, respectively. In five normal volunteers the mean total recovery in urine 48 h after dosing was 94.8%. The renal clearance in the two subjects, adjusted to 1.73 m2 body surface area, was 135 and 132 ml/min/1.73 m2, respectively, indicating that tranexamic acid is eliminated by glomerular filtration and that neither tubular excretion nor absorption takes place.
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    European journal of clinical pharmacology 7 (1974), S. 381-385 
    ISSN: 1432-1041
    Keywords: Phenazone ; pharmacokinetics ; plasma half-life ; gas chromatographic analysis ; intra-individual variability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Intra-individual variability in the plasma half-life of phenazone has been studied in 16 healthy, young volunteers. Phenazone was analysed by a simple gas chromatographic method, which is specific in relation to known metabolites; 4′-methylphenazone was employed as the internal standard. Phenazone was given on two occasions, two or three months apart, in oral doses of 10 mg/kg. The plasma half-life determined from five time points was 10.9±1.5 h and 11.2±1.3 h respectively, on the two occasions. The mean intra-individual variability (0.86 h) was close to the methodological error of 4%.
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    European journal of clinical pharmacology 7 (1974), S. 25-29 
    ISSN: 1432-1041
    Keywords: Pindolol ; uraemia ; pharmacokinetics ; β-blockade
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination of pindolol in 25 patients with various degrees of renal failure has been studied after an intravenous dose of 3 mg. A linear correlation was not found between the elimination rate of pindolol and the endogenous creatinine clearance, and the half-life of the unchanged drug was independent of the severity of the renal failure. This implies greater metabolism of pindolol in anuric patients and the extrarenal elimination rate constantk mwas increased. Three patients with severe renal failure were given 3 mg14C-pindolol. They showed almost constant plasma levels of radio-activity for 6 h and then slow excretion with a half-life of 48 h, because of accumulation of metabolites in the blood. Up to 90% of the metabolites are glucuronides and sulphates which have no beta-blocking or other clinical activity. Thus, to produce beta-adrenergic blockade the same dose of indolol is required in healthy patients as in those with uraemia.
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    European journal of clinical pharmacology 7 (1974), S. 59-60 
    ISSN: 1432-1041
    Keywords: Pizotifen ; isonicotinylhydrazine ; orexigen ; tuberculosis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pizotifen (BC 105) has an orexigenic effect in patients with pulmonary tuberculosis. As these cases are often treated with isonicotinylhydrazine (INH), any effect of one of these drugs on the absorption of the other has been examined in a cross-over study in 8 healthy male volunteers. No difference was found between the absorption of INH given alone or together with pizotifen. It should be safe, therefore, to employ the combination of the orexigenic drug and INH in the treatment of tuberculosis as there will be no change in the concentration of therapeutic drug achieved.
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  • 38
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    European journal of clinical pharmacology 7 (1974), S. 31-37 
    ISSN: 1432-1041
    Keywords: Diphenylhydantoin ; uraemia ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Diphenylhydantoin (2 mg/kg) was infused intravenously in four uraemic patients and four healthy volunteers and its plasma concentration measured during and after the infusion. The plasma concentrations were considerably lower in the uraemic subjects and the apparent volume of distribution was higher. These observations could be explained by the lower plasma protein binding of diphenylhydantoin in the uraemics. The overall elimination rate constant β was greater (shorter half-life) in the uraemic patients. This difference could not be explained by reduced plasma protein binding, but it might be due to induction of diphenylhydantoin metabolism in the uraemic state. it is concluded that monitoring of the plasma levels of drugs in uraemic patients should be combined with determination of the extent to which the compounds are bound to plasma proteins.
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  • 39
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    European journal of clinical pharmacology 4 (1972), S. 233-240 
    ISSN: 1432-1041
    Keywords: Sulphamethoxazole ; trimethoprim ; pharmacokinetics ; uraemia ; sulphonamides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulphamethoxazole (SMZ) and trimethoprim (TMP) have been investigated in four healthy volunteers, 15 patients with stable chronic renal failure and 3 patients on regular dialysis. The dosage schedule was 400 mg of SMZ and 80 mg of TMP orally every 12 h. The plasma concentrations and urinary excretion have been analysed in terms of a one compartment open model, allowing for elimination by renal excretion and metabolic processes. — At equilibrium the plasma concentrations of unchanged sulphonamide showed no significant correlation with the degree of renal impairment. The accumulation of TMP increased slightly without affecting the concentration ratio of both agents in plasma. In contrast, increasing accumulation of metabolized SMZ was demonstrated in the presence of renal insufficiency. Indirect evidence indicates that rising metabolite levels under these circumstances may lead to a displacement of unchanged sulphonamide from protein binding sites. — The cumulative urinary excretion amounted to 82.4% of the dose of sulphonamide administered, which probably corresponds to the fraction of the compound absorbed. The urinary concentration of biologically active SMZ was slightly below the plasma level, especially in advanced renal failure, but it remained above the minimum inhibitory concentrations reported in the literature. The concentration of TMP in urine was considerably higher than in plasma, it decreased with loss of renal function as did active SMZ.
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  • 40
    ISSN: 1432-1041
    Keywords: sodium valproate ; epileptic patients ; pharmacokinetics ; plasma concentration ; prediction ; maintenance dosage
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination (β phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.
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  • 41
    ISSN: 1432-1041
    Keywords: prenalterol ; beta1-adrenoceptor agonist ; metabolic effects ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective β1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables — triglycerides, glucose, lactate, pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.
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  • 42
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    European journal of clinical pharmacology 17 (1980), S. 111-116 
    ISSN: 1432-1041
    Keywords: zimelidine ; norzimelidine ; antidepressants ; pharmacokinetics ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of a new antidepressant, zimelidine, and of its pharmacologically active metabolite, norzimelidine, was studied in six healthy male volunteers. Three single doses of zimelidine (25 mg and 100 mg orally and 25 mg i.v.) and two single doses of norzimelidine (25 mg orally and i. v.) were given to each volunteer allowing at least seven days between administrations. Plasma concentrations of zimelidine and norzimelidine were determined in serial blood samples by HPLC. Following oral zimelidine peak plasma concentrations of the metabolite were attained about 3 h after dosing. Oral administration of norzimelidine itself resulted in a plasma concentration profile for this compound that was similar to that observed after oral zimelidine. Utilising the plasma concentration data following intravenous infusion of each compound, the elimination half-lives for zimelidine and norzimelidine were calculated to be 5.1 h (range 4.3–6.0) and 15.5 h (range 10.6–22.9) respectively. The total body clearances of the 2 compounds were similar at 0.52 l · min−1 (range 0.26–0.70) for zimelidine and 0.56 l · min−1 (range 0.28–0.83) for norzimelidine. The substantially longer elimination half-life of norzimelidine was apparently the result of a larger volume of distribution (9.4 l · kg−1; range 7.8–11.4) for this metabolite, as compared to zimelidine (3.21 · kg−1; range 1.6–4.9). The calculated bioavailability of zimelidine was 26% (range 9.1–39) after the 25 mg oral dose, and 29% (range 14–46) after the 100 mg dose. The bioavailability of norzimelidine was 66% (range 36–91). However, oral administration of zimelidine resulted in as much or more norzimelidine reaching the systemic circulation, as the oral administration of norzimelidine itself. This is important as a large part of the activity of the drug may be due to the metabolite.
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  • 43
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    European journal of clinical pharmacology 17 (1980), S. 129-133 
    ISSN: 1432-1041
    Keywords: dapsone ; salivary drug elimination ; pharmacokinetics ; acetylator phenotype
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high performance thin layer chromatographic assay for dapsone is described with a minimum level of detection of 20 ng ml−1 which is suitable for the study of dapsone pharmacokinetics in plasma and saliva. 100 mg dapsone was administered orally to seven normal adult volunteers, the mean plasma pharmacokinetic parameters were: α=0.23 h−1; β=0.0236 h−1, and t1/2β=30.2 h. Dapsone is also eliminated into the saliva and the t1/2 may be determined via its estimation in saliva. It is 73% bound to plasma protein and the saliva/plasma concentration ratio was found to be 27%. In two subjects the free plasma dapsone concentration was identical to the simultaneous salivary dapsone concentration. Therefore the salivary dapsone concentration is a measure of the free plasma fraction of dapsone. Saliva/plasma dapsone concentration ratios show no time or concentration dependence and little inter-individual variation but are unsuitable for acetylator phenotype determination because monoacetyldapsone is not eliminated in the saliva.
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  • 44
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    European journal of clinical pharmacology 18 (1980), S. 321-326 
    ISSN: 1432-1041
    Keywords: sotalol ; hypertension ; renal impairment ; chronic administration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten hypertensive patients with moderate to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.
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  • 45
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    European journal of clinical pharmacology 18 (1980), S. 517-520 
    ISSN: 1432-1041
    Keywords: desmethyldiazepam ; oxazepam ; cimetidine ; hepatic elimination ; pharmacokinetics ; interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single oral doses of desmethyldiazepam 20 mg or oxazepam 50 mg were studied in 5 healthy volunteers under controlled conditions, before and following a 24 h pretreatment with cimetidine 200 mg×5. Cimetidine significantly impaired (p=0.03) the elimination of desmethyldiazepam, as shown prolongation of its elimination half-life from 51.7±21.9 h to 72.6±39.4 h (mean ± SD), and a decrease in total plasma clearance from 12.0±2.7 ml/min to 8.6±3.3 ml/min. The disposition of oxazepam was not affected. From these results, and recently published data on diazepam and chlordiazepoxide, it is concluded that cimetidine impairs the hepatic elimination of those benzodiazepines which are metabolized by phase I reactions.
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  • 46
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    European journal of clinical pharmacology 19 (1981), S. 263-269 
    ISSN: 1432-1041
    Keywords: chlormethiazole ; pharmacokinetics ; pharmacodynamics ; sedatives ; blood concentrations ; amnesia
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n=5) and 113 min (Phase 2, n=5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.15 l · min−1, SD 0.49; and 1.05 l · min−1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (137 l, SD 62; and 125 l, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (308 l, SD 91; and 224 l, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg · l−1 (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.
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  • 47
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    European journal of clinical pharmacology 17 (1980), S. 449-457 
    ISSN: 1432-1041
    Keywords: alcuronium ; single dose ; multiple dose ; plasma levels ; neuromuscular response ; pharmacokinetics ; anaesthesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of alcuronium is described for nineteen patients undergoing anaesthesia for elective surgery. Eleven patients received a single bolus intravenous dose of 0.25 mg/kg, while 8 patients required additional doses of 0.125 mg/kg. A two-compartment open model was found to describe adequately both the single dose and multiple dose data for the majority of patients. No significant differences were found in the model-independent pharmacokinetic parameters between the single and multiple dose studies. Mean values for the pooled data for the half-life (t1/2β), apparent volume of distribution (Vdβ), volume of distribution at steady-state (Vdss), volume of the central compartment (Vc) and plasma clearance (Clp) were 198.75 min, 24.261, 20.891, 8.181 and 90.22 ml/min respectively. Evoked muscle twitch response was monitored in 17 of the patients to assess the degree of relaxant blockade. The bolus dose of alcuronium produced complete block in 9 patients and between 95 and 99% block in the remainder. The time of onset to maximum block ranged from 3 to 30 min with the concurrently measured plasma levels of alcuronium being 0.79 to 2.25 µg/ml. The time taken following bolus administration to 5% recovery (95% paralysis) was a mean of 42 min and the corresponding mean alcuronium plasma concentration was 0.78 µg/ml.
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  • 48
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    European journal of clinical pharmacology 18 (1980), S. 269-273 
    ISSN: 1432-1041
    Keywords: paracetamol ; thyrotoxicosis ; hypothyroidism ; drug disposition ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption, distribution and elimination of oral paracetamol have been studied in patients before and after treatment of thyrotoxicosis (n=7) and hypothyroidism (n=4). Absorption was faster in patients with untreated thyrotoxicosis than when subsequently euthyroid. The peak paracetamol concentration, however, was lower in thyrotoxic patients due to an apparent increase in the total body clearance and a shorter plasma half-life. Both absorption and elimination rates were reduced in hypothyroid patients, but were not significantly different from the euthyroid results. When estimated using a two compartment model the total volume of distribution and the hybrid distribution rate constants were unrelated to thyroid status, but the apparent volume of the central compartment was significantly greater in the thyrotoxic group. These changes in drug disposition may contribute to differences in drug response seen in thyroid disease.
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  • 49
    ISSN: 1432-1041
    Keywords: alminoprofene ; antalgic ; pharmacokinetics ; single dose ; multiple doses
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 2-(p-methylallylaminophenyl) propionic acid, alminoprofene (INN), a new antalgic drug, was administered orally to men as a single (300 mg) and multiple doses (300 mg three times daily). Plasma and urine concentrations of alminoprofene were determined by gas-liquid chromatography. After the single oral dose, the peak plasma level (36.2 to 41.5 mg/l) was reached within 0.5–1.5 h. The biological half-life ranged from 2.5 to 3.2 h. During chronic administration of alminoprofene, steady-state equilibrium quilibrium was etablished within 24 h. The urinary excretion of alminoprofene as unchanged product and as glucuronide was very important.
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  • 50
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    European journal of clinical pharmacology 18 (1980), S. 423-428 
    ISSN: 1432-1041
    Keywords: pyridostigmine ; myasthenia gravis ; pharmacokinetics ; bioavailability ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pyridostigmine was evaluated after intravenous injection in two healthy male volunteers and after oral administration to five subjects. Plasma concentrations of pyridostigmine were determined after ion pair extraction from plasma and analysis by gas chromatography — mass spectrometry with chemical ionization, using d6-pyridostigmine as internal standard. Degradation of pyridostigmine in vitro was compensated for by use of the deuterated internal standard and by rapid cooling and separation of plasma after blood sampling. After intravenous administration of pyridostigmine 2.5 mg the plasma elimination half-life was 1.52 h, the volume of distribution was 1.43 l/kg and the plasma clearance 0.65 l/kg × h. The pharmacokinetic constants were very similar after oral administration of pyridostigmine 120 mg; the elimination half-life was 1.78±0.24 h, the volume of distribution 1.64±0.29 l/kg and the plasma clearance was 0.66±0.22 l/kg × h. The bioavailability was calculated to be 7.6±2.4%. When pyridostigmine was taken together with food, the time to reach the peak plasma concentration was prolonged from 1.7 to 3.2 h. Bioavailability, however, was not influenced by concomitant food intake. “Steady-state” plasma concentrations of pyridostigmine were measured in myasthenic patients on their ordinary dose schedule of cholinesterase inhibitor drugs. More than a seven-fold difference in steady-state plasma concentration was found between patients taking approximately the same daily dose of pyridostigmine.
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  • 51
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    European journal of clinical pharmacology 18 (1980), S. 473-477 
    ISSN: 1432-1041
    Keywords: aminophylline ; asthma ; serum theophylline ; pharmacokinetics ; prediction of serum level
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration)=−0.22±1.97 mg/l (mean ± SD); r=0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error=0.58±3.88, r=0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error=3.62±13.36, r=0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.
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  • 52
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    European journal of clinical pharmacology 17 (1980), S. 459-463 
    ISSN: 1432-1041
    Keywords: colestipol ; fenofibrate ; fenofibric acid ; pharmacokinetics ; interaction ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 µg/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On Day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs.
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  • 53
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    European journal of clinical pharmacology 18 (1980), S. 51-53 
    ISSN: 1432-1041
    Keywords: pethidine ; phenobarbital ; aminoglycoside antibiotics ; pharmacokinetics ; clinical response
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  • 54
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    European journal of clinical pharmacology 18 (1980), S. 55-63 
    ISSN: 1432-1041
    Keywords: diuretics ; furosemide ; caffeine ; theophylline ; neonate ; pharmacokinetics ; disposition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination of diuretics and methylxanthines is considerably slower in the neonate than in the adult. Dose guidelines, especially during long term maintenance, must be adjusted to account for this slower drug elimination. Pharmacokinetic studies and the requisite pharmacologic evaluation on diuretics such as hydrochlorothiazide, spironolactone, ethacrynic acid and others should be done. Furosemide undergoes biotransformation in the newborn producing an acid metabolite and a glucuronide conjugate. Methylxanthines are effective in the treatment of neonatal apnea. Plasma elimination of theophylline is exceedingly slow, more so with caffeine. Decreased elimination is partly explained by decreased oxidative biotransformation. Caffeine is excreted in the urine of the newborn mainly unchanged (85%) in contrast to the adult where caffeine is a minor portion of urinary excretion (2%). Theophylline is methylated to caffeine and may possibly exert additive pharmacologic effects.
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  • 55
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    European journal of clinical pharmacology 18 (1980), S. 195-198 
    ISSN: 1432-1041
    Keywords: ampicillin ; age ; oral dose ; i. v. dose ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ampicillin (500 mg) was administered intravenously (i. v.) and orally to a small panel of young and elderly subjects in a cross-over fashion. Plasma concentrations of ampicillin were measured by a fluorimetric technique for 8 h following dosage. A two compartment-open model was used to characterise the plasma concentration-time data for the intravenous study, and a one compartment-open model incorporating an absorption lag time and a first-order absorption rate constant for the oral data. Plasma clearance after i. v. ampicillin was found to be significantly decreased in the elderly (P〈0.05, 0.08 1 h−1kg−1 versus 0.18 1 h−1kg−1), and half life and area under the plasma level-time curve were significantly increased (P〈0.05, 6.70 h versus 1.68 h, t1/2β; p〈0.01, 176.51 µg·h ml−1 versus 37.88 µg·h ml−1, AUC o ∞ ) as compared to the young. No sigificant differences were observed between the age groups for the volume of distribution terms and the changes in drug handling noted in the elderly were attributed to a decrease in the renal elimination of ampicillin. Following oral administration a significant increase in t1/2β, AUC o ∞ and the maximum plasma concentration (Cpmax P〈0.01, 6.59 µg ml−1 versus 3.42 µg ml−1) of ampicillin was found in the elderly subjects. These findings were similarly attributed to a decrease in drug elimination in the aged, since no apparent age differences were noted in the pharmacokinetic parameters governing both rate and extent of ampicillin absorption.
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  • 56
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    European journal of clinical pharmacology 18 (1980), S. 237-244 
    ISSN: 1432-1041
    Keywords: isosorbide dinitrate ; 2-isosorbide mononitrate ; 5-isosorbide mononitrate ; digital plethysmography ; hypotension ; bradycardia ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the α-wave of the digital plethysmograph did not change significantly either in the predrug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.
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  • 57
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    European journal of clinical pharmacology 21 (1982), S. 287-291 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 58
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    European journal of clinical pharmacology 21 (1982), S. 307-310 
    ISSN: 1432-1041
    Keywords: piretanide ; renal failure ; high dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 59
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    European journal of clinical pharmacology 21 (1982), S. 397-402 
    ISSN: 1432-1041
    Keywords: ergotamine ; migraine ; radioimmunoassay ; clinical effects ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 60
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    European journal of clinical pharmacology 21 (1982), S. 343-350 
    ISSN: 1432-1041
    Keywords: orphenadrine ; single dose ; multiple doses ; bioavailability ; pharmacokinetics ; N-demethylorphenadrine ; metabolism ; dog ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 61
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    European journal of clinical pharmacology 22 (1982), S. 273-279 
    ISSN: 1432-1041
    Keywords: amoxycillin ; i.v. administration ; pharmacokinetics ; two- and three-compartment models
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 62
    ISSN: 1432-1041
    Keywords: indapamide ; bioavailability ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 63
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    European journal of clinical pharmacology 22 (1982), S. 257-264 
    ISSN: 1432-1041
    Keywords: TRIS buffer ; metabolic acidosis ; pharmacokinetics ; cellular uptake ; renal excretion ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 64
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    European journal of clinical pharmacology 20 (1981), S. 147-155 
    ISSN: 1432-1041
    Keywords: azapropazone ; cirrhosis ; renal failure ; non-steroidal anti-inflammatory drug ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its free fraction in plasma, and a reduction in the free drug clearance to about half that in healthy subjects. In Group II patients total clearance was reduced to about 20% of normal. This was partly due to reduced non-renal clearance but mainly to impaired renal clearance of azapropazone. The diminished renal clearance was considered at least in part to represent a drug-induced impairment of renal function, as there was a concomitant reduction in creatinine clearance. The free fraction of azapropazone in the plasma was markedly enhanced (〉0.02), and simultaneously, free drug clearance was drastically reduced, to about 2% of that in healthy subjects. In patients with renal failure the total clearance was diminished, depending on the degree of impairment of kidney function. Anephric patients were estimated to have about one third of the total clearance in normal subjects. The free fraction of azapropazone in the plasma was increased in 4 of the 8 patients. It is concluded that patients with cirrhosis and modest impairment of liver function may require about half the normal dose of azapropazone, since free drug clearance is reduced by about 50%. Patients with severe impairment of liver function are expected to be highly susceptible to dose-related side effects, since the pronounced increase in the free fraction in plasma and the decreases in renal and non-renal clearance lead to marked reduction in free drug clearance and so to accumulation of free drug in the body. In patients with renal failure the dose of azapropazone should be reduced according to the degree of impairment of kidney function and plasma protein binding of the drug.
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  • 65
    ISSN: 1432-1041
    Keywords: pindolol ; beta-blockade ; slow release tablet ; plasma levels ; urinary excretion ; pharmacokinetics ; pharmacodynamics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken®) t. d. s., and one tablet of pindolol 20 mg retard (Visken® retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (tmax)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.
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  • 66
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    European journal of clinical pharmacology 23 (1982), S. 75-80 
    ISSN: 1432-1041
    Keywords: psoriasis ; 8-methoxypsoralen ; food influence ; suction blister fluid ; serum ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 67
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    European journal of clinical pharmacology 23 (1982), S. 189-195 
    ISSN: 1432-1041
    Keywords: befunolol ; propranolol ; pharmacokinetics ; pharmacodynamic effects ; beta-adrenoceptor blocking agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 68
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    European journal of clinical pharmacology 23 (1982), S. 235-240 
    ISSN: 1432-1041
    Keywords: ergotamine ; pharmacokinetics ; migraine ; plasma drug levels ; i.v. administration ; i.m. administration ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 69
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    European journal of clinical pharmacology 23 (1982), S. 327-330 
    ISSN: 1432-1041
    Keywords: bendroflumethiazide ; cantharides plasters ; blister fluid ; plasma levels ; pharmacokinetics ; compartmental analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 70
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    European journal of clinical pharmacology 23 (1982), S. 343-347 
    ISSN: 1432-1041
    Keywords: valproic acid ; fatty acids ; plasma protein binding ; pharmacokinetics ; drug metabolism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 71
    ISSN: 1432-1041
    Keywords: L-threo-3,4-dihydroxyphenylserine ; familial amyloid polyneuropathy ; pharmacokinetics ; norepinephrine ; pressor response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 72
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    European journal of clinical pharmacology 23 (1982), S. 501-504 
    ISSN: 1432-1041
    Keywords: cimetidine ; uraemia ; dosing regimen ; prediction ; computer program ; old age ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 73
    ISSN: 1432-1041
    Keywords: amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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    European journal of clinical pharmacology 24 (1983), S. 185-190 
    ISSN: 1432-1041
    Keywords: amezinium ; hypotension ; antihypotensive drug ; ECG ; concentration-effect relationship ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood pressure, ECG and plasma concentration were determined for up to 12h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton®) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r=0.78,p〈0.001) and between 0.75 and 5 h after i.v. administration (r=0.83,p〈0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.
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  • 75
    ISSN: 1432-1041
    Keywords: sulfinpyrazone ; pharmacokinetics ; metabolites ; inhibition of platelet aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4×200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.
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  • 76
    ISSN: 1432-1041
    Keywords: trimethoprim ; sulphadiazine ; urinary tract infection ; children ; pharmacokinetics ; urinary concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical effect and pharmacokinetics of the combination trimethoprim (TMP)-sulphadiazine (SD) were studied in 18 children with acute urinary tract infections (UTI), aged 2–56 months. A suspension of TMP-SD (9+41 mg/ml) was taken orally twice daily for 10 days. Various doses of TMP (2.9–3.7 mg/kg/day) and SD (12.9–16.7 mg/kg/day) were also given to children of different ages. After 2–4 days of treatment, bacterial cultures of urine were negative and C-reactive protein in serum, WBC count and ESR in all patients had become normal. Steady state serum levels for both components were reached after 4 or more days of treatment. At steady state, mean peak serum concentrations of TMP and SD of 1.4 µg/ml and 27 µg/ml, respectively, were found within 2–4 h after a fasting morning dose. The biological half-lives of TMP and SD were of the same order of magnitude, but the total clearance of TMP was 5 times greater than that of SD. The concentrations of TMP-SD in urine were invariably more than 10 times the minimum inhibitory concentrations (MIC) for the causative organisms (tested at the ratios 1:20 and 1:4 of TMP and SD). Non-metabolized SD constituted 77% of total SD in urine of infants, and 55% of total SD in children of 1 year or more. The TMP-SD combination showed a satisfactory clinical effect and favourable pharmacokinetic properties in children with UTI.
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  • 77
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    European journal of clinical pharmacology 24 (1983), S. 337-343 
    ISSN: 1432-1041
    Keywords: ketamine ; diazepam ; drug interaction ; pharmacokinetics ; premedication ; clorazepate ; drug metabolism ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. Four further patients had been on oral diazepam or barbiturates for 1–14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.
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  • 78
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release tablet ; absolute bioavailability ; pharmacokinetics ; individual dosage regimen
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard® 250 mg, Theolair S. R.®, Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard® 250 mg was 110.9±20.8% (mean ± SD). Maximal serum concentrations were reached after 7.3±3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h−1 (intestine), or biphasic with rate constants of 0.2 h−1 (stomach) and 0.8 h−1 (intestine). The peak levels accounted for 7.9±2.2 mg · 1−1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of cmax for 6.5±3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg · l−1 was 9.8±3.1 h.
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  • 79
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    European journal of clinical pharmacology 21 (1981), S. 61-64 
    ISSN: 1432-1041
    Keywords: acenocoumarol ; anticoagulant therapy ; breast feeding ; breast milk ; neonatal thrombotest ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 women receiving Sintrom® post partum, the acenocoumarol concentration in serum and breast milk at different times was measured. Even at the time of maximal serum concentration, or for the following 6 h, no acenocoumarol could be detected in the breast milk. In accordance with this finding, no effect of breast feeding on Thrombotest values of the infants could be demonstrated. These data suggest that mothers taking acenocoumarol for a short period may safely breast feed their infants.
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    European journal of clinical pharmacology 21 (1981), S. 45-52 
    ISSN: 1432-1041
    Keywords: caffeine ; pharmacokinetics ; plasma ; saliva ; urinary elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163±0.081 h−1 for 50 mg and 0.098±0.027 h−1 for 750 mg. The total body clearance was unaffected by dose and was 0.98±0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74±0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.
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  • 81
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    European journal of clinical pharmacology 24 (1983), S. 485-494 
    ISSN: 1432-1041
    Keywords: amiodarone ; pharmacokinetics ; therapeutic serum level ; thyroid function ; antiarrhythmic therapy ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 17 patients on long term therapy with amiodarone, serum drug levels measured by HPLC were related to pharmacological effects. At steady state, serum levels were directly proportional to the dose, 5 mg/kg per day leading to an average serum level of approximately 2.5 µmol/l. The non-amiodarone level of iodine averaged 4-times higher than the level of amiodarone iodine. The elimination half-life of amiodarone ranged from 21 to 78 days, and of non-amiodarone iodine from 24 to 160 days. Control of arrhythmias was satisfactory in all 12 evaluable patients, when the serum amiodarone level exceeded 1.5 µmol/l. Deterioration of vision and polyserositis occurred only at amiodarone levels above 4 µmol/l. Tentatively, a therapeutic range of 1.5 to 4 µmol/l is proposed. In contrast, thyroid dysfunction was observed at any amiodarone level. In view of the narrow therapeutic window, therapy with amiodarone may be optimized by monitoring its serum level and in addition, thyroid function should be regularly checked.
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  • 82
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    European journal of clinical pharmacology 24 (1983), S. 521-524 
    ISSN: 1432-1041
    Keywords: sotalol ; beta-adrenoceptor antagonist ; pregnancy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.
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  • 83
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    European journal of clinical pharmacology 24 (1983), S. 549-556 
    ISSN: 1432-1041
    Keywords: dibromosulfophthalein ; pharmacokinetics ; plasma levels ; urinary excretion ; biliary excretion ; biliary fistula ; enterohepatic circulation ; hepatic transport test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dibromosulfophthalein (DBSP), the 3,6-dibromo analogue of BSP, was studied in 7 patients with a biliary fistula, 52 h after cholecystectomy, and in 6 gynaecological patients with an indwelling urethral catheter, following extirpation of the uterus i.e. with an intact enterohepatic circulation. Plasma protein binding determined by ultrafiltration was 98–99% up to a concentration of 700 µg/ml. After an intravenous bolus injection of DBSP 5 mg/kg, a biexponential plasma decay was found in both groups, with a rapid initial t1/2 of 2–6 min and a slow secondary phase of 33–109 min (mean 66 min) in the cholecystectomy patients, and 10–30 min (mean 19 min) in the gynaecological patients. The biliary excretion rate varied considerably between the patients and was highly correlated with bile flow. Biliary output amounted to a maximum of 86% of the dose in 24 h. The excretion rate curves showed ascending and descending phases, the mean terminal t1/2 being 65 min. Urinary excretion was 3–11% of the dose in 8 h in the gynaecological patients (mean 6%) and 6–31% in the cholecystectomy group (mean 16%). Renal clearance of unbound DBSP was about ten-times greater than the glomerular filtration rate, which indicates tubular secretion. A two compartment model with elimination from the peripheral and central compartments was selected because of these data. Analysis of the plasma-disappearance curves indicated an initial plasma clearance of 500–600 ml/min, which suggests that hepatic uptake will be very dependent on flow. Steady state (biliary) clearance was about 400 ml/min in the gynaecological group and approximately half that in the cholecystectomy patients; V1 tended to be higher and V2 to be lower in the latter group. It is concluded that biliary excretion rate of DBSP in patients with a biliary fistula is probably depressed by the postoperative bile drainage and the lack of enterohepatic cycling of bile salts.
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  • 84
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    European journal of clinical pharmacology 24 (1983), S. 661-665 
    ISSN: 1432-1041
    Keywords: hydrochlorothiazide ; pharmacokinetics ; renal failure ; dosage adjustment ; excretory mechanism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of hydrochlorothiazide (HCT) was investigated in 23 subjects with normal renal function or widely varying degrees of renal failure. The half-life of elimination increased from 6.4 h in subjects with normal renal function to 11.5 h in patients with mild renal impairment (endogenous creatinine clearance between 30 and 90 ml/min), and to 20.7 h in patients with an endogenous creatinine clearance below 30 ml/min. The cumulative urinary excretion and the renal HCT clearance were correspondingly reduced in patients with impaired kidney function. In normal subjects HCT was mainly excreted by tubular secretion, but as renal HCT clearance in patients with renal impairment did not differ significantly from endogenous creatinine clearance, it was concluded that the secretory mechanism is most markedly impaired. In patients with an endogenous creatinine clearance of 30 to 90 ml/min, the dosage of HCT should be reduced to 1/2 and in patients with a endogenous creatinine clearance below 30 ml/min to 1/4 of the normal daily dose to avoid dose dependant side-effects.
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  • 85
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    European journal of clinical pharmacology 24 (1983), S. 813-818 
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; dextran 70 ; pharmacokinetics ; radioimmunoassay ; drug interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of subcutaneous dihydroergotamine (DHE) with or without dextran 70 infusion was evaluated in a single- and multiple-dose study in 30 patients. Radioimmunoassay was used to measure plasma DHE and the anthrone method to determine the dextran concentration. In the single-dose study no significant interaction between DHE and dextran was noted with respect to their plasma levels. The absorption of s.c. DHE was rapid and the disappearance curve followed a biphasic pattern, t0.5 α being 1.4 and 2.0 h, t0.5 β 22 and 21 h for DHE and DHE/dextran 70, respectively. In the multi-dose study the trough level of DHE initially had a tendency to rise, in accordance with simulated plasma concentration curves. DHE trough levels were about 0.5 ng/ml and were well above the assumed minimum effective value to induce venoconstriction (0.06 ng/ml). Dextran concentrations were significantly higher when DHE was co-administered, possibly, due to changes in plasma volume. It is concluded that DHE 0.5 mg s.c. twice daily will give an adequate plasma concentration and that there was no important interaction between it and infused dextran 70.
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  • 86
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    European journal of clinical pharmacology 25 (1983), S. 77-80 
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; multiple dosing ; plasma protein binding ; analgesic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of meptazinol (Meptid®) have been studied in nine male volunteers after single and multiple oral administration of 200 mg tablets and also after a single 25 mg intravenous dose. Plasma concentrations of meptazinol were determined by HPLC using fluorescence detection. Drug absorption after oral dosage was rapid, peak plasma concentrations being reached between 0.25 and 2 h after drug administration. Subsequent elimination proceeded in an apparently mono-exponential fashion with a half-life of 2 h, although after intravenous dosage there was evidence of an initial rapid distributive phase. The mean total plasma clearance was 2.21/min and the mean apparent volume of distribution (Vdβ) was 4.99 l/min. The bioavailability ranged from 1.9 to 18.5% (mean=8.7%) and was related to the rate of absorption. Multiple dosing, 6-hourly for 3 days, did not produce any accumulation above that predicted from a single dose. Plasma protein binding of the drug was 27.1% and did not vary over the therapeutic concentration range of 25 to 250 ng/ml.
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  • 87
    ISSN: 1432-1041
    Keywords: carteolol ; pharmacokinetics ; beta-adrenoreceptor blocking drug ; absolute bioavailability ; plasma levels ; urinary excretion ; renal handling
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and absolute bioavailability of a new nonselective β-adrenoreceptor blocking agent, carteolol, were investigated after administration of single intravenous and oral doses to eight normal volunteers. Plasma and urine drug concentrations were measured by an HPLC method. The pharmacokinetic parameters after intravenous dosing were obtained by a two-compartment analysis: elimination or β-phase t1/2 4.7±0.3 h; Vc, 0.74±0.101/kg; Vd, 4.05±0.48 l/kg; Cl, 10.13±0.94 ml/min/kg; ClR, 6.56±0.58 ml/min/kg; and ClNR, 3.57±0.40 ml/min/kg. The absolute bioavailability obtained from plasma data was 83.7±8.0%, which was consistent with that derived from analysis of urine of 82.7±4.2%. The amounts excreted unchanged in urine up to 48 h after the intravenous and oral doses were 65.0±1.5% and 53.8±3.2% of the administered doses, respectively. The t1/2 for removal of the drug derived from plasma and urine findings after intravenous and oral dosing were similar, which indicates that the main route of elimination of carteolol is via the kidneys. As the ClR of carteolol exceeded the Cl of creatinine there may be renal tubular secretion of the drug.
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  • 88
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    European journal of clinical pharmacology 25 (1983), S. 237-241 
    ISSN: 1432-1041
    Keywords: triamterene ; bioavailability ; pharmacokinetics ; metabolism ; hydroxy triamterene sulphate ; urinary excretion ; i.v. administration ; first-pass-effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary With a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.
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  • 89
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    European journal of clinical pharmacology 25 (1983), S. 369-373 
    ISSN: 1432-1041
    Keywords: pengitoxin ; pharmacokinetics ; 16-acetylgitoxin ; absorption ; urinary excretion ; healthy subjects ; cardiac glycoside
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng · ml−1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (Vdarea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC0-∞-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml · min−1 (7.0 to 18.6 ml · min−1) and 3.0 ml · min−1 (1.9 to 3.9 ml · min−1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.
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  • 90
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    European journal of clinical pharmacology 25 (1983), S. 399-405 
    ISSN: 1432-1041
    Keywords: ceftriaxone ; pharmacokinetics ; concentration-dependent binding ; volume of distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both Vβ and the model-independent VSS) were inaccurate/invalid; b) V β based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms ( $$\bar f_P $$ and $$\bar V_{SS}^T $$ ) were introduced which provide additional insight concerning the disposition of this type of drug. The $$\bar f_P $$ is the area-weighted average fraction unbound in the plasma and $$\bar V_{SS}^T $$ is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.
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  • 91
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    European journal of clinical pharmacology 25 (1983), S. 455-457 
    ISSN: 1432-1041
    Keywords: digoxin ; concentration plateau ; pharmacokinetics ; systolic time intervals ; optimal infusion scheme ; dose-response data
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a volume-controlled infusion pump, a mean serum plateau level of digoxin of 4–5 ng/ml was rapidly achieved and maintained in 6 healthy volunteers. The infusion scheme was calculated on the basis of data published on the pharmacokinetics and pharmacodynamics of digoxin following bolus intravenous injection. The magnitude of the response (change in electromechanical systole) at the end of the plateau phase was comparable to that observed with the concentration in the therapeutic range at steady state.
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  • 92
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    European journal of clinical pharmacology 25 (1983), S. 449-453 
    ISSN: 1432-1041
    Keywords: canrenone ; pharmacokinetics ; plasma level ; bioavailability ; urinary excretion ; spironolactone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy male volunteers received canrenoate-K 200 mg (Sincomen® pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen®-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066±876 ng/ml was found after 29±15 min and thereafter the concentration declined with a half-life of 3.7±1.2 h. Total clearance was 4.2±1.7 ml/min·kg. After oral ingestion, the maximum concentration of 177±33 ng/ml was observed at 4.4±0.9 h. The absolute bioavailability of canrenone was 25±9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9±1.8 h (i.v.) and 3.9±1.2 h (p.o.).
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  • 93
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    European journal of clinical pharmacology 25 (1983), S. 497-501 
    ISSN: 1432-1041
    Keywords: methadone ; pharmacokinetics ; steady state ; addiction rehabilitation ; therapeutic failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Deuterated methadone (M-d3) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d3 was administered intravenously instead of the oral M-dose (M-d0). The pharmacokinetic parameters, half-life in the β-phase (t1/2β), volume of distribution during the postdistributive phase (Vdβ) and during steady state (Vdss) were determined as well as the body (ClS) and renal (ClR) clearances of M. Pronounced differences in Vdβ and Vdss were found between the two groups. The therapeutic failures had a smaller Vdβ and Vdss 3.09±0.96 l/kg and 2.74±0.96 l/kg vs 4.56±1.00 l/kg and 4.20±0.78 l/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t1/2β — 24.5±2.6 h in the therapeutic failures and 34.0±7.0 h (p〈0.001) in the comparison group. However, the change in t1/2β was probably a consequence of the change in Vdβ, as the body clearance of M was similar in the two groups — 104±36 ml/min vs 111±36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval. The appropriate treatment of this subgroup of patients on methadone treatment is not to increase the dose but to shorten the dosage interval. Alternatively, a longer-acting opiate, such as 1-α-acetylmethadol (LAAM), may be used.
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  • 94
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    European journal of clinical pharmacology 25 (1983), S. 529-534 
    ISSN: 1432-1041
    Keywords: penbutolol ; pharmacokinetics ; blood pressure effect ; heart rate effect ; dose response relationship ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n=8) or placebo (n=4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32–42 l. All doses were well tolerated.
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  • 95
    ISSN: 1432-1041
    Keywords: delta-9-tetrahydrocannabinol ; mood ratings ; pharmacodynamics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This study explored the relationships in man between various pharmacological effect of Δ9-tetrahydrocannabinol (THC), plasma THC concentration, and pharmacokinetic parameters of THC. Three male and three female experienced marihuana users smoked two standard marihuana cigarettes. The relationships between heart rate, subjective “high” rating, Linear Mood Scale factors, and plasma THC concentration were assessed. Significant correlations were observed between various Linear Mood Scale factors and pharmacokinetic parameters reflecting the magnitude of drug intake and the degree of temporal dissociation between the time courses of plasma THC concentration and pharmacological effects (tachycardiac effect, “high”). In particular, the disturbed/weird and sensitive/aware mood factors correlated positively with pharmacokinetic measures of drug intake and time lag to effect. A more reliable index of intoxication with THC may be provided by the global subjective “high” rating, rather than other ratings more specific for particular moods.
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  • 96
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    European journal of clinical pharmacology 23 (1982), S. 1-5 
    ISSN: 1432-1041
    Keywords: clonidine ; noradrenaline ; pharmacokinetics ; arterial blood pressure ; plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 97
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    European journal of clinical pharmacology 23 (1982), S. 43-47 
    ISSN: 1432-1041
    Keywords: timolol ; pharmacokinetics ; pharmacodynamics ; healthy subjects ; cardiac infarction patients ; i.v. therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: 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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  • 98
    ISSN: 1432-1041
    Keywords: cyclobarbital ; aminopyrine ; liver disease ; 14CO2 breath test ; barbiturate ; pharmacokinetics ; hepatic drug metabolism ; cirrhosis ; alcoholic liver disease ; viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The exhalation of 14CO2 derived from an i.v. tracer dose of [dimethylamine-14C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled 14CO2 occurred 0.5–2 h after 14C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of 14CO2 exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.
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  • 99
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    European journal of clinical pharmacology 26 (1984), S. 121-124 
    ISSN: 1432-1041
    Keywords: methotrexate ; psoriasis ; pharmacokinetics ; plasma levels ; urinary excretion ; renal clearance ; tubular absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).
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  • 100
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    European journal of clinical pharmacology 26 (1984), S. 87-93 
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; renal elimination ; renal insufficiency ; healthy subjects ; creatinine clearance ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, Vβ and Vss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.
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